Folic acid × Increase in source-defined category-a progressive motility in male-factor infertility

Required evidence, verification status and materials actually read
Item	AVerification status	BReading scope	CReview item	DCurrent findings	EWhy unverified	FRequired materials and conditions	GFurther research
1	Met	Full text not readStored summary read	N01 · Separate questionWhich distinct comparison of population, exposure, comparator and endpoint is addressed?Required	The question is whether, in men aged 18–60 in infertile couples planning IVF-ICSI, oral folic acid 15 mg/day as the sole randomized added active ingredient increases the M3−M0 change in source-defined category-a progressive motility compared with matched placebo. S01	The original claim has been linked to the narrow boundaries of the actual comparison. This status does not indicate that clinical improvement has been verified.	The original claim; the identity of the population, single added ingredient, comparator and M3 change endpoint, and the boundaries of exclusion	Cross-check the elements of the question in the current manuscript and structure, and separate other questions such as PR, a+b and pregnancy in the boundary records.
2	Partly verified	Full text not readStored summary read	N02 · Identity of the main trialBy which identifiers are the FOLFIV article, index record and registration linked?Required	S01 is the FOLFIV article PDF, S02 is the PubMed record for the same article, and S03 is the NCT01407432 registration record. DOI 10.3390/jcm10091876, PMID 33925981 and PMCID PMC8123699 are retained. The registration history, protocol and SAP were not obtained at the time. S01 S02 S03	The article family is linked bibliographically, but a complete comparison with the registration text and plans remains outstanding.	Identifiers and report types/locations for the S01 article, S02 index record and S03 registration	Cross-check the identifiers and related reports, group them into one trial family, and separately record the lack of comparison against the registration text/history.
3	Partly verified	Full text not readStored summary read	N03 · Study families and missing referencesHave overlap and missing references in the report list and study families been distinguished?Required	The evidence distinguishes FOLFIV, SILVA2013, RAIGANI2014, HUANG2020, WONG2002 and FAZST. S07/S14 refer to the same Huang trial; S09/S10 are FAZST and its correction. The S16 reference for FOLFIV and the S15 reference for FAZST are absent from the current 14 bibliographic entries, so their URLs and separate report identities have not been established. S01 S02 S03 S04 S06 S07 S08 S09 S10 S14	The provided families and actual bibliography have been linked, but report identities for S15/S16 were not provided. Family counts and counts of replications within the exact boundaries have not been interchanged.	The actual bibliography, the families and linked-source lists in the evidence, and materials linked as S15/S16	Cross-check the shared families of S01/S02/S03, S07/S14 and S09/S10, and leave missing references on a list awaiting identity verification.
4	Met	Full text not readStored summary read	N04 · Current and historical readingHave the stored summaries read in the present task been distinguished from historical external access?Required	The Korean manuscript, structured evidence, 14 bibliographic entries and metadata in the currently stored manuscript were read. PDF/visual table checking for S01, HTML for S07/S04/S09, the S11 label and partial search extracts for S05 are records from the time of retention. No external lookup was performed in this task. Actual per-report access dates are empty, and the original material review date of 2026-09-16 is preserved separately. S01 S12 S13 S03 S07 S14 S04 S06 S08 S09 S10 S02 S05 S11	The recording criterion of separating actual actions from historical access levels is met. No external full texts were read in this task.	The access_level/locations of each bibliographic entry, the overall review date, the actual reading scope in this task and safe URLs	Transfer each bibliographic access level as a historical record, and separately cross-check the current material-type statuses, dates and link types.
5	Partly verified	Full text not readStored summary read	N05 · Scope of search and correction checksAt which cutoff date and within which verification scope are evidence and corrections discussed?Required	The evidence cutoff is 2026-09-16, and the retained stored-material review date is 2026-10-05. evidence_status records the scope of the ChatGPT search at that time and absence_proven=false. The corrections array is empty, but S10 and the Korean text preserve the FAZST Table1 correction. S10	The cutoff date and known correction have been linked. Completeness of the latest search, registrations, corrections and retractions was not checked in this task.	The search/review record dated 2026-09-16, the actual S10 correction and revision_triggers	Cross-check the retained search/correction records against the empty structured array, and limit statements about absence and currency without conducting a new search.
6	Partly verified	Full text not readStored summary read	N06 · Ingredient identityWhich folate form is the trial's active ingredient?Required	The trial used folic acid as the single added ingredient. It is distinguished from dietary folate, 5-MTHF and folinic acid; its manufacturing source, exact salt and crystal form are unverified. S01	The active ingredient is verified, but chemical details and equivalence to other forms have not been verified.	Trial ingredient specifications and materials verifying the salt, crystal form and manufacturing source	Cross-check the trial ingredient designation against the original specifications, and separate other folate forms/combined active ingredients as different exposures.
7	Partly verified	Full text not readStored summary read	N07 · Product and placebo formulationWhich formulation details of the tablets and matched placebo are known?Required	The regimen comprised 3 folic acid 5 mg tablets/day from Bailly-Creat Laboratory and 3 placebo tablets/day matched in appearance, size, taste and weight. Release formulation, batch, purity, details of the active tablets and placebo excipients are unverified. S01 S11	The manufacturer, tablet count and nominal placebo matching are retained, but actual product details remain to be verified.	Specifications for the Bailly-Creat trial tablets and placebo: release formulation, batch, purity and excipients	Cross-check the article and product-supply specifications without automatically transferring information about a different authorized product to this trial product.
8	Met	Full text not readStored summary read	N08 · Route of administrationWhat was the actual route of administration?Required	The trial treatment was an oral tablet. Folate exposure through other routes is not treated as the same direct comparison. S01	The actual oral-exposure boundary has been linked. This is not a judgment about superiority of the route or its suitability for an individual.	The original designation of the trial's oral route	Cross-check the original exposure-route designation and limit it to the conditions of the comparison in this table.
9	Partly verified	Full text not readStored summary read	N09 · Nominal dose and actual intakeCan the planned 15 mg/day regimen be distinguished from actual intake?Required	The nominal dose was 15 mg/day, comprising 3 tablets of 5 mg. Collection of adherence data at M3 was planned, but actual dosing times, the proportion of prescribed doses taken and total dietary folate exposure are currently unverified. This is not used as a trial comparing optimal doses. S01	The assigned dose is verified, and actual intake and background exposure have not been filled in with the same value.	Originally prescribed tablet count and dose, actual adherence/intake records and total dietary folate	Compare nominal assignment with individual intake records, and distinguish adherence analyses according to their analytical purpose and population.
10	Partly verified	Full text not readStored summary read	N10 · Assessment time and exposure durationAre the M3 semen assessment and the full treatment/pregnancy follow-up periods the same?Required	The selected endpoint is the semen change at M3, that is, at 3 months minus baseline. Treatment could continue until semen collection for IVF, so total treatment and pregnancy assessment periods are not described as identical to M3. S01	The selected assessment time is retained, but each individual's total exposure and discontinuation time are unverified.	Actual timing records for M0/M3 semen assessment, treatment discontinuation, semen collection for IVF and pregnancy follow-up	Record the timeline by separately cross-checking the measurement time of each endpoint and the start/end of exposure.
11	Partly verified	Full text not readStored summary read	N11 · Actual male eligibility criteriaWhich men were selected, and did they all have the same motility impairment?Required	Participants were male partners aged 18–60 in couples planning IVF-ICSI, with at least 1 abnormal semen parameter required for inclusion. The article specifies one of concentration <15 million/mL, motility <50%, vitality <60% or normal morphology <4%. Participants were not all a group with the same OAT or impairment confined to progressive motility. S01	Actual eligibility criteria are available, but the distribution of combinations of abnormalities and representativeness cannot currently be established.	Male inclusion/exclusion criteria and the distribution of age and abnormal semen parameters	Cross-check eligibility criteria against the distribution of actual baseline characteristics, recording the narrow applicable population and unverified mixed composition.
12	Unverified	Full text not readStored summary read	N12 · Deficiency, B12 and genotypeAre baseline folate-deficiency, B12 and MTHFR status known?Required	Deficiency was defined as serum folate <3.5 ng/mL, but baseline deficiency counts and B12/MTHFR distributions are unverified. This population is not described as a group receiving correction of confirmed deficiency or as an entirely nondeficient group. S01	The criterion is retained, but materials verifying the actual baseline distribution or deficiency/genotype-specific effects in this comparison are unavailable.	Serum folate criteria, baseline deficiency counts, B12/MTHFR distributions and prespecified subgroup plans	Cross-check baseline status against planned subgroup/interaction analyses without transferring genotype findings from the separate Huang trial.
13	Conflicting information	Full text not readStored summary read	N13 · Female causes and couples with mixed causesDoes the description of excluding female causes agree with the baseline table of mixed causes?Required	The female eligibility age range was 18–38. The methods describe exclusion of female causes, but the baseline table lists mixed causes in 18 participants in the folic acid arm and 17 in the placebo arm. The couples are therefore not assumed to have purely male-factor infertility. S01	The currently retained manuscript explicitly identifies a discrepancy between the methods and baseline composition. It was not resolved through external comparison in this task.	Female inclusion/exclusion criteria, the baseline table of causes and an explanation/correction of the discrepancy	Cross-check the same cause classification in the methods and baseline table, updating the discrepancy only if an explanation or correction from the original authors is available.
14	Met	Full text not readStored summary read	N14 · Actual comparatorAgainst what shared background care was the placebo compared?Required	The comparator was 3 placebo tablets/day, matched in appearance, size, taste and weight, under common IVF-ICSI care. It has not been converted into a no-treatment control. S01	This is a recording criterion linking the nominal comparator and background care. Details of placebo excipients remain under N07.	Actual specifications of the matched placebo and background IVF care	Distinguish the added active ingredient from common treatment to prevent extension to no treatment or a different comparator.
15	Partly verified	Full text not readStored summary read	N15 · Concomitant treatment and deviationsHave IVF treatment and other male medications been distinguished from the added trial ingredient?Required	The IVF-ICSI care policy was shared, but individual women's stimulation regimens were not identical. The report states that no other male hormonal or vitamin treatment was used. Individual concomitant treatments, changes and the actual handling of adherence are not currently verified. S01	A description of concomitant treatment is retained, but comparison of actual exposures/changes by arm is insufficient.	IVF/female stimulation regimens by arm, concurrent male treatment, rescue treatment and handling of deviations	Cross-check concomitant-treatment/change records by arm against the effect of interest, and distinguish female background factors for pregnancy endpoints from semen change.
16	Met	Full text not readStored summary read	N16 · Endpoint, direction and unitsThe selected value represents change at which time, in which sperm category and in which units?Required	The selected endpoint is the M3−M0 change in Progressive motility (a) % in Table4. Change is measured in %p, and a higher change is the proposed direction of benefit. The endpoint percentage (%) and total motility (a+b+c) are separate. S01	The exact endpoint, time and unit boundaries have been linked. The direction of the numerical result has not been turned into certification of efficacy.	The label, time, units and direction of the effect of interest for the selected Table4 row	Cross-check the row label and change/endpoint columns, labeling the time and units of each value separately.
17	Unverified	Full text not readStored summary read	N17 · Correspondence to WHO classificationsCan source-defined category a be mapped to modern WHO aggregate PR?Required	The article cites WHO 2010, but the speed criteria for category a and its correspondence to modern WHO aggregate PR were not verified at the time. S12 contains only official metadata for edition 6, while S13 records failed attempts to access the edition 5 page/PDF. No conversion to a+b or aggregate PR was made. S01 S12 S13	The relevant definition section and actual measurement correspondence are unverified. Historical access failure is not a status of Inaccessible in the present task.	The original motility-classification/speed criteria and the relevant definition section in the cited WHO edition	Cross-check the trial's classification rules against the definitions in the actual relevant WHO edition, recording only verified correspondences.
18	Partly verified	Full text not readStored summary read	N18 · Specimen collection and measurement proceduresWhat were the actual abstinence, specimen-collection and motility-reading procedures?Required	Semen was collected after 3–5 days of abstinence. The retained manuscript explicitly states that the DNA fixation/freezing methods and 2-reader procedure were not transferred to motility assessment. Detailed information on the equipment, speed criteria, readers and differences between arms for motility itself is not currently available. S01	Collection conditions are retained, but detailed measurement procedures for the selected endpoint are unverified.	Semen-collection conditions, motility equipment/reading rules, assessors/blinding and measurement differences between arms	Cross-check the semen-motility and DNA-testing sections separately, using only information that applies to the actual motility measurement.
19	Partly verified	Full text not readStored summary read	N19 · Endpoint hierarchy and advance planningDoes the page's primary endpoint match the endpoint hierarchy in the article and registration?Required	Category-a semen change is a secondary endpoint in the article and the primary endpoint on the page. The original trial's primary outcomes were biochemical and clinical pregnancy. The complete registration history, protocol, SAP and prespecified rank of this category-a row are unverified; the page's boundaries were an editorial choice after reviewing the literature. S01 S03	The published hierarchy and editorial selection are verified, but comparison with the planned analyses remains outstanding.	The complete NCT01407432 version history, protocol, SAP and records of endpoint/analysis changes	Compare the planned endpoints, times and analyses in the registration/protocol with the Table4 report, recording changes or the scope not compared.
20	Partly verified	Full text not readStored summary read	N20 · Design and allocationTo what extent are the actual parallel-group design and randomization procedures known?Required	FOLFIV is retained as a double-blind, parallel-group randomized trial with matched placebo. Randomization involved 83 versus 79 participants. The currently stored summaries do not provide detailed extraction of allocation-sequence generation or concealment. S01	The design type and allocation counts are retained, but detailed verification of allocation methods remains outstanding.	Methods/tables for allocation-sequence generation, concealment, personnel responsible and baseline balance between arms	Cross-check the Methods, flow diagram and baseline tables against allocation procedures, without filling in unverified concealment details.
21	Partly verified	Full text not readStored summary read	N21 · Maintenance of blindingWere matched placebo and double blinding actually maintained through assessment and analysis?Required	The trial was double-blind, with placebo matched in appearance, size, taste and weight. The current inputs alone cannot establish in detail whether motility assessors/analysts were blinded, whether blinding was maintained or whether it was broken. S01	The nominal design and placebo matching are described, but evidence of maintained blinding for the actual selected endpoint is insufficient.	Blinding of participants, personnel, motility assessors/analysts, and checks of unblinding or successful treatment guesses	Cross-check who was blinded and records of actual maintenance/breaking of blinding against measurement and analysis of the selected semen endpoint.
22	Met	Full text not readStored summary read	N22 · Allocation, visit and analysis denominatorsDoes each number count people allocated, attending a visit, included in change analysis or included in endpoint analysis?Required	162 participants were randomized (83 folic acid, 79 placebo), and 76 and 72 attended M3 visits. Category-a change analysis included 126 participants (66 and 60), while M3 endpoint analysis included 67 and 62. The baseline, endpoint and change analysis populations are not identical. S01	The attribution of the different provided denominators is preserved. This status does not indicate that handling of missing data has also been adequately verified.	The Figure3 flow and person counts in the baseline, M3 and change columns of Table4	Cross-check the denominators for each stage/endpoint column, recording allocated, measured and analyzed populations separately.
23	Unverified	Full text not readStored summary read	N23 · Missing data and the scope of ITTHow can missing data in the change analysis and the reference to ITT be interpreted?Required	The article mentions the ITT principle, but category-a change analysis includes 66/60 participants rather than all 83/79 randomized participants. Reasons for missing data, imputation and missing-data sensitivity analyses for this row were not verified at the time. S01	The reduction in denominators is verified, but materials establishing the handling and impact of missing data for the selected row are unavailable.	Reasons for missing endpoint data, losses by assigned arm, imputation rules, analysis populations and sensitivity analyses	Cross-check the population and missing-data rules for the selected category-a change row against the Methods/plans and flow, recording the limitations of the assignment effect and complete-case results.
24	Partly verified	Full text not readStored summary read	N24 · Reported main result valuesWhat are the mean, SD, median, IQR and P value for change in source-defined category a?Required	Mean (SD) change was +0.6 (7.5) %p with folic acid and +0.8 (6.9) %p with placebo. The median was 0 %p in both arms; IQRs were 0–2 versus 0–5 %p. With a between-arm Wilcoxon–Mann–Whitney P = 0.7871, the retained manuscript records failure to demonstrate improvement in this comparison. This does not mean an effect of 0, equivalence or exclusion of meaningful benefit. S01	The main reported values and direction are available, but the formal between-arm effect estimate/CI and a current external comparison of the original row remain outstanding.	Mean (SD), median/IQR, test, P value and original denominators for the selected change row in Table4	Cross-check the columns/units of each statistic and the location of the between-arm test, separating interpretation of means, distribution summaries and significance.
25	Met	Full text not readStored summary read	N25 · Historical arithmetic and endpoint valuesHas historical arithmetic on means been distinguished from the formal between-arm estimator?Required	The descriptive arithmetic difference between change means at the time of retention was −0.2 %p. Endpoint means were 6.4 (SD 8.5) % versus 5.8 (SD 8.6) %, with a historical simple endpoint difference of +0.6 %p. The −0.2 %p is neither an adjusted estimate nor a Wilcoxon location difference; baseline/endpoint means from different analysis populations were not subtracted to create a new change value. S01	The attribution and limitations of existing arithmetic values have been linked. This does not mean verification of a formal effect estimate or a new calculation.	Existing arithmetic records, their respective change/endpoint columns and the formal test definition	Cross-check the attribution of arithmetic already in the manuscript against the change/endpoint columns, and preserve it as historical material distinct from a new analysis.
26	Partly verified	Full text not readStored summary read	N26 · Between-arm test and effect of interestWhat does P = 0.7871 compare, and which effect estimates are unverified?Required	P = 0.7871 is the Wilcoxon–Mann–Whitney comparison of category-a change between the two arms. adjusted_effect in the original structure is null, and the formal between-arm effect estimate is also unverified. It is not relabeled as a within-arm P value or an adjusted effect on means. S01	The test type and between-arm direction are retained, but details of the formal effect and analytical objective are insufficient.	Definitions of the between-arm test, analysis population, effect of interest and formal estimator for the selected row	Cross-check the test and analysis population in the Methods/plans and Table4, distinguishing between-arm/within-arm comparisons and assignment/adherence effects.
27	Unverified	Full text not readStored summary read	N27 · Intervals and precisionWhat range of benefits can be assessed using a reported formal between-arm CI?Required	In the original structure, ci for the direct category-a change is null. Change SDs and denominators are available, but the formal between-arm CI was not verified at the time, so the extent to which meaningful benefit can be excluded cannot be stated. S01	The formal effect interval for the selected question is unavailable, so the range of precision cannot be verified.	The formal between-arm effect estimate/CI, dispersion, denominators and estimation method for the selected category-a change	Verify only effect intervals actually reported in the original results/plans; do not reconstruct a new CI from SD in this case.
28	Unverified	Full text not readStored summary read	N28 · Threshold for an important differenceIs there an MCID applicable to this category a, population and time point?Required	For a validated MCID for this exact category a, population and time point, the record is value=null, not_verified. No new arbitrary threshold for %p, trial count, duration or sample size has been set. S01	An applicable importance threshold has not been verified, so the reported values are not adjudicated as a clinically meaningful difference.	A validated threshold for important change and its validation context for this source-defined category, population and M3 time point	Cross-check the threshold's fit to the population, scale and time point; if no verified threshold is available, keep importance unverified.
29	Conflicting information	Full text not readStored summary read	N29 · Positive adjacent evidenceHave Huang's different dose/genotype results and the conflicting test descriptions been preserved?Required	Huang's positive result at 0.8 mg/day for 3 months in MTHFR 677 TT is retained: 32.36→40.63 % versus 36.84→33.97 %. The Table3 footnote describes a within-arm comparison with baseline, whereas the text describes a between-arm comparison. The 769 participants are the total eligible population; the exact between-arm CI, P value and motility denominators are unverified. S07 S14	There is an actual retained conflict in test attribution for the same positive result. Evidence from a different dose/genotype has not been combined as direct replication or refutation.	Huang Table3/footnote and text, genotype-specific motility analysis denominators, tests/CIs and prespecified subgroup plans	Cross-check the within-arm/between-arm attribution of the tests in the table footnote and text, and organize differences in dose, genotype and definition by family.
30	Partly verified	Full text not readStored summary read	N30 · Another single-ingredient doseWhat adjacent information does da Silva's 5 mg single-ingredient result provide?Required	da Silva was a double-blind, placebo-controlled trial of a single ingredient at 5 mg/day for 3 months, with 49 protocol completers; the initial allocation count is unverified. It reported no significant improvement in the semen outcomes assessed, but used the older a+b definition and does not provide the exact category-a estimator. S04	The direction and different conditions of the adjacent single-ingredient trial are retained, but exact endpoint, allocation and denominator details are unverified.	da Silva's single-ingredient-arm results/denominators, motility definition, initial allocation and funding scope	Cross-check the dose, motility definition and analysis population of the adjacent trial separately, avoiding aggregation into the direct category-a change.
31	Partly verified	Full text not readStored summary read	N31 · Single-ingredient candidates in factorial and 4-arm trialsWhat remains unknown while the folic-acid-only arms of Wong and Raigani are retained?Required	Wong was a 4-arm trial with fertile/subfertile strata; Raigani was a 4-arm trial with 83 participants in total. Both had folic-acid-only arms. Exact single-ingredient category-a change estimates and endpoint-specific analysis denominators are currently unverified, so they were not added as direct quantitative replications. S06 S08	The single-ingredient candidates have not been deleted, but denominators and quantitative results for the exact comparison have not been verified.	Endpoints, denominators and quantitative results for each single-ingredient arm in Wong's fertile/subfertile strata and Raigani's 4-arm trial	Cross-check comparisons by actual active ingredient and stratified analyses in factorial/4-arm trials, distinguishing single-ingredient contrasts from combination contrasts.
32	Met	Full text not readStored summary read	N32 · Combination-product and correction boundariesHave the FAZST combination, total motility and correction been distinguished from the direct question?Required	FAZST administered folic acid 5 mg plus zinc 30 mg/day for 6 months in a trial of 2370 participants. The total-motility difference was −0.5 %p, with a 95.1% CI of −2.5 to 1.5 %p. S10 corrects transposed previous-multivitamin yes/no rows in Table1; it was not counted as a new sample or as a correction to the direct category-a effect. S09 S10	The attribution boundaries of the original combination, different endpoint and correction are preserved. This does not mean current comparison against the original source or verification of a folic-acid-only effect.	FAZST Table3, the multiplicity footnote and original Table1 correction, and boundaries between combination/single-ingredient comparisons	Separate the combination exposure and total-motility estimator from direct category-a change, linking only the columns/rows actually changed by the correction.
33	Met	Full text not readStored summary read	N33 · Other endpoints and clinical extensionsHow were pregnancy and DNA results from the same trial separated?Required	In the embryo-transfer subgroup of the same trial, the retained results are biochemical pregnancy 26/59 versus 11/49, P = 0.018; clinical pregnancy at 7 weeks 21/59 versus 10/49, P = 0.082; and miscarriage 5/59 versus 1/49, P = 0.146. These denominators do not represent all randomized couples. DNA change or these pregnancy results are not converted into success for category-a motility or live birth. S01	Positive and nonsignificant findings for other endpoints are retained with their respective denominators, and boundaries are set for them as separate questions.	FOLFIV Table6, selection/denominators of the embryo-transfer subgroup and separate DNA/live-birth outcomes	Cross-check the analysis population and time of each pregnancy event against the original table, limiting extension from a semen surrogate to clinical events.
34	Conflicting information	Full text not readStored summary read	N34 · Printing and unit conflicts in other endpointsHave concerns about serum folate units and printed DNA values been left unresolved rather than arbitrarily corrected?Required	The retained manuscript leaves the serum folate unit conflict and suspicious printed values in the DNA change row, a different endpoint, as candidate errors. The units on both sides and exact DNA numbers are not provided in the currently stored summaries, so they were not reproduced or used to calculate a motility effect. S01	The conflict/candidate errors are retained, but the exact values on both sides and comparison with the original table remain unverified within the current scope.	Original tables, earlier/later versions, corrections and author explanations for serum folate units and the DNA change row	Cross-check the original table and printed units/change-row values, without arbitrary correction based only on the current general record of candidate errors.
35	Partly verified	Full text not readStored summary read	N35 · Funding, sponsorship and product supplyCan public funding, sponsorship and product manufacture be verified separately?Required	FOLFIV's public funding from the French Ministry of Health through PHRC 2010(10-052), AP-HP sponsorship and tablet manufacture by Bailly-Creat are retained. Disclosed roles are not used as an independent audit of all relationships or as replication in a separate trial. S01	Funding, sponsorship and the manufacturer are named, but product contracts and the full actual roles of sponsors were not independently verified.	Actual disclosures of FOLFIV funding, sponsorship, product manufacture/supply and roles/contracts	Cross-check Funding/Acknowledgments and product specifications, examining separately the roles of funding, operational sponsorship and product relationships.
36	Partly verified	Full text not readStored summary read	N36 · Conflicts of interest and funding of adjacent trialsHave author declarations been distinguished from limits on funding verification in other families?Required	FOLFIV's authors declared no conflicts of interest. Huang reported no funding; da Silva had CAPES fellowships for 2 investigators, but overall trial funding is unverified; Raigani's funding is unverified; details of Wong's PubMed designation of non-US government support are unverified; and FAZST had NIH/NICHD public support. None of these records was treated as an independent audit. S01 S04 S06 S07 S08 S09	The level of disclosure for each family is retained, but independent verification of all relationships remains outstanding.	Each trial's Funding/COI, product relationships, author/institution disclosures and scope of verification	Cross-check each family's level of disclosure and funding separately, recording shared sponsors/institutions only where links are actually verified.
37	Unverified	Full text not readStored summary read	N37 · Adverse events and their collectionHave harm collection, events and denominators been verified for the same 15 mg exposure?Required	FOLFIV planned M3 adherence and tolerability questionnaires, but exact AE, SAE and toxicity-withdrawal counts and analysis denominators were not obtained at the time. Gaps in the currently stored summaries are not treated as nonreporting throughout the entire article, 0 events or long-term safety. S01	Actual harm counts, the scope of collection and denominators for the selected exposure are not currently verified.	AE definitions, collection and severity; person/event counts for SAEs and toxicity withdrawals; exposure/analysis denominators and duration	Cross-check harm-collection methods for the same population/dose and person, event and follow-up denominators by arm, distinguishing reported frequency from collection limitations.
38	Partly verified	Full text not readStored summary read	N38 · Background on B12 and drug interactionsHave general B12/drug precautions been distinguished from trial harms?Required	The historical partial NIH extracts and the SmPC for another 5 mg product support the background concerning possible masking of hematologic signs of B12 deficiency and delayed recognition of neurological injury, and interactions involving anticonvulsants, methotrexate and other drugs. This content is not FOLFIV's actual event count, a personal risk estimate or an instruction for personal administration. S05 S11 S01	General safety background is retained, but direct trial harms/personal risks are unverified, and external materials were not read in this task.	The partial NIH extracts and relevant B12/interaction sections of the SmPC, and medication/use contexts	Cross-check the relevant warnings, jurisdiction, formulation and use context in official materials, reviewing these separately from harms observed in the trial.
39	Met	Full text not readStored summary read	N39 · Another authorized product and regimenAre the indications and regimen on the Flamingo 5 mg label the same as those of the 15 mg trial?Required	S11 is the label for Flamingo Pharma's Folic Acid Tablets BP 5 mg, PL43461/0091. The retained locations concern the label context of folate-deficient megaloblastic anemia and 5 mg/day for 4 months in adults, which differs from the Bailly-Creat 15 mg/day infertility trial. The revision date of 2026-05-20 and eMC update of 2026-06-05 are retained version information. S11 S01	The boundaries of product, regimen, indication and version have been recorded. This does not mean authorization or safety certification for the trial in question.	Ingredient/route, indications, regimen and version of the Flamingo Pharma PL43461/0091 SmPC	Cross-check the label's actual product, jurisdiction, indications/regimen and version against the trial specifications, requiring more than a shared 5 mg designation to establish equivalence.
40	Not applicable	Full text not readStored summary read	N40 · Boundaries for long-term use and special populationsDoes this table also adjudicate optimal dose, long-term use, vulnerable groups and personal treatment?Supplementary and extension boundaries	The current manuscript discloses limitations concerning long-term high doses, severe liver/kidney disease, cancer history, pregnancy/lactation and use in children. Optimal dose, sustained long-term effects, personal safety/infertility treatment and ART changes are outside the scope of this narrow M3 category-a change verdict. S01 S05 S11	Establishing extension outcomes does not apply to the current narrow original question. Direct high-dose harm gaps remain under N37; Not applicable is not safety certification.	Direct dose comparisons, long-term/vulnerable-population exposures and harm follow-up needed when addressing extended questions	If an extension is requested, define a direct design for its population, dose, duration and endpoint, and review it separately from the original M3 question.
41	Met	Full text not readStored summary read	N41 · Historical verdict and the role of the current tableHave the existing D/30-point verdict and document self-review been kept from being used as a new criteria-based judgment?Required	The existing D/30-point verdict and B/S/R1/I2/E0/B1/CX are preserved as original values. The existing E0 wording means failure to demonstrate improvement in this narrow comparison, not an effect of 0 or equivalence. Document quality B in editorial_review and single-assistant self-review do not constitute independent clinical certification. S01	Historical verdict values have been separated from preparation of the current table and criterion statuses. The existing score has not been revalidated or regraded.	The original grade/score/axes, assessment_profile, editorial_review and the scope of the current task	Cross-check the original verdict/axes and retained interpretive wording, leaving them as historical quotations without performing a new clinical reassessment.
42	Conflicting information	Full text not readStored summary read	N42 · Boundaries for update and publication metadataHow are updates under the same ID and differing server metadata preserved?Required	The original policy is to append history under the same ID/URLs in response to new trials matching the exact question, registration/methods, corrections, retractions, numerical/classification errors and harm information. publication_notes records server_deployed=false; the top level records true and a deployment date of 2026-09-16, together with server_write_performed=false. These metadata differences are retained, and the new table is labeled as an unpublished stored-summary preparation stage.	The original inputs contain differences between publication metadata fields, so actual events were not consolidated from these values alone. This is separate from conflicts in clinical content.	Original ID/URLs, revision_policy/history/triggers, and event/server-verification records for publication metadata	Cross-check events/times in publication metadata and link criteria revisions, material additions and actual publication to separate receipts.

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42 itemsWhat the statuses mean

Assessment scope

Stored-material review date: 2026-10-05
Original evidence cut-off: 2026-09-16
Scope actually checked: Stored Korean and English manuscripts and case-specific criteria and application records. Full papers, supplements, registrations, plans and original data were not read.
What the dates mean: This is the date the stored materials were checked, not the date of an up-to-date clinical literature search.
Population: Male partners aged 18–60 in infertile couples planning IVF-ICSI, with at least 1 abnormal semen parameter; mixed female causes are included; this is not treated as a group receiving correction of confirmed folate deficiency
Ingredient, formulation and route: folic acid; the sole randomized added active ingredient
Dose: 15 mg/day (3 tablets of 5 mg); actual dosing times and numerical adherence data are unverified
Comparator: 3 matched placebo tablets/day under the same IVF-ICSI care; no other male hormonal or vitamin interventions were reported
Measured outcome: Progressive motility (a) in Table4, compared between arms for M3−M0; %p; a secondary endpoint in the article; mapping to modern WHO aggregate PR is unverified
Duration: The main semen assessment is M3 (3 months); treatment could continue until semen collection for IVF, so this is distinguished from the pregnancy assessment period
Questions outside this scope: Modern PR/a+b, total motility, DNA/serum measures, pregnancy/live birth, other doses/genotypes, combinations/other folate forms/routes, optimal dose, long-term outcomes and personal safety are separate questions.

Evidence and sources

The links below lead to the sources. A link alone does not mean the original source was read or its latest publication status verified.

S01 · Mathieu d’Argent et al. 2021 FOLFIV original article

Source

Material type: Original article PDF (historical visual table check)
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: single added oral folic acid 15 mg/day (3 tablets of 5 mg) versus matched placebo in men aged 18–60 under IVF-ICSI care, for M3−M0 change in source-defined category a. Counts were 83/79 randomized, 76/72 at M3 visits, 66/60 in change analysis and 67/62 in endpoint analysis. Mean (SD) change was +0.6 (7.5) versus +0.8 (6.9) %p; medians were 0 %p in both arms, IQRs 0–2 versus 0–5 %p, and the between-arm Wilcoxon–Mann–Whitney P = 0.7871. The formal effect/CI and MCID are unverified. The historical change arithmetic of −0.2 %p, endpoint means of 6.4 (SD 8.5) versus 5.8 (SD 8.6) % and simple endpoint difference of +0.6 %p are separate descriptive values. Biochemical pregnancy 26/59 versus 11/49 (P = 0.018), clinical pregnancy at 7 weeks 21/59 versus 10/49 (P = 0.082) and miscarriage 5/59 versus 1/49 (P = 0.146) in the same embryo-transfer subgroup differ from category-a motility/live-birth effects. Candidate errors concerning female causes, serum units/DNA printing and gaps in AE/SAE/withdrawal denominators are retained. PHRC 2010(10-052), AP-HP, Bailly-Creat manufacture and the authors' no-COI declaration represent separate levels of disclosure.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full article text in PDF Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual PDF URL in the current bibliography. PDF reading and visual table checking are records from the time of retention; the external material was not read in this task.
Supplementary material Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The identity and direct URL of supplementary material are not currently provided. Its existence/public availability was not newly verified.
Protocol and SAP Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	A registration number is available, but the actual URLs and content of the complete protocol/SAP were not obtained at the time.

S12 · WHO laboratory manual, sixth edition, 2021

Source

Material type: Official publication metadata for WHO edition 6
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: verification of official publication-overview metadata for WHO edition 6, 2021. The overview dated 2021-07-27 and ISBN 9789240030787 are retained, but the definition/speed criteria of source-defined category a and its correspondence to modern PR were not verified.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official publication-page metadata Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This URL is a publication-overview page. It is not presented as the actual manual PDF URL.
Motility-definition section of the manual PDF Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The relevant definition section and direct PDF URL are currently unverified.

S13 · WHO fifth-edition manual, attempted retrieval

Source

Material type: Record of search/access attempts for WHO edition 5
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: historical failed access to the WHO edition 5 publication page, ISBN 9789241547789, and IRIS PDF. There was no access attempt in this task, and the actual manual definitions/speed criteria are unverified.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official publication page Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	The actual bibliographic entry gives a publication-page URL. The failure record is historical and is not inherited as Inaccessible in the present task.
Motility-definition section of the manual PDF Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The direct IRIS PDF URL is absent from the current bibliography and is left null.

S03 · FOLFIV ClinicalTrials.gov record

Source

Material type: Registration record and history/plans not obtained
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: the NCT01407432 identifier was verified in S01 §2.1, but the complete registration version history, protocol, SAP and prespecified rank of the selected category-a row were not obtained at the time. Failure to obtain the registration is not treated as confirmed nonregistration or selective reporting.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Registration-record webpage Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the retained URL for the exact registration number. The historical shell/access-failure level is distinguished from access not attempted in this task.
Registration version history, protocol and SAP Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The actual URLs and full texts of the individual documents are currently unverified.

S07 · Huang et al. 2020 MTHFR-stratified folic-acid trial

Source

Material type: Publisher's full article HTML (historical access)
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: a positive result of 32.36→40.63 % versus 36.84→33.97 % was recorded for folic acid 0.8 mg/day for 3 months in MTHFR 677 TT. The Table3 footnote describes a within-arm comparison with baseline, while the text describes a between-arm comparison, creating a conflict. The 769 participants are the total eligible population; overlapping genotype strata were not summed, and exact motility denominators and between-arm CI/P values are unverified. No funding is an author report. This is not used as a direct replication of the 15 mg/source-defined category-a comparison.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Publisher's full article HTML Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual publisher's full HTML URL; only the historical full-text access record is retained.
Supplementary material and detailed analysis plan Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The identity and direct URLs of the relevant original-trial materials are not currently provided.

S14 · Huang PubMed cross-check

Source

Material type: PubMed abstract and bibliography
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: an abstract/bibliographic record linked to S07 by PMID 31127676 and DOI 10.1111/andr.12652. It is the same Huang trial; the positive TT result, test-description conflict and unverified quantitative scope are attributed to the manuscript related to S07.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed abstract/bibliographic page Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the relevant PubMed abstract/metadata URL; it is not presented as a publisher's full-text link or as full-text reading.

S04 · da Silva et al. 2013: Folic acid does not improve semen parameters

Source

Material type: Publisher's full article HTML (historical access)
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: the single-ingredient, double-blind placebo trial of folic acid 5 mg/day for 3 months reported no significant improvement in the semen parameters assessed. There were 49 protocol completers, while the initial randomized count is unverified. It used the older a+b definition and does not provide the exact category-a change estimator. CAPES fellowships for 2 investigators are retained, but overall trial funding is unverified.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Publisher's full article HTML Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual JBRA HTML URL and the historical full-text access record. It was not read in this task.
Original tables and supplementary material Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	Separate URLs for the relevant tables/appendices and actual current acquisition are unverified.

S06 · Raigani et al. 2014 OAT four-arm trial

Source

Material type: PubMed abstract and bibliography
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: a 4-arm randomized placebo trial with 83 participants in total included a folic-acid-only arm. It was retained as a candidate with the exact category-a effect estimate, endpoint-specific analysis denominators and funding unverified; the entire study was not discarded as a combination trial or added to direct replication counts/scores.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed abstract/bibliographic page Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual abstract/bibliographic URL.
Full text of the original article Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The abstract's bibliographic URL is not substituted for a publisher's full-text URL. The direct full-text URL and current acquisition are unverified.

S08 · Wong et al. 2002 folic acid and zinc factorial trial

Source

Material type: PubMed abstract and bibliography
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: a 4-arm factorial trial with fertile/subfertile strata included a folic-acid-only arm. Exact single-ingredient motility denominators and the category-a change estimator are unverified. PubMed's designation of non-US government support was distinguished from unverified funding details.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed abstract/bibliographic page Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual abstract/bibliographic URL.
Full text of the original article Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	The direct full-text URL and current acquisition of the original article are unverified; PubMed is not presented as the full text.

S09 · Schisterman et al. 2020 FAZST

Source

Material type: Publisher's full article HTML (historical access)
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: FAZST was a 2370-participant combination trial of folic acid 5 mg plus zinc 30 mg/day for 6 months. The total-motility difference of −0.5 %p and multiplicity-adjusted 95.1% CI of −2.5 to 1.5 %p are retained. This is not the single-ingredient, source-defined category-a endpoint or repeated refutation. NIH/NICHD public support is recorded, and zinc-related harms from the combination are not transferred to folic acid. S10 is the Table1 correction for the same trial.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Publisher's full article HTML Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual JAMA original-article HTML URL and the historical full-text access record.
Supplementary material and protocol Material URL unverified	Unverified (no external lookup in this task)	Access not attempted	Not read	Actual direct URLs and current acquisition of the appendices/plans are unverified.

S10 · FAZST correction: Two Rows Transposed in Table 1

Source

Material type: Official correction notice
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: the correction is titled Two Rows Transposed in Table 1 and corrects transposition of the previous-multivitamin yes/no rows. It is not counted as a direct category-a motility result, independent participants or a new trial. This actual bibliographic/textual correction record is retained separately from the empty corrections array.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official correction HTML Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This URL is the actual correction notice; it is not presented as the original article's full text or a new study.

S02 · FOLFIV PubMed record

Source

Material type: PubMed abstract and bibliography
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Record at the time of retention: linked to S01 by PMID 33925981, PMCID PMC8123699 and DOI 10.3390/jcm10091876. The current verification level is the historical abstract/metadata level; the main Table4 numbers and denominators are attributed to the Korean/structured summaries related to S01. This is not independent replication.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed abstract/bibliographic page Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual PubMed abstract/bibliographic URL. A designation of having read the full PDF is not transferred to this report.

S05 · NIH ODS Folate health-professional fact sheet

Source

Material type: Partial search extracts from official NIH ODS safety web material
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Historical general-safety background record: background explaining possible masking of hematologic signs of B12 deficiency, delayed recognition of neurological injury and drug interactions with folic acid in general. Retained access consisted of partial search extracts followed by failure; the partial scope of Health risks/medication interactions is not presented as reading the entire webpage. This does not verify FOLFIV's actual AE frequency or personal safety.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official full web text Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual NIH webpage URL. The historical level was partial search extracts/failure of subsequent access; current access was not attempted and the page was not read.

S11 · Flamingo Pharma folic acid 5 mg tablet SmPC, text revised 20 May 2026

Source

Material type: Official manufacturer SmPC for another product
Materials actually read: Summary read: the relevant bibliographic entries and associated manuscript/structured records in the currently stored source summaries were actually read. External materials were not read in this task.
Findings recorded in the stored summary: Historical general-safety background record: the SmPC for Flamingo Pharma Folic Acid Tablets BP 5 mg, PL43461/0091. Retained locations are §4.3–4.4 for B12, §4.5 for interactions, §4.6 for pregnancy/lactation and §4.8 for AEs, with a different label context of anemia in §4.1 and 5 mg/day for 4 months in adults in §4.2. The revision date 2026-05-20 and eMC update 2026-06-05 are retained as original records. This does not certify authorization or direct harm counts for the Bailly-Creat 15 mg infertility trial.
Record level: Conversion of retained Korean/structured evidence, bibliography and historical location records dated 2026-09-16. This is not new verification of external content, clinical calculation or reassessment.
Study overlap and independent replication: False

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official manufacturer SmPC full web text Open material ↗	Unverified (no external lookup in this task)	Access not attempted	Not read	This is the actual eMC URL for the relevant SmPC. It records historical access to a label for another product/jurisdiction; it was not read in this task.

Report counts versus independent study counts

These are report links in the stored manuscript. One trial family of decisive direct evidence (S01, S02, S03) / adjacent evidence at another dose and with another endpoint definition (S04) / a candidate with the exact endpoint unverified (S06) / positive adjacent evidence at another dose and genotype (S07, S14) / a candidate whose quantitative results were not reconstructed (S08) / evidence excluded because of a combination and different endpoint (S09, S10). References not found in the bibliography: S16, S15. They were not created as separate reports. This is advance fixing of the independent boundaries and individual criteria for the stored materials, application to stored summaries and the author's own cross-check. QA by another author, external clinical full texts/searches, new calculations/reassessment, official methodological/clinical certification, CSV/MD/HTML/browser work and shared registration/publication have not yet been performed. Report and family labels are not summed as independent trial counts or participant counts.

Review criteria

Version NGM-v3110-FOLIC15-CATEGORYA-M3-1.0 · Criteria record date 2026-10-05. These are Chamgap's own application conditions, informed by the referenced methods. They do not constitute official assessment-tool certification or a new efficacy score.

N01 · Which distinct comparison of population, exposure, comparator and endpoint is addressed?

Required materials and conditions: The original claim; the identity of the population, single added ingredient, comparator and M3 change endpoint, and the boundaries of exclusion
Conditions for verification: Preserve the original /ko/effect unchanged and link it to the single question of 15 mg/day, M3−M0, source-defined category a and matched placebo.
Requirement and applicability: Required
Application exceptions: The current subclaims array is empty. No additional main tables are created for other doses, pregnancy or live birth.
Why this condition is needed: This is needed to avoid combining all male infertility, semen parameters and pregnancy outcomes into the judgment of one table merely because they share the ingredient name folic acid.
Referenced methods: C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E09: M03 §3.2.4; internally defined boundaries for extending the claim. Reason for applying this in this case: This is needed to avoid combining all male infertility, semen parameters and pregnancy outcomes into the judgment of one table merely because they share the ingredient name folic acid. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N02 · By which identifiers are the FOLFIV article, index record and registration linked?

Required materials and conditions: Identifiers and report types/locations for the S01 article, S02 index record and S03 registration
Conditions for verification: Link the DOI, PMID, PMCID, NCT and report types in the current bibliography, while retaining limitations on access to original sources.
Requirement and applicability: Required
Application exceptions: Verification of the NCT identifier does not establish verification of the complete registration history or the plan for the relevant outcome.
Why this condition is needed: This is needed to avoid counting the PDF, PubMed record and registration of the same trial as evidence replicated three times.
Referenced methods: C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed. Reason for applying this in this case: This is needed to avoid counting the PDF, PubMed record and registration of the same trial as evidence replicated three times. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N03 · Have overlap and missing references in the report list and study families been distinguished?

Required materials and conditions: The actual bibliography, the families and linked-source lists in the evidence, and materials linked as S15/S16
Conditions for verification: Preserve the links between the actual 14 bibliographic entries and 6 evidence families, and identify references for which bibliographic information was not provided.
Requirement and applicability: Required
Application exceptions: The current inputs do not contain sources/trial_families/detailed numerical arrays. References to S15/S16 in the evidence are not issued as separate actual reports.
Why this condition is needed: This is needed to avoid adding the main trial, correction and index records as independent samples or inventing sources that were not provided.
Referenced methods: C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid adding the main trial, correction and index records as independent samples or inventing sources that were not provided. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N04 · Have the stored summaries read in the present task been distinguished from historical external access?

Required materials and conditions: The access_level/locations of each bibliographic entry, the overall review date, the actual reading scope in this task and safe URLs
Conditions for verification: Separate reading of the currently stored summaries from external material types that were not accessed, acquired or read, and leave historical access dates empty.
Requirement and applicability: Required
Application exceptions: verified_date is the overall evidence review date. Because there is no per-report access-date key, it is not used as an actual access date.
Why this condition is needed: This is needed to avoid upgrading historical full_text records, access failures or links to full-text reading or access failure in the present task.
Referenced methods: C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid upgrading historical full_text records, access failures or links to full-text reading or access failure in the present task. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N05 · At which cutoff date and within which verification scope are evidence and corrections discussed?

Required materials and conditions: The search/review record dated 2026-09-16, the actual S10 correction and revision_triggers
Conditions for verification: Distinguish the evidence cutoff, current review date and historical search scope from the absence of a current comparison for corrections/retractions.
Requirement and applicability: Required
Application exceptions: Even though the corrections array is empty, the Korean manuscript and S10 contain the FAZST correction. The empty array is not used to mean that there are no corrections.
Why this condition is needed: This is needed to avoid exaggerating the retained search scope into an up-to-date search of all literature or an absence of studies worldwide.
Referenced methods: C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid exaggerating the retained search scope into an up-to-date search of all literature or an absence of studies worldwide. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N06 · Which folate form is the trial's active ingredient?

Required materials and conditions: Trial ingredient specifications and materials verifying the salt, crystal form and manufacturing source
Conditions for verification: Distinguish folic acid as the sole randomized added active ingredient from unknown chemical details.
Requirement and applicability: Required
Application exceptions: Even when the ingredient name is the same, the exact salt and crystal form remain unverified in the current materials.
Why this condition is needed: This is needed to avoid substituting dietary folate, 5-MTHF, folinic acid or folic acid plus zinc for the results of folic acid alone.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed. Reason for applying this in this case: This is needed to avoid substituting dietary folate, 5-MTHF, folinic acid or folic acid plus zinc for the results of folic acid alone. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N07 · Which formulation details of the tablets and matched placebo are known?

Required materials and conditions: Specifications for the Bailly-Creat trial tablets and placebo: release formulation, batch, purity and excipients
Conditions for verification: Separate tablet count, manufacturer and matching appearance from unverified release formulation, purity, batch and excipients.
Requirement and applicability: Required
Application exceptions: The 5 mg SmPC of another company is not evidence for the batch or excipients of these Bailly-Creat trial tablets.
Why this condition is needed: This is needed to avoid turning the manufacturer's name or the 5 mg designation into certification of the equivalence or quality of all products.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid turning the manufacturer's name or the 5 mg designation into certification of the equivalence or quality of all products. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N08 · What was the actual route of administration?

Required materials and conditions: The original designation of the trial's oral route
Conditions for verification: Align the oral-route designation in the current manuscript and actual_trial_fields.
Requirement and applicability: Required
Application exceptions: This item does not adjudicate the absence of evidence or lack of efficacy for other routes.
Why this condition is needed: This is needed to avoid extending oral-tablet results to injection, other routes or food exposures.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed. Reason for applying this in this case: This is needed to avoid extending oral-tablet results to injection, other routes or food exposures. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N09 · Can the planned 15 mg/day regimen be distinguished from actual intake?

Required materials and conditions: Originally prescribed tablet count and dose, actual adherence/intake records and total dietary folate
Conditions for verification: Distinguish the verification levels for the planned dose, actual dosing times, adherence and dietary exposure.
Requirement and applicability: Required
Application exceptions: 3 tablets of 5 mg and a total of 15 mg/day are values in the original materials. No new conversion or dosing recommendation is created.
Why this condition is needed: This is needed to avoid presenting the assigned dose as every participant's actual intake or the optimal dose.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed. Reason for applying this in this case: This is needed to avoid presenting the assigned dose as every participant's actual intake or the optimal dose. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N10 · Are the M3 semen assessment and the full treatment/pregnancy follow-up periods the same?

Required materials and conditions: Actual timing records for M0/M3 semen assessment, treatment discontinuation, semen collection for IVF and pregnancy follow-up
Conditions for verification: Distinguish the M3−M0 timing from possible continuation of treatment and the different pregnancy follow-up period.
Requirement and applicability: Required
Application exceptions: Treatment could continue until semen collection for IVF. No new estimate of a sustained effect after treatment cessation is made.
Why this condition is needed: This is needed to avoid turning the 3-month semen endpoint into the full observation period for pregnancy outcomes or every participant's total treatment duration.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / H02: M19 §19.2 harm questions by study design; details of temporal relationships are internally designed. Reason for applying this in this case: This is needed to avoid turning the 3-month semen endpoint into the full observation period for pregnancy outcomes or every participant's total treatment duration. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N11 · Which men were selected, and did they all have the same motility impairment?

Required materials and conditions: Male inclusion/exclusion criteria and the distribution of age and abnormal semen parameters
Conditions for verification: Explain the age range, IVF setting, requirement for at least one abnormal semen parameter and limitations of the mixed eligibility criteria.
Requirement and applicability: Required
Application exceptions: Preserve the article's WHO 2010 designation and criteria as written; do not replace them with modern criteria.
Why this condition is needed: This is needed to avoid treating all IVF partners with at least one semen abnormality as having the same OAT or isolated motility disorder.
Referenced methods: C04: M03 §3.2.1; detailed population criteria are internally designed. Reason for applying this in this case: This is needed to avoid treating all IVF partners with at least one semen abnormality as having the same OAT or isolated motility disorder. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N12 · Are baseline folate-deficiency, B12 and MTHFR status known?

Required materials and conditions: Serum folate criteria, baseline deficiency counts, B12/MTHFR distributions and prespecified subgroup plans
Conditions for verification: Separate the serum-deficiency definition from the unverified actual baseline distribution and subgroup effects.
Requirement and applicability: Required
Application exceptions: An unverified deficiency count is not filled in as 0 deficient participants or as all participants being deficient.
Why this condition is needed: This is needed to avoid mixing effects of correcting deficiency with supplementation effects in people without deficiency or genotype-specific effects.
Referenced methods: C04: M03 §3.2.1; detailed population criteria are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / H08: M19 §19.1.2–19.2.4; internal application. Reason for applying this in this case: This is needed to avoid mixing effects of correcting deficiency with supplementation effects in people without deficiency or genotype-specific effects. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N13 · Does the description of excluding female causes agree with the baseline table of mixed causes?

Required materials and conditions: Female inclusion/exclusion criteria, the baseline table of causes and an explanation/correction of the discrepancy
Conditions for verification: Preserve female age, the exclusion description and the discrepancy involving mixed causes in 18/17 participants, and explain the limitation on applicability.
Requirement and applicability: Required
Application exceptions: Do not silently resolve the conflict between the original methods and baseline table by creating new inclusion criteria.
Why this condition is needed: This is needed to avoid deleting female factors in the couples and extending the findings to an effect in purely male-factor infertility.
Referenced methods: C04: M03 §3.2.1; detailed population criteria are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid deleting female factors in the couples and extending the findings to an effect in purely male-factor infertility. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N14 · Against what shared background care was the placebo compared?

Required materials and conditions: Actual specifications of the matched placebo and background IVF care
Conditions for verification: Display both the 3 matched placebo tablets/day and background IVF-ICSI care in the two arms.
Requirement and applicability: Required
Application exceptions: A shared IVF care policy in both arms does not establish that every individual's treatment was identical.
Why this condition is needed: This is needed to avoid equating the placebo comparison with the natural course under no treatment.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid equating the placebo comparison with the natural course under no treatment. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N15 · Have IVF treatment and other male medications been distinguished from the added trial ingredient?

Required materials and conditions: IVF/female stimulation regimens by arm, concurrent male treatment, rescue treatment and handling of deviations
Conditions for verification: Explain the common policy, differences in individual treatments, and the reporting scope and unverified information about other male interventions.
Requirement and applicability: Required
Application exceptions: The reported absence of male hormonal/vitamin treatment does not mean independent verification in this task or the absence of all concomitant exposures.
Why this condition is needed: This is needed to avoid automatically attributing differences in female stimulation regimens or other treatments to the contribution of folic acid in men.
Referenced methods: E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / H05: M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed. Reason for applying this in this case: This is needed to avoid automatically attributing differences in female stimulation regimens or other treatments to the contribution of folic acid in men. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N16 · The selected value represents change at which time, in which sperm category and in which units?

Required materials and conditions: The label, time, units and direction of the effect of interest for the selected Table4 row
Conditions for verification: Link Progressive motility (a), M3−M0, percentage point and the original direction of benefit.
Requirement and applicability: Required
Application exceptions: Setting higher values as the proposed direction of benefit does not establish clinical importance or actual improvement.
Why this condition is needed: This is needed to avoid mixing endpoint percentages, total motility, changes and %/%p.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid mixing endpoint percentages, total motility, changes and %/%p. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N17 · Can source-defined category a be mapped to modern WHO aggregate PR?

Required materials and conditions: The original motility-classification/speed criteria and the relevant definition section in the cited WHO edition
Conditions for verification: Retain the unverified correspondence between source category a and a+b/aggregate PR, and the unverified speed criteria, without automatic conversion.
Requirement and applicability: Required
Application exceptions: Verification of metadata for WHO edition 6 or a record of failed access to edition 5 alone does not establish verification of definitions/speed criteria.
Why this condition is needed: This is needed to avoid converting historical sperm classifications merely because they use the same terminology.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid converting historical sperm classifications merely because they use the same terminology. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N18 · What were the actual abstinence, specimen-collection and motility-reading procedures?

Required materials and conditions: Semen-collection conditions, motility equipment/reading rules, assessors/blinding and measurement differences between arms
Conditions for verification: Distinguish collection after 3–5 days of abstinence from the assessment procedures and limitations specific to motility.
Requirement and applicability: Required
Application exceptions: The 2 readers used for DNA assessment are not evidence of the number or blinding of motility assessors.
Why this condition is needed: This is needed to avoid transferring fixation/freezing methods or reader counts from DNA testing to motility assessment.
Referenced methods: E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid transferring fixation/freezing methods or reader counts from DNA testing to motility assessment. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N19 · Does the page's primary endpoint match the endpoint hierarchy in the article and registration?

Required materials and conditions: The complete NCT01407432 version history, protocol, SAP and records of endpoint/analysis changes
Conditions for verification: Distinguish the article's secondary endpoint and the page's primary endpoint from the unverified prespecified hierarchy, and disclose when the editorial boundaries were selected.
Requirement and applicability: Required
Application exceptions: Failure to obtain the registration/plans does not establish nonregistration or selective reporting.
Why this condition is needed: This is needed to avoid presenting a category-a row selected after reading the literature as a preregistered primary endpoint.
Referenced methods: E06: M08 Table 8.2.a, M04 §4.6.3; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid presenting a category-a row selected after reading the literature as a preregistered primary endpoint. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N20 · To what extent are the actual parallel-group design and randomization procedures known?

Required materials and conditions: Methods/tables for allocation-sequence generation, concealment, personnel responsible and baseline balance between arms
Conditions for verification: Distinguish the description of a double-blind parallel randomized trial from the actual level of verification of allocation procedures.
Requirement and applicability: Required
Application exceptions: The trial is explicitly described as parallel-group in the current materials. Absence of crossover/cluster adjustment is not turned into a new defect in this design.
Why this condition is needed: This is needed to avoid claiming that all details of allocation sequence, concealment and baseline balance have been verified merely from the RCT label.
Referenced methods: E01: M08 §8.1–8.2.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid claiming that all details of allocation sequence, concealment and baseline balance have been verified merely from the RCT label. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N21 · Were matched placebo and double blinding actually maintained through assessment and analysis?

Required materials and conditions: Blinding of participants, personnel, motility assessors/analysts, and checks of unblinding or successful treatment guesses
Conditions for verification: Separate nominal double blinding and matched placebo from gaps in information on who was actually blinded and whether blinding was broken.
Requirement and applicability: Required
Application exceptions: Unverified blinding details are not labeled as confirmed absence of blinding or automatic failure.
Why this condition is needed: This is needed to avoid automatically extending matching appearance into verification that assessor/analyst blinding was maintained.
Referenced methods: E01: M08 §8.1–8.2.3; internal application / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid automatically extending matching appearance into verification that assessor/analyst blinding was maintained. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N22 · Does each number count people allocated, attending a visit, included in change analysis or included in endpoint analysis?

Required materials and conditions: The Figure3 flow and person counts in the baseline, M3 and change columns of Table4
Conditions for verification: Link each denominator separately: 83/79 allocated, 76/72 attending visits, 66/60 in change analysis and 67/62 in endpoint analysis.
Requirement and applicability: Required
Application exceptions: Person counts are not treated as sperm-cell counts or repeated-specimen counts. Means from different populations are not subtracted.
Why this condition is needed: This is needed to avoid using the total of 162 participants or visit counts as the denominator for the selected change analysis.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid using the total of 162 participants or visit counts as the denominator for the selected change analysis. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N23 · How can missing data in the change analysis and the reference to ITT be interpreted?

Required materials and conditions: Reasons for missing endpoint data, losses by assigned arm, imputation rules, analysis populations and sensitivity analyses
Conditions for verification: Distinguish the complete paired data for 66/60 participants in the selected row from unverified imputation/sensitivity analyses.
Requirement and applicability: Required
Application exceptions: Unverified missing-data sensitivity is a current evidence gap. The direction or magnitude of missing-data effects is not newly estimated, and no additional score is assigned.
Why this condition is needed: This is needed to avoid turning a statement of the ITT principle into an analysis of all randomized participants in the selected row.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / E06: M08 Table 8.2.a, M04 §4.6.3; internal application. Reason for applying this in this case: This is needed to avoid turning a statement of the ITT principle into an analysis of all randomized participants in the selected row. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N24 · What are the mean, SD, median, IQR and P value for change in source-defined category a?

Required materials and conditions: Mean (SD), median/IQR, test, P value and original denominators for the selected change row in Table4
Conditions for verification: Preserve the original values and direction of both arms' change means (SDs), medians/IQRs and the between-arm test.
Requirement and applicability: Required
Application exceptions: The estimands of the mean difference and rank test are not assumed to be identical. SD is not converted into SE or a CI.
Why this condition is needed: This is needed to avoid substituting different summary statistics or types of dispersion, or equating nonsignificance with an effect of 0.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid substituting different summary statistics or types of dispersion, or equating nonsignificance with an effect of 0. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N25 · Has historical arithmetic on means been distinguished from the formal between-arm estimator?

Required materials and conditions: Existing arithmetic records, their respective change/endpoint columns and the formal test definition
Conditions for verification: Explain the different meanings of historical arithmetic on change means, endpoint means/arithmetic and the formal test.
Requirement and applicability: Required
Application exceptions: Both arithmetic values are quotations from the existing manuscript. No new calculation, adjustment, standardized effect, NNT or CI is produced.
Why this condition is needed: This is needed to avoid treating the descriptive arithmetic of −0.2 %p and the endpoint difference of +0.6 %p as the same change effect.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid treating the descriptive arithmetic of −0.2 %p and the endpoint difference of +0.6 %p as the same change effect. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N26 · What does P = 0.7871 compare, and which effect estimates are unverified?

Required materials and conditions: Definitions of the between-arm test, analysis population, effect of interest and formal estimator for the selected row
Conditions for verification: Separate the between-arm Wilcoxon–Mann–Whitney comparison of change from the unverified formal/adjusted effect estimates.
Requirement and applicability: Required
Application exceptions: A nonparametric test result is not presented as equivalent to an adjusted effect on means or an adherence effect.
Why this condition is needed: This is needed to avoid turning a between-arm P value into within-arm improvement or a CI for the mean difference.
Referenced methods: E04: M08 §8.2.2, M15 §15.3.1; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid turning a between-arm P value into within-arm improvement or a CI for the mean difference. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N27 · What range of benefits can be assessed using a reported formal between-arm CI?

Required materials and conditions: The formal between-arm effect estimate/CI, dispersion, denominators and estimation method for the selected category-a change
Conditions for verification: Retain the null CI for the direct question and the reason precision cannot be interpreted.
Requirement and applicability: Required
Application exceptions: The 95.1% CI from FAZST is for a different combination and total motility; it does not substitute for the CI of this row.
Why this condition is needed: This is needed to avoid inventing a narrow CI or exclusion of meaningful benefit from SD, sample size or nonsignificance alone.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E05: M15 §15.3.1–15.3.3; internal application. Reason for applying this in this case: This is needed to avoid inventing a narrow CI or exclusion of meaningful benefit from SD, sample size or nonsignificance alone. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N28 · Is there an MCID applicable to this category a, population and time point?

Required materials and conditions: A validated threshold for important change and its validation context for this source-defined category, population and M3 time point
Conditions for verification: Retain the null applicable MCID and the limitation on interpreting clinical importance.
Requirement and applicability: Required
Application exceptions: Pregnancy-event trials are not unconditionally imposed as mandatory for the question about motility change itself.
Why this condition is needed: This is needed to avoid declaring criteria met or therapeutic value based on arbitrary minimum changes, participant counts or trial counts.
Referenced methods: E05: M15 §15.3.1–15.3.3; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid declaring criteria met or therapeutic value based on arbitrary minimum changes, participant counts or trial counts. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N29 · Have Huang's different dose/genotype results and the conflicting test descriptions been preserved?

Required materials and conditions: Huang Table3/footnote and text, genotype-specific motility analysis denominators, tests/CIs and prespecified subgroup plans
Conditions for verification: Retain together the 0.8 mg/day dose, TT genotype, original baseline/endpoint values, conflict between the table footnote and text about the test, and unverified between-arm CI/P value/denominators.
Requirement and applicability: Required
Application exceptions: The 769 eligible participants are not used as the denominator for TT motility analysis, and overlapping genotype strata are not summed.
Why this condition is needed: This is needed to avoid concealing favorable adjacent results or combining them with the category-a effect at 15 mg.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed. Reason for applying this in this case: This is needed to avoid concealing favorable adjacent results or combining them with the category-a effect at 15 mg. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N30 · What adjacent information does da Silva's 5 mg single-ingredient result provide?

Required materials and conditions: da Silva's single-ingredient-arm results/denominators, motility definition, initial allocation and funding scope
Conditions for verification: Distinguish 5 mg/day, 3 months, the older a+b definition and the difference between completion/allocation denominators from the direct question.
Requirement and applicability: Required
Application exceptions: The 49 protocol completers are not used as the initial allocation count.
Why this condition is needed: This is needed to avoid turning a finding of no difference at another dose and for an a+b endpoint into repeated refutation of the exact category-a question.
Referenced methods: E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C04: M03 §3.2.1; detailed population criteria are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid turning a finding of no difference at another dose and for an a+b endpoint into repeated refutation of the exact category-a question. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N31 · What remains unknown while the folic-acid-only arms of Wong and Raigani are retained?

Required materials and conditions: Endpoints, denominators and quantitative results for each single-ingredient arm in Wong's fertile/subfertile strata and Raigani's 4-arm trial
Conditions for verification: Distinguish the existence of single-ingredient arms, strata/total counts and the unverified exact category-a effects/denominators.
Requirement and applicability: Required
Application exceptions: Unverified progressive-motility estimators for the individual single-ingredient arms are not described as absence of human studies.
Why this condition is needed: This is needed to avoid discarding an entire 4-arm trial as a combination trial or filling unverified single-ingredient effects with figures from the entire trial.
Referenced methods: E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid discarding an entire 4-arm trial as a combination trial or filling unverified single-ingredient effects with figures from the entire trial. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N32 · Have the FAZST combination, total motility and correction been distinguished from the direct question?

Required materials and conditions: FAZST Table3, the multiplicity footnote and original Table1 correction, and boundaries between combination/single-ingredient comparisons
Conditions for verification: Preserve 5 mg plus zinc 30 mg, 6 months, 2370 participants, the original total-motility values and the scope of the Table1 correction.
Requirement and applicability: Required
Application exceptions: The 95.1% CI is not changed to 95%, and zinc-related harms from the combination are not transferred to folic acid.
Why this condition is needed: This is needed to avoid counting different-endpoint results for combined active ingredients and a correction report as a folic-acid-only effect or an independent replication.
Referenced methods: C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid counting different-endpoint results for combined active ingredients and a correction report as a folic-acid-only effect or an independent replication. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N33 · How were pregnancy and DNA results from the same trial separated?

Required materials and conditions: FOLFIV Table6, selection/denominators of the embryo-transfer subgroup and separate DNA/live-birth outcomes
Conditions for verification: Distinguish the original values, denominators and P values for biochemical pregnancy, clinical pregnancy at 7 weeks and miscarriage from the different questions of the category-a endpoint and live birth.
Requirement and applicability: Required
Application exceptions: The denominator of the embryo-transfer subgroup is not replaced with all 162 randomized participants. Other endpoint results are not deleted.
Why this condition is needed: This is needed to avoid turning favorable pregnancy results into proof of success for sperm motility or improved live birth.
Referenced methods: E09: M03 §3.2.4; internally defined boundaries for extending the claim / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application. Reason for applying this in this case: This is needed to avoid turning favorable pregnancy results into proof of success for sperm motility or improved live birth. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N34 · Have concerns about serum folate units and printed DNA values been left unresolved rather than arbitrarily corrected?

Required materials and conditions: Original tables, earlier/later versions, corrections and author explanations for serum folate units and the DNA change row
Conditions for verification: Specify the retained candidate errors and the limitation that exact values/original locations were not provided, separating them from the main numbers.
Requirement and applicability: Required
Application exceptions: Because the currently stored summaries do not provide the exact units on both sides of the conflict or the DNA numbers, actual values are not newly invented and quoted.
Why this condition is needed: This is needed to avoid silently correcting candidate errors in other endpoints or importing them into category-a motility calculations.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid silently correcting candidate errors in other endpoints or importing them into category-a motility calculations. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N35 · Can public funding, sponsorship and product manufacture be verified separately?

Required materials and conditions: Actual disclosures of FOLFIV funding, sponsorship, product manufacture/supply and roles/contracts
Conditions for verification: Record PHRC 2010(10-052), AP-HP, Bailly-Creat and the limits of verification separately.
Requirement and applicability: Required
Application exceptions: The manufacturer's name alone is not used to newly infer free product supply or detailed contracts governing involvement in the study.
Why this condition is needed: This is needed to avoid turning public funding and a named manufacturer into independent replication or an independent audit of all relationships.
Referenced methods: C10: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application. Reason for applying this in this case: This is needed to avoid turning public funding and a named manufacturer into independent replication or an independent audit of all relationships. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N36 · Have author declarations been distinguished from limits on funding verification in other families?

Required materials and conditions: Each trial's Funding/COI, product relationships, author/institution disclosures and scope of verification
Conditions for verification: Distinguish FOLFIV's declaration, Huang's reported absence of funding, Silva's fellowships and unverified overall funding, and the levels of information for other families.
Requirement and applicability: Required
Application exceptions: Relevant interests do not lead to automatic exclusion, and a declaration of no interests alone does not establish absence of bias.
Why this condition is needed: This is needed to avoid turning no funding/no COI declarations or unverified information into certification of independence.
Referenced methods: C10: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid turning no funding/no COI declarations or unverified information into certification of independence. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N37 · Have harm collection, events and denominators been verified for the same 15 mg exposure?

Required materials and conditions: AE definitions, collection and severity; person/event counts for SAEs and toxicity withdrawals; exposure/analysis denominators and duration
Conditions for verification: Separate the M3 questionnaire plan from unverified AE/SAE and toxicity-withdrawal person/event counts and denominators.
Requirement and applicability: Required
Application exceptions: Efficacy results are not deleted because harm data are unverified. Spontaneous/systematic collection methods are not filled in arbitrarily either.
Why this condition is needed: This is needed to avoid turning a tolerability-questionnaire plan into a complete tally of all AEs/SAEs and toxicity withdrawals or a count of 0 events.
Referenced methods: E10: M19 §19.1.2–19.2.4; internal application / H01: M19 §19.1.2–19.2.4; detailed differentiation is internally designed / H04: M19 §19.1.2–19.2.4; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid turning a tolerability-questionnaire plan into a complete tally of all AEs/SAEs and toxicity withdrawals or a count of 0 events. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N38 · Have general B12/drug precautions been distinguished from trial harms?

Required materials and conditions: The partial NIH extracts and relevant B12/interaction sections of the SmPC, and medication/use contexts
Conditions for verification: Separate background sources and access limitations concerning B12 masking/delayed recognition of neurological injury and interactions from trial events.
Requirement and applicability: Required
Application exceptions: Anticonvulsant/MTX interactions require boundaries specific to the use context, and the study dose is not an instruction for personal dosing or ART changes.
Why this condition is needed: This is needed to avoid turning warnings in general labels/summaries into events that actually occurred in FOLFIV or a magnitude of personal risk.
Referenced methods: E10: M19 §19.1.2–19.2.4; internal application / H05: M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed. Reason for applying this in this case: This is needed to avoid turning warnings in general labels/summaries into events that actually occurred in FOLFIV or a magnitude of personal risk. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N39 · Are the indications and regimen on the Flamingo 5 mg label the same as those of the 15 mg trial?

Required materials and conditions: Ingredient/route, indications, regimen and version of the Flamingo Pharma PL43461/0091 SmPC
Conditions for verification: Separate the 5 mg anemia label from another manufacturer/jurisdiction from the 15 mg infertility trial.
Requirement and applicability: Required
Application exceptions: Providing the link here does not mean that the label was newly read in this task.
Why this condition is needed: This is needed to avoid using the anemia regimen of another authorized product as authorization or certification of efficacy/safety for 15 mg in male infertility.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed / E10: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied. Reason for applying this in this case: This is needed to avoid using the anemia regimen of another authorized product as authorization or certification of efficacy/safety for 15 mg in male infertility. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N40 · Does this table also adjudicate optimal dose, long-term use, vulnerable groups and personal treatment?

Required materials and conditions: Direct dose comparisons, long-term/vulnerable-population exposures and harm follow-up needed when addressing extended questions
Conditions for verification: Distinguish extensions outside the selected question by the reasons they do not apply and the separate designs they would require.
Requirement and applicability: Supplementary and extension boundaries
Application exceptions: Each extension is a separate question. Completion of all extension studies is not imposed as a mandatory condition for this narrow category-a change table.
Why this condition is needed: This is needed to avoid extending the limited M3 comparison to optimal dose, long-term maintenance/safety or all populations, including children and pregnancy/lactation.
Referenced methods: E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / E10: M19 §19.1.2–19.2.4; internal application / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied. Reason for applying this in this case: This is needed to avoid extending the limited M3 comparison to optimal dose, long-term maintenance/safety or all populations, including children and pregnancy/lactation. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N41 · Have the existing D/30-point verdict and document self-review been kept from being used as a new criteria-based judgment?

Required materials and conditions: The original grade/score/axes, assessment_profile, editorial_review and the scope of the current task
Conditions for verification: Separate preservation of the existing original values from statuses for individual data/recording criteria.
Requirement and applicability: Required
Application exceptions: The original grade/score/axes and favorable/unfavorable results are preserved unchanged as historical values. No new score or percentage of criteria met is created.
Why this condition is needed: This is needed to avoid reusing a historical score, self-assessed document quality or verification wording as current clinical certification or a criteria score.
Referenced methods: C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid reusing a historical score, self-assessed document quality or verification wording as current clinical certification or a criteria score. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

N42 · How are updates under the same ID and differing server metadata preserved?

Required materials and conditions: Original ID/URLs, revision_policy/history/triggers, and event/server-verification records for publication metadata
Conditions for verification: Preserve original ID/URLs, revision history/triggers and metadata differences, distinguishing them from the present local stored-summary stage.
Requirement and applicability: Required
Application exceptions: The difference between publication_notes.server_deployed=false and top-level server_deployed=true is not silently overwritten.
Why this condition is needed: This is needed to avoid mistaking historical publication metadata in the original record for actual completed publication of the new table.
Referenced methods: C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed. Reason for applying this in this case: This is needed to avoid mistaking historical publication metadata in the original record for actual completed publication of the new table. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Referenced methods and the sections actually reviewed

M03 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13

Referenced principle: Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.
Extent of review: Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools.

M04 · Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03

Official methodology · §4.5, §4.6.1–4.6.3, MECIR C42

Referenced principle: Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.
Extent of review: Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools.

M08 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §8.1–8.2.3, Table 8.2.a

Referenced principle: Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.
Extent of review: Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools.

M15 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §15.2.4, §15.3.1–15.3.3

Referenced principle: Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.
Extent of review: Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools.

M19 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §19.1.2, §19.2.1–19.2.4

Referenced principle: Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.
Extent of review: Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools.

What the statuses mean

Met: The relevant narrow recording criterion has been met, such as the exact question, attribution of numbers/historical calculations, reading or version. This is not certification of clinical efficacy/safety or verification of external full texts in this task.
Partly verified: Relevant retained reports are available, but some comparisons with original methods, plans, denominators, intervals, identities or access needed for the criterion remain outstanding.
Unverified: The necessary values/materials could not be established within the currently retained inputs and the scope of verification at the time. This does not mean an effect of 0 or absence of studies worldwide.
Not reported: Used only for the scope of nonreporting in materials/sections actually read or in explicitly identified historical summaries. It is not extended to the entirety of external full texts not read in this task.
Conflicting information: Each row identifies a retained discrepancy/candidate error concerning the same fact or a difference in publication metadata. Mere numerical differences arising from different questions or endpoint/change values are not labeled as conflicts.
Inaccessible: Used only when actual external access fails in the present task. Because access was not attempted here, historical failures are not transferred to the current status.
Review incomplete: The scope of review actually remaining or external materials not yet compared in the present task. This does not mean that the entire already completed review of retained stored summaries is incomplete.
Not applicable: Limited to establishing optimal dose, long-term/special-population outcomes or personal safety outside the current narrow M3 category-a question. It is not a substitute for materials not read or certification of safety.

Change history

2026-11-05 · Public page/material version 1.0

The public-facing display and data were prepared from the existing 42 items. No new clinical search, change to verification statuses or scoring was performed.

The stored-material review date (2026-10-05) and original evidence cut-off (2026-09-16) were retained unchanged.

Researcher downloads

These materials provide the same evidence, scope and verification status as this page.

View all item details

N01 · Which distinct comparison of population, exposure, comparator and endpoint is addressed?

Current findings: The question is whether, in men aged 18–60 in infertile couples planning IVF-ICSI, oral folic acid 15 mg/day as the sole randomized added active ingredient increases the M3−M0 change in source-defined category-a progressive motility compared with matched placebo.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The original claim has been linked to the narrow boundaries of the actual comparison. This status does not indicate that clinical improvement has been verified.
Reason for missing information: Effects on aggregate PR, pregnancy, live birth and effects of other doses are not adjudicated in this table.
Required materials and conditions: The original claim; the identity of the population, single added ingredient, comparator and M3 change endpoint, and the boundaries of exclusion
Materials to obtain first: The original claim; the identity of the population, single added ingredient, comparator and M3 change endpoint, and the boundaries of exclusion
Further research: Cross-check the elements of the question in the current manuscript and structure, and separate other questions such as PR, a+b and pregnancy in the boundary records.
Remaining uncertainty: Effects on aggregate PR, pregnancy, live birth and effects of other doses are not adjudicated in this table. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Preserve the original /ko/effect unchanged and link it to the single question of 15 mg/day, M3−M0, source-defined category a and matched placebo.
Why this condition is needed: This is needed to avoid combining all male infertility, semen parameters and pregnancy outcomes into the judgment of one table merely because they share the ingredient name folic acid.
Application exceptions: The current subclaims array is empty. No additional main tables are created for other doses, pregnancy or live birth.
Referenced methods: C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E09: M03 §3.2.4; internally defined boundaries for extending the claim. Reason for applying this in this case: This is needed to avoid combining all male infertility, semen parameters and pregnancy outcomes into the judgment of one table merely because they share the ingredient name folic acid. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N02 · By which identifiers are the FOLFIV article, index record and registration linked?

Current findings: S01 is the FOLFIV article PDF, S02 is the PubMed record for the same article, and S03 is the NCT01407432 registration record. DOI 10.3390/jcm10091876, PMID 33925981 and PMCID PMC8123699 are retained. The registration history, protocol and SAP were not obtained at the time.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The article family is linked bibliographically, but a complete comparison with the registration text and plans remains outstanding.
Reason for missing information: The complete registration version history, and the original-source identity and content of the protocol and SAP.
Required materials and conditions: Identifiers and report types/locations for the S01 article, S02 index record and S03 registration
Materials to obtain first: Identifiers and report types/locations for the S01 article, S02 index record and S03 registration
Further research: Cross-check the identifiers and related reports, group them into one trial family, and separately record the lack of comparison against the registration text/history.
Remaining uncertainty: The complete registration version history, and the original-source identity and content of the protocol and SAP. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Link the DOI, PMID, PMCID, NCT and report types in the current bibliography, while retaining limitations on access to original sources.
Why this condition is needed: This is needed to avoid counting the PDF, PubMed record and registration of the same trial as evidence replicated three times.
Application exceptions: Verification of the NCT identifier does not establish verification of the complete registration history or the plan for the relevant outcome.
Referenced methods: C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed. Reason for applying this in this case: This is needed to avoid counting the PDF, PubMed record and registration of the same trial as evidence replicated three times. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S02 S03

N03 · Have overlap and missing references in the report list and study families been distinguished?

Current findings: The evidence distinguishes FOLFIV, SILVA2013, RAIGANI2014, HUANG2020, WONG2002 and FAZST. S07/S14 refer to the same Huang trial; S09/S10 are FAZST and its correction. The S16 reference for FOLFIV and the S15 reference for FAZST are absent from the current 14 bibliographic entries, so their URLs and separate report identities have not been established.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The provided families and actual bibliography have been linked, but report identities for S15/S16 were not provided. Family counts and counts of replications within the exact boundaries have not been interchanged.
Reason for missing information: Actual bibliographic information for S15/S16 and the detailed family/numerical extraction files not embedded in the current inputs.
Required materials and conditions: The actual bibliography, the families and linked-source lists in the evidence, and materials linked as S15/S16
Materials to obtain first: The actual bibliography, the families and linked-source lists in the evidence, and materials linked as S15/S16
Further research: Cross-check the shared families of S01/S02/S03, S07/S14 and S09/S10, and leave missing references on a list awaiting identity verification.
Remaining uncertainty: Actual bibliographic information for S15/S16 and the detailed family/numerical extraction files not embedded in the current inputs. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Preserve the links between the actual 14 bibliographic entries and 6 evidence families, and identify references for which bibliographic information was not provided.
Why this condition is needed: This is needed to avoid adding the main trial, correction and index records as independent samples or inventing sources that were not provided.
Application exceptions: The current inputs do not contain sources/trial_families/detailed numerical arrays. References to S15/S16 in the evidence are not issued as separate actual reports.
Referenced methods: C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid adding the main trial, correction and index records as independent samples or inventing sources that were not provided. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S02 S03 S04 S06 S07 S08 S09 S10 S14

N04 · Have the stored summaries read in the present task been distinguished from historical external access?

Current findings: The Korean manuscript, structured evidence, 14 bibliographic entries and metadata in the currently stored manuscript were read. PDF/visual table checking for S01, HTML for S07/S04/S09, the S11 label and partial search extracts for S05 are records from the time of retention. No external lookup was performed in this task. Actual per-report access dates are empty, and the original material review date of 2026-09-16 is preserved separately.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The recording criterion of separating actual actions from historical access levels is met. No external full texts were read in this task.
Reason for missing information: Actual per-report access dates, whether historical binary files were retained, and their SHAs cannot be established from the current materials alone.
Required materials and conditions: The access_level/locations of each bibliographic entry, the overall review date, the actual reading scope in this task and safe URLs
Materials to obtain first: The access_level/locations of each bibliographic entry, the overall review date, the actual reading scope in this task and safe URLs
Further research: Transfer each bibliographic access level as a historical record, and separately cross-check the current material-type statuses, dates and link types.
Remaining uncertainty: Actual per-report access dates, whether historical binary files were retained, and their SHAs cannot be established from the current materials alone. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate reading of the currently stored summaries from external material types that were not accessed, acquired or read, and leave historical access dates empty.
Why this condition is needed: This is needed to avoid upgrading historical full_text records, access failures or links to full-text reading or access failure in the present task.
Application exceptions: verified_date is the overall evidence review date. Because there is no per-report access-date key, it is not used as an actual access date.
Referenced methods: C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid upgrading historical full_text records, access failures or links to full-text reading or access failure in the present task. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S12 S13 S03 S07 S14 S04 S06 S08 S09 S10 S02 S05 S11

N05 · At which cutoff date and within which verification scope are evidence and corrections discussed?

Current findings: The evidence cutoff is 2026-09-16, and the retained stored-material review date is 2026-10-05. evidence_status records the scope of the ChatGPT search at that time and absence_proven=false. The corrections array is empty, but S10 and the Korean text preserve the FAZST Table1 correction.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The cutoff date and known correction have been linked. Completeness of the latest search, registrations, corrections and retractions was not checked in this task.
Reason for missing information: The complete historical search log and comparison of publications/registrations, corrections and retractions after the cutoff.
Required materials and conditions: The search/review record dated 2026-09-16, the actual S10 correction and revision_triggers
Materials to obtain first: The search/review record dated 2026-09-16, the actual S10 correction and revision_triggers
Further research: Cross-check the retained search/correction records against the empty structured array, and limit statements about absence and currency without conducting a new search.
Remaining uncertainty: The complete historical search log and comparison of publications/registrations, corrections and retractions after the cutoff. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the evidence cutoff, current review date and historical search scope from the absence of a current comparison for corrections/retractions.
Why this condition is needed: This is needed to avoid exaggerating the retained search scope into an up-to-date search of all literature or an absence of studies worldwide.
Application exceptions: Even though the corrections array is empty, the Korean manuscript and S10 contain the FAZST correction. The empty array is not used to mean that there are no corrections.
Referenced methods: C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid exaggerating the retained search scope into an up-to-date search of all literature or an absence of studies worldwide. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S10

N06 · Which folate form is the trial's active ingredient?

Current findings: The trial used folic acid as the single added ingredient. It is distinguished from dietary folate, 5-MTHF and folinic acid; its manufacturing source, exact salt and crystal form are unverified.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The active ingredient is verified, but chemical details and equivalence to other forms have not been verified.
Reason for missing information: Specifications for the exact salt, crystal form and manufacturing source.
Required materials and conditions: Trial ingredient specifications and materials verifying the salt, crystal form and manufacturing source
Materials to obtain first: Trial ingredient specifications and materials verifying the salt, crystal form and manufacturing source
Further research: Cross-check the trial ingredient designation against the original specifications, and separate other folate forms/combined active ingredients as different exposures.
Remaining uncertainty: Specifications for the exact salt, crystal form and manufacturing source. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish folic acid as the sole randomized added active ingredient from unknown chemical details.
Why this condition is needed: This is needed to avoid substituting dietary folate, 5-MTHF, folinic acid or folic acid plus zinc for the results of folic acid alone.
Application exceptions: Even when the ingredient name is the same, the exact salt and crystal form remain unverified in the current materials.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed. Reason for applying this in this case: This is needed to avoid substituting dietary folate, 5-MTHF, folinic acid or folic acid plus zinc for the results of folic acid alone. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N07 · Which formulation details of the tablets and matched placebo are known?

Current findings: The regimen comprised 3 folic acid 5 mg tablets/day from Bailly-Creat Laboratory and 3 placebo tablets/day matched in appearance, size, taste and weight. Release formulation, batch, purity, details of the active tablets and placebo excipients are unverified.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The manufacturer, tablet count and nominal placebo matching are retained, but actual product details remain to be verified.
Reason for missing information: Batch, purity, release-formulation and excipient specifications for the trial product and placebo.
Required materials and conditions: Specifications for the Bailly-Creat trial tablets and placebo: release formulation, batch, purity and excipients
Materials to obtain first: Specifications for the Bailly-Creat trial tablets and placebo: release formulation, batch, purity and excipients
Further research: Cross-check the article and product-supply specifications without automatically transferring information about a different authorized product to this trial product.
Remaining uncertainty: Batch, purity, release-formulation and excipient specifications for the trial product and placebo. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate tablet count, manufacturer and matching appearance from unverified release formulation, purity, batch and excipients.
Why this condition is needed: This is needed to avoid turning the manufacturer's name or the 5 mg designation into certification of the equivalence or quality of all products.
Application exceptions: The 5 mg SmPC of another company is not evidence for the batch or excipients of these Bailly-Creat trial tablets.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid turning the manufacturer's name or the 5 mg designation into certification of the equivalence or quality of all products. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S11

N08 · What was the actual route of administration?

Current findings: The trial treatment was an oral tablet. Folate exposure through other routes is not treated as the same direct comparison.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The actual oral-exposure boundary has been linked. This is not a judgment about superiority of the route or its suitability for an individual.
Reason for missing information: Effects of other routes are outside this question.
Required materials and conditions: The original designation of the trial's oral route
Materials to obtain first: The original designation of the trial's oral route
Further research: Cross-check the original exposure-route designation and limit it to the conditions of the comparison in this table.
Remaining uncertainty: Effects of other routes are outside this question. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Align the oral-route designation in the current manuscript and actual_trial_fields.
Why this condition is needed: This is needed to avoid extending oral-tablet results to injection, other routes or food exposures.
Application exceptions: This item does not adjudicate the absence of evidence or lack of efficacy for other routes.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed. Reason for applying this in this case: This is needed to avoid extending oral-tablet results to injection, other routes or food exposures. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N09 · Can the planned 15 mg/day regimen be distinguished from actual intake?

Current findings: The nominal dose was 15 mg/day, comprising 3 tablets of 5 mg. Collection of adherence data at M3 was planned, but actual dosing times, the proportion of prescribed doses taken and total dietary folate exposure are currently unverified. This is not used as a trial comparing optimal doses.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The assigned dose is verified, and actual intake and background exposure have not been filled in with the same value.
Reason for missing information: Individual dosing times, the proportion of prescribed doses taken, dietary exposure and adherence analyses by arm.
Required materials and conditions: Originally prescribed tablet count and dose, actual adherence/intake records and total dietary folate
Materials to obtain first: Originally prescribed tablet count and dose, actual adherence/intake records and total dietary folate
Further research: Compare nominal assignment with individual intake records, and distinguish adherence analyses according to their analytical purpose and population.
Remaining uncertainty: Individual dosing times, the proportion of prescribed doses taken, dietary exposure and adherence analyses by arm. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the verification levels for the planned dose, actual dosing times, adherence and dietary exposure.
Why this condition is needed: This is needed to avoid presenting the assigned dose as every participant's actual intake or the optimal dose.
Application exceptions: 3 tablets of 5 mg and a total of 15 mg/day are values in the original materials. No new conversion or dosing recommendation is created.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed. Reason for applying this in this case: This is needed to avoid presenting the assigned dose as every participant's actual intake or the optimal dose. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N10 · Are the M3 semen assessment and the full treatment/pregnancy follow-up periods the same?

Current findings: The selected endpoint is the semen change at M3, that is, at 3 months minus baseline. Treatment could continue until semen collection for IVF, so total treatment and pregnancy assessment periods are not described as identical to M3.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The selected assessment time is retained, but each individual's total exposure and discontinuation time are unverified.
Reason for missing information: Individual treatment end dates and actual timing of semen collection and pregnancy follow-up.
Required materials and conditions: Actual timing records for M0/M3 semen assessment, treatment discontinuation, semen collection for IVF and pregnancy follow-up
Materials to obtain first: Actual timing records for M0/M3 semen assessment, treatment discontinuation, semen collection for IVF and pregnancy follow-up
Further research: Record the timeline by separately cross-checking the measurement time of each endpoint and the start/end of exposure.
Remaining uncertainty: Individual treatment end dates and actual timing of semen collection and pregnancy follow-up. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the M3−M0 timing from possible continuation of treatment and the different pregnancy follow-up period.
Why this condition is needed: This is needed to avoid turning the 3-month semen endpoint into the full observation period for pregnancy outcomes or every participant's total treatment duration.
Application exceptions: Treatment could continue until semen collection for IVF. No new estimate of a sustained effect after treatment cessation is made.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / H02: M19 §19.2 harm questions by study design; details of temporal relationships are internally designed. Reason for applying this in this case: This is needed to avoid turning the 3-month semen endpoint into the full observation period for pregnancy outcomes or every participant's total treatment duration. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N11 · Which men were selected, and did they all have the same motility impairment?

Current findings: Participants were male partners aged 18–60 in couples planning IVF-ICSI, with at least 1 abnormal semen parameter required for inclusion. The article specifies one of concentration <15 million/mL, motility <50%, vitality <60% or normal morphology <4%. Participants were not all a group with the same OAT or impairment confined to progressive motility.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Actual eligibility criteria are available, but the distribution of combinations of abnormalities and representativeness cannot currently be established.
Reason for missing information: Baseline composition by combinations and severity of abnormalities, and recruitment/exclusion details.
Required materials and conditions: Male inclusion/exclusion criteria and the distribution of age and abnormal semen parameters
Materials to obtain first: Male inclusion/exclusion criteria and the distribution of age and abnormal semen parameters
Further research: Cross-check eligibility criteria against the distribution of actual baseline characteristics, recording the narrow applicable population and unverified mixed composition.
Remaining uncertainty: Baseline composition by combinations and severity of abnormalities, and recruitment/exclusion details. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Explain the age range, IVF setting, requirement for at least one abnormal semen parameter and limitations of the mixed eligibility criteria.
Why this condition is needed: This is needed to avoid treating all IVF partners with at least one semen abnormality as having the same OAT or isolated motility disorder.
Application exceptions: Preserve the article's WHO 2010 designation and criteria as written; do not replace them with modern criteria.
Referenced methods: C04: M03 §3.2.1; detailed population criteria are internally designed. Reason for applying this in this case: This is needed to avoid treating all IVF partners with at least one semen abnormality as having the same OAT or isolated motility disorder. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N12 · Are baseline folate-deficiency, B12 and MTHFR status known?

Current findings: Deficiency was defined as serum folate <3.5 ng/mL, but baseline deficiency counts and B12/MTHFR distributions are unverified. This population is not described as a group receiving correction of confirmed deficiency or as an entirely nondeficient group.
Verification status: Unverified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The criterion is retained, but materials verifying the actual baseline distribution or deficiency/genotype-specific effects in this comparison are unavailable.
Reason for missing information: Actual deficiency counts, B12/MTHFR distributions and appropriate subgroup analyses.
Required materials and conditions: Serum folate criteria, baseline deficiency counts, B12/MTHFR distributions and prespecified subgroup plans
Materials to obtain first: Serum folate criteria, baseline deficiency counts, B12/MTHFR distributions and prespecified subgroup plans
Further research: Cross-check baseline status against planned subgroup/interaction analyses without transferring genotype findings from the separate Huang trial.
Remaining uncertainty: Actual deficiency counts, B12/MTHFR distributions and appropriate subgroup analyses. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate the serum-deficiency definition from the unverified actual baseline distribution and subgroup effects.
Why this condition is needed: This is needed to avoid mixing effects of correcting deficiency with supplementation effects in people without deficiency or genotype-specific effects.
Application exceptions: An unverified deficiency count is not filled in as 0 deficient participants or as all participants being deficient.
Referenced methods: C04: M03 §3.2.1; detailed population criteria are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / H08: M19 §19.1.2–19.2.4; internal application. Reason for applying this in this case: This is needed to avoid mixing effects of correcting deficiency with supplementation effects in people without deficiency or genotype-specific effects. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N13 · Does the description of excluding female causes agree with the baseline table of mixed causes?

Current findings: The female eligibility age range was 18–38. The methods describe exclusion of female causes, but the baseline table lists mixed causes in 18 participants in the folic acid arm and 17 in the placebo arm. The couples are therefore not assumed to have purely male-factor infertility.
Verification status: Conflicting information
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The currently retained manuscript explicitly identifies a discrepancy between the methods and baseline composition. It was not resolved through external comparison in this task.
Reason for missing information: The original table and eligibility rules for mixed causes, and an explanation of the discrepancy.
Required materials and conditions: Female inclusion/exclusion criteria, the baseline table of causes and an explanation/correction of the discrepancy
Materials to obtain first: Female inclusion/exclusion criteria, the baseline table of causes and an explanation/correction of the discrepancy
Further research: Cross-check the same cause classification in the methods and baseline table, updating the discrepancy only if an explanation or correction from the original authors is available.
Remaining uncertainty: The original table and eligibility rules for mixed causes, and an explanation of the discrepancy. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Preserve female age, the exclusion description and the discrepancy involving mixed causes in 18/17 participants, and explain the limitation on applicability.
Why this condition is needed: This is needed to avoid deleting female factors in the couples and extending the findings to an effect in purely male-factor infertility.
Application exceptions: Do not silently resolve the conflict between the original methods and baseline table by creating new inclusion criteria.
Referenced methods: C04: M03 §3.2.1; detailed population criteria are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid deleting female factors in the couples and extending the findings to an effect in purely male-factor infertility. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N14 · Against what shared background care was the placebo compared?

Current findings: The comparator was 3 placebo tablets/day, matched in appearance, size, taste and weight, under common IVF-ICSI care. It has not been converted into a no-treatment control.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: This is a recording criterion linking the nominal comparator and background care. Details of placebo excipients remain under N07.
Reason for missing information: Differences in individual background treatments and actual changes require separate verification.
Required materials and conditions: Actual specifications of the matched placebo and background IVF care
Materials to obtain first: Actual specifications of the matched placebo and background IVF care
Further research: Distinguish the added active ingredient from common treatment to prevent extension to no treatment or a different comparator.
Remaining uncertainty: Differences in individual background treatments and actual changes require separate verification. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Display both the 3 matched placebo tablets/day and background IVF-ICSI care in the two arms.
Why this condition is needed: This is needed to avoid equating the placebo comparison with the natural course under no treatment.
Application exceptions: A shared IVF care policy in both arms does not establish that every individual's treatment was identical.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid equating the placebo comparison with the natural course under no treatment. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N15 · Have IVF treatment and other male medications been distinguished from the added trial ingredient?

Current findings: The IVF-ICSI care policy was shared, but individual women's stimulation regimens were not identical. The report states that no other male hormonal or vitamin treatment was used. Individual concomitant treatments, changes and the actual handling of adherence are not currently verified.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: A description of concomitant treatment is retained, but comparison of actual exposures/changes by arm is insufficient.
Reason for missing information: Concomitant treatment, treatment changes, deviations/rescue treatment by arm, and how these were handled in the analysis.
Required materials and conditions: IVF/female stimulation regimens by arm, concurrent male treatment, rescue treatment and handling of deviations
Materials to obtain first: IVF/female stimulation regimens by arm, concurrent male treatment, rescue treatment and handling of deviations
Further research: Cross-check concomitant-treatment/change records by arm against the effect of interest, and distinguish female background factors for pregnancy endpoints from semen change.
Remaining uncertainty: Concomitant treatment, treatment changes, deviations/rescue treatment by arm, and how these were handled in the analysis. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Explain the common policy, differences in individual treatments, and the reporting scope and unverified information about other male interventions.
Why this condition is needed: This is needed to avoid automatically attributing differences in female stimulation regimens or other treatments to the contribution of folic acid in men.
Application exceptions: The reported absence of male hormonal/vitamin treatment does not mean independent verification in this task or the absence of all concomitant exposures.
Referenced methods: E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / H05: M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed. Reason for applying this in this case: This is needed to avoid automatically attributing differences in female stimulation regimens or other treatments to the contribution of folic acid in men. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N16 · The selected value represents change at which time, in which sperm category and in which units?

Current findings: The selected endpoint is the M3−M0 change in Progressive motility (a) % in Table4. Change is measured in %p, and a higher change is the proposed direction of benefit. The endpoint percentage (%) and total motility (a+b+c) are separate.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The exact endpoint, time and unit boundaries have been linked. The direction of the numerical result has not been turned into certification of efficacy.
Reason for missing information: The correspondence of this source-defined category a to modern WHO categories remains unverified under N17.
Required materials and conditions: The label, time, units and direction of the effect of interest for the selected Table4 row
Materials to obtain first: The label, time, units and direction of the effect of interest for the selected Table4 row
Further research: Cross-check the row label and change/endpoint columns, labeling the time and units of each value separately.
Remaining uncertainty: The correspondence of this source-defined category a to modern WHO categories remains unverified under N17. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Link Progressive motility (a), M3−M0, percentage point and the original direction of benefit.
Why this condition is needed: This is needed to avoid mixing endpoint percentages, total motility, changes and %/%p.
Application exceptions: Setting higher values as the proposed direction of benefit does not establish clinical importance or actual improvement.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid mixing endpoint percentages, total motility, changes and %/%p. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N17 · Can source-defined category a be mapped to modern WHO aggregate PR?

Current findings: The article cites WHO 2010, but the speed criteria for category a and its correspondence to modern WHO aggregate PR were not verified at the time. S12 contains only official metadata for edition 6, while S13 records failed attempts to access the edition 5 page/PDF. No conversion to a+b or aggregate PR was made.
Verification status: Unverified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The relevant definition section and actual measurement correspondence are unverified. Historical access failure is not a status of Inaccessible in the present task.
Reason for missing information: Definitions and speed criteria in the relevant WHO edition, and their measurement correspondence to the trial's category a.
Required materials and conditions: The original motility-classification/speed criteria and the relevant definition section in the cited WHO edition
Materials to obtain first: The original motility-classification/speed criteria and the relevant definition section in the cited WHO edition
Further research: Cross-check the trial's classification rules against the definitions in the actual relevant WHO edition, recording only verified correspondences.
Remaining uncertainty: Definitions and speed criteria in the relevant WHO edition, and their measurement correspondence to the trial's category a. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Retain the unverified correspondence between source category a and a+b/aggregate PR, and the unverified speed criteria, without automatic conversion.
Why this condition is needed: This is needed to avoid converting historical sperm classifications merely because they use the same terminology.
Application exceptions: Verification of metadata for WHO edition 6 or a record of failed access to edition 5 alone does not establish verification of definitions/speed criteria.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid converting historical sperm classifications merely because they use the same terminology. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S12 S13

N18 · What were the actual abstinence, specimen-collection and motility-reading procedures?

Current findings: Semen was collected after 3–5 days of abstinence. The retained manuscript explicitly states that the DNA fixation/freezing methods and 2-reader procedure were not transferred to motility assessment. Detailed information on the equipment, speed criteria, readers and differences between arms for motility itself is not currently available.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Collection conditions are retained, but detailed measurement procedures for the selected endpoint are unverified.
Reason for missing information: Reading procedures/equipment, assessment blinding and procedures by arm for motility testing itself.
Required materials and conditions: Semen-collection conditions, motility equipment/reading rules, assessors/blinding and measurement differences between arms
Materials to obtain first: Semen-collection conditions, motility equipment/reading rules, assessors/blinding and measurement differences between arms
Further research: Cross-check the semen-motility and DNA-testing sections separately, using only information that applies to the actual motility measurement.
Remaining uncertainty: Reading procedures/equipment, assessment blinding and procedures by arm for motility testing itself. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish collection after 3–5 days of abstinence from the assessment procedures and limitations specific to motility.
Why this condition is needed: This is needed to avoid transferring fixation/freezing methods or reader counts from DNA testing to motility assessment.
Application exceptions: The 2 readers used for DNA assessment are not evidence of the number or blinding of motility assessors.
Referenced methods: E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid transferring fixation/freezing methods or reader counts from DNA testing to motility assessment. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N19 · Does the page's primary endpoint match the endpoint hierarchy in the article and registration?

Current findings: Category-a semen change is a secondary endpoint in the article and the primary endpoint on the page. The original trial's primary outcomes were biochemical and clinical pregnancy. The complete registration history, protocol, SAP and prespecified rank of this category-a row are unverified; the page's boundaries were an editorial choice after reviewing the literature.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The published hierarchy and editorial selection are verified, but comparison with the planned analyses remains outstanding.
Reason for missing information: The prespecified endpoint hierarchy, timing/analysis plans and change history.
Required materials and conditions: The complete NCT01407432 version history, protocol, SAP and records of endpoint/analysis changes
Materials to obtain first: The complete NCT01407432 version history, protocol, SAP and records of endpoint/analysis changes
Further research: Compare the planned endpoints, times and analyses in the registration/protocol with the Table4 report, recording changes or the scope not compared.
Remaining uncertainty: The prespecified endpoint hierarchy, timing/analysis plans and change history. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the article's secondary endpoint and the page's primary endpoint from the unverified prespecified hierarchy, and disclose when the editorial boundaries were selected.
Why this condition is needed: This is needed to avoid presenting a category-a row selected after reading the literature as a preregistered primary endpoint.
Application exceptions: Failure to obtain the registration/plans does not establish nonregistration or selective reporting.
Referenced methods: E06: M08 Table 8.2.a, M04 §4.6.3; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid presenting a category-a row selected after reading the literature as a preregistered primary endpoint. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S03

N20 · To what extent are the actual parallel-group design and randomization procedures known?

Current findings: FOLFIV is retained as a double-blind, parallel-group randomized trial with matched placebo. Randomization involved 83 versus 79 participants. The currently stored summaries do not provide detailed extraction of allocation-sequence generation or concealment.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The design type and allocation counts are retained, but detailed verification of allocation methods remains outstanding.
Reason for missing information: The actual sections/tables on allocation sequence, concealment and baseline characteristics.
Required materials and conditions: Methods/tables for allocation-sequence generation, concealment, personnel responsible and baseline balance between arms
Materials to obtain first: Methods/tables for allocation-sequence generation, concealment, personnel responsible and baseline balance between arms
Further research: Cross-check the Methods, flow diagram and baseline tables against allocation procedures, without filling in unverified concealment details.
Remaining uncertainty: The actual sections/tables on allocation sequence, concealment and baseline characteristics. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the description of a double-blind parallel randomized trial from the actual level of verification of allocation procedures.
Why this condition is needed: This is needed to avoid claiming that all details of allocation sequence, concealment and baseline balance have been verified merely from the RCT label.
Application exceptions: The trial is explicitly described as parallel-group in the current materials. Absence of crossover/cluster adjustment is not turned into a new defect in this design.
Referenced methods: E01: M08 §8.1–8.2.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid claiming that all details of allocation sequence, concealment and baseline balance have been verified merely from the RCT label. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N21 · Were matched placebo and double blinding actually maintained through assessment and analysis?

Current findings: The trial was double-blind, with placebo matched in appearance, size, taste and weight. The current inputs alone cannot establish in detail whether motility assessors/analysts were blinded, whether blinding was maintained or whether it was broken.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The nominal design and placebo matching are described, but evidence of maintained blinding for the actual selected endpoint is insufficient.
Reason for missing information: Who was blinded, maintenance/breaking of blinding and motility assessment procedures.
Required materials and conditions: Blinding of participants, personnel, motility assessors/analysts, and checks of unblinding or successful treatment guesses
Materials to obtain first: Blinding of participants, personnel, motility assessors/analysts, and checks of unblinding or successful treatment guesses
Further research: Cross-check who was blinded and records of actual maintenance/breaking of blinding against measurement and analysis of the selected semen endpoint.
Remaining uncertainty: Who was blinded, maintenance/breaking of blinding and motility assessment procedures. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate nominal double blinding and matched placebo from gaps in information on who was actually blinded and whether blinding was broken.
Why this condition is needed: This is needed to avoid automatically extending matching appearance into verification that assessor/analyst blinding was maintained.
Application exceptions: Unverified blinding details are not labeled as confirmed absence of blinding or automatic failure.
Referenced methods: E01: M08 §8.1–8.2.3; internal application / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid automatically extending matching appearance into verification that assessor/analyst blinding was maintained. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N22 · Does each number count people allocated, attending a visit, included in change analysis or included in endpoint analysis?

Current findings: 162 participants were randomized (83 folic acid, 79 placebo), and 76 and 72 attended M3 visits. Category-a change analysis included 126 participants (66 and 60), while M3 endpoint analysis included 67 and 62. The baseline, endpoint and change analysis populations are not identical.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The attribution of the different provided denominators is preserved. This status does not indicate that handling of missing data has also been adequately verified.
Reason for missing information: The exact baseline analysis counts and detailed reasons for losses at each stage are not currently provided.
Required materials and conditions: The Figure3 flow and person counts in the baseline, M3 and change columns of Table4
Materials to obtain first: The Figure3 flow and person counts in the baseline, M3 and change columns of Table4
Further research: Cross-check the denominators for each stage/endpoint column, recording allocated, measured and analyzed populations separately.
Remaining uncertainty: The exact baseline analysis counts and detailed reasons for losses at each stage are not currently provided. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Link each denominator separately: 83/79 allocated, 76/72 attending visits, 66/60 in change analysis and 67/62 in endpoint analysis.
Why this condition is needed: This is needed to avoid using the total of 162 participants or visit counts as the denominator for the selected change analysis.
Application exceptions: Person counts are not treated as sperm-cell counts or repeated-specimen counts. Means from different populations are not subtracted.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid using the total of 162 participants or visit counts as the denominator for the selected change analysis. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N23 · How can missing data in the change analysis and the reference to ITT be interpreted?

Current findings: The article mentions the ITT principle, but category-a change analysis includes 66/60 participants rather than all 83/79 randomized participants. Reasons for missing data, imputation and missing-data sensitivity analyses for this row were not verified at the time.
Verification status: Unverified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The reduction in denominators is verified, but materials establishing the handling and impact of missing data for the selected row are unavailable.
Reason for missing information: Reasons for endpoint-specific losses, imputation/sensitivity analyses and the analytical definition of the effect of interest.
Required materials and conditions: Reasons for missing endpoint data, losses by assigned arm, imputation rules, analysis populations and sensitivity analyses
Materials to obtain first: Reasons for missing endpoint data, losses by assigned arm, imputation rules, analysis populations and sensitivity analyses
Further research: Cross-check the population and missing-data rules for the selected category-a change row against the Methods/plans and flow, recording the limitations of the assignment effect and complete-case results.
Remaining uncertainty: Reasons for endpoint-specific losses, imputation/sensitivity analyses and the analytical definition of the effect of interest. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the complete paired data for 66/60 participants in the selected row from unverified imputation/sensitivity analyses.
Why this condition is needed: This is needed to avoid turning a statement of the ITT principle into an analysis of all randomized participants in the selected row.
Application exceptions: Unverified missing-data sensitivity is a current evidence gap. The direction or magnitude of missing-data effects is not newly estimated, and no additional score is assigned.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / E06: M08 Table 8.2.a, M04 §4.6.3; internal application. Reason for applying this in this case: This is needed to avoid turning a statement of the ITT principle into an analysis of all randomized participants in the selected row. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N24 · What are the mean, SD, median, IQR and P value for change in source-defined category a?

Current findings: Mean (SD) change was +0.6 (7.5) %p with folic acid and +0.8 (6.9) %p with placebo. The median was 0 %p in both arms; IQRs were 0–2 versus 0–5 %p. With a between-arm Wilcoxon–Mann–Whitney P = 0.7871, the retained manuscript records failure to demonstrate improvement in this comparison. This does not mean an effect of 0, equivalence or exclusion of meaningful benefit.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The main reported values and direction are available, but the formal between-arm effect estimate/CI and a current external comparison of the original row remain outstanding.
Reason for missing information: The formal between-arm effect estimate and interval, and comparison with the original Table4.
Required materials and conditions: Mean (SD), median/IQR, test, P value and original denominators for the selected change row in Table4
Materials to obtain first: Mean (SD), median/IQR, test, P value and original denominators for the selected change row in Table4
Further research: Cross-check the columns/units of each statistic and the location of the between-arm test, separating interpretation of means, distribution summaries and significance.
Remaining uncertainty: The formal between-arm effect estimate and interval, and comparison with the original Table4. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Preserve the original values and direction of both arms' change means (SDs), medians/IQRs and the between-arm test.
Why this condition is needed: This is needed to avoid substituting different summary statistics or types of dispersion, or equating nonsignificance with an effect of 0.
Application exceptions: The estimands of the mean difference and rank test are not assumed to be identical. SD is not converted into SE or a CI.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid substituting different summary statistics or types of dispersion, or equating nonsignificance with an effect of 0. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N25 · Has historical arithmetic on means been distinguished from the formal between-arm estimator?

Current findings: The descriptive arithmetic difference between change means at the time of retention was −0.2 %p. Endpoint means were 6.4 (SD 8.5) % versus 5.8 (SD 8.6) %, with a historical simple endpoint difference of +0.6 %p. The −0.2 %p is neither an adjusted estimate nor a Wilcoxon location difference; baseline/endpoint means from different analysis populations were not subtracted to create a new change value.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The attribution and limitations of existing arithmetic values have been linked. This does not mean verification of a formal effect estimate or a new calculation.
Reason for missing information: The formal between-arm change estimator is currently unverified.
Required materials and conditions: Existing arithmetic records, their respective change/endpoint columns and the formal test definition
Materials to obtain first: Existing arithmetic records, their respective change/endpoint columns and the formal test definition
Further research: Cross-check the attribution of arithmetic already in the manuscript against the change/endpoint columns, and preserve it as historical material distinct from a new analysis.
Remaining uncertainty: The formal between-arm change estimator is currently unverified. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Explain the different meanings of historical arithmetic on change means, endpoint means/arithmetic and the formal test.
Why this condition is needed: This is needed to avoid treating the descriptive arithmetic of −0.2 %p and the endpoint difference of +0.6 %p as the same change effect.
Application exceptions: Both arithmetic values are quotations from the existing manuscript. No new calculation, adjustment, standardized effect, NNT or CI is produced.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid treating the descriptive arithmetic of −0.2 %p and the endpoint difference of +0.6 %p as the same change effect. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N26 · What does P = 0.7871 compare, and which effect estimates are unverified?

Current findings: P = 0.7871 is the Wilcoxon–Mann–Whitney comparison of category-a change between the two arms. adjusted_effect in the original structure is null, and the formal between-arm effect estimate is also unverified. It is not relabeled as a within-arm P value or an adjusted effect on means.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The test type and between-arm direction are retained, but details of the formal effect and analytical objective are insufficient.
Reason for missing information: The formal estimator and the effect of interest/analysis population in the planned analysis.
Required materials and conditions: Definitions of the between-arm test, analysis population, effect of interest and formal estimator for the selected row
Materials to obtain first: Definitions of the between-arm test, analysis population, effect of interest and formal estimator for the selected row
Further research: Cross-check the test and analysis population in the Methods/plans and Table4, distinguishing between-arm/within-arm comparisons and assignment/adherence effects.
Remaining uncertainty: The formal estimator and the effect of interest/analysis population in the planned analysis. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate the between-arm Wilcoxon–Mann–Whitney comparison of change from the unverified formal/adjusted effect estimates.
Why this condition is needed: This is needed to avoid turning a between-arm P value into within-arm improvement or a CI for the mean difference.
Application exceptions: A nonparametric test result is not presented as equivalent to an adjusted effect on means or an adherence effect.
Referenced methods: E04: M08 §8.2.2, M15 §15.3.1; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid turning a between-arm P value into within-arm improvement or a CI for the mean difference. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N27 · What range of benefits can be assessed using a reported formal between-arm CI?

Current findings: In the original structure, ci for the direct category-a change is null. Change SDs and denominators are available, but the formal between-arm CI was not verified at the time, so the extent to which meaningful benefit can be excluded cannot be stated.
Verification status: Unverified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The formal effect interval for the selected question is unavailable, so the range of precision cannot be verified.
Reason for missing information: The formal between-arm estimate, confidence interval and estimation method.
Required materials and conditions: The formal between-arm effect estimate/CI, dispersion, denominators and estimation method for the selected category-a change
Materials to obtain first: The formal between-arm effect estimate/CI, dispersion, denominators and estimation method for the selected category-a change
Further research: Verify only effect intervals actually reported in the original results/plans; do not reconstruct a new CI from SD in this case.
Remaining uncertainty: The formal between-arm estimate, confidence interval and estimation method. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Retain the null CI for the direct question and the reason precision cannot be interpreted.
Why this condition is needed: This is needed to avoid inventing a narrow CI or exclusion of meaningful benefit from SD, sample size or nonsignificance alone.
Application exceptions: The 95.1% CI from FAZST is for a different combination and total motility; it does not substitute for the CI of this row.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E05: M15 §15.3.1–15.3.3; internal application. Reason for applying this in this case: This is needed to avoid inventing a narrow CI or exclusion of meaningful benefit from SD, sample size or nonsignificance alone. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N28 · Is there an MCID applicable to this category a, population and time point?

Current findings: For a validated MCID for this exact category a, population and time point, the record is value=null, not_verified. No new arbitrary threshold for %p, trial count, duration or sample size has been set.
Verification status: Unverified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: An applicable importance threshold has not been verified, so the reported values are not adjudicated as a clinically meaningful difference.
Reason for missing information: Validation materials for an important-change threshold matching the category, population and time point.
Required materials and conditions: A validated threshold for important change and its validation context for this source-defined category, population and M3 time point
Materials to obtain first: A validated threshold for important change and its validation context for this source-defined category, population and M3 time point
Further research: Cross-check the threshold's fit to the population, scale and time point; if no verified threshold is available, keep importance unverified.
Remaining uncertainty: Validation materials for an important-change threshold matching the category, population and time point. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Retain the null applicable MCID and the limitation on interpreting clinical importance.
Why this condition is needed: This is needed to avoid declaring criteria met or therapeutic value based on arbitrary minimum changes, participant counts or trial counts.
Application exceptions: Pregnancy-event trials are not unconditionally imposed as mandatory for the question about motility change itself.
Referenced methods: E05: M15 §15.3.1–15.3.3; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid declaring criteria met or therapeutic value based on arbitrary minimum changes, participant counts or trial counts. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N29 · Have Huang's different dose/genotype results and the conflicting test descriptions been preserved?

Current findings: Huang's positive result at 0.8 mg/day for 3 months in MTHFR 677 TT is retained: 32.36→40.63 % versus 36.84→33.97 %. The Table3 footnote describes a within-arm comparison with baseline, whereas the text describes a between-arm comparison. The 769 participants are the total eligible population; the exact between-arm CI, P value and motility denominators are unverified.
Verification status: Conflicting information
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: There is an actual retained conflict in test attribution for the same positive result. Evidence from a different dose/genotype has not been combined as direct replication or refutation.
Reason for missing information: Comparison with the original source and explanation of the conflict, and the exact TT analysis denominators and between-arm effect/CI.
Required materials and conditions: Huang Table3/footnote and text, genotype-specific motility analysis denominators, tests/CIs and prespecified subgroup plans
Materials to obtain first: Huang Table3/footnote and text, genotype-specific motility analysis denominators, tests/CIs and prespecified subgroup plans
Further research: Cross-check the within-arm/between-arm attribution of the tests in the table footnote and text, and organize differences in dose, genotype and definition by family.
Remaining uncertainty: Comparison with the original source and explanation of the conflict, and the exact TT analysis denominators and between-arm effect/CI. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Retain together the 0.8 mg/day dose, TT genotype, original baseline/endpoint values, conflict between the table footnote and text about the test, and unverified between-arm CI/P value/denominators.
Why this condition is needed: This is needed to avoid concealing favorable adjacent results or combining them with the category-a effect at 15 mg.
Application exceptions: The 769 eligible participants are not used as the denominator for TT motility analysis, and overlapping genotype strata are not summed.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed. Reason for applying this in this case: This is needed to avoid concealing favorable adjacent results or combining them with the category-a effect at 15 mg. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S07 S14

N30 · What adjacent information does da Silva's 5 mg single-ingredient result provide?

Current findings: da Silva was a double-blind, placebo-controlled trial of a single ingredient at 5 mg/day for 3 months, with 49 protocol completers; the initial allocation count is unverified. It reported no significant improvement in the semen outcomes assessed, but used the older a+b definition and does not provide the exact category-a estimator.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The direction and different conditions of the adjacent single-ingredient trial are retained, but exact endpoint, allocation and denominator details are unverified.
Reason for missing information: Initial allocation counts, endpoint-specific analysis denominators, exact effect estimates and the motility definition.
Required materials and conditions: da Silva's single-ingredient-arm results/denominators, motility definition, initial allocation and funding scope
Materials to obtain first: da Silva's single-ingredient-arm results/denominators, motility definition, initial allocation and funding scope
Further research: Cross-check the dose, motility definition and analysis population of the adjacent trial separately, avoiding aggregation into the direct category-a change.
Remaining uncertainty: Initial allocation counts, endpoint-specific analysis denominators, exact effect estimates and the motility definition. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish 5 mg/day, 3 months, the older a+b definition and the difference between completion/allocation denominators from the direct question.
Why this condition is needed: This is needed to avoid turning a finding of no difference at another dose and for an a+b endpoint into repeated refutation of the exact category-a question.
Application exceptions: The 49 protocol completers are not used as the initial allocation count.
Referenced methods: E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C04: M03 §3.2.1; detailed population criteria are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid turning a finding of no difference at another dose and for an a+b endpoint into repeated refutation of the exact category-a question. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S04

N31 · What remains unknown while the folic-acid-only arms of Wong and Raigani are retained?

Current findings: Wong was a 4-arm trial with fertile/subfertile strata; Raigani was a 4-arm trial with 83 participants in total. Both had folic-acid-only arms. Exact single-ingredient category-a change estimates and endpoint-specific analysis denominators are currently unverified, so they were not added as direct quantitative replications.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The single-ingredient candidates have not been deleted, but denominators and quantitative results for the exact comparison have not been verified.
Reason for missing information: Person counts by stratum/endpoint and progressive-motility estimators for each single-ingredient arm.
Required materials and conditions: Endpoints, denominators and quantitative results for each single-ingredient arm in Wong's fertile/subfertile strata and Raigani's 4-arm trial
Materials to obtain first: Endpoints, denominators and quantitative results for each single-ingredient arm in Wong's fertile/subfertile strata and Raigani's 4-arm trial
Further research: Cross-check comparisons by actual active ingredient and stratified analyses in factorial/4-arm trials, distinguishing single-ingredient contrasts from combination contrasts.
Remaining uncertainty: Person counts by stratum/endpoint and progressive-motility estimators for each single-ingredient arm. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the existence of single-ingredient arms, strata/total counts and the unverified exact category-a effects/denominators.
Why this condition is needed: This is needed to avoid discarding an entire 4-arm trial as a combination trial or filling unverified single-ingredient effects with figures from the entire trial.
Application exceptions: Unverified progressive-motility estimators for the individual single-ingredient arms are not described as absence of human studies.
Referenced methods: E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid discarding an entire 4-arm trial as a combination trial or filling unverified single-ingredient effects with figures from the entire trial. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S06 S08

N32 · Have the FAZST combination, total motility and correction been distinguished from the direct question?

Current findings: FAZST administered folic acid 5 mg plus zinc 30 mg/day for 6 months in a trial of 2370 participants. The total-motility difference was −0.5 %p, with a 95.1% CI of −2.5 to 1.5 %p. S10 corrects transposed previous-multivitamin yes/no rows in Table1; it was not counted as a new sample or as a correction to the direct category-a effect.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The attribution boundaries of the original combination, different endpoint and correction are preserved. This does not mean current comparison against the original source or verification of a folic-acid-only effect.
Reason for missing information: This cannot substitute for the interval of the direct single-ingredient category-a comparison, and the identity of the additional S15 reference was not provided.
Required materials and conditions: FAZST Table3, the multiplicity footnote and original Table1 correction, and boundaries between combination/single-ingredient comparisons
Materials to obtain first: FAZST Table3, the multiplicity footnote and original Table1 correction, and boundaries between combination/single-ingredient comparisons
Further research: Separate the combination exposure and total-motility estimator from direct category-a change, linking only the columns/rows actually changed by the correction.
Remaining uncertainty: This cannot substitute for the interval of the direct single-ingredient category-a comparison, and the identity of the additional S15 reference was not provided. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Preserve 5 mg plus zinc 30 mg, 6 months, 2370 participants, the original total-motility values and the scope of the Table1 correction.
Why this condition is needed: This is needed to avoid counting different-endpoint results for combined active ingredients and a correction report as a folic-acid-only effect or an independent replication.
Application exceptions: The 95.1% CI is not changed to 95%, and zinc-related harms from the combination are not transferred to folic acid.
Referenced methods: C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid counting different-endpoint results for combined active ingredients and a correction report as a folic-acid-only effect or an independent replication. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S09 S10

N33 · How were pregnancy and DNA results from the same trial separated?

Current findings: In the embryo-transfer subgroup of the same trial, the retained results are biochemical pregnancy 26/59 versus 11/49, P = 0.018; clinical pregnancy at 7 weeks 21/59 versus 10/49, P = 0.082; and miscarriage 5/59 versus 1/49, P = 0.146. These denominators do not represent all randomized couples. DNA change or these pregnancy results are not converted into success for category-a motility or live birth.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Positive and nonsignificant findings for other endpoints are retained with their respective denominators, and boundaries are set for them as separate questions.
Reason for missing information: The embryo-transfer selection process, detailed analyses of other endpoints and direct evidence of improved live birth were not verified in this table.
Required materials and conditions: FOLFIV Table6, selection/denominators of the embryo-transfer subgroup and separate DNA/live-birth outcomes
Materials to obtain first: FOLFIV Table6, selection/denominators of the embryo-transfer subgroup and separate DNA/live-birth outcomes
Further research: Cross-check the analysis population and time of each pregnancy event against the original table, limiting extension from a semen surrogate to clinical events.
Remaining uncertainty: The embryo-transfer selection process, detailed analyses of other endpoints and direct evidence of improved live birth were not verified in this table. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish the original values, denominators and P values for biochemical pregnancy, clinical pregnancy at 7 weeks and miscarriage from the different questions of the category-a endpoint and live birth.
Why this condition is needed: This is needed to avoid turning favorable pregnancy results into proof of success for sperm motility or improved live birth.
Application exceptions: The denominator of the embryo-transfer subgroup is not replaced with all 162 randomized participants. Other endpoint results are not deleted.
Referenced methods: E09: M03 §3.2.4; internally defined boundaries for extending the claim / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application. Reason for applying this in this case: This is needed to avoid turning favorable pregnancy results into proof of success for sperm motility or improved live birth. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N34 · Have concerns about serum folate units and printed DNA values been left unresolved rather than arbitrarily corrected?

Current findings: The retained manuscript leaves the serum folate unit conflict and suspicious printed values in the DNA change row, a different endpoint, as candidate errors. The units on both sides and exact DNA numbers are not provided in the currently stored summaries, so they were not reproduced or used to calculate a motility effect.
Verification status: Conflicting information
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The conflict/candidate errors are retained, but the exact values on both sides and comparison with the original table remain unverified within the current scope.
Reason for missing information: The exact original table, conflicting units/printed values, and explanations/corrections.
Required materials and conditions: Original tables, earlier/later versions, corrections and author explanations for serum folate units and the DNA change row
Materials to obtain first: Original tables, earlier/later versions, corrections and author explanations for serum folate units and the DNA change row
Further research: Cross-check the original table and printed units/change-row values, without arbitrary correction based only on the current general record of candidate errors.
Remaining uncertainty: The exact original table, conflicting units/printed values, and explanations/corrections. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Specify the retained candidate errors and the limitation that exact values/original locations were not provided, separating them from the main numbers.
Why this condition is needed: This is needed to avoid silently correcting candidate errors in other endpoints or importing them into category-a motility calculations.
Application exceptions: Because the currently stored summaries do not provide the exact units on both sides of the conflict or the DNA numbers, actual values are not newly invented and quoted.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid silently correcting candidate errors in other endpoints or importing them into category-a motility calculations. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N35 · Can public funding, sponsorship and product manufacture be verified separately?

Current findings: FOLFIV's public funding from the French Ministry of Health through PHRC 2010(10-052), AP-HP sponsorship and tablet manufacture by Bailly-Creat are retained. Disclosed roles are not used as an independent audit of all relationships or as replication in a separate trial.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Funding, sponsorship and the manufacturer are named, but product contracts and the full actual roles of sponsors were not independently verified.
Reason for missing information: Sponsor/manufacturer involvement in design, analysis and disclosure, and details of supply contracts.
Required materials and conditions: Actual disclosures of FOLFIV funding, sponsorship, product manufacture/supply and roles/contracts
Materials to obtain first: Actual disclosures of FOLFIV funding, sponsorship, product manufacture/supply and roles/contracts
Further research: Cross-check Funding/Acknowledgments and product specifications, examining separately the roles of funding, operational sponsorship and product relationships.
Remaining uncertainty: Sponsor/manufacturer involvement in design, analysis and disclosure, and details of supply contracts. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Record PHRC 2010(10-052), AP-HP, Bailly-Creat and the limits of verification separately.
Why this condition is needed: This is needed to avoid turning public funding and a named manufacturer into independent replication or an independent audit of all relationships.
Application exceptions: The manufacturer's name alone is not used to newly infer free product supply or detailed contracts governing involvement in the study.
Referenced methods: C10: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application. Reason for applying this in this case: This is needed to avoid turning public funding and a named manufacturer into independent replication or an independent audit of all relationships. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N36 · Have author declarations been distinguished from limits on funding verification in other families?

Current findings: FOLFIV's authors declared no conflicts of interest. Huang reported no funding; da Silva had CAPES fellowships for 2 investigators, but overall trial funding is unverified; Raigani's funding is unverified; details of Wong's PubMed designation of non-US government support are unverified; and FAZST had NIH/NICHD public support. None of these records was treated as an independent audit.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The level of disclosure for each family is retained, but independent verification of all relationships remains outstanding.
Reason for missing information: Full funding, product provision, employment/patent and institutional relationships for the relevant families.
Required materials and conditions: Each trial's Funding/COI, product relationships, author/institution disclosures and scope of verification
Materials to obtain first: Each trial's Funding/COI, product relationships, author/institution disclosures and scope of verification
Further research: Cross-check each family's level of disclosure and funding separately, recording shared sponsors/institutions only where links are actually verified.
Remaining uncertainty: Full funding, product provision, employment/patent and institutional relationships for the relevant families. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish FOLFIV's declaration, Huang's reported absence of funding, Silva's fellowships and unverified overall funding, and the levels of information for other families.
Why this condition is needed: This is needed to avoid turning no funding/no COI declarations or unverified information into certification of independence.
Application exceptions: Relevant interests do not lead to automatic exclusion, and a declaration of no interests alone does not establish absence of bias.
Referenced methods: C10: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid turning no funding/no COI declarations or unverified information into certification of independence. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S04 S06 S07 S08 S09

N37 · Have harm collection, events and denominators been verified for the same 15 mg exposure?

Current findings: FOLFIV planned M3 adherence and tolerability questionnaires, but exact AE, SAE and toxicity-withdrawal counts and analysis denominators were not obtained at the time. Gaps in the currently stored summaries are not treated as nonreporting throughout the entire article, 0 events or long-term safety.
Verification status: Unverified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Actual harm counts, the scope of collection and denominators for the selected exposure are not currently verified.
Reason for missing information: Event definitions, collection/severity, person/event counts, denominators by arm, follow-up and toxicity withdrawals.
Required materials and conditions: AE definitions, collection and severity; person/event counts for SAEs and toxicity withdrawals; exposure/analysis denominators and duration
Materials to obtain first: AE definitions, collection and severity; person/event counts for SAEs and toxicity withdrawals; exposure/analysis denominators and duration
Further research: Cross-check harm-collection methods for the same population/dose and person, event and follow-up denominators by arm, distinguishing reported frequency from collection limitations.
Remaining uncertainty: Event definitions, collection/severity, person/event counts, denominators by arm, follow-up and toxicity withdrawals. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate the M3 questionnaire plan from unverified AE/SAE and toxicity-withdrawal person/event counts and denominators.
Why this condition is needed: This is needed to avoid turning a tolerability-questionnaire plan into a complete tally of all AEs/SAEs and toxicity withdrawals or a count of 0 events.
Application exceptions: Efficacy results are not deleted because harm data are unverified. Spontaneous/systematic collection methods are not filled in arbitrarily either.
Referenced methods: E10: M19 §19.1.2–19.2.4; internal application / H01: M19 §19.1.2–19.2.4; detailed differentiation is internally designed / H04: M19 §19.1.2–19.2.4; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid turning a tolerability-questionnaire plan into a complete tally of all AEs/SAEs and toxicity withdrawals or a count of 0 events. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N38 · Have general B12/drug precautions been distinguished from trial harms?

Current findings: The historical partial NIH extracts and the SmPC for another 5 mg product support the background concerning possible masking of hematologic signs of B12 deficiency and delayed recognition of neurological injury, and interactions involving anticonvulsants, methotrexate and other drugs. This content is not FOLFIV's actual event count, a personal risk estimate or an instruction for personal administration.
Verification status: Partly verified
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: General safety background is retained, but direct trial harms/personal risks are unverified, and external materials were not read in this task.
Reason for missing information: The original sections for the relevant medications/use contexts, concomitant trial exposures and actual harm data.
Required materials and conditions: The partial NIH extracts and relevant B12/interaction sections of the SmPC, and medication/use contexts
Materials to obtain first: The partial NIH extracts and relevant B12/interaction sections of the SmPC, and medication/use contexts
Further research: Cross-check the relevant warnings, jurisdiction, formulation and use context in official materials, reviewing these separately from harms observed in the trial.
Remaining uncertainty: The original sections for the relevant medications/use contexts, concomitant trial exposures and actual harm data. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate background sources and access limitations concerning B12 masking/delayed recognition of neurological injury and interactions from trial events.
Why this condition is needed: This is needed to avoid turning warnings in general labels/summaries into events that actually occurred in FOLFIV or a magnitude of personal risk.
Application exceptions: Anticonvulsant/MTX interactions require boundaries specific to the use context, and the study dose is not an instruction for personal dosing or ART changes.
Referenced methods: E10: M19 §19.1.2–19.2.4; internal application / H05: M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed. Reason for applying this in this case: This is needed to avoid turning warnings in general labels/summaries into events that actually occurred in FOLFIV or a magnitude of personal risk. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S05 S11 S01

N39 · Are the indications and regimen on the Flamingo 5 mg label the same as those of the 15 mg trial?

Current findings: S11 is the label for Flamingo Pharma's Folic Acid Tablets BP 5 mg, PL43461/0091. The retained locations concern the label context of folate-deficient megaloblastic anemia and 5 mg/day for 4 months in adults, which differs from the Bailly-Creat 15 mg/day infertility trial. The revision date of 2026-05-20 and eMC update of 2026-06-05 are retained version information.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The boundaries of product, regimen, indication and version have been recorded. This does not mean authorization or safety certification for the trial in question.
Reason for missing information: Correspondence of the trial product/indication to the authorization was not verified in this task.
Required materials and conditions: Ingredient/route, indications, regimen and version of the Flamingo Pharma PL43461/0091 SmPC
Materials to obtain first: Ingredient/route, indications, regimen and version of the Flamingo Pharma PL43461/0091 SmPC
Further research: Cross-check the label's actual product, jurisdiction, indications/regimen and version against the trial specifications, requiring more than a shared 5 mg designation to establish equivalence.
Remaining uncertainty: Correspondence of the trial product/indication to the authorization was not verified in this task. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate the 5 mg anemia label from another manufacturer/jurisdiction from the 15 mg infertility trial.
Why this condition is needed: This is needed to avoid using the anemia regimen of another authorized product as authorization or certification of efficacy/safety for 15 mg in male infertility.
Application exceptions: Providing the link here does not mean that the label was newly read in this task.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed / E10: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied. Reason for applying this in this case: This is needed to avoid using the anemia regimen of another authorized product as authorization or certification of efficacy/safety for 15 mg in male infertility. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S11 S01

N40 · Does this table also adjudicate optimal dose, long-term use, vulnerable groups and personal treatment?

Current findings: The current manuscript discloses limitations concerning long-term high doses, severe liver/kidney disease, cancer history, pregnancy/lactation and use in children. Optimal dose, sustained long-term effects, personal safety/infertility treatment and ART changes are outside the scope of this narrow M3 category-a change verdict.
Verification status: Not applicable
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Establishing extension outcomes does not apply to the current narrow original question. Direct high-dose harm gaps remain under N37; Not applicable is not safety certification.
Reason for missing information: Direct evidence for separate extension questions was not verified in the present task.
Required materials and conditions: Direct dose comparisons, long-term/vulnerable-population exposures and harm follow-up needed when addressing extended questions
Materials to obtain first: Direct dose comparisons, long-term/vulnerable-population exposures and harm follow-up needed when addressing extended questions
Further research: If an extension is requested, define a direct design for its population, dose, duration and endpoint, and review it separately from the original M3 question.
Remaining uncertainty: Direct evidence for separate extension questions was not verified in the present task. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Distinguish extensions outside the selected question by the reasons they do not apply and the separate designs they would require.
Why this condition is needed: This is needed to avoid extending the limited M3 comparison to optimal dose, long-term maintenance/safety or all populations, including children and pregnancy/lactation.
Application exceptions: Each extension is a separate question. Completion of all extension studies is not imposed as a mandatory condition for this narrow category-a change table.
Referenced methods: E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / E10: M19 §19.1.2–19.2.4; internal application / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied. Reason for applying this in this case: This is needed to avoid extending the limited M3 comparison to optimal dose, long-term maintenance/safety or all populations, including children and pregnancy/lactation. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01 S05 S11

N41 · Have the existing D/30-point verdict and document self-review been kept from being used as a new criteria-based judgment?

Current findings: The existing D/30-point verdict and B/S/R1/I2/E0/B1/CX are preserved as original values. The existing E0 wording means failure to demonstrate improvement in this narrow comparison, not an effect of 0 or equivalence. Document quality B in editorial_review and single-assistant self-review do not constitute independent clinical certification.
Verification status: Met
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: Historical verdict values have been separated from preparation of the current table and criterion statuses. The existing score has not been revalidated or regraded.
Reason for missing information: Independent clinical verification and reconsideration of the original verdict are outside the scope of this task.
Required materials and conditions: The original grade/score/axes, assessment_profile, editorial_review and the scope of the current task
Materials to obtain first: The original grade/score/axes, assessment_profile, editorial_review and the scope of the current task
Further research: Cross-check the original verdict/axes and retained interpretive wording, leaving them as historical quotations without performing a new clinical reassessment.
Remaining uncertainty: Independent clinical verification and reconsideration of the original verdict are outside the scope of this task. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Separate preservation of the existing original values from statuses for individual data/recording criteria.
Why this condition is needed: This is needed to avoid reusing a historical score, self-assessed document quality or verification wording as current clinical certification or a criteria score.
Application exceptions: The original grade/score/axes and favorable/unfavorable results are preserved unchanged as historical values. No new score or percentage of criteria met is created.
Referenced methods: C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid reusing a historical score, self-assessed document quality or verification wording as current clinical certification or a criteria score. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources S01

N42 · How are updates under the same ID and differing server metadata preserved?

Current findings: The original policy is to append history under the same ID/URLs in response to new trials matching the exact question, registration/methods, corrections, retractions, numerical/classification errors and harm information. publication_notes records server_deployed=false; the top level records true and a deployment date of 2026-09-16, together with server_write_performed=false. These metadata differences are retained, and the new table is labeled as an unpublished stored-summary preparation stage.
Verification status: Conflicting information
Materials actually read: Summary read: the relevant pointers/original values in the currently stored manuscript were actually read. External material types were not accessed, acquired or read in this task.
Why unverified: The original inputs contain differences between publication metadata fields, so actual events were not consolidated from these values alone. This is separate from conflicts in clinical content.
Reason for missing information: Actual receipts for those historical publication events/server checks. Derived formats, UI and registration for this table are subsequent tasks for root.
Required materials and conditions: Original ID/URLs, revision_policy/history/triggers, and event/server-verification records for publication metadata
Materials to obtain first: Original ID/URLs, revision_policy/history/triggers, and event/server-verification records for publication metadata
Further research: Cross-check events/times in publication metadata and link criteria revisions, material additions and actual publication to separate receipts.
Remaining uncertainty: Actual receipts for those historical publication events/server checks. Derived formats, UI and registration for this table are subsequent tasks for root. This limitation concerns the currently retained inputs and the scope of verification at the time. It does not mean an effect of 0, the absence of studies worldwide, certification of personal safety, or failure of external access in this task.
Conditions for verification: Preserve original ID/URLs, revision history/triggers and metadata differences, distinguishing them from the present local stored-summary stage.
Why this condition is needed: This is needed to avoid mistaking historical publication metadata in the original record for actual completed publication of the new table.
Application exceptions: The difference between publication_notes.server_deployed=false and top-level server_deployed=true is not silently overwritten.
Referenced methods: C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed. Reason for applying this in this case: This is needed to avoid mistaking historical publication metadata in the original record for actual completed publication of the new table. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.

Related sources