{
  "schema_version": "chamgap-public-criteria-1.0",
  "title": "Ordinary thiamine (vitamin B1), hydrochloride × Eight-week salbutamol-responsive digital reflective-index response",
  "criteria_version": "v3122-ORAL-THIAMINE-RI-1.1",
  "criteria_date": "2026-10-04",
  "condition_origin": "Chamgap application criteria",
  "method_sources": [
    {
      "id": "M03",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03",
      "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13",
      "official_principle": "Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.",
      "review_level": "Historical reuse of the actual HTML copies, SHA and methodological principles retained in 1585. This is not new reading of full methodological texts, formal implementation or clinical certification in this work."
    },
    {
      "id": "M04",
      "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04",
      "section": "§4.5, §4.6.1–4.6.3, MECIR C42",
      "official_principle": "Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.",
      "review_level": "Historical reuse of the actual HTML copies, SHA and methodological principles retained in 1585. This is not new reading of full methodological texts, formal implementation or clinical certification in this work."
    },
    {
      "id": "M08",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08",
      "section": "§8.1–8.2.3, Table 8.2.a",
      "official_principle": "Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.",
      "review_level": "Historical reuse of the actual HTML copies, SHA and methodological principles retained in 1585. This is not new reading of full methodological texts, formal implementation or clinical certification in this work."
    },
    {
      "id": "M15",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15",
      "section": "§15.2.4, §15.3.1–15.3.3",
      "official_principle": "Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.",
      "review_level": "Historical reuse of the actual HTML copies, SHA and methodological principles retained in 1585. This is not new reading of full methodological texts, formal implementation or clinical certification in this work."
    },
    {
      "id": "M19",
      "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10",
      "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19",
      "section": "§19.1.2, §19.2.1–19.2.4",
      "official_principle": "Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.",
      "review_level": "Historical reuse of the actual HTML copies, SHA and methodological principles retained in 1585. This is not new reading of full methodological texts, formal implementation or clinical certification in this work."
    }
  ],
  "status_dictionary": {
    "Met": "The relevant distinctions in identity, boundaries and retained records have been verified. This does not establish clinical benefit/safety or constitute official certification.",
    "Partly verified": "Some design details, numerical values and methods are retained, but dimensions needed for verification remain unresolved.",
    "Unverified": "The required values cannot be established within the retained scope read. This does not mean absence of all studies, an effect of 0 or 0 events.",
    "Conflicting information": "Design checkboxes, completion dates and identifier entries in the original registration differ across the relevant records. Do not expand this into a conflict over actual treatment durations or clinical effects as a whole.",
    "Not applicable": "Between-study comparison does not apply within the single verified direct family. Do not fill in unverified candidates or other formulations as independent results.",
    "Not reported": "Limited to an information gap at the retained location actually read; do not expand this into nonreporting throughout the external article.",
    "Inaccessible": "Requires an actual failed access attempt in the current work. External access not attempted in this work differs from historical access failure.",
    "Review incomplete": "Pending individual review during table preparation, distinct from unverified/unread materials."
  },
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Independent claim",
      "question": "Which population, regimen and 8-week functional response does the independent table address?",
      "needed": "Original locations of the current claim, PICOT, surrogate measure and excluded questions",
      "role": "Required",
      "role_reason": "Needed to distinguish the entire ordinary-thiamine page from the selected functional outcome.",
      "application_exception": "Preserve the original claim exactly as recorded at /ko/effect, without automatically creating new efficacy subclaims for FMD, clinical events or TDP.",
      "criterion": "Link the selected population, actual comparison, regimen and timing to the original identity of digital RI.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed; M03 §3.2.1; detailed population criteria are self-designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed — Case-specific adaptation for Independent claim. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "In subsequent research, first fix the population, oral regimen, placebo and RI measurement time, and distinguish other outcomes alongside them."
    },
    {
      "item_id": "N02",
      "question_type": "Molecule and actual product",
      "question": "Have the single registered active ingredient and the actual product batch been distinguished?",
      "needed": "Actual trial product ingredient list, batch, excipients and manufacturing-origin information",
      "role": "Required",
      "role_reason": "Because active-ingredient identity and the actual formulation/batch do not have the same level of verification.",
      "application_exception": "Do not substitute Flamingo product information from a different era for registered Tyvera, or automatically equate it with benfotiamine or combination products.",
      "criterion": "Record ordinary thiamine hydrochloride and the registered product identity separately from the unverified actual batch/excipients.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.3, M08 §8.2.2–8.2.3; own application — Case-specific adaptation for Molecule and actual product. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a replication procedure that obtains product analyses and batch records and verifies actual administration of the single active ingredient."
    },
    {
      "item_id": "N03",
      "question_type": "Nominal amount and active amount",
      "question": "Have the reported 300 mg/day and the free-thiamine equivalent been distinguished?",
      "needed": "Actual dose records, product content/units, 1-time dosing schedule and amount actually taken",
      "role": "Required",
      "role_reason": "Needed to avoid converting the nominal total hydrochloride amount into the active contribution or an optimal personal dose.",
      "application_exception": "Do not newly calculate the actual number of tablets taken per administration or the dosing schedule from the 100 mg tablets and 300 mg/day.",
      "criterion": "Preserve the reported daily total and mark the free-thiamine conversion and actual 1-time schedule as unverified.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed — Case-specific adaptation for Nominal amount and active amount. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "After verifying actual administration records and content units, address any necessary dose comparison under a separate protocol."
    },
    {
      "item_id": "N04",
      "question_type": "Treatment and washout periods",
      "question": "Have each 8-week treatment period and the 2-week washout been linked to the outcome time?",
      "needed": "Information on administration and visit schedules by period and RI measurement times",
      "role": "Required",
      "role_reason": "Needed to avoid confusing the crossover trial's two treatment periods, washout and original outcome time as the same total duration.",
      "application_exception": "Do not turn the discrepancy in registered calendar completion dates into a conflict over the reported treatment duration of 8 weeks.",
      "criterion": "Link each 8-week period, the 2-week washout and RI at the end of treatment to their original locations.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed — Case-specific adaptation for Treatment and washout periods. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Check implementation of each treatment and washout against visit/exposure records, and plan long-term persistence questions under separate follow-up."
    },
    {
      "item_id": "N05",
      "question_type": "Actual population and selection",
      "question": "Have the actual high-risk adults with type 2 diabetes and the registered eligibility plan been distinguished?",
      "needed": "Baseline characteristics by group/sequence, actual inclusion/exclusion flow and definitions of risk and endothelial function",
      "role": "Required",
      "role_reason": "Needed to avoid promoting planned registered selection criteria into actual characteristics of all participants or baseline endothelial dysfunction.",
      "application_exception": "Verify the target scope from registered eligibility/the institutional abstract, without inferring detailed diagnoses or the population mix for all participants.",
      "criterion": "Distinguish the actual high-risk adult population with type 2 diabetes and mean age from the remaining baseline-data gaps.",
      "basis": "M03 §3.2.1; detailed population criteria are self-designed; M08 §8.1–8.2.3; own application — Case-specific adaptation for Actual population and selection. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "In subsequent comparisons, prespecify risk selection and baseline vascular function and disclose actual participant characteristics."
    },
    {
      "item_id": "N06",
      "question_type": "Baseline nutritional status",
      "question": "Can baseline thiamine deficiency and the conditions for additional supplementation be established?",
      "needed": "Baseline thiamine/TDP, deficiency thresholds, dietary/supplement intake and prespecified stratification data",
      "role": "Required (nutritional applicability)",
      "role_reason": "Needed to distinguish possible correction of deficiency from the effect of additional supplementation in a population of unknown status.",
      "application_exception": "Do not use the thesis abstract's general discussion of deficiency as an actual measurement of deficiency in participants.",
      "criterion": "Retain the actual level of verification of baseline status, deficiency criteria and total intake.",
      "basis": "M03 §3.2.1; detailed population criteria are self-designed; M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed — Case-specific adaptation for Baseline nutritional status. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Measure baseline status and assess effect modification by deficiency status in a separately planned, prespecified analysis."
    },
    {
      "item_id": "N07",
      "question_type": "Crossover placebo and background treatment",
      "question": "Have the placebo comparison and background-medication balance between periods been distinguished?",
      "needed": "Information on medications, rescue treatment, disease status/changes and their handling for the effect of interest by period",
      "role": "Required",
      "role_reason": "Because changes in background diabetes/cardiovascular treatment may be mixed with the contribution of thiamine.",
      "application_exception": "Even in a crossover comparison in the same participants, do not assume that all medication and disease changes were identical between periods.",
      "criterion": "Distinguish the actual placebo comparison from gaps in period-specific concomitant/rescue treatment and the handling of changes.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.3, M08 §8.2.2–8.2.3; own application — Case-specific adaptation for Crossover placebo and background treatment. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a comparison that records common treatment and prespecifies how period-specific changes and rescue treatment will be handled in analysis."
    },
    {
      "item_id": "N08",
      "question_type": "Conflicting design labels",
      "question": "Have the actual crossover design and the registry's parallel/crossover checkboxes been distinguished?",
      "needed": "Full protocol, registry amendment history, actual allocation sequences and design explanation",
      "role": "Required",
      "role_reason": "Needed to avoid hiding the conflicting registry labels or arbitrarily changing the actually reported design to a parallel trial.",
      "application_exception": "Do not reassess conflicting registry checkboxes as errors in all RI numbers or as absence of random allocation.",
      "criterion": "Preserve the actual crossover report and the registry's Yes entries for both designs at their respective original locations.",
      "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed; M08 §8.1–8.2.3; own application; M08 Table 8.2.a, M04 §4.6.3; own application — Case-specific adaptation for Conflicting design labels. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Compare the original protocol and amendment history to verify why both boxes were checked, and reconcile the design actually implemented with its reporting."
    },
    {
      "item_id": "N09",
      "question_type": "Sequence generation and concealment",
      "question": "Have random sequence generation and allocation concealment been verified?",
      "needed": "Information on sequence generation, allocation concealment and actual baseline balance by sequence",
      "role": "Required (causal efficacy)",
      "role_reason": "Because the labels randomized and double-blind alone do not establish that allocation issues were resolved.",
      "application_exception": "The crossover/pilot label does not establish detailed generation, concealment or baseline balance, or completion of a formal RoB assessment.",
      "criterion": "Record the allocation label and the verified scope of actual sequence generation, concealment and balance.",
      "basis": "M08 §8.1–8.2.3; own application — Case-specific adaptation for Sequence generation and concealment. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a comparison that prespecifies sequence-generation and concealment procedures and baseline balance and discloses their actual implementation."
    },
    {
      "item_id": "N10",
      "question_type": "Completion, allocation and analysis denominators",
      "question": "Have the 34 completers been distinguished from the randomized count and number of analyzed RI pairs?",
      "needed": "CONSORT/crossover flow, allocation/completion/measurement by sequence and number of paired RI analyses",
      "role": "Required",
      "role_reason": "Needed to avoid counting the same person's two periods as independent people or turning completers into a confirmed analysis denominator.",
      "application_exception": "Do not add up the 34 unique completers as 68 people; keep the randomized count, denominators by sequence and number of analyzed RI pairs unverified.",
      "criterion": "Link completion, allocation, sequence, measurement and analysis to the denominator at each stage.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are self-designed; M08 §8.2.2, M15 §15.3.1; own application — Case-specific adaptation for Completion, allocation and analysis denominators. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose reporting participant flow and paired denominators for each endpoint, with differences between allocation, completion and analysis disclosed."
    },
    {
      "item_id": "N11",
      "question_type": "Missing data and analysis populations",
      "question": "Can the handling of attrition/missing data and the ITT/PP analysis populations be established?",
      "needed": "Data on allocation/attrition, reasons for missingness, definitions of analysis populations and sensitivity analyses",
      "role": "Required",
      "role_reason": "Needed to avoid automatically concluding from the completer count that only completers were analyzed.",
      "application_exception": "Do not arbitrarily label the completer report as complete-case, ITT or PP, or describe the information as unreported throughout the unread full text.",
      "criterion": "Link the verified scope of the actual analysis population, missing-data handling and attrition by sequence to the effect of interest.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are self-designed; M08 §8.2.2, M15 §15.3.1; own application — Case-specific adaptation for Missing data and analysis populations. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Prespecify the effect of interest and analysis population, and plan sensitivity analyses that account for missing crossover data."
    },
    {
      "item_id": "N12",
      "question_type": "Washout and carryover",
      "question": "Can it be established whether the 2-week washout excluded carryover?",
      "needed": "Crossover protocol, baseline/exposure by period and information on carryover assessment and handling",
      "role": "Required (crossover trial)",
      "role_reason": "Because residual effects of the previous treatment may be mixed with RI in the next period.",
      "application_exception": "Do not conclude from the nominal 2-week washout alone that there was no carryover or that washout was sufficient.",
      "criterion": "Distinguish the washout report from direct information on carryover assessment/handling and restoration of baseline in each period.",
      "basis": "M08 §8.1–8.2.3; own application; M08 §8.2.2, M15 §15.3.1; own application — Case-specific adaptation for Washout and carryover. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Prespecify the rationale for washout and baseline measurements by period, and plan a crossover analysis that examines residual/carryover effects."
    },
    {
      "item_id": "N13",
      "question_type": "Sequence and period effects",
      "question": "Were sequence and period effects handled in the actual RI analysis?",
      "needed": "RI, baseline/medications, interactions and analysis model by sequence/period",
      "role": "Required (crossover trial)",
      "role_reason": "Because calendar time/period and allocation sequence can affect treatment differences even in before-and-after observations of the same person.",
      "application_exception": "Do not state that sequence and period effects were automatically removed because the participants were the same.",
      "criterion": "Link sequence/period-specific data to the model's effect of interest and its handling.",
      "basis": "M08 §8.1–8.2.3; own application; M08 §8.2.2, M15 §15.3.1; own application — Case-specific adaptation for Sequence and period effects. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Prespecify the treatment, period and sequence terms of interest and disclose sequence-specific data and sensitivity analyses."
    },
    {
      "item_id": "N14",
      "question_type": "Paired effect of interest",
      "question": "Can the adjusted paired RI effect and the actual choice of test be established?",
      "needed": "RI analysis plan, paired source data/covariance, adjusted model, test type and effect estimator",
      "role": "Required",
      "role_reason": "Because a descriptive difference between two summary values differs from the actual paired causal estimate and test statistic.",
      "application_exception": "Do not back-calculate the outcome-specific ANOVA/Friedman choice, covariance or degrees of freedom from P=.63.",
      "criterion": "Retain the verified scope of the effect of interest, analysis population, pairing/covariance and actual test definition.",
      "basis": "M08 §8.2.2, M15 §15.3.1; own application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed — Case-specific adaptation for Paired effect of interest. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose an analysis that prespecifies the paired effect of interest and period/sequence adjustment and reports that effect and its interval."
    },
    {
      "item_id": "N15",
      "question_type": "RI measurement procedure",
      "question": "Have salbutamol RI measurement timing, sign convention and assessor blinding been verified?",
      "needed": "Measurement protocol, challenge dose/time afterward, sign convention, baseline RI and operator-blinding/quality information",
      "role": "Required",
      "role_reason": "Because post-challenge timing, sign convention and assessment conditions may change interpretation even when the measure has the same name.",
      "application_exception": "Do not arbitrarily fill in operator blinding, challenge dose/timing or directional sign convention from the double-blind label.",
      "criterion": "Record the actual digital photoplethysmography/inhalation-challenge method and the remaining measurement dimensions.",
      "basis": "M08 Table 8.2.a, M03 §3.2.4; own application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed — Case-specific adaptation for RI measurement procedure. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a method that standardizes the RI challenge, collection time, sign convention and assessor blinding and reports baseline/reproducibility data."
    },
    {
      "item_id": "N16",
      "question_type": "Surrogate measure and clinical boundary",
      "question": "Has digital RI been distinguished from FMD and prevention of clinical events?",
      "needed": "Measurement definition and separate direct results for claims about event prevention/quality of life",
      "role": "Required (claim boundary); separate evidence for extension to events",
      "role_reason": "Needed to avoid automatically translating the selected functional response into other vascular measures or long-term events.",
      "application_exception": "Do not mechanically require cardiovascular-event trials merely to preserve observations for the RI question itself; extension to event prevention remains separately unverified.",
      "criterion": "Identify the distinct questions concerning RI, brachial artery FMD, VCAM-1, TDP and clinical events.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M03 §3.2.4; own boundaries on extrapolation — Case-specific adaptation for Surrogate measure and clinical boundary. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If a clinical-event question is requested, address it through a study with a separate protocol, follow-up and event adjudication."
    },
    {
      "item_id": "N17",
      "question_type": "Reported RI values and P",
      "question": "Have the two reported RI values and P=0.63 been attributed to the original time point?",
      "needed": "P72 RI result sentence, original table/units, explanation of variance and analysis location",
      "role": "Required",
      "role_reason": "Needed to avoid deleting favorable or nonsignificant results or transferring them as values for another functional endpoint.",
      "application_exception": "Do not arbitrarily assign the type of ± value, absolute change or percentage to 5.3±9.2/6.8±6.9.",
      "criterion": "Retain the reported values, 8-week RI and original P together with the gaps in units/variance.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed — Case-specific adaptation for Reported RI values and P. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Check the original results table to compare definitions of summary statistics, and specify units, variance and effect estimates in subsequent reporting."
    },
    {
      "item_id": "N18",
      "question_type": "Units and variance type",
      "question": "Have the original RI units and whether the ± values are SD or SE been verified?",
      "needed": "RI units, explanation of summary statistics, SD/SE, paired covariance and denominator data",
      "role": "Required",
      "role_reason": "Needed to avoid creating a CI, percentage points or causal estimate from ± values of unknown type.",
      "application_exception": "Do not supplement a report lacking units with FMD %, absolute percentage points or relative percentage change.",
      "criterion": "Clearly retain the absence of an original location providing the units/variance type.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are self-designed; M15 §15.3.1–15.3.3; own application — Case-specific adaptation for Units and variance type. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose reporting the RI units, variance type and number of analyzed pairs explicitly, with intervals appropriate to the paired structure."
    },
    {
      "item_id": "N19",
      "question_type": "Historical descriptive difference",
      "question": "Has the existing difference of −1.5 been distinguished from an adjusted paired causal estimate?",
      "needed": "Source location of the existing calculation, effect of interest and actual adjusted paired-estimate data",
      "role": "Required",
      "role_reason": "Because a simple difference between two reported values is not guaranteed to equal the actual crossover trial's effect of interest.",
      "application_exception": "Only cite the existing calculation record; perform no new arithmetic, paired CI/SE calculation or FMD conversion in this work.",
      "criterion": "Record the historical calculation location for −1.5 together with its descriptive nature and unit limitations.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M08 §8.2.2, M15 §15.3.1; own application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed — Case-specific adaptation for Historical descriptive difference. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If the original analysis is acquired, report the descriptive summary difference separately from the prespecified paired effect of interest."
    },
    {
      "item_id": "N20",
      "question_type": "Nonsignificance and equivalence",
      "question": "Has P=0.63 been distinguished from a benefit of 0, equivalence or exclusion of important benefit?",
      "needed": "Direct RI effect interval, justified importance/equivalence criteria and testing plan",
      "role": "Required",
      "role_reason": "Because a nonsignificant comparison in a small pilot trial alone cannot establish an exactly null effect or equivalence.",
      "application_exception": "Retain the original nonsignificant result; do not back-calculate effect direction or magnitude without a CI or override it with positive results for other preparations.",
      "criterion": "Identify the significance information provided by P and the different evidence required to judge no effect, equivalence and importance.",
      "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed; M15 §15.3.1–15.3.3; own application — Case-specific adaptation for Nonsignificance and equivalence. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If equivalence or exclusion of important benefit is the question, plan separate verification with prespecified criteria, an effect of interest and adequate precision."
    },
    {
      "item_id": "N21",
      "question_type": "Intervals and clinical importance",
      "question": "Can the direct RI CI and an important difference be established?",
      "needed": "RI effect/CI, confidence level, variance, denominator and validated criteria for clinical importance",
      "role": "Required",
      "role_reason": "Because precision/clinical importance cannot be determined from the number of completers or trial families alone.",
      "application_exception": "Do not adopt a common minimum participant count, duration or arbitrary MCID; retain unverified intervals/criteria.",
      "criterion": "Explain the relationship between the interval for the actual effect of interest and justified evidence of importance, or why interpretation is not possible.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are self-designed; M15 §15.3.1–15.3.3; own application — Case-specific adaptation for Intervals and clinical importance. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "First define the RI effect of interest and the basis for importance, then design the required precision to match that basis."
    },
    {
      "item_id": "N22",
      "question_type": "Registered endpoints and reporting",
      "question": "Have the registered primary (1st) VCAM-1 endpoint and the prespecified rank/analysis of RI been distinguished?",
      "needed": "Full registration/protocol, SAP, prespecified RI rank and multiple-comparison/amendment history",
      "role": "Required",
      "role_reason": "Needed to avoid promoting the page's functional endpoint to the registered primary (1st) endpoint or to a significant secondary (2nd) success.",
      "application_exception": "Do not change the registered primary (1st) endpoint or use the unverified prespecified RI rank/SAP as proof of selective reporting.",
      "criterion": "Indicate the extent of comparison between registered endpoints and the original RI report, and reasons for multiple comparisons/changes.",
      "basis": "M08 Table 8.2.a, M04 §4.6.3; own application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed — Case-specific adaptation for Registered endpoints and reporting. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose subsequent reporting that prespecifies the RI of interest, time point and model and discloses reasons for changes and all endpoints."
    },
    {
      "item_id": "N23",
      "question_type": "Planned schedule and actual administration",
      "question": "Have the registered schedule of 1 time per 1 day and the actual daily total/meal timing been distinguished?",
      "needed": "Actual administration times/frequency, meal conditions, dosing diaries and plan-change information",
      "role": "Required",
      "role_reason": "Because a planned schedule does not guarantee actual administration frequency, meal conditions or adherence implementation.",
      "application_exception": "Do not confirm the HRA plan's once daily as the actual 1-time schedule or adopt overnight fasting from the S18 mirror as an original-trial fact.",
      "criterion": "Separate the verification levels of the reported total, registered plan and actual schedule/meal conditions.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.3, M08 §8.2.2–8.2.3; own application; M08 Table 8.2.a, M04 §4.6.3; own application — Case-specific adaptation for Planned schedule and actual administration. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Record actual administration and meal conditions and prespecify how changes/deviations from the plan will be handled."
    },
    {
      "item_id": "N24",
      "question_type": "Exposure and individual adherence",
      "question": "Does an increase in blood TDP establish individual adherence or RI benefit?",
      "needed": "Data on individual intake, exposure/TDP by period and handling of treatment deviations",
      "role": "Required",
      "role_reason": "Because biochemical exposure, individual dosing adherence and functional benefit are different outcomes.",
      "application_exception": "Do not add new exact numbers to the retained TDP increase or convert it into adherence by all participants, baseline deficiency or RI efficacy.",
      "criterion": "Distinguish the existence of an increased exposure marker from individual adherence, deviations by period and functional outcomes.",
      "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3; own application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M03 §3.2.4; own boundaries on extrapolation — Case-specific adaptation for Exposure and individual adherence. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Collect adherence records and exposure markers separately from the RI effect of interest, and prespecify how deviations will be handled."
    },
    {
      "item_id": "N25",
      "question_type": "Reports and trial families",
      "question": "Have the thesis, P72, registration/ethics records and mirror been linked as the same F01?",
      "needed": "Identity linkage across reports, registrations and ethics/trial records, cohort overlap and original locations for each endpoint",
      "role": "Required",
      "role_reason": "Needed to avoid counting multiple reports of the same trial as independent replications or duplicated participant populations.",
      "application_exception": "This is a documentary comparison linking authors, institution, regimen/duration, the 34 completers and registered title, not verification at the level of individual identifiers.",
      "criterion": "Preserve the evidence linking documents in the same family and the original record of 1 direct family and 34 completers.",
      "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this work; M04 §4.6.1–4.6.2, M15 §15.3.1; own application — Case-specific adaptation for Reports and trial families. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a subsequent review that maintains a family table and an endpoint/time-point/analysis linkage table centered on the original trial."
    },
    {
      "item_id": "N26",
      "question_type": "Exception for between-study comparisons",
      "question": "Can between-study heterogeneity be estimated from the single verified direct family?",
      "needed": "Results, populations, dose/duration and analysis information for additional independent direct RI families",
      "role": "Required if multiple direct families are verified; currently not applicable",
      "role_reason": "Needed to avoid presenting multiple reports of the same trial as between-study consistency or replicated effects.",
      "application_exception": "Nonapplicability is limited to between-study comparison within the 1 verified direct family for the narrow RI question. Do not erase the unverified S19 candidate or other formulations as NA or conclude that there is 1 study worldwide.",
      "criterion": "Specify when comparisons between families apply and the manuscript's scope of a single direct family.",
      "basis": "M04 §4.6.1–4.6.2, M15 §15.3.1; own application; Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this work — Case-specific adaptation for Exception for between-study comparisons. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If a new direct family is acquired, separate its conditions and results and compare them according to prespecified heterogeneity hypotheses."
    },
    {
      "item_id": "N27",
      "question_type": "Completion dates and posting events",
      "question": "Have the two registered completion dates and the results posting date been distinguished?",
      "needed": "Registry amendment history, definitions of completion dates, end-of-study report and posted-version information",
      "role": "Required (reporting history)",
      "role_reason": "Needed to avoid hiding differences in registry calendar dates or using the results posting date as the end of treatment.",
      "application_exception": "Do not turn the difference between 2011-07-04/2011-07-31 into an error in the nominal 8-week treatment period.",
      "criterion": "Preserve the completion dates in protocol/results metadata and the posting event in 2019 separately.",
      "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed; M08 Table 8.2.a, M04 §4.6.3; own application; M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and own design — Case-specific adaptation for Completion dates and posting events. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Compare event definitions and amendment history in the original registration/end-of-study report to verify the meaning of the two dates and the reason for their difference."
    },
    {
      "item_id": "N28",
      "question_type": "Registered identifier labels",
      "question": "Have both HRA's n/a and the original registry's ISRCTN linkage been retained?",
      "needed": "Ethics/registry identifier amendment history, original ISRCTN record and explanation linking the same trial",
      "role": "Required (identity linkage)",
      "role_reason": "Needed to avoid hiding differences between identifier fields or claiming to have read the ISRCTN record text.",
      "application_exception": "Do not use HRA's n/a as proof of no ISRCTN or an unregistered trial; link the S03 identifier with the shared EudraCT/ethics number.",
      "criterion": "Distinguish the original registered identifier, the different ethics-record entry and the unacquired ISRCTN record text.",
      "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this work; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed; M08 Table 8.2.a, M04 §4.6.3; own application — Case-specific adaptation for Registered identifier labels. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Maintain a common trial identity table and compare the original registry/ethics history for the reason behind the different identifier entries."
    },
    {
      "item_id": "N29",
      "question_type": "Current and historical reading",
      "question": "Have reading the summaries and currently not reading the 21 external sources been separated?",
      "needed": "Records of exact locations in the retained inputs, material types/access, reading/byte hashes and dates",
      "role": "Required",
      "role_reason": "Needed to avoid promoting historical reading of abstracts, P72, registration/product information into direct reading in this work.",
      "application_exception": "Existence of a link/DOI is not full-text reading. Do not label access not attempted in this work as Inaccessible.",
      "criterion": "Record exact retained source-summary pointers/hashes, current access/acquisition/reading by material type and historical dates separately.",
      "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed; M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and own design — Case-specific adaptation for Current and historical reading. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If actual sources are read in a specified subsequent update, add their material type, date, original bytes/location and status as a separate event."
    },
    {
      "item_id": "N30",
      "question_type": "Gaps in major original reports",
      "question": "Can methods and original results in the full thesis and end-of-study attachment be compared?",
      "needed": "Full thesis, end-of-study report attachment, original RI tables/methods and appendix/analysis/safety data",
      "role": "Required (comparison of full methods)",
      "role_reason": "Because the institutional abstract and complete P72 conference abstract do not replace the full trial report.",
      "application_exception": "S02 covers the P72 abstract text/pages; do not claim to have read all 49 pages of the abstract collection or the full trial report. Separate historical S06/S07 failures from access not attempted now.",
      "criterion": "Record the scope of reports read at the time and content gaps in major original full texts that were not accessed.",
      "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed; M08 Table 8.2.a, M04 §4.6.3; own application — Case-specific adaptation for Gaps in major original reports. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a document review that first acquires the permitted original full text/end-of-study attachment and compares the current RI methods, denominators, plan and safety information."
    },
    {
      "item_id": "N31",
      "question_type": "Adjacent intravenous and blood-flow evidence",
      "question": "Has transfer of the acute intravenous BAVA in S09 to oral 8-week RI been avoided?",
      "needed": "Actual route, challenge conditions, BAVA definition and original methods in S09",
      "role": "Required (eligibility boundary)",
      "role_reason": "Needed to avoid merging evidence with the same thiamine name but different routes, challenge conditions and measures as independent replications of oral RI.",
      "application_exception": "In S09, the blood-flow augmentation with 100 mg intravenous thiamine after glucose challenge is neither brachial diameter FMD nor an oral RI effect.",
      "criterion": "Preserve only the adjacent evidence's route/measure differences and reasons for exclusion.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed; M04 §4.6.1–4.6.2, M15 §15.3.1; own application — Case-specific adaptation for Adjacent intravenous and blood-flow evidence. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If an intravenous challenge-function question is requested, review it using a separate route/measure protocol and population."
    },
    {
      "item_id": "N32",
      "question_type": "Dietary association",
      "question": "Has use of the dietary thiamine association in S10 as a single-ingredient causal effect been avoided?",
      "needed": "The dietary study's exposure, population, adjustment/timing and whether an actual treatment comparison exists",
      "role": "Required (eligibility boundary)",
      "role_reason": "Because dietary intake/status associations differ in exposure direction and design from randomized comparisons of additional supplementation.",
      "application_exception": "Do not extract the incremental effect of single-ingredient oral 300 mg/day from dietary associations with EPC/endothelial function.",
      "criterion": "Indicate the actual scope of exclusion based on observational design, dietary exposure and absence of a treatment comparison.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M08 §8.1–8.2.3; own application; M04 §4.6.1–4.6.2, M15 §15.3.1; own application — Case-specific adaptation for Dietary association. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Address dietary associations through separate prospective observation and supplementation efficacy alone through comparisons with matched background treatment."
    },
    {
      "item_id": "N33",
      "question_type": "Other B1 derivatives",
      "question": "Have benfotiamine FMD results been separated from ordinary-thiamine RI?",
      "needed": "Original ingredient, route, FMD/challenge conditions and identity of original results for each derivative",
      "role": "Required (ingredient boundary)",
      "role_reason": "Needed to avoid using data for different active molecules or smoking/meal challenge conditions as replications of the ordinary thiamine hydrochloride trial.",
      "application_exception": "Even within the same vitamin class, do not transfer benfotiamine in S11–S13 as RI values for the same ingredient/route. Do not describe title/index-level exclusion as verification of the full methods.",
      "criterion": "Record differences in active ingredients, challenge populations and measures, together with the actual access level for each material.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are self-designed; M04 §4.6.1–4.6.2, M15 §15.3.1; own application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed — Case-specific adaptation for Other B1 derivatives. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Design/review derivative questions using separate ingredients and measures, and distinguish them from the current ordinary-thiamine RI family."
    },
    {
      "item_id": "N34",
      "question_type": "Combination products and attribution",
      "question": "Has use of the combination products in S14/S15 as a direct effect of adding B1 been avoided?",
      "needed": "Combination-product ingredients/populations, comparisons, report lineage/funding and actual evidence of the isolated contribution",
      "role": "Required (ingredient/duplication boundary)",
      "role_reason": "Because results involving multiple active ingredients and uncontrolled/healthy populations are not comparisons of thiamine alone in high-risk diabetes.",
      "application_exception": "Attribute Valerio's interests only to that family, and do not count the unclear link between S15 and earlier reports as independent replication.",
      "criterion": "Indicate combined ingredients, population/design, access level and gaps concerning possible overlap.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed; M03 §3.2.3, M08 §8.2.2–8.2.3; own application; M04 §4.6.1–4.6.2, M15 §15.3.1; own application; Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all of these detailed items — Case-specific adaptation for Combination products and attribution. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Keep combination products as separate questions; if the isolated contribution is asked about, propose a component comparison with matched background ingredients."
    },
    {
      "item_id": "N35",
      "question_type": "Information levels of mirrors and reviews",
      "question": "Has use of the S18 mirror and S20/S21 reviews as original-trial numbers/funding been avoided?",
      "needed": "Original trial/registration funding, measurement methods/dates and linkage tables for studies/families included in reviews",
      "role": "Required (attribution boundary)",
      "role_reason": "Because discovery maps and disclosure excerpts do not replace direct verification of original-trial results/funding.",
      "application_exception": "Do not adopt the mirror's internal departmental funding, fasting/GTN or dates as facts verified in the original sources, or transfer review funding/disclosures to F01.",
      "criterion": "Link the information levels of original registrations/trials and secondary (2nd) discovery materials.",
      "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this work; Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed; Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all of these detailed items; M04 §4.6.1–4.6.2, M15 §15.3.1; own application — Case-specific adaptation for Information levels of mirrors and reviews. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Limit discovery materials to maps for tracing original trials, and compare original funding, methods and results separately."
    },
    {
      "item_id": "N36",
      "question_type": "Unverified registry candidate",
      "question": "Can the registered ingredient, status and results of NCT06322212 be established?",
      "needed": "Original NCT06322212 registry record, amendment history, ingredient/population, endpoints and actual results",
      "role": "Supplementary (candidate tracking)",
      "role_reason": "Needed to avoid inventing recruitment/formulation/numbers from an empty app screen or silently excluding the candidate.",
      "application_exception": "Do not establish current status, lack of posting or trial eligibility for a candidate for which only an HTML shell was seen previously.",
      "criterion": "Separate candidate identity from gaps in actual content and mark current access as not attempted.",
      "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed; M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and own design; M08 Table 8.2.a, M04 §4.6.3; own application — Case-specific adaptation for Unverified registry candidate. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Propose a subsequent review that first acquires the permitted official registry record and compares eligibility for the question and reported results."
    },
    {
      "item_id": "N37",
      "question_type": "Funding and independence",
      "question": "Have a noncommercial sponsor and trial-specific funding, product supply and COI been distinguished?",
      "needed": "Declarations of trial funding, product supply, author employment/disclosed COI and sponsor roles",
      "role": "Supplementary; required for independence claims",
      "role_reason": "Needed to avoid converting unverified funding into confirmed independent/mixed funding or absence of bias.",
      "application_exception": "The blank S03 B.4 field and a noncommercial sponsor do not verify original-trial funding. Do not transfer declarations from the S18 mirror or the 2011 review.",
      "criterion": "Link what is verified about the sponsor to the unverified trial-specific funding and product/author relationships.",
      "basis": "Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all of these detailed items; Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this work — Case-specific adaptation for Funding and independence. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Disclose funding, product supply and analysis/publication roles in subsequent trials, and verify independent replication separately."
    },
    {
      "item_id": "N38",
      "question_type": "Official oral-product information",
      "question": "Has transfer of the S16 product/route cautions to actual trial risks been avoided?",
      "needed": "Exact trial-product information, GI/hypersensitivity events by period, collection/denominators and route information",
      "role": "Supplementary; required for safety claims",
      "role_reason": "Because official cautions for a different product and era differ from events/frequencies observed in the trial.",
      "application_exception": "Flamingo 100 mg product information does not describe the actual Tyvera batch. Do not convert the predominantly parenteral hypersensitivity context into oral incidence.",
      "criterion": "Record the information level of official oral gastrointestinal/hypersensitivity cautions and the limits of applicability by product and route.",
      "basis": "M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are self-designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no formal causality tool is applied; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are self-designed — Case-specific adaptation for Official oral-product information. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Systematically collect harms for the exact product/route and report official cautions separately from trial observations."
    },
    {
      "item_id": "N39",
      "question_type": "UL and medication context",
      "question": "Has use of an unestablished UL and medication cautions as unlimited safety/efficacy been avoided?",
      "needed": "Updates to official source information, exact concomitant medications/exposure and safety data by baseline risk",
      "role": "Supplementary (general safety interpretation)",
      "role_reason": "Because an unestablished upper limit and general medication context do not guarantee safety testing or benefit for the exact high-risk regimen.",
      "application_exception": "Descriptions concerning furosemide and fluorouracil are not trial efficacy findings or self-dosing instructions. Do not infer from general information that all interactions have been excluded.",
      "criterion": "Separate the UL/medication context in general thiamine information from the unverified exact population and regimen.",
      "basis": "M19 §19.1.2–19.2.4; own application; Design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is self-designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no formal causality tool is applied — Case-specific adaptation for UL and medication context. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Design a safety study that records exact concomitant treatments and exposure, and separately compare the applicability of general information."
    },
    {
      "item_id": "N40",
      "question_type": "Harms and discontinuations by period",
      "question": "Can event/person counts and discontinuation denominators be established for each crossover period?",
      "needed": "Exposure denominators, event/person counts such as GI/hypersensitivity events, discontinuations/serious events and collection/loss tables for each treatment period",
      "role": "Supplementary; required for safety claims",
      "role_reason": "Because the number of trial completers differs from harm collection/event frequency.",
      "application_exception": "Do not convert efficacy grade D, the 34 completers or the existence of general product information into 0 events, 0 discontinuations or NNH.",
      "criterion": "Link exposure by period, event/person counts, severity/reasons for discontinuation and collection/missingness.",
      "basis": "M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are self-designed; M19 §19.1.2–19.2.4, M04 §4.6.3; own application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are self-designed — Case-specific adaptation for Harms and discontinuations by period. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Systematically collect prespecified harms while distinguishing exposure by crossover period, recurrent events/person counts and reasons for discontinuation."
    },
    {
      "item_id": "N41",
      "question_type": "Long-term and subgroup extensions",
      "question": "Can 8-week RI be extended to long-term persistence, optimal doses or special populations?",
      "needed": "Post-discontinuation/long-term RI, direct dose comparisons, interactions with baseline status/special populations and long-term safety",
      "role": "Supplementary; required for the relevant extension",
      "role_reason": "Needed to avoid transferring the narrow short-term functional result to long-term efficacy/safety, special populations or dose optimization.",
      "application_exception": "Do not mechanically require every long-term/event/subgroup trial for the 8-week RI observation; extension questions require separate evidence.",
      "criterion": "Indicate separately the defined original duration and gaps in direct estimates/safety for extensions.",
      "basis": "M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed; M03 §3.2.4; own boundaries on extrapolation; M19 §19.1.2–19.2.4; own application — Case-specific adaptation for Long-term and subgroup extensions. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "Plan long-term, dose and subgroup questions as separate prespecified comparative/follow-up studies and distinguish them from the current result."
    },
    {
      "item_id": "N42",
      "question_type": "Historical search and update scope",
      "question": "Has use of the 42 web searches and 3 failed attempts as current comprehensive verification been avoided?",
      "needed": "Records of the historical search/access scope and verification of unpublished materials/candidates and correction/retraction/publication status",
      "role": "Required (scope limitation)",
      "role_reason": "Needed to avoid exaggerating the historical limited search and current conversion of retained content into a table as an up-to-date exhaustive search or guarantee of absence.",
      "application_exception": "The 42 are historical search records, not new searches or a study count. The 3 failed native searches are not API/network actions in this work either.",
      "criterion": "Specify the evidence cutoff, actual review date, historical search/access limitations and scope of correction/retraction updates.",
      "basis": "M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and own design; Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed — Case-specific adaptation for Historical search and update scope. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "In an explicitly permitted subsequent update, record search sources, queries, inaccessible/negative materials and corrections/retractions by date."
    },
    {
      "item_id": "N43",
      "question_type": "Original verdict and preparation status",
      "question": "Have D/28, the original axes and self-review been distinguished from a new table verdict or clinical certification?",
      "needed": "Current original verdict/axes, grading reasons, self-review/technical-publication history and canonical identity",
      "role": "Required (preservation traceability)",
      "role_reason": "Because the original verdict/score, document quality and completion of the current table are different statuses.",
      "application_exception": "R1 does not mean a confirmatory trial was conducted; I1 does not mean mixed funding was verified, E0 does not mean an exactly null effect, and CX does not mean important benefit was excluded. Document grade A is not external certification either.",
      "criterion": "Record the original D/28, Caution, historical handling/limitations of the axes, canonical URL and current local preparation scope.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed; M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and own design; Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all of these detailed items — Case-specific adaptation for Original verdict and preparation status. This is not formal implementation or certification of the methods.",
      "condition_origin": "Development criteria individually designed with knowledge of the currently retained 3122 content. Neither blinded nor preregistered.",
      "proposed_research": "If an update of evidence/rules is requested, preserve the complete before-and-after original versions and version/decision reasons as a separate event, and update only the table's linked criteria within that scope."
    }
  ]
}