# Riboflavin (vitamin B2), reported single-ingredient oral supplementation × 16-week research-visit peripheral cuff systolic blood pressure in hypertensive MTHFR 677TT adults Verdict 3123 · Evidence Check Stored-material review date: 2026-10-04 Original evidence date: 2026-09-16 Review-criteria version: v3123-MTHFR677TT-SBP16W-1.0 Public page/material preparation date: 2026-11-07 Clinical papers were not read directly; existing review summaries were checked. No new clinical-literature search was performed. Unverified does not mean that research is absent or that there is no effect. ## Assessment scope - Population: Hypertensive MTHFR 677TT adults without overt CVD from the predominantly older TUDA population; mean age 69.1 years. Most were receiving medication, with a small untreated fraction included; the treated-only effect is unverified. - Ingredient, formulation and route: Additional oral supplementation reported as ordinary single-ingredient riboflavin tablets. Exact chemical form, product/batch and manufacturing origin are unverified; equivalence to other formulations, combinations, injections or dietary exposure is not assumed. - Dose: An additional 1.6 mg/day. Administration frequency per day and total dietary/concurrent nutrient intake are unverified; this is not personal dosing advice. - Comparator: Placebo on top of existing usual care. Arm-specific antihypertensive medication changes/stability and details of placebo matching are unverified. - Measured outcome: The treatment×time between-group contrast in investigator-measured peripheral cuff SBP at the 16-week research visit (mmHg). Classified as office-type; the exact physical site, posture/rest are unverified; distinguished from ABPM/self-measured home/central/daytime-nighttime values. - Duration: 16 weeks of supplementation. Individual actual exposure/dropout periods and longer-term persistence/optimal duration are unverified. - Questions outside this scope: Do not extend this to all hypertension/other genotypes, treated-only/untreated-only populations, existing CVD, testing utility, cardiovascular event prevention, medication replacement, optimal dose, or personal safety/dosing advice. ## Checklist items ### N01 · Which blood-pressure question does this table address? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The original claim is “16-week research-visit peripheral cuff systolic blood pressure in hypertensive MTHFR 677TT adults.” The current identity is one clinical efficacy question, and the subclaims array is empty. General hypertension, genotype testing and cardiovascular events are separate questions. - Why unverified: Meets the documentation criterion linking the exact independent question to the inclusion/exclusion boundaries. This is not a verification status for efficacy or personal safety. - Reason for missing information: Direct data and the authorized scope for separate extension questions - Required materials and conditions: Current claim identity, source-text pointer, and population/intervention/comparator/endpoint/time-point boundaries - Materials to obtain first: Current claim identity, source-text pointer, and population/intervention/comparator/endpoint/time-point boundaries - Further research: Compare the current identity, population, actual contrast and measurement boundaries to record included and excluded questions. - Conditions for verification: Preserve the exact /ko/effect and link TT, single-ingredient oral B2, placebo/usual care and 16-week cuff SBP as one question. - Why this condition is needed: This is needed to avoid extending numerical changes in a TT-selected trial to effects on all hypertension or cardiovascular prevention. - Application exceptions: The subclaims array is empty. Do not automatically split the Korean/English manuscripts and related reports into additional tables. - Remaining uncertainty: Verification remains outstanding for: Direct data and the authorized scope for separate extension questions. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C04: M03 §3.2.1; detailed population criteria are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid extending numerical changes in a TT-selected trial to effects on all hypertension or cardiovascular prevention. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N02 · Have TT selection and validation of genotype testing itself been distinguished? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Participants were preselected for MTHFR 677TT. Genotyping methods and HWE assessment are unverified items in the current manuscript. This does not mean that the trial validated the accuracy of TT screening or health benefits after testing. - Why unverified: The selected genotype is verified, but a detailed comparison of the actual testing procedures and classification remains outstanding. - Reason for missing information: Original genotyping/recruitment methods and HWE assessment - Required materials and conditions: MTHFR 677TT selection, assay method, genotype confirmation, HWE assessment and recruitment criteria - Materials to obtain first: MTHFR 677TT selection, assay method, genotype confirmation, HWE assessment and recruitment criteria - Further research: Link recruitment and genotype-confirmation procedures to the original methods to review population classification and applicability. - Conditions for verification: Preserve TT selection while distinguishing unverified assay methods/HWE from non-applicability of the testing-utility question. - Why this condition is needed: This is needed to avoid presenting intervention results in the selected TT population as testing accuracy or benefits of genotype screening. - Application exceptions: CC/CT data and testing care pathways are not substitute evidence for the current TT intervention endpoint. - Remaining uncertainty: Verification remains outstanding for: Original genotyping/recruitment methods and HWE assessment. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C04: M03 §3.2.1; detailed population criteria are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid presenting intervention results in the selected TT population as testing accuracy or benefits of genotype screening. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N03 · To which adults can the predominantly older TUDA population be applied? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Hypertensive MTHFR 677TT adults from the TUDA aging cohort, with a mean age of 69.1 years and a boundary of no overt cardiovascular disease. Exact age eligibility criteria are unverified. This does not answer effects in other disease, age or normotensive populations. - Why unverified: The actual recruitment boundary and mean age are recorded, but the full eligibility criteria and basis for generalization are unverified. - Reason for missing information: Exact age/hypertension inclusion and exclusion criteria and the baseline characteristics table - Required materials and conditions: Original criteria for age eligibility, baseline hypertension, TUDA recruitment, overt CVD exclusion and representativeness - Materials to obtain first: Original criteria for age eligibility, baseline hypertension, TUDA recruitment, overt CVD exclusion and representativeness - Further research: Compare inclusion/exclusion criteria and the baseline characteristics table to record population alignment and differences in applicability for the current question. - Conditions for verification: Preserve the mean age of 69.1 years, TUDA and absence of overt CVD together with unverified exact age eligibility. - Why this condition is needed: This is needed to avoid treating the mean age and recruitment cohort as evidence of representativeness for all hypertensive adults. - Application exceptions: Do not extend this to existing overt CVD, hypertension in pregnancy, CKD/dialysis or healthy normotensive populations. - Remaining uncertainty: Verification remains outstanding for: Exact age/hypertension inclusion and exclusion criteria and the baseline characteristics table. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C04: M03 §3.2.1; detailed population criteria are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid treating the mean age and recruitment cohort as evidence of representativeness for all hypertensive adults. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N04 · Can this be described as an effect only in people receiving medication? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Most participants were taking antihypertensive medication, but a small untreated fraction was also included. The current between-group value is attributed to this mixed population. Treated-only or untreated-only denominators and separate effects are unverified. - Why unverified: The mixed treatment status is verified, but data to separate effects by treatment status cannot be established within the currently retained scope. - Reason for missing information: Arm-specific treatment status/history and separate estimates for treated and untreated participants - Required materials and conditions: Treatment status by arm, antihypertensive medication history, treated/untreated denominators and separate between-group estimates - Materials to obtain first: Treatment status by arm, antihypertensive medication history, treated/untreated denominators and separate between-group estimates - Further research: Compare treatment status, arm composition and the presence of prespecified subgroup/interaction analyses and separate estimates. - Conditions for verification: Distinguish the main effect in the mixed population from the unverified separate estimates by treatment status. - Why this condition is needed: This is needed to avoid turning the description of most participants being treated into a treated-only effect. - Application exceptions: Do not remove the trial or reattribute its result to all untreated people because a small untreated fraction was included. - Remaining uncertainty: Verification remains outstanding for: Arm-specific treatment status/history and separate estimates for treated and untreated participants. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C04: M03 §3.2.1; detailed population criteria are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid turning the description of most participants being treated into a treated-only effect. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N05 · Can the trial tablets be equated with FMN/FAD or combination products? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The intervention was reported as ordinary single-ingredient riboflavin tablets. Exact chemical form, manufacturer, excipients, release profile and product batch are unverified. Do not equate this with FMN/FAD, B-complex products, injections or dietary exposure. - Why unverified: The reported ingredient and ordinary-tablet description are known, but actual product identity and formulation equivalence have not been verified. - Reason for missing information: Original specifications for chemical form, manufacturing/product, excipients and batch/release profile - Required materials and conditions: Specifications for the riboflavin tablets' chemical form, release profile, manufacturing origin, excipients and product/batch - Materials to obtain first: Specifications for the riboflavin tablets' chemical form, release profile, manufacturing origin, excipients and product/batch - Further research: Link the original product specifications to the original trial, without inferring equivalence between formulations in the absence of direct comparisons. - Conditions for verification: Preserve both the report of ordinary single-ingredient tablets and the unverified exact chemical form/product. - Why this condition is needed: This is needed to avoid converting the reported ordinary single-ingredient tablets into efficacy claims for other chemical forms or combination products. - Application exceptions: Plant part is not applicable, but gaps concerning the chemical certificate and manufacturing origin remain. - Remaining uncertainty: Verification remains outstanding for: Original specifications for chemical form, manufacturing/product, excipients and batch/release profile. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid converting the reported ordinary single-ingredient tablets into efficacy claims for other chemical forms or combination products. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N06 · What route and actual administration regimen does 1.6 mg/day represent? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Tablet intake in the registry and the trial's pill-box description support the oral route. Supplemental riboflavin is 1.6 mg/day. Administration frequency per day, meal timing, total dietary intake and other nutrient intake are unverified, and the study dose is not personal advice. - Why unverified: The oral route and nominal supplemental amount are recorded, but the administration regimen and individual total exposure have not been verified. - Reason for missing information: Records of administration frequency/timing, total dietary intake and concurrent supplementation - Required materials and conditions: Oral tablets, supplemental amount, administration frequency, meal timing and total dietary/concurrent nutrient intake - Materials to obtain first: Oral tablets, supplemental amount, administration frequency, meal timing and total dietary/concurrent nutrient intake - Further research: Compare administration procedures, frequency, meals and total-exposure records to distinguish the nominal dose from actual exposure. - Conditions for verification: Link the oral route described by tablet intake in the registry and pill boxes in the trial to the supplemental amount of 1.6 mg/day. - Why this condition is needed: This is needed to avoid turning a supplemental amount into total intake or personal dosing advice. - Application exceptions: If daily frequency and total dietary intake are absent, do not arbitrarily specify taking it 1 time or fill in a total amount. - Remaining uncertainty: Verification remains outstanding for: Records of administration frequency/timing, total dietary intake and concurrent supplementation. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid turning a supplemental amount into total intake or personal dosing advice. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N07 · Whose records do 16 weeks and overall adherence of 99% represent? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Supplementation was reported for 16 weeks. Overall adherence based on pill counts was 99%, but arm-specific values are unverified. The current summary also does not establish actual dosing/assessment periods for dropouts or individual exposure. - Why unverified: The planned duration and overall adherence are reported, but detailed verification of arm-specific implementation and individual exposure periods remains outstanding. - Reason for missing information: Arm-specific adherence, administration/visits and dropout/discontinuation timing - Required materials and conditions: Individual administration/assessment timing, pill counts, arm-specific adherence and discontinuation/dropout periods - Materials to obtain first: Individual administration/assessment timing, pill counts, arm-specific adherence and discontinuation/dropout periods - Further research: Link administration/visit, returned-pill and arm-specific discontinuation records to review actual exposure and outcome timing. - Conditions for verification: Separate the planned 16 weeks and overall pill-count adherence of 99% from unverified arm-specific/individual information. - Why this condition is needed: This is needed to avoid presenting the planned duration and overall adherence as every participant's actual exposure. - Application exceptions: Do not extend the 16-week result to optimal duration, persistence after discontinuation or long-term effects. - Remaining uncertainty: Verification remains outstanding for: Arm-specific adherence, administration/visits and dropout/discontinuation timing. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / H02: Design-specific harms questions in M19 §19.2; details on temporal relationships are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid presenting the planned duration and overall adherence as every participant's actual exposure. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N08 · Can mean EGRac establish that everyone was deficient? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Baseline EGRac mean(SD) was 1.34(0.20) overall, 1.37(0.26) for riboflavin and 1.31(0.11) for placebo. The original suboptimal criterion was ≥1.3. Individual deficiency prevalence, assay interference and treatment effects by deficiency status are unverified; the mean is not used to classify every participant. - Why unverified: The functional measure and group means/criterion are recorded, but data to verify individual classification, total intake and effects by deficiency status are unavailable. - Reason for missing information: Individual EGRac distributions, deficiency/diet, assay interference and subgroup data - Required materials and conditions: Functional B2 status, individual distributions/deficiency criteria, diet, assay interference and effects by deficiency status - Materials to obtain first: Functional B2 status, individual distributions/deficiency criteria, diet, assay interference and effects by deficiency status - Further research: Compare individual nutritional distributions, assay procedures/interference, total intake and prespecified estimates by deficiency status. - Conditions for verification: Preserve the EGRac means with SD and the original ≥1.3 criterion, and leave individual deficiency/separate effects unverified. - Why this condition is needed: This is needed to avoid turning group means into individual diagnoses or effects exclusively in deficient participants. - Application exceptions: Deficiency was not a required eligibility criterion, and a population consisting exclusively of nutrient-replete participants is not asserted either. - Remaining uncertainty: Verification remains outstanding for: Individual EGRac distributions, deficiency/diet, assay interference and subgroup data. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C04: M03 §3.2.1; detailed population criteria are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid turning group means into individual diagnoses or effects exclusively in deficient participants. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N09 · Have placebo on top of usual care and medication changes been distinguished? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The actual comparison is additional riboflavin versus placebo on top of existing usual care. Actual antihypertensive medication changes/stability and details of placebo matching are unverified. Shared care alone does not establish that implementation was identical across arms. - Why unverified: The comparator and background care are known, but the extent to which actual changes and placebo matching affected the selected effect has not been compared. - Reason for missing information: Original records of arm-specific medication changes/rescue treatment and placebo composition/matching - Required materials and conditions: Placebo composition/matching, existing antihypertensive medication, actual changes/rescue treatment by arm and the effect of interest - Materials to obtain first: Placebo composition/matching, existing antihypertensive medication, actual changes/rescue treatment by arm and the effect of interest - Further research: Compare original arm-specific concomitant treatments/changes, placebo preparation and the analytical treatment of the effect of interest. - Conditions for verification: Link the contrast against placebo on top of usual care with unverified arm-specific medication changes and placebo matching. - Why this condition is needed: This is needed to avoid merging differences in existing treatment or treatment changes into the effect of B2 itself. - Application exceptions: Do not present the existence of background treatment as meaning that its stability was verified. - Remaining uncertainty: Verification remains outstanding for: Original records of arm-specific medication changes/rescue treatment and placebo composition/matching. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid merging differences in existing treatment or treatment changes into the effect of B2 itself. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N10 · Has implementation of SBP-stratified randomization also been verified? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Reported as an SBP-stratified, randomized, placebo-controlled parallel trial. Random sequence generation and implementation of allocation concealment are unverified. No new judgment about the adequacy of allocation or magnitude of bias is made from the current records alone. - Why unverified: The reported design and stratification are verified, but original methods for checking implementation are insufficient. - Reason for missing information: Original methods/tables for sequence generation, concealment implementation and baseline characteristics - Required materials and conditions: Original methods for the parallel design, stratification, sequence generation, allocation concealment and baseline balance - Materials to obtain first: Original methods for the parallel design, stratification, sequence generation, allocation concealment and baseline balance - Further research: Link allocation procedures and the baseline table to the selected SBP result to review the level of verification. - Conditions for verification: Separate the report of SBP-stratified parallel randomization from gaps in sequence generation and concealment implementation. - Why this condition is needed: This is needed to avoid presenting allocation issues as resolved solely because of the randomized label. - Application exceptions: Do not convert unverified sequence generation/concealment into nonrandomization or an established magnitude of bias. - Remaining uncertainty: Verification remains outstanding for: Original methods/tables for sequence generation, concealment implementation and baseline characteristics. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E01: M08 §8.1–8.2.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid presenting allocation issues as resolved solely because of the randomized label. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N11 · Are reported blinding and maintained blinding/placebo matching the same verification? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Blinding of participants, blood-pressure assessors and laboratory staff was reported. The record states that the same blinded researcher measured blood pressure. Detailed verification of maintained blinding and placebo matching remains outstanding. - Why unverified: Who was blinded is recorded, but actual maintenance and placebo matching remain unverified. - Reason for missing information: Original records of maintained blinding, placebo matching and implementation - Required materials and conditions: Blinding procedures for participants, assessors and laboratory staff; maintenance, placebo matching and arm-specific deviations - Materials to obtain first: Blinding procedures for participants, assessors and laboratory staff; maintenance, placebo matching and arm-specific deviations - Further research: Link who was blinded, the procedures, verification of maintenance and access to assessment data to the original methods. - Conditions for verification: Record reported participant/assessor/laboratory blinding separately from unverified maintenance/placebo matching. - Why this condition is needed: This is needed to avoid elevating reported blinding to complete verification of its maintenance and measurement independence. - Application exceptions: Do not erase gaps in blinding and implementation solely because cuff measurement is objective. - Remaining uncertainty: Verification remains outstanding for: Original records of maintained blinding, placebo matching and implementation. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating reported blinding to complete verification of its maintenance and measurement independence. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N12 · Does the office-type classification establish an actual office location? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: At research visits, a researcher repeatedly measured peripheral cuff blood pressure using an A&D UA-787. This is classified as office-type, but the exact physical site, posture and rest time are unverified. Do not turn this classification into confirmation of an actual office room. - Why unverified: The device and repeated measurements by a researcher are recorded, but verification of the original methods for the full measurement setting remains outstanding. - Reason for missing information: Original methods for the physical site, posture/rest and repeated-reading averaging procedure - Required materials and conditions: Research visits, A&D UA-787, repeated cuff readings, posture/rest time, physical site and collection procedures - Materials to obtain first: Research visits, A&D UA-787, repeated cuff readings, posture/rest time, physical site and collection procedures - Further research: Compare the measurement protocol, visit procedures, device and averaging method with the original methods/supplement. - Conditions for verification: Preserve reported cuff/repeated measurements and the unverified exact site, posture and rest time. - Why this condition is needed: This is needed to avoid confusing the measurement classification at research visits with the physical site. - Application exceptions: office-type is a classification based on the research-visit protocol and does not mean a verified office-room. - Remaining uncertainty: Verification remains outstanding for: Original methods for the physical site, posture/rest and repeated-reading averaging procedure. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid confusing the measurement classification at research visits with the physical site. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N13 · Has research-visit SBP been kept separate from other blood-pressure values? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The selected endpoint is the treatment×time between-group contrast in peripheral cuff SBP at the 16-week research visit, in mmHg. It is distinguished from ambulatory, serial self-measured home, central, daytime and nighttime SBP. Do not transfer ABPM data into the office-type main effect. - Why unverified: Meets the documentation criterion preserving the endpoint, unit, time point and exclusion boundaries for other measurements. - Reason for missing information: Direct results and comparability data for separate measurement questions - Required materials and conditions: Distinction between 16-week SBP, mmHg, the treatment×time contrast and ambulatory/home/central/daytime-nighttime blood pressure - Materials to obtain first: Distinction between 16-week SBP, mmHg, the treatment×time contrast and ambulatory/home/central/daytime-nighttime blood pressure - Further research: Compare endpoint definitions, time points, units and analysis locations to record attribution by outcome. - Conditions for verification: Link the between-group contrast in 16-week research-visit peripheral cuff SBP to the excluded measurements. - Why this condition is needed: This is needed to avoid merging different measures into the same effect because of similar blood-pressure names or durations. - Application exceptions: Do not force DBP or mechanistic/methylation data to serve as substitute endpoints for SBP. - Remaining uncertainty: Verification remains outstanding for: Direct results and comparability data for separate measurement questions. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid merging different measures into the same effect because of similar blood-pressure names or durations. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S05, S06 ### N14 · Are 91 participants and 46/45 participants the actual analyzed denominators? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: 91 participants were randomized: 46 participants to riboflavin and 45 participants to placebo. Actual analyzed arm denominators are null. The analysis total of 87 in the original family record is historical arithmetic from reported exclusions, not newly verified analysis flow/arm-specific n. - Why unverified: Allocation denominators are known, but actual analyzed arm denominators for the selected SBP result are unverified. - Reason for missing information: Outcome-specific analyzed n, the full flow diagram and original tables attributing exclusions - Required materials and conditions: Arm-specific n for allocation, assessment, completion and analysis; flow/exclusions and result-table headings - Materials to obtain first: Arm-specific n for allocation, assessment, completion and analysis; flow/exclusions and result-table headings - Further research: Compare the flow diagram, result tables and original analysis-population records to link actual denominators by outcome. - Conditions for verification: Separate the randomized 91(46/45) from null analyzed arm denominators and the historical arithmetic total. - Why this condition is needed: This is needed to avoid turning randomized counts into analyzed n or denominators for CI calculation. - Application exceptions: Do not back-calculate arm-specific n from the historical arithmetic analysis total of 87. - Remaining uncertainty: Verification remains outstanding for: Outcome-specific analyzed n, the full flow diagram and original tables attributing exclusions. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E01: M08 §8.1–8.2.3; self-developed application / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid turning randomized counts into analyzed n or denominators for CI calculation. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N15 · What analysis does LOCF for 3 dropouts form part of? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The record states that LOCF was applied for 3 dropouts. The current summary does not provide all arm-specific reasons, timing, last observations and alternative analyses for dropouts. The existence of a missing-data procedure alone does not mean that missingness had no impact. - Why unverified: The reported handling method is verified, but material for reviewing attribution of missingness, assumptions and sensitivity remains outstanding. - Reason for missing information: Dropout arms/reasons/timing, LOCF inputs and sensitivity analyses - Required materials and conditions: Dropout arms/reasons/timing, LOCF inputs, missing-data assumptions and alternative analyses - Materials to obtain first: Dropout arms/reasons/timing, LOCF inputs, missing-data assumptions and alternative analyses - Further research: Compare dropout flow, last observations, LOCF application and original alternative analyses. - Conditions for verification: Separate reported LOCF for 3 dropouts from gaps in arm-specific/timing and sensitivity data. - Why this condition is needed: This is needed to avoid presenting the use of LOCF as evidence that missing-data issues were resolved. - Application exceptions: Do not newly estimate a definite magnitude of bias or loss of effect from gaps concerning LOCF. - Remaining uncertainty: Verification remains outstanding for: Dropout arms/reasons/timing, LOCF inputs and sensitivity analyses. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid presenting the use of LOCF as evidence that missing-data issues were resolved. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N16 · Was the exclusion of 4 participants with SBP outlier values planned in advance? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: 4 participants with SBP outlier values were excluded. Prespecified exclusion criteria and arm attribution are currently unverified. Do not read the authors' ITT label as meaning that all randomized participants were analyzed without exclusions. - Why unverified: The exclusions are recorded, but comparison of the advance plans, arm attribution and results before and after exclusion with the originals remains outstanding. - Reason for missing information: Prespecified exclusion criteria, arm-specific exclusions and the original SAP/analyses before and after exclusion - Required materials and conditions: Outlier definition, arm-specific exclusions, advance plans and original analyses/denominators before and after exclusion - Materials to obtain first: Outlier definition, arm-specific exclusions, advance plans and original analyses/denominators before and after exclusion - Further research: Compare exclusion criteria and the timing of their planning with the original SAP/flow and analyses before and after exclusion. - Conditions for verification: Preserve the exclusion of 4 participants as outliers, the unverified prespecified criteria and the difference from ITT without exclusions. - Why this condition is needed: This is needed to avoid confusing possible post hoc exclusions and the authors' ITT label with an analysis of everyone without exclusions. - Application exceptions: Do not infer fabrication, invalidity or a quantitative magnitude of bias from the exclusion record alone. - Remaining uncertainty: Verification remains outstanding for: Prespecified exclusion criteria, arm-specific exclusions and the original SAP/analyses before and after exclusion. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid confusing possible post hoc exclusions and the authors' ITT label with an analysis of everyone without exclusions. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N17 · What estimate does the reported treatment×time difference represent? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The current manuscript reports a treatment×time between-group comparison for 16-week SBP. The original calculation fields use the reported contrast with its direction normalized and distinguish mean_changes as descriptive arithmetic from rounded values. A detailed comparison of actual analyzed n by arm and the model/adjustment remains outstanding. - Why unverified: The reported contrast is distinguished from within-group arithmetic, but the effect of interest, model and full analysis population have not been verified. - Reason for missing information: Original model/adjustment, ITT definition, analysis population and contrast of interest - Required materials and conditions: Original explanation of the treatment×time model, adjustment, effect of interest, ITT/PP definitions and analysis population - Materials to obtain first: Original explanation of the treatment×time model, adjustment, effect of interest, ITT/PP definitions and analysis population - Further research: Compare the original model, contrast of interest, denominators and handling of missing data/exclusions with the corresponding SBP result. - Conditions for verification: Link the reported treatment×time between-group comparison to limits on verification of actual analyzed n/exclusions and adjustment. - Why this condition is needed: This is needed to avoid newly establishing a between-group effect of assignment from within-group changes or labels alone. - Application exceptions: Do not arbitrarily relabel the authors' reported ITT as PP or apply a new model. - Remaining uncertainty: Verification remains outstanding for: Original model/adjustment, ITT definition, analysis population and contrast of interest. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid newly establishing a between-group effect of assignment from within-group changes or labels alone. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N18 · Are the parenthetical values in Table 3 SD or SEM? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Table 3 mean(SEM) values are riboflavin 141.8(2.9)→137.1(3.0) and placebo 143.5(3.0)→144.3(3.1) mmHg. Do not label the parenthetical values as individual SDs or change-score SDs. Change-score SDs and actual analyzed n by arm are unverified. - Why unverified: The reported means, time points and SEM have been preserved, but the original table/denominators and change-score variance have not been compared in this review. - Reason for missing information: Original Table 3/notes, analyzed n and change-score variance - Required materials and conditions: Table 3 mean/SEM headings, pre/post time points, analyzed n by arm and the original table - Materials to obtain first: Table 3 mean/SEM headings, pre/post time points, analyzed n by arm and the original table - Further research: Compare the original headings, notes, time points and variance types without performing new variance conversions. - Conditions for verification: Preserve each arm's pre/post means(SEM) and the unverified n/change SD exactly as recorded. - Why this condition is needed: This is needed to avoid reusing the standard error of the mean as a between-person SD or change-score SD. - Application exceptions: The SD of nutritional EGRac and the SEM in SBP Table 3 refer to different variables/variance measures. - Remaining uncertainty: Verification remains outstanding for: Original Table 3/notes, analyzed n and change-score variance. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid reusing the standard error of the mean as a between-person SD or change-score SD. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N19 · Have the favorable reported between-group value and within-group arithmetic been distinguished? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The reported value with the between-group direction normalized is −5.6 mmHg versus placebo, with P=0.033. The statistically favorable report is preserved as it stands. This value is not a within-group change from rounded group means or a newly calculated causal estimate. - Why unverified: Meets the documentation criterion distinguishing the direction of the retained effect/P and the corresponding between-group contrast. Precision or clinical importance has not been established. - Reason for missing information: Original estimate/P locations and analysis/interval data - Required materials and conditions: Reported between-group estimate with direction normalized, the contrast to which P applies and the original result location - Materials to obtain first: Reported between-group estimate with direction normalized, the contrast to which P applies and the original result location - Further research: Compare the original result text/table, contrast direction and attribution of P, and distinguish them from other arithmetic. - Conditions for verification: Attribute the reported between-group −5.6 mmHg and P=0.033 to the corresponding 16-week contrast. - Why this condition is needed: This is needed to avoid erasing the favorable result or combining it with within-group changes to create a different effect. - Application exceptions: Do not substitute P=0.033 for a CI, clinical threshold or established effect. - Remaining uncertainty: Verification remains outstanding for: Original estimate/P locations and analysis/interval data. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid erasing the favorable result or combining it with within-group changes to create a different effect. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N20 · Can 5.6±2.6 be read as an exact CI? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The overall reduction is reported as 5.6±2.6 mmHg, but the variance type of ± for this overall contrast has not been separately established. Exact CI, SE and degrees of freedom are null. No new CI was calculated using the SEM in Table 3 or the P value. - Why unverified: No stored material establishes the variance type and exact CI of the selected between-group contrast. This does not mean an effect of 0 or exclusion of clinical benefit. - Reason for missing information: Variance definition for the overall contrast, exact CI and model output/denominators - Required materials and conditions: Variance type of ±2.6 for the overall contrast, exact CI, degrees of freedom/model and analyzed n - Materials to obtain first: Variance type of ±2.6 for the overall contrast, exact CI, degrees of freedom/model and analyzed n - Further research: Obtain the original heading/model output and exact interval for the overall contrast to review precision. - Conditions for verification: Preserve the reported overall reduction of 5.6±2.6, the unverified variance type and null CI. - Why this condition is needed: This is needed to avoid reconstructing a CI from a ± value of unverified type and P or randomized n. - Application exceptions: Do not automatically treat the fact that Table 3 reports SEM as verification that ±2.6 for the overall contrast is an SE. - Remaining uncertainty: Verification remains outstanding for: Variance definition for the overall contrast, exact CI and model output/denominators. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid reconstructing a CI from a ± value of unverified type and P or randomized n. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N21 · Does statistical standardization validate a between-group MCID? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The between-group MCID for the selected contrast is unverified. Approximately −0.286 is the historical approximation obtained by dividing the reported contrast by the pooled baseline between-person SD; it is not an author-reported SMD, within-person dz or validated MCID. Do not borrow a threshold or CVD risk from the drug-related blood-pressure reduction/risk relationship in S20. - Why unverified: The currently retained scope contains no validated between-group importance threshold or exact CI for the selected population/endpoint. Statistical classification is not used to judge that clinical benefit is absent. - Reason for missing information: Importance evidence appropriate for the population/endpoint, exact CI and limits on applicability - Required materials and conditions: A justified between-group importance threshold and exact interval appropriate for this population, intervention and 16-week SBP contrast - Materials to obtain first: A justified between-group importance threshold and exact interval appropriate for this population, intervention and 16-week SBP contrast - Further research: Review the applicability conditions of evidence on importance for the selected SBP contrast and link it to the reported interval. - Conditions for verification: Maintain the null between-group clinical threshold and the separate attribution of the historical approximately −0.286 standardization. - Why this condition is needed: This is needed to avoid substituting statistical conventions or risk relationships from other drugs for a minimum clinically important difference. - Application exceptions: Do not unconditionally require a cardiovascular-event trial for an SBP-change question. - Remaining uncertainty: Verification remains outstanding for: Importance evidence appropriate for the population/endpoint, exact CI and limits on applicability. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: E05: M15 §15.3.1–15.3.3; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid substituting statistical conventions or risk relationships from other drugs for a minimum clinically important difference. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S20 ### N22 · Have −5.5 and the analysis total of 87 been kept from becoming newly reported values? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The manuscript's rounded difference-in-differences of −5.5 and within-group changes of −4.7/0.8 are historical descriptive arithmetic. The original family's analysis total of 87 is also labeled as arithmetic derived from reported exclusions. Do not replace the reported effect of −5.6 or null actual analyzed n by arm with these values. - Why unverified: Meets the documentation criterion separating historical arithmetic from reported estimates/unverified denominators. The original calculation files were not read, and no recalculation was performed. - Reason for missing information: Comparison of the historical separate calculation files/inputs with original flow/denominators - Required materials and conditions: Inputs and attribution of the descriptive arithmetic at that time, and its distinction from reported estimates and denominators - Materials to obtain first: Inputs and attribution of the descriptive arithmetic at that time, and its distinction from reported estimates and denominators - Further research: Compare inputs in the historical arithmetic records and their attribution to original reports/flow to distinguish descriptive values from analysis values. - Conditions for verification: Preserve −5.5, −4.7/0.8 and 87 only as original historical arithmetic, and retain −5.6 and arm-specific nulls. - Why this condition is needed: This is needed to avoid elevating arithmetic from rounded mean differences and exclusion counts to the authors' causal estimate/actual analyzed n. - Application exceptions: The historical calculation files were not read in this review; values are not recalculated and no CI is added. - Remaining uncertainty: Verification remains outstanding for: Comparison of the historical separate calculation files/inputs with original flow/denominators. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating arithmetic from rounded mean differences and exclusion counts to the authors' causal estimate/actual analyzed n. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N23 · Did registration occur before recruitment? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: First recruitment is reported as 2010-05-01 and registration as 2012-02-02, making registration retrospective. Retained S02 records the last edit as 2015-09-02. Do not present this registration as the original prospective protocol/SAP. - Why unverified: The registration/recruitment dates at that time are available, but comparison of the full original plans and change history remains outstanding. - Reason for missing information: Original registry versions/full change history and initial plans - Required materials and conditions: Recruitment/registration/edit timing for ISRCTN23620802 and the original planning history - Materials to obtain first: Recruitment/registration/edit timing for ISRCTN23620802 and the original planning history - Further research: Compare registry versions/change history and recruitment/planning timing with the original results. - Conditions for verification: Preserve the scope of the records for first recruitment on 2010-05-01, registration on 2012-02-02 and the edit on 2015-09-02. - Why this condition is needed: This is needed to avoid automatically turning retrospective registration into preregistration or nonregistration. - Application exceptions: The existence of an official registration does not replace the full original prospective protocol/SAP. - Remaining uncertainty: Verification remains outstanding for: Original registry versions/full change history and initial plans. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid automatically turning retrospective registration into preregistration or nonregistration. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S02 ### N24 · Does a broad blood-pressure primary (1st) endpoint guarantee a prespecified single-SBP hierarchy? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The registered primary (1st) endpoint is broadly blood pressure. A prospective SAP, single-SBP hierarchy, multiplicity and prespecified outlier exclusions could not be established within the currently retained scope. Preservation of the favorable result and gaps in planning are recorded separately. - Why unverified: Planning materials to verify the prespecified hierarchy and handling of multiplicity for the selected SBP analysis are unavailable. This is not an established finding of selective reporting. - Reason for missing information: Prospective protocol/SAP, SBP hierarchy and multiplicity/exclusion plans - Required materials and conditions: Prospective protocol/SAP, SBP hierarchy, time points/subgroups, multiplicity and exclusion plans - Materials to obtain first: Prospective protocol/SAP, SBP hierarchy, time points/subgroups, multiplicity and exclusion plans - Further research: Compare planned and reported endpoints, time points, analyses/exclusions, multiplicity and reasons for changes. - Conditions for verification: Distinguish the registry's broad blood-pressure primary (1st) outcome from the unverified single-SBP hierarchy/SAP/multiplicity. - Why this condition is needed: This is needed to avoid turning a broad registered endpoint into established prespecification of the selected SBP analysis. - Application exceptions: Do not use unverified plans to mean that selective reporting or fabrication has been established. - Remaining uncertainty: Verification remains outstanding for: Prospective protocol/SAP, SBP hierarchy and multiplicity/exclusion plans. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules. The specific reason for applying this to this case is as follows: This is needed to avoid turning a broad registered endpoint into established prespecification of the selected SBP analysis. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N25 · Do 20 sources represent 20 directly eligible trials? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: TF01 is recorded as the only directly eligible family within the locked boundary. The S02 registration and Ward 2013 companion abstract discovered in S10 (original not acquired) are not new trials. Independent replication within the same boundary is unverified, and absence of data has not been proved. - Why unverified: The directly eligible family is distinguished from companion reports, but data to verify independent replication within the same boundary are unavailable. - Reason for missing information: Original companion reports, recruitment independence and direct-replication data within the same boundary - Required materials and conditions: Linkage of S01/S02 and related reports to TF01 recruitment and outcomes/time points, and independent-replication data - Materials to obtain first: Linkage of S01/S02 and related reports to TF01 recruitment and outcomes/time points, and independent-replication data - Further research: Link report→family→selected outcome, and review actual independence of recruitment and whether replication falls within the same boundary. - Conditions for verification: Distinguish the single TF01 family from its registry/unacquired companion abstract, and retain the unverified status of replication within the same boundary. - Why this condition is needed: This is needed to avoid summing registrations/reports as trials or independent replications. - Application exceptions: The original count of 1 directly eligible family does not mean 1 study worldwide or the count of all human studies. - Remaining uncertainty: Verification remains outstanding for: Original companion reports, recruitment independence and direct-replication data within the same boundary. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C10: Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all these detailed items / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid summing registrations/reports as trials or independent replications. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02, S10 ### N26 · Were the existing CVD trial and its 4-year follow-up combined as independent replications? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: S03 is a mixed CC/CT/TT cohort with existing overt CVD, and S01 links the 4-year follow-up/reintervention in S04 to that same cohort. Do not count the two reports as two independent replications. Access to the original full text of S04 failed at that time, and unverified exact values were not imported. - Why unverified: Meets the criterion documenting exclusion/duplication boundaries for a different population and follow-up of the same cohort. The full text of S04 has not been verified in this review. - Reason for missing information: Original S04 full text, cohort/denominator linkage and original tables for each outcome - Required materials and conditions: Cohort, genotype and reintervention/follow-up linkage for Horigan 2010/Wilson 2012, and result locations - Materials to obtain first: Cohort, genotype and reintervention/follow-up linkage for Horigan 2010/Wilson 2012, and result locations - Further research: Compare recruitment, cohort linkage and follow-up/reintervention to record independence and population differences. - Conditions for verification: Preserve the single TF02 family comprising the initial study/4-year follow-up and its different CVD/mixed-genotype boundary. - Why this condition is needed: This is needed to avoid counting a different CVD population and follow-up of the same cohort as replications of the current TT trial without CVD. - Application exceptions: Exclusion from the original direct question does not mean that the study had 0 participants or no effect. - Remaining uncertainty: Verification remains outstanding for: Original S04 full text, cohort/denominator linkage and original tables for each outcome. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C04: M03 §3.2.1; detailed population criteria are self-designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid counting a different CVD population and follow-up of the same cohort as replications of the current TT trial without CVD. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S03, S04, S01 ### N27 · Have the table/change-row discrepancies in the 10 mg ambulatory blood-pressure abstracts been preserved? Verification status: Conflicting information Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: TF03 is grouped as a family of ambulatory blood-pressure abstracts with 10 mg/day, 16 weeks and n 81, but individual IDs and official registry content are unverified. Dose, age, baseline-SBP subgroup and ABPM differ from the selected question. The sign/rounding discrepancies between the S06 pre/post table and change row are preserved without resolution. - Why unverified: Limited to the sign/rounding conflict within the related ABPM report explicitly identified in retained S06. Do not extend this to mean that the reported effect in selected TF01 is conflicting. - Reason for missing information: Original S05/S06 tables/change rows, individual/registry linkage and correction materials - Required materials and conditions: Original S05/S06 abstracts, pre/post and change rows, signs/rounding, denominators and registry/participant linkage - Materials to obtain first: Original S05/S06 abstracts, pre/post and change rows, signs/rounding, denominators and registry/participant linkage - Further research: Compare original tables/change rows and participant/registry linkages to review the scope of the conflict and the candidate same-family relationship. - Conditions for verification: Retain TF03's different dose/age/baseline subgroup/measurement and the sign/rounding conflict in S06. - Why this condition is needed: This is needed to avoid transferring favorable ABPM findings or numerical differences to the selected 1.6 mg cuff SBP question or arbitrarily correcting them. - Application exceptions: The same research network, n 81 and similar dose/duration do not constitute complete verification of independence at the individual-ID level. - Remaining uncertainty: Verification remains outstanding for: Original S05/S06 tables/change rows, individual/registry linkage and correction materials. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid transferring favorable ABPM findings or numerical differences to the selected 1.6 mg cuff SBP question or arbitrarily correcting them. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S05, S06, S16 ### N28 · Is methylation reanalysis a new SBP trial? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The S07 abstract uses blood samples from previous trials, and the exact mixture of parent cohorts is unverified. Do not add a new treatment-specific SBP effect or participant count. S19 is a candidate methylation abstract whose original abstract and parent linkage are unverified. - Why unverified: The roles as previous-sample reanalysis and candidate report are known, but exact parent linkage/original results have not been verified. - Reason for missing information: Sample/parent-trial linkage, the original S19 abstract and treatment-specific results - Required materials and conditions: Parent trials, sample/participant linkage, treatment-specific SBP results and access scope for S07/S19 - Materials to obtain first: Parent trials, sample/participant linkage, treatment-specific SBP results and access scope for S07/S19 - Further research: Link original sample sources, parent recruitment and analysis results to review new-trial/duplicate/unclear relationships. - Conditions for verification: Preserve gaps in the parent-cohort mixture for previous-trial blood in S07 and the unacquired candidate S19. - Why this condition is needed: This is needed to avoid adding mechanistic analyses of samples from previous trials as new participants or independent SBP effects. - Application exceptions: If the parent family is null, do not assign an arbitrary family or add to the direct-replication count. - Remaining uncertainty: Verification remains outstanding for: Sample/parent-trial linkage, the original S19 abstract and treatment-specific results. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid adding mechanistic analyses of samples from previous trials as new participants or independent SBP effects. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S07, S19 ### N29 · Is the planned dose in the Gambia protocol an actual result? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Gambia TF04 is a protocol planned for CC/CT with 5 mg/day for 16 weeks. Actual sample and results are null, and the current registry status is also unverified. Do not present the planned different recruitment population as a completed TT blood-pressure effect. - Why unverified: The plan's identity/population are recorded, but comparison of actual implementation, original results and current registry status remains outstanding. - Reason for missing information: Actual recruitment/results, original registry versions/status and protocol linkage - Required materials and conditions: S08 protocol, original NCT03151096 registry, actual recruitment/denominators and results/status - Materials to obtain first: S08 protocol, original NCT03151096 registry, actual recruitment/denominators and results/status - Further research: Compare the protocol with actual implementation/original results to record differences in plans, implementation and population. - Conditions for verification: Preserve the TF04 plan for CC/CT in a different deficiency context and null actual_sample/result. - Why this condition is needed: This is needed to avoid elevating a plan involving different genotypes and a different deficiency context into an actual replication of the TT trial. - Application exceptions: Do not present the planned 5 mg and 16 weeks as actual administration, measurements, sample/effect. - Remaining uncertainty: Verification remains outstanding for: Actual recruitment/results, original registry versions/status and protocol linkage. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C04: M03 §3.2.1; detailed population criteria are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating a plan involving different genotypes and a different deficiency context into an actual replication of the TT trial. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S08, S18 ### N30 · Does blinded FMD in the thesis abstract answer treatment-specific SBP? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: At that time, only the thesis abstract of S09 was read, and a planned 2026-10-31 embargo end was recorded. The early blinded FMD description is not a treatment-specific SBP estimate. TF05's actual sample/SBP effect are null; do not turn unverified results into absence of a study. - Why unverified: The currently retained scope contains no original materials to verify treatment-specific SBP results and actual implementation/registry status. - Reason for missing information: Thesis manuscript, treatment-specific SBP results and registry/trial linkage - Required materials and conditions: S09 thesis, InteRVENE candidate registry and treatment-specific SBP denominators/original results - Materials to obtain first: S09 thesis, InteRVENE candidate registry and treatment-specific SBP denominators/original results - Further research: Link the access/publication scope of the thesis manuscript, registration and treatment-specific results to review endpoint attribution. - Conditions for verification: Distinguish the abstract's early blinded FMD from null actual SBP effect/sample. - Why this condition is needed: This is needed to avoid turning an early blinded endothelial analysis into a treatment-separated blood-pressure effect or absence of research. - Application exceptions: The planned 2026-10-31 embargo end is metadata from that time; release/current status has not been verified in this review. - Remaining uncertainty: Verification remains outstanding for: Thesis manuscript, treatment-specific SBP results and registry/trial linkage. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid turning an early blinded endothelial analysis into a treatment-separated blood-pressure effect or absence of research. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S09, S17 ### N31 · Have official content and current status been verified from a registry link alone? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Readable official content for the RIBOGENE, InteRVENE and Gambia candidate registries was not acquired at that time. Do not elevate registry links and discoveries in protocols/reviews to current verification of official endpoints, dates or status. Access was not attempted in this review. - Why unverified: No stored material establishes official registry content/current status and candidate linkage. This does not mean an actual Inaccessible status in this review. - Reason for missing information: Actual content/history of the three official registries and linkage to original reports - Required materials and conditions: Full official S16/S17/S18 registries, versions/history, result/recruitment status and report linkage - Materials to obtain first: Full official S16/S17/S18 registries, versions/history, result/recruitment status and report linkage - Further research: In an authorized follow-up check, compare official registry versions with original reports/results to review identity. - Conditions for verification: Preserve unverified original registry content and the level of candidate linkage, leaving access to all of them unattempted in this review. - Why this condition is needed: This is needed to distinguish links/discovered candidates from official content actually read. - Application exceptions: Do not present historical API failures/JavaScript shell responses as access failures in this review. - Remaining uncertainty: Verification remains outstanding for: Actual content/history of the three official registries and linkage to original reports. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to distinguish links/discovered candidates from official content actually read. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S16, S17, S18 ### N32 · Have the review's pooled effects been kept from being imported as verification of the original trials? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The Cochrane 2025 review is recorded as having been used only for study-family discovery and context. Do not import its pooled effects, denominators, doses or author correspondence as facts verified from the originals. Its search end date of 2024-10-24 differs from the original task's 2026-09-16 cutoff. - Why unverified: Meets the documentation criterion distinguishing discovery/context from direct verification of originals. Pooled effects were not verified or recalculated. - Reason for missing information: Actual verification of discovered original reports and families/numbers - Required materials and conditions: S10 inclusion/exclusion and trial-family discovery, numbers/denominators in each original report and the search cutoff date - Materials to obtain first: S10 inclusion/exclusion and trial-family discovery, numbers/denominators in each original report and the search cutoff date - Further research: Link the review's references/candidate families to original reports to distinguish discovery from direct verification. - Conditions for verification: Link S10 only in its discovery/context role, and do not adopt pooled values as new observations. - Why this condition is needed: This is needed to avoid elevating review averages, author correspondence or denominators to facts verified directly from the originals or additional replications. - Application exceptions: Distinguish the review's search end date of 2024-10-24 from the original task's search cutoff of 2026-09-16. - Remaining uncertainty: Verification remains outstanding for: Actual verification of discovered original reports and families/numbers. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating review averages, author correspondence or denominators to facts verified directly from the originals or additional replications. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S10 ### N33 · Have observations of B2 levels/genotype been kept from becoming effects of additional supplementation? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: S14 concerns observational associations of riboflavin levels/genotype with hypertension. S15 concerns a retrospective genotype association in H-type hypertension, not B2 supplementation. Do not import either study's table values or associations as the current single-ingredient B2 between-group effect. - Why unverified: Meets the criterion documenting actual designs/exposures and exclusion boundaries for the intervention question. This is not a separate clinical reassessment of the observational results. - Reason for missing information: Original designs/results of each observational study and data for the separate association questions - Required materials and conditions: Distinction between the designs, actual exposures, populations and analyses of S14/S15 and oral intervention - Materials to obtain first: Distinction between the designs, actual exposures, populations and analyses of S14/S15 and oral intervention - Further research: Compare original designs and the exposure→outcome direction to record differences between related association questions and intervention questions. - Conditions for verification: Exclude S14 level/genotype associations and S15 retrospective associations from oral B2 intervention evidence. - Why this condition is needed: This is needed to avoid reversing observed level/genotype associations into causal effects of assignment to single-ingredient B2. - Application exceptions: Preserve observational data without assigning new clinical families or issuing genotype-testing recommendations. - Remaining uncertainty: Verification remains outstanding for: Original designs/results of each observational study and data for the separate association questions. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C04: M03 §3.2.1; detailed population criteria are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E01: M08 §8.1–8.2.3; self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid reversing observed level/genotype associations into causal effects of assignment to single-ingredient B2. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S14, S15 ### N34 · Do SBP results answer event prevention, testing utility or medication replacement? Verification status: Not applicable Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The current materials do not answer treatment of all hypertension, stroke prevention, genotype screening or antihypertensive medication replacement. Optimal dose and long-term persistence are also separate questions. Do not transfer event benefits from blood-pressure/risk relationships for other drugs. - Why unverified: Establishing effects on events, testing, medication replacement or optimal/long-term regimens is outside the scope of this narrow SBP table. This is not a judgment of no effect or safety. - Reason for missing information: Direct comparisons/patient-outcome data for separate extension questions - Required materials and conditions: Direct comparative data on events/testing pathways, medication replacement and dose/duration for each extension question - Materials to obtain first: Direct comparative data on events/testing pathways, medication replacement and dose/duration for each extension question - Further research: If an extension question is separately requested, newly define the population, outcome of interest and pathway/comparison, and review direct evidence. - Conditions for verification: Separate the current SBP question from questions about events/testing/medication replacement, optimal dose and long-term persistence. - Why this condition is needed: This is needed to avoid extending a surrogate and the main effect in a specific population to health outcomes, testing benefits or an optimal regimen. - Application exceptions: Do not require every extension trial for the narrow 16-week SBP question itself. - Remaining uncertainty: Verification remains outstanding for: Direct comparisons/patient-outcome data for separate extension questions. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid extending a surrogate and the main effect in a specific population to health outcomes, testing benefits or an optimal regimen. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S20 ### N35 · To what level have public funding, DSM support and related patents been verified? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Public/nonprofit funding and DSM support were mixed, and DSM-affiliated authors and related patent holders were reported. Funder noninvolvement in design/conduct/analysis/interpretation is an author statement. Recruitment differs from the earlier CVD cohort, but the research network and some corporate support overlap. - Why unverified: Declarations and the research network are recorded, but comparison of actual roles, provision/contracts and complete independence remains outstanding. - Reason for missing information: Original disclosure sections, funding/product provision, actual roles and research-network linkage - Required materials and conditions: Funding/product provision, DSM employment, patents, declarations of funder roles and the family research network - Materials to obtain first: Funding/product provision, DSM employment, patents, declarations of funder roles and the family research network - Further research: Compare declarations, funding sources, product provision and institution/family linkages to record the scope of independence verification. - Conditions for verification: Distinguish mixed public/nonprofit and DSM support and employment/patents from the authors' noninvolvement statement. - Why this condition is needed: This is needed to avoid presenting mixed funding as independent funding or turning conflicts of interest into evidence of fabrication. - Application exceptions: Do not elevate the authors' statement of noninvolvement to independent verification of actual roles. - Remaining uncertainty: Verification remains outstanding for: Original disclosure sections, funding/product provision, actual roles and research-network linkage. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C10: Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all these detailed items / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid presenting mixed funding as independent funding or turning conflicts of interest into evidence of fabrication. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02 ### N36 · Have trial-specific AE counts and people/denominators been verified? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Trial-specific adverse-event counts, numbers of people, arm-specific denominators and collection/discontinuation definitions are unverified in the current manuscript. Do not fill in dropouts or SBP outlier exclusions as harm events. Do not turn unverified harms into 0 events or absence of efficacy results. - Why unverified: No retained numbers/methods link trial-specific exposure with AE collection, people/events and discontinuation. This does not mean established safety or demonstrated harm. - Reason for missing information: Original arm-specific AE tables, collection/discontinuation, person/event/exposure denominators and duration - Required materials and conditions: Arm-specific AE event/person counts, exposure denominators/duration, definitions/collection, severity and reasons for discontinuation - Materials to obtain first: Arm-specific AE event/person counts, exposure denominators/duration, definitions/collection, severity and reasons for discontinuation - Further research: Link original arm-specific AE tables, collection/discontinuation and exposure time to review reporting scope and comparability. - Conditions for verification: Preserve unverified trial-specific harm counts, denominators/collection, and distinguish people/events and efficacy denominators. - Why this condition is needed: This is needed to avoid turning the existence of an efficacy trial and general safety information into 0 events or safety in the trial. - Application exceptions: Do not arbitrarily attribute the 3 dropouts or the 4 participants excluded from the SBP analysis to AEs or absence of AEs. - Remaining uncertainty: Verification remains outstanding for: Original arm-specific AE tables, collection/discontinuation, person/event/exposure denominators and duration. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E10: M19 §19.1.2–19.2.4; self-developed application / H01: M19 §19.1.2–19.2.4; detailed distinctions are self-designed / H02: Design-specific harms questions in M19 §19.2; details on temporal relationships are self-designed / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; self-developed application / H04: M19 §19.1.2–19.2.4; self-developed application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; self-developed application / H09: Chamgap's own interpretive boundary. References M19 principles; no formal causality tool was applied. The specific reason for applying this to this case is as follows: This is needed to avoid turning the existence of an efficacy trial and general safety information into 0 events or safety in the trial. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N37 · Are the NIH and NHS explanations AE observations from this trial? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: NIH consumer material is general nutritional safety information and does not mean 0 events in the trial or unlimited high-dose safety. Orange urine/tear changes in NHS migraine material are general information for a different population and a much higher dose. The S13 full text/UL value were unverified at that time, and an actual NHS update after the printed planned review date was not verified either. - Why unverified: Meets the documentation criterion separating general background from direct trial-harm observations. This does not mean that the trial meets a safety criterion. - Reason for missing information: Original trial AE data and actual versions/scope of official safety materials - Required materials and conditions: Material types, populations/doses and access scope of S11/S12/S13, and original trial harms tables - Materials to obtain first: Material types, populations/doses and access scope of S11/S12/S13, and original trial harms tables - Further research: Compare official materials' populations, doses and versions/access scope to separate trial observations from general context. - Conditions for verification: Distinguish general safety background and urine/tear changes at a different dose from the lack of verification of 0 events in the trial. - Why this condition is needed: This is needed to avoid transferring general nutrition information or migraine information at a different dose into incidence in the 1.6 mg trial. - Application exceptions: Only a search excerpt of S13 was read at that time, and no numerical UL was adopted; all full texts remain unread in this review. - Remaining uncertainty: Verification remains outstanding for: Original trial AE data and actual versions/scope of official safety materials. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C04: M03 §3.2.1; detailed population criteria are self-designed / E10: M19 §19.1.2–19.2.4; self-developed application / H07: M04 §4.6.1–4.6.2; adaptation for harms data is self-designed / H08: M19 §19.1.2–19.2.4; self-developed application / H09: Chamgap's own interpretive boundary. References M19 principles; no formal causality tool was applied. The specific reason for applying this to this case is as follows: This is needed to avoid transferring general nutrition information or migraine information at a different dose into incidence in the 1.6 mg trial. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S11, S12, S13 ### N38 · Do limited 16-week data answer long-term safety or safety in vulnerable populations? Verification status: Unverified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Long-term, rare-harm/special-population safety and detailed harms in the setting of concomitant hypertension treatment are unverified. The original Caution label does not mean demonstrated harm. Do not create instructions to stop, reduce or replace antihypertensive medication, self-diagnose genotype or self-administer B2. - Why unverified: Data to verify safety beyond the current trial's duration/population are unavailable; general guidance is not used to fill the gap. - Reason for missing information: Population/duration-specific safety, rare-event and concomitant-treatment interaction data - Required materials and conditions: Long-term/rare harms, vulnerable populations, concomitant-treatment interactions, actual exposure and suitable safety data - Materials to obtain first: Long-term/rare harms, vulnerable populations, concomitant-treatment interactions, actual exposure and suitable safety data - Further research: Link question-specific populations, exposure durations, interactions and safety-collection designs to review applicability. - Conditions for verification: Preserve unverified long-term/special-population safety and the exclusion of personal medication-discontinuation/administration advice. - Why this condition is needed: This is needed to avoid extending reporting gaps in a limited population/duration to safety in all populations or dosing recommendations. - Application exceptions: Do not make preservation of the narrow SBP result conditional on obtaining all rare-harm data. - Remaining uncertainty: Verification remains outstanding for: Population/duration-specific safety, rare-event and concomitant-treatment interaction data. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / E10: M19 §19.1.2–19.2.4; self-developed application / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are self-designed / H08: M19 §19.1.2–19.2.4; self-developed application / H09: Chamgap's own interpretive boundary. References M19 principles; no formal causality tool was applied. The specific reason for applying this to this case is as follows: This is needed to avoid extending reporting gaps in a limited population/duration to safety in all populations or dosing recommendations. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S11, S12, S13 ### N39 · Have the author copy/partial supplement and unread figures been distinguished? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: S01 records that original Tables 1–3 were read at that time in an HTML transcription of the author-uploaded copy. Access to the publisher PDF and separate supplement failed, and only some additional supplement text was transcribed. Figure 1 and embedded graphs were not visually verified, and their numbers were not interpreted. None of these external materials were read in this review. - Why unverified: Historical access levels and limitations are recorded, but no actual current comparison of original PDFs/supplements/figures has been performed. - Reason for missing information: Versions and actual reading of the original PDF, complete supplement and figures/tables - Required materials and conditions: S01 publisher PDF, author HTML, supplements/figures, original tables and access history/versions - Materials to obtain first: S01 publisher PDF, author HTML, supplements/figures, original tables and access history/versions - Further research: Compare actual acquisition and reading locations by file/version and text/table/figure to review access scope. - Conditions for verification: Preserve the historical HTML reading of Tables 1–3 and the unverified partial supplement, Figure 1/embedded graphs. - Why this condition is needed: This is needed to avoid elevating reading tables in an author copy to visual verification of all original PDFs/supplements/figures. - Application exceptions: Do not import numerical interpretations of unread figures or unrelated recommended articles. - Remaining uncertainty: Verification remains outstanding for: Versions and actual reading of the original PDF, complete supplement and figures/tables. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating reading tables in an author copy to visual verification of all original PDFs/supplements/figures. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01 ### N40 · Were pre-submission manuscript corrections presented as new publisher corrections? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The 2026-09-16 pre-submission manuscript corrections record corrections or preservation of mixed treatment status, physical site, SD/SEM, denominators, table discrepancies and registry/trial linkage. They explicitly state that previous verdicts were not changed. These are not official publisher corrections or new clinical revisions in this review. - Why unverified: The scope of the retained correction event is known, but current comparison of the separate original correction file/publication history remains outstanding. - Reason for missing information: Separate original correction files, source text before/after correction and publication/retraction verification records - Required materials and conditions: Pre-submission corrections on 2026-09-16, original corrections.json, publication/retraction checks and event history - Materials to obtain first: Pre-submission corrections on 2026-09-16, original corrections.json, publication/retraction checks and event history - Further research: Compare source text before/after correction, reasons, events/versions and the scope of publication-status verification. - Conditions for verification: Record, by event, the historical correction/preservation of mixed treatment status, site, SD/SEM, denominators and conflicts/linkages. - Why this condition is needed: This is needed to separate self-made manuscript corrections from official journal corrections/retractions and revisions to the verdict in this review. - Application exceptions: The historical separate corrections.json and ZIP were not read in this review; the existence/absence of official corrections is not newly established. - Remaining uncertainty: Verification remains outstanding for: Separate original correction files, source text before/after correction and publication/retraction verification records. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to separate self-made manuscript corrections from official journal corrections/retractions and revisions to the verdict in this review. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02, S06 ### N41 · Were C/46 and self-verification reused as a new judgment on criteria? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: Preserve the current original verdict as C, fixed score 46 and safety Caution. Document quality A and the single-assistant self-verification at that time are distinct from efficacy/safety, independent external clinical review, journal certification or exhaustive-search assurance. Do not automatically inherit scores or axes into the new table's statuses or family selection. - Why unverified: Meets the criterion of separating the original verdict from the new table's documentation criteria and avoiding recalculation/regrading. - Reason for missing information: Separate review of new source-material/error events and preservation of the previous verdict - Required materials and conditions: Original grade/score/safety, grade rationale, scope of self-verification/document quality and current criterion status - Materials to obtain first: Original grade/score/safety, grade rationale, scope of self-verification/document quality and current criterion status - Further research: Separate original verdict/quality metadata from the basis for new criterion statuses to review their linkage and display. - Conditions for verification: Preserve the original verdict and self-review scope without creating a new score, regrading or independent certification. - Why this condition is needed: This is needed to avoid turning historical scores or document quality A into a criterion-fulfillment rate, clinical certification or a new efficacy conclusion. - Application exceptions: Leave the original C/46, Caution, axes and historical calculations unchanged, as records separate from the table's criteria. - Remaining uncertainty: Verification remains outstanding for: Separate review of new source-material/error events and preservation of the previous verdict. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid turning historical scores or document quality A into a criterion-fulfillment rate, clinical certification or a new efficacy conclusion. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: ### N42 · Have the historical unassigned identity and current URL been kept from being read as contemporaneous? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The initial lock retains needs_id_assignment, while current ID 3123, assigned status, canonical URL and prior publication/deployment on 2026-09-16 are recorded. The historical linked-source list has 13 entries, whereas actual sources/citations have 20. Original fields were not corrected and separate publication receipts were not read in this review; this table is unpublished on the website. - Why unverified: The timing difference between current identity and residual metadata has been preserved, but event linkage to actual assignment/deployment receipts has not been compared. - Reason for missing information: Actual receipts for initial locking/subsequent assignment and publication - Required materials and conditions: Lock timing, current assigned ID/URL, publication/deployment history and source-array identity - Materials to obtain first: Lock timing, current assigned ID/URL, publication/deployment history and source-array identity - Further research: Link original fields for identity/assignment/publication events to separate receipts to review timing differences. - Conditions for verification: Distinguish, by event, the initial needs_id_assignment, current assigned/URL/prior deployment and nondeployment of the new table. - Why this condition is needed: This is needed to avoid confusing initial lock metadata with subsequent assignment/publication and the current unpublished table. - Application exceptions: Preserve both the historical linked-source list of 13 and the actual 20 sources/citations, without correcting original fields. - Remaining uncertainty: Verification remains outstanding for: Actual receipts for initial locking/subsequent assignment and publication. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules. The specific reason for applying this to this case is as follows: This is needed to avoid confusing initial lock metadata with subsequent assignment/publication and the current unpublished table. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: ### N43 · Within what verification scope are replication/data described as unverified? Verification status: Partly verified Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: The original evidence cutoff/review date is 2026-09-16. The manuscript records 53 general-web searches, native searches failing 3 times, and retention of a log of reproducible search queries. The review on 2026-10-04 concerns conversion of retained stored summaries; it is not a new search, verification of the latest publication/correction/registry status or proof of complete absence. - Why unverified: The cutoff and search scope at that time are recorded, but separate logs/current complete literature and publication status were not compared. - Reason for missing information: Original search logs, registry/publication/correction history and an explicit update scope - Required materials and conditions: Original 2026-09-16 search queries/results, scope of registry/publication/correction checks and the current review date - Materials to obtain first: Original 2026-09-16 search queries/results, scope of registry/publication/correction checks and the current review date - Further research: In an authorized follow-up update, compare search sources, queries, timing, versions/results and the scope of absence statements. - Conditions for verification: Separate the original evidence cutoff and records of 53 web searches/3 native-search failures from the date of this stored-summary conversion. - Why this condition is needed: This is needed to avoid retrospectively recasting historical web searches and failures as a current exhaustive search or proof of research absence. - Application exceptions: Historical search logs were not read in this review, and no new searches/API queries or author contact are performed. - Remaining uncertainty: Verification remains outstanding for: Original search logs, registry/publication/correction history and an explicit update scope. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid retrospectively recasting historical web searches and failures as a current exhaustive search or proof of research absence. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02, S09, S10 ### N44 · Are summary reading and historical full-text access separated? Verification status: Met Reading scope: Summary read: the actual pointers/values in the designated retained stored summary were read. External materials were not accessed, acquired or read in this review; access was not attempted. - Current findings: What was actually read in this review is the full KO content, structured evidence/identity/bibliography and assessments/gaps in the currently stored summary. All external material types were unattempted, unacquired and unread in this review; historical full texts/abstracts/partial supplements, visual checks/failures are preserved in separate historical fields. The 5 methods sources are historical reuse of actual copies/SHA from 1585 and the principles at that time, not new full-text methods reading. - Why unverified: Meets the narrow documentation criterion separating actual local-summary reading, exact locations and current/historical reading. This is not a status of external original full-text verification. - Reason for missing information: Actual acquisition/reading of external source materials and new methods review within a separately authorized scope - Required materials and conditions: Current input bytes, exact pointer/literal, current/historical access by material type and methods copies/SHA - Materials to obtain first: Current input bytes, exact pointer/literal, current/historical access by material type and methods copies/SHA - Further research: Compare input bytes, source-text locations, methods copies and actual actions by material type to verify the scope of reading badges. - Conditions for verification: Separate actual reading of the currently stored manuscript from historical_access_level, and leave all external material types unread in this review. - Why this condition is needed: This is needed to avoid presenting historical HTML/PDF/abstract access, partial visual checks or access failures as full-text reading in this review. - Application exceptions: Do not elevate actual methods HTML copies and references to historical ZIPs/separate calculations to new clinical/methods full-text reading. - Remaining uncertainty: Verification remains outstanding for: Actual acquisition/reading of external source materials and new methods review within a separately authorized scope. This gap is limited to the current inputs and the scope of verification at that time; it does not mean absence of research, an effect of 0, established safety, or a failed external access attempt in this review. - Referenced methods: C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules. The specific reason for applying this to this case is as follows: This is needed to avoid presenting historical HTML/PDF/abstract access, partial visual checks or access failures as full-text reading in this review. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria. - Related sources: S01, S02, S03, S04, S05, S06, S07, S08, S09, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20 ## Evidence and sources ### S01 Wilson et al. Blood Pressure in Treated Hypertensive Individuals With the MTHFR 677TT Genotype… Hypertension 2013;61:1302–1308 [Source](https://www.researchgate.net/publication/236265737_Blood_Pressure_in_Treated_Hypertensive_Individuals_With_the_MTHFR_677TT_Genotype_Is_Responsive_to_Intervention_With_Riboflavin_Findings_of_a_Targeted_Randomized_Trial) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: placebo-controlled single-ingredient oral B2 at 1.6 mg/day for 16 weeks in a mixed TUDA population selected for TT, without overt CVD, and predominantly treated. Preserve randomized 91(46/45), LOCF for 3 dropouts, 4 outlier exclusions and unverified analyzed n by arm. Distinguish Table 3 means(SEM), between-group −5.6 mmHg/P=0.033, the unverified type of overall ±2.6 and CI, and historical arithmetic. Separate reading of author HTML Tables 1–3 and the partial supplement from unverified figures/publisher PDF. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | HTML transcription of the author copy of the original article | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Publisher PDF of the original article | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Partial online-supplement transcription | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Separate online supplement (current acquisition unverified) | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Original Tables 1–3/Figure 1 and embedded graphs | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S02 ISRCTN23620802 official registry PDF [Source](https://www.isrctn.com/pdf/ISRCTN23620802) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: ISRCTN23620802 is the same trial as TF01, not a new result/replication. Registration on 2012-02-02 followed first recruitment on 2010-05-01, and the primary (1st) endpoint is broadly blood pressure. Distinguish the 2015-09-02 edit record from the unverified original prospective protocol/SAP and single-SBP hierarchy. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Official registry PDF and full change history | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Original prospective protocol/SAP (existence/publication unverified) | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S03 Horigan et al. Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C→T polymorphism in MTHFR. J Hypertens 2010;28:478–486 [Source](https://fileadmin.cs.lth.se/luarchive/www.oresund.org/food/content/download/67080/391472/file/Horigan_%20Riboflavin-blood%20pressure%20_J%20Hyperten%202010.pdf) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: a mixed CC/CT/TT cohort with existing overt CVD, differing from the selected TT population without CVD. Published genotype totals are not treatment-arm totals. Group it with the S04 follow-up/reintervention as the same cohort, without presenting it as independent direct replication or a current sample of 0 participants. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Repository PDF of the original article | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Table 5 and original denominator/population tables | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S04 Wilson et al. Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. AJCN 2012;95:766–772 [Source](https://www.sciencedirect.com/science/article/pii/S000291652302703X) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: the original S01 report links the 4-year follow-up/reintervention to the same existing CVD cohort as S03. Access to the original full text failed at that time, and unverified exact values were not imported. Do not count follow-up of the same cohort as a second independent replication. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Publisher full text of the original article | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Publisher search excerpt from that time | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S05 Hughes et al. A randomised controlled trial to investigate ambulatory blood pressure response… Proceedings of the Nutrition Society 2018;77(OCE3) [Source](https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/randomised-controlled-trial-to-investigate-ambulatory-blood-pressure-response-to-riboflavin-supplementation-in-adults-with-the-mthfr-677tt-genotype/B8F75D2FEA0A3EE4AF56E312C52034A6) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: an ambulatory blood-pressure abstract with 10 mg/day, 16 weeks and n 81, differing in dose/age/baseline-SBP subgroup/measurement. It was grouped with S06 on the basis of the same research network, n and dose/duration description, but individual IDs are unavailable and official NCT02463513 content is unverified. Do not combine it as direct replication of the selected 1.6 mg cuff SBP question. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Original conference-abstract HTML/results table | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Complete trial report (existence/publication unverified) | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Trial SAP (existence/publication unverified) | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S06 Ward et al. P3566 Ambulatory blood pressure response… EHJ 2019;40 Suppl1 [Source](https://academic.oup.com/eurheartj/article/40/Supplement_1/ehz745.0428/5596353) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: a companion abstract overlapping with S05 in investigators, dose, n and trial description; it is not counted as a new independent replication. Sign/rounding discrepancies between the pre/post table and change row remain. Do not invent exact ABPM values absent from the currently retained stored summary that was read or repair the table. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Original conference-abstract HTML | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Original daytime SBP table with pre/post values and change row | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S07 Amenyah et al. DNA methylation of hypertension-related genes… Int J Cardiol 2021;322:233–239 [Source](https://pubmed.ncbi.nlm.nih.gov/32920065/) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: the abstract explicitly states that blood samples from previous trials were used. The exact mixture of parent cohorts is unverified, and no new treatment-specific SBP effect, participant count or independent replication is added. The original study_id is null. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Original article abstract | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Conflict-of-interest statement | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Original article full text | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S08 Jobe et al. Effect of riboflavin supplementation on blood pressure… rural Gambia. F1000Research 2020;9:1034 [Source](https://www.researchgate.net/publication/343842809_Effect_of_riboflavin_supplementation_on_blood_pressure_and_possible_effect_modification_by_the_MTHFR_C677T_polymorphism_a_randomised_trial_in_rural_Gambia) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: a protocol planned for 5 mg/day and 16 weeks in CC/CT in Gambia, in a different deficiency context. Actual sample/results are null. Preserve the author copy's prepublication format, publisher 403 and unverified current registry status; do not turn the planned dose into actual results. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Author protocol HTML transcription | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Publisher's original protocol text | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S09 Barlow R. Functional and health consequences of insufficiency of riboflavin and vitamin B6 in adults. Ulster doctoral thesis, Oct2024 [Source](https://pure.ulster.ac.uk/en/studentTheses/functional-and-health-consequences-of-insufficiency-of-riboflavin/) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: the abstract's early blinded FMD is not a treatment-specific SBP estimate. Preserve the planned 2026-10-31 embargo end and candidate registry linkage recorded at that time. Actual sample/SBP effect and current status are unverified, not interpreted as absence of research. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Thesis abstract/metadata | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Thesis full text | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S10 Bradbury et al. Riboflavin supplements for blood pressure lowering in adults. Cochrane 2025 [Source](https://pmc.ncbi.nlm.nih.gov/articles/PMC12541901/) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: the review's role is family discovery and linkage of included/excluded literature. Do not import pooled effects, denominators, doses or author correspondence as facts verified from the originals. The search end date of 2024-10-24 is separate from the original task's 2026-09-16 cutoff, and the review itself is not a new trial. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Systematic-review HTML full text | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S11 NIH ODS Riboflavin Fact Sheet for Consumers, updated 2022-05-11 [Source](https://ods.od.nih.gov/pdf/factsheets/Riboflavin-Consumer.pdf) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: general nutritional safety/interaction information, not 0 events by arm in this trial or unlimited high-dose safety. Parsed text was used at that time, with visually checked pages distinguished from unrendered pages. The original study_id is null. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | NIH official consumer PDF | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Visual material from PDF pages | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S12 Torbay and South Devon NHS Foundation Trust. Vitamins and supplements that can help with migraine and headache, version May2024 [Source](https://www.torbayandsouthdevon.nhs.uk/uploads/25396.pdf) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: orange urine/tear changes are general information for a different migraine population and a much higher dose, not observations/incidence in the selected 1.6 mg trial. An actual update after the printed planned review date of May 2026 was not verified. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | NHS patient information PDF | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S13 NIH ODS Riboflavin Health Professional fact sheet [Source](https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: only a search excerpt about interactions was read at that time; reading the official full text is not claimed. The UL explanation was not verified from the original inaccessible page, and no numerical UL was adopted. Access was not attempted in this review. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full text of the NIH official health-professional webpage | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Official search excerpt from that time | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S14 Zhang et al. The relationship between riboflavin and hypertension with MTHFR genotype. APJCN 2025 [Source](https://apjcn.qdu.edu.cn/34_4_619.pdf) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: observational associations of riboflavin levels/genotype with hypertension, not assignment to single-ingredient oral supplementation. Table values were not used, and it is not counted as an additional directly eligible trial. The original study_id is null. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Original observational article PDF | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Original abstract/methods | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S15 Cao et al. MTHFR C677T TT genotype associated with poor blood pressure control in H-type hypertension without folic acid. Front Pharmacol 2026-09-04 [Source](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1885629/full) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: a retrospective genotype association, not a riboflavin supplementation study. Do not extrapolate causal effects or genotype-testing recommendations. The publication record dated 2026-09-04 has not been reverified through a current search in this review. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Original observational article HTML full text | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Original abstract/methods | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S16 NCT02463513 RIBOGENE candidate registry [Source](https://clinicaltrials.gov/study/NCT02463513) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: NCT02463513 is a discovered candidate linkage, and a readable official record was not acquired at that time. Official primary (1st) endpoints, time points and current status are unverified; do not fill in registry content from the link alone. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official registry/change history | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S17 NCT05488106 InteRVENE candidate registry [Source](https://clinicaltrials.gov/study/NCT05488106) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: readable official content for NCT05488106 was not acquired at that time. Status and planned/actual sample were not imported from mirrors, and treatment-specific SBP results are also unverified. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official registry/change history | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S18 NCT03151096 Gambia registry [Source](https://clinicaltrials.gov/study/NCT03151096) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: the NCT03151096 identifier/date were discovered in the S08 protocol. Current recruitment, termination and result status have not been verified from official content. Distinguish plans from current actual implementation. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official registry/change history | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S19 Amenyah et al. Epigenetic effects… PNS 2018 [Source](https://doi.org/10.1017/S0029665118000666) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: a candidate methylation conference abstract with the same investigators and topic, but parent-cohort linkage has not been directly verified. The original study_id is null, and no new SBP trial, participants or replication is added. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | DOI/abstract bibliographic metadata | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Full text of the original conference abstract | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ### S20 Pharmacological blood pressure lowering for primary and secondary prevention… Lancet 2021 [Source](https://pmc.ncbi.nlm.nih.gov/articles/PMC8102467/) Materials actually read: Summary read: only the actual designated locations in the retained stored manuscript were read. External material types were not read in this review. Findings recorded in the summary: Record at the time of retention: blood-pressure reduction/risk relationships or unit increments from drug trials are not a validated between-group MCID for the selected 16-week B2/TT cuff SBP contrast. No CVD-risk estimate or numerical threshold was borrowed. Record level: This currently converts the extraction/access records from the stored source summary dated 2026-09-16. It is not new external full-text verification, clinical calculation or reassessment. Independent replication: False | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Search excerpt from that time | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | | Full text of the original article analyzing pooled randomized data | Unverified (no external query in this review) | Access not attempted | Not read | Distinguish historical access/partial reading by material type from current summary reading. | ## Review criteria and methods These are Chamgap's own application conditions, informed by the relevant sections of official methodological guidance. They do not constitute official assessment-tool certification or a new efficacy score. - M03 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03) · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13 · Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention. · Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/certification. - M04 [Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04) · §4.5, §4.6.1–4.6.3, MECIR C42 · Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported. · Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/certification. - M08 [Cochrane Handbook 6.5 (2024), chapter updated 2019-10](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08) · §8.1–8.2.3, Table 8.2.a · Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting. · Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/certification. - M15 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15) · §15.2.4, §15.3.1–15.3.3 · Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision. · Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/certification. - M19 [Cochrane Handbook 6.5 (2024), chapter updated 2019-10](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19) · §19.1.2, §19.2.1–19.2.4 · Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence. · Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/certification. ## What the statuses mean - Met: The narrow documentation criteria for identity, endpoint, attribution, family/exclusions and separation of the original verdict from current reading are met. This is not verification of clinical efficacy, safety or external full texts. - Partly verified: Some retained reports address the criterion, but verification of the actual original methods, denominators/implementation, precision and access remains outstanding. - Unverified: The necessary values/materials cannot be established from the currently retained inputs and the scope of verification at that time. - Not reported: Limited to nonreporting in the specific material/section actually read; not extended to the entirety of external full texts. - Conflicting information: Limited to sign/rounding discrepancies between the pre/post table and change row in the related S06 ABPM report. Differences in other endpoints/doses/populations are not automatically labeled as conflicts. - Inaccessible: Used only when an actual external access attempt failed in this review. External access was unattempted and materials were unread in this review; historical failures are not inherited. - Review incomplete: Means that external materials have not been compared in this review or that actual work remains, distinguished from unverified information in materials already reviewed within a defined scope. - Not applicable: Not applicable to establishing event/testing/medication-replacement effects or optimal/long-term regimens outside the narrow 16-week cuff SBP question. This does not certify no effect, safety or absence of research. ## Change history 2026-11-07 · Public page/materials 1.0. Public-facing display and data were created from the existing 44 items. No new clinical search, change to verification statuses or scoring was performed. ## Material-specific source addresses - [S01-M1 · HTML transcription of the author copy of the original article](https://www.researchgate.net/publication/236265737_Blood_Pressure_in_Treated_Hypertensive_Individuals_With_the_MTHFR_677TT_Genotype_Is_Responsive_to_Intervention_With_Riboflavin_Findings_of_a_Targeted_Randomized_Trial) - S01-M2 · Publisher PDF of the original article: Material URL unverified; external material unread. - [S01-M3 · Partial online-supplement transcription](https://www.researchgate.net/publication/236265737_Blood_Pressure_in_Treated_Hypertensive_Individuals_With_the_MTHFR_677TT_Genotype_Is_Responsive_to_Intervention_With_Riboflavin_Findings_of_a_Targeted_Randomized_Trial) - S01-M4 · Separate online supplement (current acquisition unverified): Material URL unverified; external material unread. - [S01-M5 · Original Tables 1–3/Figure 1 and embedded graphs](https://www.researchgate.net/publication/236265737_Blood_Pressure_in_Treated_Hypertensive_Individuals_With_the_MTHFR_677TT_Genotype_Is_Responsive_to_Intervention_With_Riboflavin_Findings_of_a_Targeted_Randomized_Trial) - [S02-M1 · Official registry PDF and full change history](https://www.isrctn.com/pdf/ISRCTN23620802) - S02-M2 · Original prospective protocol/SAP (existence/publication unverified): Material URL unverified; external material unread. - [S03-M1 · Repository PDF of the original article](https://fileadmin.cs.lth.se/luarchive/www.oresund.org/food/content/download/67080/391472/file/Horigan_%20Riboflavin-blood%20pressure%20_J%20Hyperten%202010.pdf) - [S03-M2 · Table 5 and original denominator/population tables](https://fileadmin.cs.lth.se/luarchive/www.oresund.org/food/content/download/67080/391472/file/Horigan_%20Riboflavin-blood%20pressure%20_J%20Hyperten%202010.pdf) - [S04-M1 · Publisher full text of the original article](https://www.sciencedirect.com/science/article/pii/S000291652302703X) - [S04-M2 · Publisher search excerpt from that time](https://www.sciencedirect.com/science/article/pii/S000291652302703X) - [S05-M1 · Original conference-abstract HTML/results table](https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/randomised-controlled-trial-to-investigate-ambulatory-blood-pressure-response-to-riboflavin-supplementation-in-adults-with-the-mthfr-677tt-genotype/B8F75D2FEA0A3EE4AF56E312C52034A6) - S05-M2 · Complete trial report (existence/publication unverified): Material URL unverified; external material unread. - S05-M3 · Trial SAP (existence/publication unverified): Material URL unverified; external material unread. - [S06-M1 · Original conference-abstract HTML](https://academic.oup.com/eurheartj/article/40/Supplement_1/ehz745.0428/5596353) - [S06-M2 · Original daytime SBP table with pre/post values and change row](https://academic.oup.com/eurheartj/article/40/Supplement_1/ehz745.0428/5596353) - [S07-M1 · Original article abstract](https://pubmed.ncbi.nlm.nih.gov/32920065/) - [S07-M2 · Conflict-of-interest statement](https://pubmed.ncbi.nlm.nih.gov/32920065/) - [S07-M3 · Original article full text](https://pubmed.ncbi.nlm.nih.gov/32920065/) - [S08-M1 · Author protocol HTML transcription](https://www.researchgate.net/publication/343842809_Effect_of_riboflavin_supplementation_on_blood_pressure_and_possible_effect_modification_by_the_MTHFR_C677T_polymorphism_a_randomised_trial_in_rural_Gambia) - S08-M2 · Publisher's original protocol text: Material URL unverified; external material unread. - [S09-M1 · Thesis abstract/metadata](https://pure.ulster.ac.uk/en/studentTheses/functional-and-health-consequences-of-insufficiency-of-riboflavin/) - [S09-M2 · Thesis full text](https://pure.ulster.ac.uk/en/studentTheses/functional-and-health-consequences-of-insufficiency-of-riboflavin/) - [S10-M1 · Systematic-review HTML full text](https://pmc.ncbi.nlm.nih.gov/articles/PMC12541901/) - [S11-M1 · NIH official consumer PDF](https://ods.od.nih.gov/pdf/factsheets/Riboflavin-Consumer.pdf) - [S11-M2 · Visual material from PDF pages](https://ods.od.nih.gov/pdf/factsheets/Riboflavin-Consumer.pdf) - [S12-M1 · NHS patient information PDF](https://www.torbayandsouthdevon.nhs.uk/uploads/25396.pdf) - [S13-M1 · Full text of the NIH official health-professional webpage](https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/) - [S13-M2 · Official search excerpt from that time](https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/) - [S14-M1 · Original observational article PDF](https://apjcn.qdu.edu.cn/34_4_619.pdf) - [S14-M2 · Original abstract/methods](https://apjcn.qdu.edu.cn/34_4_619.pdf) - [S15-M1 · Original observational article HTML full text](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1885629/full) - [S15-M2 · Original abstract/methods](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1885629/full) - [S16-M1 · Full official registry/change history](https://clinicaltrials.gov/study/NCT02463513) - [S17-M1 · Full official registry/change history](https://clinicaltrials.gov/study/NCT05488106) - [S18-M1 · Full official registry/change history](https://clinicaltrials.gov/study/NCT03151096) - [S19-M1 · DOI/abstract bibliographic metadata](https://doi.org/10.1017/S0029665118000666) - [S19-M2 · Full text of the original conference abstract](https://doi.org/10.1017/S0029665118000666) - [S20-M1 · Search excerpt from that time](https://pmc.ncbi.nlm.nih.gov/articles/PMC8102467/) - [S20-M2 · Full text of the original article analyzing pooled randomized data](https://pmc.ncbi.nlm.nih.gov/articles/PMC8102467/)