{
  "title": "Biotin (vitamin B7), sole-active oral product × Reduction of recurrent brittle-nail breakage events over a standardized observation period",
  "criteria_version": "NGM-v3104-BIOTIN-RECURRENT-NAIL-BREAKAGE-1.2",
  "criteria_date": "2026-10-05",
  "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 document the question, eligibility conditions, and reasons for changes, and distinguish variations in interventions.",
      "review_level": "Reuse of original bytes, SHA, and historical methodological principles preserved in 1585. This does not represent new reading of the full methodological texts, application of official methods, or certification in this review."
    },
    {
      "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 studies solely because outcomes were unreported.",
      "review_level": "Reuse of original bytes, SHA, and historical methodological principles preserved in 1585. This does not represent new reading of the full methodological texts, application of official methods, or certification in this review."
    },
    {
      "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": "Fix the outcome and effect of interest when reviewing randomization, deviations, missing data, measurement, and selective reporting.",
      "review_level": "Reuse of original bytes, SHA, and historical methodological principles preserved in 1585. This does not represent new reading of the full methodological texts, application of official methods, or certification in this review."
    },
    {
      "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": "Reuse of original bytes, SHA, and historical methodological principles preserved in 1585. This does not represent new reading of the full methodological texts, application of official methods, or certification in this review."
    },
    {
      "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": "Harm questions may require different designs, populations, and follow-up from efficacy questions. Case reports do not establish incidence.",
      "review_level": "Reuse of original bytes, SHA, and historical methodological principles preserved in 1585. This does not represent new reading of the full methodological texts, application of official methods, or certification in this review."
    }
  ],
  "status_dictionary": {
    "Met": "The question identity/record conditions were verified within the currently preserved scope. This does not establish clinical efficacy.",
    "Partly verified": "Some information is available, while gaps in direct conditions/material remain.",
    "Unverified": "The actual material and values needed for the selected condition could not be verified within the current scope.",
    "Not met": "The verified ingredient, endpoint, or comparison does not meet the selected direct conditions. This is not a verdict of no effect.",
    "Conflicting information": "A wording inconsistency preserved within the same report. This is distinguished from differences between analyses or current independent verification of the original full text.",
    "Not read": "The external material was not actually read in this review."
  },
  "schema_version": "chamgap-public-criteria-1.0",
  "condition_origin": "Chamgap’s own application conditions",
  "requirements": [
    {
      "item_id": "N01",
      "question_type": "Independent question boundary",
      "question": "Does this table address a single question about recurrent breakage events per person with oral biotin alone?",
      "needed": "Exact original wording of the current claim, population, ingredient, route, comparator, and recurrent-event endpoint",
      "role": "Required",
      "role_reason": "Needed to avoid combining improved thickness or hardness and reduced breakage counts as the same efficacy outcome.",
      "application_exception": "Fingernails and toenails remain separate strata. The fact that direct results are currently unverified does not by itself justify creating a new, separate completed table for each stratum.",
      "criterion": "Link the same question as in the original /ko/effect and specify event counts per person over a prespecified period and the excluded endpoints.",
      "basis": "M03 §3.1, §3.2.1–3.2.4 question-clarification principles; detailed separation rules are internally designed; M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.4; internally designed extension boundary",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "In a comparative study with a fixed question, prespecify the event definition and observation period and separate estimates by site."
    },
    {
      "item_id": "N02",
      "question_type": "Sole active ingredient",
      "question": "Is biotin the only additional active ingredient in the actual study product?",
      "needed": "Original text on product composition, active ingredients, background treatment, and batch by arm",
      "role": "Required",
      "role_reason": "Needed to avoid attributing the effects of other active ingredients in a biotin-labeled product to biotin alone.",
      "application_exception": "If both arms receive the same background topical product, retain the comparison as a candidate for the add-on effect of biotin. Do not recast a plant extract itself as pure biotin.",
      "criterion": "Indicate the sole-active question and the differences between actual products with a sole active ingredient, combinations, and a common background treatment.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Design a comparison that keeps active ingredients other than biotin and background care identical, and disclose product composition."
    },
    {
      "item_id": "N03",
      "question_type": "Formulation identity",
      "question": "Was an eligible sole-active product used whose chemical form, source, tablet/capsule form, excipients, and batch were verified?",
      "needed": "Chemical form, manufacturing source, dosage form, excipients, and batch/purity records for the eligible product",
      "role": "Required",
      "role_reason": "Needed to avoid concealing an unverified product identity behind an assumption that the biotin formulations are identical.",
      "application_exception": "The word biotin in a bibliographic title does not establish the exact chemical form or purity. Do not invent an unknown brand to fill the gap.",
      "criterion": "Link only verified product identity information and preserve the null values in actual_trial_fields.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Obtain quantitative content, purity, and dosage-form data for the same batch in a comparative study, and track differences other than the active ingredient."
    },
    {
      "item_id": "N04",
      "question_type": "Dose and total exposure",
      "question": "Were the original dose and the actual dosing frequency, dietary intake, and concurrent supplements contributing to total exposure distinguished?",
      "needed": "Dose, dosing frequency, administration records, dietary/concurrent supplement intake, and actual exposure",
      "role": "Required",
      "role_reason": "Needed to avoid recasting a nominal dose from another regimen as an effective dose for reducing breakage frequency.",
      "application_exception": "Preserve the original studies' 2.5 mg/day and 10 mg/day, but do not perform new conversions, identify an optimal dose, or give individual dosing recommendations.",
      "criterion": "Distinguish each study's originally stated dose from the unverified eligible regimen.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "If dose-specific questions are needed in a direct comparison that collects total exposure and adherence, design them separately in advance."
    },
    {
      "item_id": "N05",
      "question_type": "Treatment and observation periods",
      "question": "Are the treatment duration and the prespecified observation period for counting recurrent breakage each verified?",
      "needed": "Treatment start/end, prespecified event observation window, and follow-up/missingness records at each time point",
      "role": "Required",
      "role_reason": "Needed to prevent the number of treatment months from being used as event observation time.",
      "application_exception": "Preserve study treatment durations, but do not assume that events were captured completely during those periods.",
      "criterion": "Link treatment duration, event observation period, and exposure time as separate items.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Set the same observation window for both arms and collect individual observation time and discontinuation/missingness data to distinguish event counts from event rates."
    },
    {
      "item_id": "N06",
      "question_type": "Brittle-nail population",
      "question": "Do the actual diagnoses and severity in the materials match adults with general brittle nails?",
      "needed": "Age, diagnosis/severity, inclusion/exclusion, secondary causes, and the composition of mixed populations",
      "role": "Required",
      "role_reason": "Needed to avoid pooling other secondary disease, trauma, or drug-related causes with general brittle nails.",
      "application_exception": "Retain mixed populations as well, but leave direct applicability unverified when population composition or separate results are unavailable.",
      "criterion": "Distinguish the question's scope of general adults, how the actual population matches it, and exclusions that could not be verified.",
      "basis": "M03 §3.2.1; detailed population conditions are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Report selection flow and baseline characteristics by site in a population whose secondary causes and severity have been verified."
    },
    {
      "item_id": "N07",
      "question_type": "Baseline biotin status",
      "question": "Are baseline biotin testing and the method used to determine deficiency verified?",
      "needed": "Baseline testing, deficiency definition, diet, concurrent supplements, and whether confirmed deficiency was corrected",
      "role": "Required",
      "role_reason": "Needed to avoid treating an unreported status as normal or nondeficient.",
      "application_exception": "Separate confirmed deficiency correction from this general brittle-nail question. Retain applicability limitations without deleting all data from participants whose status was not measured.",
      "criterion": "Distinguish actually measured status from unreported status, and do not invent an arbitrary criterion for normality.",
      "basis": "M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Record the assay method and classification criteria and analyze the deficiency-correction stratum separately, without making arbitrary subgroup efficacy determinations."
    },
    {
      "item_id": "N08",
      "question_type": "Fingernail and toenail strata",
      "question": "Are the actual observed sites, numbers observed, and direct recurrent breakage-event results verified separately for fingernails and toenails?",
      "needed": "Fingernails/toenails, target sites, numbers observed, and site-specific results and denominators",
      "role": "Required",
      "role_reason": "Needed to avoid transferring great-toenail severity results to fingernail breakage frequency.",
      "application_exception": "Retain null values when direct results by site are unavailable, and do not mechanically produce two completed tables.",
      "criterion": "Check the extent of verification of actual observed sites, numbers of nails, and site-specific recurrent-event results and denominators. Distinguish materials in which only great-toenail severity was verified from the gap in direct event results by site.",
      "basis": "M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Prespecify event definitions and measurements by site, and plan appropriate stratified comparisons and interaction analyses."
    },
    {
      "item_id": "N09",
      "question_type": "Breakage-event definition",
      "question": "Were the breakage-event definition, collection method, and recurrent-event recording fixed in advance?",
      "needed": "Event identification, distinction between recurrent/new events, recording intervals, validation, and assessor blinding",
      "role": "Required",
      "role_reason": "Needed to avoid converting splitting presence or severity scores into event counts.",
      "application_exception": "Subjective event reports may also be retained, but their actual definitions and measurement limitations must be disclosed. Do not impose blinding unconditionally.",
      "criterion": "Clearly distinguish recurrent breakage events per person from severity and responder measures.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Use identical event definitions and diary/validation procedures, and manage recurrent-event recording, duplicate entries, and missing measurements."
    },
    {
      "item_id": "N10",
      "question_type": "Person, nail, and event denominators",
      "question": "Were the numbers of people allocated and analyzed, the number of nails observed, and recurrent-event counts distinguished?",
      "needed": "Arm-specific counts of people allocated/analyzed/completing follow-up, nails, and events, and observation time",
      "role": "Required",
      "role_reason": "Needed to avoid converting the number of evaluable people into a denominator for observed nails, events, or event rates.",
      "application_exception": "Preserve the denominators in case materials and abstracts, but do not calculate unavailable event counts, exposure time, or CIs.",
      "criterion": "Use only the denominator types supplied by the current input and preserve eligible-event denominators as null.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Record clustering and recurrence structures for people and nails, and prespecify an analysis denominator suited to the effect of interest."
    },
    {
      "item_id": "N11",
      "question_type": "Actual comparator and direction",
      "question": "Are within-group before–after comparisons and the direction of the actual comparison for added biotin distinguished?",
      "needed": "Design, actual added ingredients by arm, comparator, and direction of between-group/within-group estimation",
      "role": "Required",
      "role_reason": "Needed to avoid presenting before–after improvement as a between-group causal effect.",
      "application_exception": "Retain add-on comparisons with common topical care, while specifying the effect of interest and the differing endpoint.",
      "criterion": "Record within-group before–after comparisons, conditional add-on comparisons, and independent controls separately; do not present a planned comparison as an actual comparison.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Prespecify the effect of assignment and the direction of analysis in a comparison that maintains identical background care."
    },
    {
      "item_id": "N12",
      "question_type": "Colombo surrogate endpoints",
      "question": "Do Colombo's thickness and surface data provide controlled recurrent breakage-event results for biotin alone?",
      "needed": "Colombo's actual design, surface/thickness measurements, treatment comparator, and event records",
      "role": "Required",
      "role_reason": "Needed to distinguish structural and thickness changes from recurrent breakage events.",
      "application_exception": "Even if healthy comparators are present, verify whether they constitute the same treatment-assignment control. Do not label an older study as a newly read full text.",
      "criterion": "Check whether the actual ingredient, treatment comparator, and endpoint meet the direct recurrent-event conditions, and preserve the original thickness and surface results.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.1–8.2.3; internal application; M03 §3.2.4; internally designed extension boundary",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "In a comparison that collects both thickness and recurrent events, estimate endpoint-specific results and their relationship separately."
    },
    {
      "item_id": "N13",
      "question_type": "Hochman response evaluation",
      "question": "Does Hochman's response evaluation provide controlled recurrent breakage-event results over a prespecified period?",
      "needed": "Original response criteria, participant selection, recall period, comparator, and recurrent-event records",
      "role": "Required",
      "role_reason": "Needed to avoid elevating reports of improved hardness or splitting to prospectively specified event records.",
      "application_exception": "Retain retrospective uncontrolled data as signals and descriptive material, and do not fill in absent time denominators for events.",
      "criterion": "Compare response criteria, comparator, and observation period with the selected recurrent-event conditions, and preserve mismatched endpoints in their original role.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Use the same prospectively specified event definition and observation period, and plan the comparator and handling of missing data."
    },
    {
      "item_id": "N14",
      "question_type": "Floersheim person denominators",
      "question": "In the report of 71 people treated, 45 evaluated, and 41 reporting improved hardness, are the reasons for exclusion from evaluation and the analysis denominators for recurrent breakage events verified?",
      "needed": "Original data on treated/evaluated/responder denominators, reasons for exclusion, event counts, and comparator",
      "role": "Required",
      "role_reason": "Needed to avoid expressing 41 people as a reduction in recurrent-event counts or generalizing a proportion among evaluated people to an effect among everyone treated.",
      "application_exception": "Retain the person counts in the abstract, but do not infer reasons for exclusion from evaluation or calculate between-group effects or event rates.",
      "criterion": "Attribute 71, 45, and 41 to their original-text roles as treated, evaluated, and hardness responders, and assess the extent to which reasons for exclusion from evaluation, numbers of nails observed, recurrent-event denominators, and the comparator are verified by actual data. Do not convert person counts into event counts.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Report follow-up and reasons for exclusion from evaluation for all allocated participants, and prespecify the recurrent-event analysis population."
    },
    {
      "item_id": "N15",
      "question_type": "Floersheim duration and dispersion",
      "question": "For the report of 2.5 mg/day and a mean of 5.5 ± 2.3 months, are actual exposure records, the definition of ±, and the prespecified breakage observation period verified?",
      "needed": "Original dose and duration, definition of ±, observation window, and administration records",
      "role": "Required",
      "role_reason": "Needed to avoid interpreting the ± accompanying variable treatment duration as an SD/SE/CI or a standardized event observation window.",
      "application_exception": "If the type of ± is not verified in the abstract, retain it as unverified. Do not indicate that the original German full text was read.",
      "criterion": "Preserve the original dose and mean treatment duration while checking the extent of verification of the type of ±, actual administration records, and the prespecified breakage observation period. Do not assume that the treatment duration's ± is an SD, SE, CI, or standardized event observation window.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Specify treatment duration and the event observation window separately, and report actual exposure records and an explanation of dispersion."
    },
    {
      "item_id": "N16",
      "question_type": "Chiavetta add-on design",
      "question": "Are the allocation, treatment/assessor blinding, and recurrent-event measurement conditions in the comparison of biotin added to the same lacquer actually verified?",
      "needed": "Lacquer and biotin composition by arm, allocation, treatment/assessor blinding, and target site",
      "role": "Required",
      "role_reason": "Needed to distinguish the effect of common topical care, the add-on effect of biotin, and measurement blinding.",
      "application_exception": "Preserve the fact that assessment was assessor-blinded even with open treatment. Adapt the common background treatment to the sole-active add-on condition while retaining the endpoint mismatch.",
      "criterion": "Preserve the actual randomized add-on design with open treatment and blinded assessors, and check the extent of verification of allocation concealment, actual adherence, recurrent-event collection, and blinding of event measurement. Do not confirm that event-comparison conditions are met solely from a great-toenail severity assessment.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M08 §8.1–8.2.3; internal application; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 Table 8.2.a, M03 §3.2.4; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Use the same background care and products, and document allocation, measurement and rescue treatment in line with the effect of interest."
    },
    {
      "item_id": "N17",
      "question_type": "Chiavetta arm denominators",
      "question": "For the 24 participants in the add-on group and 26 in the lacquer group, are the actual denominators for allocation, completion, endpoint-specific analysis and recurrent events verified?",
      "needed": "Arm-specific denominators for allocation, measurement, completion and endpoint analysis, and handling of withdrawals/missing data",
      "role": "Required",
      "role_reason": "Required to avoid automatically reusing the number of people in a group as the event count or as the denominator for every endpoint analysis.",
      "application_exception": "Preserve the 24/26 retained in the source, but do not back-calculate integer responder counts from the proportions.",
      "criterion": "Compare the reported 24 and 26 participants with the scope of actual verification of arm-specific denominators for completion, endpoint analysis, recurrent events and observation time. Do not reuse participant counts as event counts or as denominators for every endpoint analysis.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Report the arm-specific flow of people, nails, events and missing data, and separately plan for the effect of assignment and the effect among completers."
    },
    {
      "item_id": "N18",
      "question_type": "Positive severity result",
      "question": "Is Chiavetta's severity reduction of 1.4 versus 0.9 points with P=0.03 a direct recurrent breakage-event result?",
      "needed": "Original severity scale, change/analysis, score difference, CI and separate event results",
      "role": "Required",
      "role_reason": "Required to preserve the positive result without turning it into a reduction in the number of breakages.",
      "application_exception": "Preserve the nominal between-group P value, but do not calculate a CI, a new difference, an effect size or clinical importance.",
      "criterion": "Compare the original severity definition behind the positive figures with the conditions for direct recurrent events, and preserve the original values.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M15 §15.3.1–15.3.3; internal application; M03 §3.2.4; internally defined extension boundary",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "If severity and recurrent events are collected together, distinguish each endpoint in advance and report a separate estimate and interval for each."
    },
    {
      "item_id": "N19",
      "question_type": "OGSS response criteria",
      "question": "Do the different OGSS responder proportions meet the conditions for direct recurrent breakage events?",
      "needed": "Each threshold, responder denominator, analysis, time point, multiple-comparison plan and interval",
      "role": "Required",
      "role_reason": "Required to avoid conflating proportions of people who improved and their thresholds with recurrent events or equivalence.",
      "application_exception": "Improvement of at least 50% and of at least 1 point are different definitions. Do not interpret a nonsignificant finding as equivalence or an effect of 0.",
      "criterion": "Preserve 80%/53% with P=.05 and 91%/73% with P=.2 under their respective original criteria, and assess whether they match the conditions for direct recurrent events.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Prespecify the original response criteria and multiple-comparison plan, and analyze recurrent events as a separate endpoint."
    },
    {
      "item_id": "N20",
      "question_type": "Shemer access and results",
      "question": "Has Shemer's retrospective comparison been documented with the current scope of reading and with direct event results remaining unverified?",
      "needed": "Product, dose, arm denominators, event collection and analysis in the original full text, and actual scope of access",
      "role": "Required",
      "role_reason": "Required to avoid promoting indexed response categories to verified breakage events or full-text results.",
      "application_exception": "The historical journal 403 and empty PubMed response are not new access failures in the current review, nor do they mean study absence or negative results.",
      "criterion": "Link the indexed retrospective response categories with the fact that direct event results remain unverified.",
      "basis": "M04 §4.5–4.6 principles for data collection/selection; separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.1–8.2.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "If the full text is obtained, examine the actual comparison, ingredients and event definition, and assess limitations from retrospective selection/recall."
    },
    {
      "item_id": "N21",
      "question_type": "Patel product boundary",
      "question": "Does Patel's Sesbania extract isolate the effect of biotin alone on recurrent breakage events?",
      "needed": "Complete product composition, active ingredients, biotin content and additional ingredients in each arm",
      "role": "Required",
      "role_reason": "Required to avoid wrongly attributing contributions from the extract's other ingredients to biotin alone.",
      "application_exception": "A product described as biotin is different from isolated biotin. Do not import specific product amounts or doses from an adjacent manuscript when those values are absent from the current inputs.",
      "criterion": "Compare the actual product ingredients and endpoints with the conditions for biotin alone and recurrent events, and use only a contribution that can be isolated as a direct effect.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Directly estimate the ingredient's contribution through a comparison that distinguishes biotin as the sole active ingredient from a control with the same background care."
    },
    {
      "item_id": "N22",
      "question_type": "Patel endpoint hierarchy conflict",
      "question": "Does the primary/secondary endpoint hierarchy for Patel's nail PGA agree across Methods, Results and the registry?",
      "needed": "Original Methods/Results, registry/protocol/SAP, explanation of hierarchy changes and corrections",
      "role": "Required",
      "role_reason": "Required to avoid converting severity PGA to event frequency or arbitrarily correcting the hierarchy conflict in the source text.",
      "application_exception": "Preserve the discrepancy in the hierarchy of the same endpoint between Methods/Results, but do not conclude that selective reporting is established. Do not mark the original PDF containing the conflict as having been read on this occasion.",
      "criterion": "Compare the PGA 0–5 definition and agreement/disagreement in the Methods/Results primary/secondary hierarchy, and distinguish registry/SAP material that has not been obtained from corrections.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Prespecify measurement, endpoint hierarchy and analysis order, and disclose the reasons for changes if the registry and source text disagree."
    },
    {
      "item_id": "N23",
      "question_type": "Patel analysis population",
      "question": "Were the statement \"withdrawals excluded\" and the actual denominators for allocation, completion and analysis distinguished?",
      "needed": "Participant flow by arm, reasons for withdrawal, analysis population and PGA analysis denominators",
      "role": "Required",
      "role_reason": "Required to avoid supplementing the statement that withdrawals were excluded with an assumed ITT analysis or arbitrary completer counts.",
      "application_exception": "Do not import allocation or completion counts from other manuscripts that are absent from the current inputs. Verify allocation, completion and endpoint analysis separately.",
      "criterion": "Distinguish the actual statement \"withdrawals excluded\" from unverified denominators and the scope of handling.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Report the flow through allocation, measurement, withdrawal and analysis for each endpoint, and prespecify a plan for sensitivity analyses of missing data."
    },
    {
      "item_id": "N24",
      "question_type": "Patel paper and registry family",
      "question": "For S05 and NCT05972512 in the same F06 family, is material verified that permits comparison of the actual registered endpoint hierarchy, change history and SAP with the paper?",
      "needed": "Same-trial identifiers, registry history, protocol, SAP and comparison with the paper's results",
      "role": "Required",
      "role_reason": "Required to avoid counting the paper and registry record as two independent replication trials.",
      "application_exception": "The fact that NCT/CTRI identifiers are reported in the paper is distinct from verification of the actual registry history, timing and plan.",
      "criterion": "Preserve the same-family relationship between S05 and S31, and compare the identifiers reported in the paper with the scope of the registry plan, change history and SAP actually obtained. Do not promote a registry shell to verification of the full plan.",
      "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5, §4.6.3; constraints on the current data conversion reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "After linking trial identities, compare the original plan with actual endpoints, time points and analyses, and document the reasons for changes."
    },
    {
      "item_id": "N25",
      "question_type": "Collagen event data",
      "question": "Do Hexsel's before-and-after collagen data provide controlled effects of biotin alone on recurrent breakage events?",
      "needed": "Original text on the actual active substance, control, breakage collection and before-and-after versus between-group analyses",
      "role": "Required",
      "role_reason": "Required to avoid importing the effect of a different molecule merely because the endpoint wording is similar.",
      "application_exception": "Event measurements in studies of other molecules can be retained as pointers for future design, but are not evidence of biotin's effects.",
      "criterion": "Compare the actual substance, contrast and endpoint with the controlled event conditions for biotin alone, and retain measurement data from another molecule in a separate role.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Even when using methods for collecting breakage frequency as a reference, separately design the control comparison for biotin alone and fix the substance identity."
    },
    {
      "item_id": "N26",
      "question_type": "NCT05800496 identity",
      "question": "Have the PGA wording in the registry shell and the unverified composition and event results been distinguished?",
      "needed": "Original registry text, composition, actual population/endpoints, status, results and change history",
      "role": "Required",
      "role_reason": "Required to avoid overstating the existence of a registry number as acquisition of eligible-product information and trial results.",
      "application_exception": "Do not turn historical API access failure into a current retrieval failure, negative results, termination or 0 participants.",
      "criterion": "Separate shell/indexed PGA clues from unverified event results.",
      "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for data collection/selection; separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.5, §4.6.3; constraints on the current data conversion reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "If the registry and protocol are obtained, first compare the substance, endpoint, observation window and result identities, then reassess eligibility."
    },
    {
      "item_id": "N27",
      "question_type": "NCT07373574 identity",
      "question": "Did the review avoid inferring timing, composition or results from the registry number and title?",
      "needed": "Actual registry text, initiation/changes, composition, endpoints, results and identifiers",
      "role": "Required",
      "role_reason": "Required to avoid inventing current trial status or breakage results from search clues.",
      "application_exception": "Do not infer dates, recruitment or completion status from the order of registry numbers. A nail/hair title is not a direct event definition.",
      "criterion": "Distinguish the currently verified shell/indexed metadata from what remains unverified by source location.",
      "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for data collection/selection; separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; constraints on the current data conversion reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "After obtaining the formal original registry text, assess agreement in timing, intervention, population and endpoints, and preserve the change history."
    },
    {
      "item_id": "N28",
      "question_type": "Role of reviews",
      "question": "Have the discovery and diagnostic context provided by reviews been distinguished from unique direct trials?",
      "needed": "Review full text, included references, search cutoff date, diagnostic context and links to original trials",
      "role": "Required",
      "role_reason": "Required to avoid using a review as evidence of a new randomized replication trial or an up-to-date exhaustive search.",
      "application_exception": "Preserve older reviews and indexed metadata while distinguishing included trials, citation context and the actual reading scope.",
      "criterion": "Attribute the roles and access levels of Lipner/Scher, Chessa and Zaraa/Richert to their respective materials.",
      "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for data collection/selection; separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.1; detailed population conditions are internally designed; M04 §4.5, §4.6.3; constraints on the current data conversion reflect the user-defined scope and internal design",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Link the original trial families of the included references, examine direct-event eligibility individually and do not substitute an average from a review."
    },
    {
      "item_id": "N29",
      "question_type": "Overlap among families and prior verdicts",
      "question": "Has overlap among same-family reports, repeated citations and previous broad nail verdicts been managed?",
      "needed": "Report-to-trial families, the same results/time points, boundaries of earlier verdicts and actual overlap identities",
      "role": "Required",
      "role_reason": "Required to avoid importing report counts and past grades as independent evidence for the new question.",
      "application_exception": "F01–F09 are structural family IDs in the current source. Without a separate family table verifying actual overlap, do not establish the final count of unique trials.",
      "criterion": "Preserve the current evidence families and the S05/S31 link; do not revise or carry forward the different endpoints or original grade of 866.",
      "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Link papers, registry records and reviews at the trial level, verify overlap in the original participants and results, then describe independent comparisons."
    },
    {
      "item_id": "N30",
      "question_type": "Allocation and measurement limitations",
      "question": "Have allocation and treatment/assessment blinding been reviewed in relation to the actual endpoint concerned?",
      "needed": "Allocation/concealment, baseline characteristics, event measurement by arm and assessor blinding/verification",
      "role": "Required",
      "role_reason": "Required to avoid claiming that recurrent-event measurement/confounding issues are resolved solely from RCT and blinding labels.",
      "application_exception": "Do not treat inability to blind as automatic failure. Open treatment and blinded assessors can coexist within the same material.",
      "criterion": "Separate the actual severity-assessment design from the unverified measurement of eligible recurrent events.",
      "basis": "M08 §8.1–8.2.3; internal application; M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Document allocation, baseline and measurement procedures, and apply the same event collection and assessment verification in both groups."
    },
    {
      "item_id": "N31",
      "question_type": "Background care, adherence and rescue care",
      "question": "Are shared care, concurrent exposure, adherence and rescue treatment actually verified for each arm?",
      "needed": "Nail care, concurrent products, actual adherence, changes, rescue care and handling in analysis by arm",
      "role": "Required",
      "role_reason": "Required to avoid attributing differences in concurrent care or adherence to biotin itself.",
      "application_exception": "Do not require all changes in both groups to be identical. Distinguish the actual effect of assignment/effect of adherence and the scope of handling.",
      "criterion": "Document use of the same lacquer separately from unverified concomitant treatment and adherence in the actual eligible event comparison.",
      "basis": "M03 §3.2.2–3.2.3; reverse-direction marking and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Prospectively collect data on care, concurrent supplementation, rescue treatment and adherence, and handle them using an analysis aligned with the effect of interest."
    },
    {
      "item_id": "N32",
      "question_type": "Attrition and estimation",
      "question": "Are missing data, completer analysis and clustered/recurrent structures linked to the actual effect of interest?",
      "needed": "Endpoint-specific analysis populations, reasons for missing data/withdrawal, within-participant correlations, adjustment and model/SAP",
      "role": "Required",
      "role_reason": "Required to avoid producing precision estimates that ignore correlations involving people, nails and recurrent events, or selective evaluation.",
      "application_exception": "Preserve the limitations of Floersheim's evaluable participants and Patel's exclusion of withdrawals. Do not fill unreported analyses with ITT, PP or complete follow-up.",
      "criterion": "Distinguish the currently described scope of withdrawal/evaluation from gaps in eligible direct event analysis.",
      "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Prespecify the flow of allocation, completion and analysis and within-person recurrent-event/nail correlations, and plan sensitivity analyses for missing data."
    },
    {
      "item_id": "N33",
      "question_type": "Effect, interval and importance",
      "question": "Have the direct between-group breakage-event effect, CI and important difference been reported?",
      "needed": "Direct between-group event-count estimate, units, denominators, CI, variance and a justified important difference",
      "role": "Required",
      "role_reason": "Required to avoid substituting trial count, sample size or nominal P values for the precision or importance of the direct effect.",
      "application_exception": "If the clinically important difference remains undetermined, retain that status. Do not create a common minimum sample, duration or number of studies, even as proposed numbers.",
      "criterion": "Distinguish null values for the direct effect, CI, P and MCID from nominal P values for other endpoints.",
      "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M15 §15.3.1–15.3.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Plan precision in line with the event distribution, recurrent structure and justified important difference, and report the actual intervals."
    },
    {
      "item_id": "N34",
      "question_type": "Scope of planning and selective reporting",
      "question": "Can prespecified event endpoints, time points and analyses be compared with actual reporting?",
      "needed": "Protocol, registry history, SAP, corrections, actual event results and reasons for changes",
      "role": "Required",
      "role_reason": "Required to avoid treating registry material that has not been obtained as confirmation of nonregistration or selective reporting.",
      "application_exception": "Preserve the Patel hierarchy conflict separately. Do not automatically classify unverified plans in other studies as the same conflict.",
      "criterion": "Distinguish the scope in which plans and reports have been compared from the event questions for which they have not yet been compared.",
      "basis": "M04 §4.5, §4.6.3; limits on the current material conversion follow the user's scope and are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Preregister the event definition, window, effect of interest, and multiple comparisons, and report the reasons for changes and all planned outcomes."
    },
    {
      "item_id": "N35",
      "question_type": "Funding, companies, and independence",
      "question": "Are product provision, funding, and authors' competing interests verified through the actual disclosure wording?",
      "needed": "Actual wording on disclosed COI, research funding, product provision, author employment/patents, and institutions/study families",
      "role": "Required",
      "role_reason": "Needed to prevent historical identification of a COI location or a referenced filename from being treated as proof of independent funding or independent replication.",
      "application_exception": "Do not automatically exclude a study because of corporate relationships, or judge it independent or free from bias because disclosure wording is absent. Do not infer company names or employment facts absent from the current material.",
      "criterion": "Distinguish the clues to original COI locations in the current 3104 record from the unverified funding details.",
      "basis": "Chamgap's own independence and attribution conditions. The official method sections used in this demonstration do not validate all of these detailed items; the distinction between studies and reports in M04 §4.6.1–4.6.2; linking cohorts/outcomes is an internal application",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Disclose product provision, funding sources, analysts' roles, and declarations, and actually verify whether replications share funding/study families."
    },
    {
      "item_id": "N36",
      "question_type": "Adverse events by arm",
      "question": "Are the actual adverse events, discontinuations, and data-collection denominators for this use verified?",
      "needed": "Adverse-event definitions, collection methods, exposure/events by arm, discontinuations, and loss to follow-up",
      "role": "Supplementary; required for harm claims",
      "role_reason": "Needed to prevent safety from being regarded as verified merely because efficacy data exist or harms are unreported.",
      "application_exception": "Separate recurrent breakage events used to assess efficacy from adverse events. Do not remove other prior efficacy outcomes because harms were unreported.",
      "criterion": "Separate the verified safety context from the unverified harms by arm for this use.",
      "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Plan systematic adverse-event collection, discontinuation assessment, and follow-up for the same exposure/population, and report denominators and duration by arm."
    },
    {
      "item_id": "N37",
      "question_type": "Assay-interference signals",
      "question": "Are the actual populations, exposures, timing, and assay-specific scope of applicability of interference with thyroid, NT-proBNP, and troponin tests verified?",
      "needed": "Original assay methods, doses/timing, healthy-participant denominators, collection, official restatements, and limitations",
      "role": "Supplementary; required to explain assay-related harms",
      "role_reason": "Needed to prevent assay-dependent interference from being generalized to an identical risk rate or stopping interval for all tests and people.",
      "application_exception": "Official restatements do not constitute independent case counts. Short-term exposure in healthy people does not answer the question of long-term safety in brittle nails.",
      "criterion": "Preserve the single/repeated doses, timing, populations, and specific assay signals in the historical material, and compare the scope of verified original material with what is needed for applicability by assay, reagent, and population and for general risk estimation. Do not treat inherited summaries as current reverification of external full texts or as universal risk rates.",
      "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; design-specific harm questions in M19 §19.2; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; Chamgap's own interpretation boundaries. M19 principles are referenced; no official causality tool was applied",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Verify the scope of interference through assay-specific validation that records applicability conditions such as the assay platform, exposure/blood-sampling times, and renal function."
    },
    {
      "item_id": "N38",
      "question_type": "Vulnerable groups, intake, and UL",
      "question": "Are there actual exposure, event, and follow-up data to verify long-term safety and safety during pregnancy/lactation, in children, and in liver or kidney disease for this use?",
      "needed": "Actual exposure by population, long-term/rare harms, interactions, and original nutritional standards",
      "role": "Supplementary; required for extended safety claims",
      "role_reason": "Needed to prevent adequate intake and the absence of an established upper limit from being treated as a therapeutic dose or unlimited safety.",
      "application_exception": "Not every rare-harm study is required for the current narrow event-efficacy question, but broader safety remains separately unverified.",
      "criterion": "Assess whether actual exposure, event denominators, and long-term follow-up by population answer the questions underlying extended safety claims. Do not use adequate intake or the absence of an established UL as evidence for a therapeutic dose, an optimal dose, or unlimited safety.",
      "basis": "M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretation boundaries. M19 principles are referenced; no official causality tool was applied; M03 §3.2.1; detailed population conditions are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "Investigate long-term harms and harms in vulnerable groups through actual use and systematic follow-up by population, and separate nutritional standards from treatment questions."
    },
    {
      "item_id": "N39",
      "question_type": "Extensions to dose, persistence, and anatomical site",
      "question": "Is there direct material supporting extensions to optimal dose, persistence after discontinuation, or effects by anatomical site?",
      "needed": "Direct dose comparisons, follow-up after discontinuation/over the long term, anatomical-site strata, and prespecified interactions",
      "role": "Supplementary; required for the relevant extension",
      "role_reason": "Needed to prevent short-term or variable-duration treatment data on other endpoints from being treated as evidence for an optimal regimen or persistent effects.",
      "application_exception": "Do not require every extension study for the narrow assessment target. Retain each as a separate research question and gap.",
      "criterion": "Distinguish the unverified main effect from the separate lack of direct verification for extensions to dose, persistence, or anatomical site.",
      "basis": "M03 §3.2.1–3.2.4; dose, persistence, and effect-modification details are internally designed; M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and assay adaptations are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "When extension questions are actually needed, design separate comparisons with prespecified hypotheses on dose, follow-up after discontinuation, and anatomical site."
    },
    {
      "item_id": "N40",
      "question_type": "Current and historical reading",
      "question": "Has the actual reading of local retained summaries in this review been separated from historical external access, failures, and inherited material?",
      "needed": "Each material's identity, actual material type, URL, existence/public availability/access/acquisition/reading, and original location/date",
      "role": "Required",
      "role_reason": "Needed to prevent bibliographic information, URLs, or historical full-text records from being treated as acquisition or reading of original material in this review.",
      "application_exception": "No attempt at external access is different from failure. If the actual access date is absent from the source, leave it null and separate it from the original review date of 2026-09-15.",
      "criterion": "Mark the preserved retained summaries as read in this review, and separately mark external materials as access not attempted, not acquired, and Not read.",
      "basis": "Material collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the current material conversion follow the user's scope and are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "When original material is actually acquired, record the timing, safe URL, material type, and content location separately, and preserve the historical original text."
    },
    {
      "item_id": "N41",
      "question_type": "Original verdict and scope of absence",
      "question": "Have the original ?/null, B/P, document quality, and the scope of unverified direct evidence been preserved?",
      "needed": "Original verdict/axes, scope of absence, related human material, document quality, and self-review metadata",
      "role": "Required",
      "role_reason": "Needed to prevent bounded stage0 from being treated as an effect of 0, an absence of human studies, or a new score.",
      "application_exception": "human_study_exists=false/no_human_study=true refers to eligible direct results for the fixed question and is compatible with related_human_studies_exist=true.",
      "criterion": "Preserve grade ?, score null, B/P, subsequent axes null, bounded scope, and document quality A unchanged.",
      "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed; M04 §4.5, §4.6.3; limits on the current material conversion follow the user's scope and are internally designed; M03 §3.2.4; internally defined extension boundaries",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "When new direct material is actually received, review an update to the original verdict and a change to the table's condition version as separate events, without automatic rescoring."
    },
    {
      "item_id": "N42",
      "question_type": "Boundaries for updates and follow-up material",
      "question": "To what extent have follow-up material, corrections/retractions, and public release status actually been verified in relation to the original revision policy and the current authoring history?",
      "needed": "Complete pre-change content, material/condition/verdict events, version, original location, and current verification date",
      "role": "Required",
      "role_reason": "Needed to prevent creation of new retained summaries or passage of technical checks from being confused with a current clinical verdict or completed public release.",
      "application_exception": "The historical server_deployed value in the current manuscript does not represent deployment of the new gap table. If conditions change, preserve the entire original text, then freeze the new version before applying it.",
      "criterion": "Link the original revision policy with the current preservation, freezing, and application history, and assess subsequent external evidence, corrections/retractions, and publication status within the scope of material actually verified. The existence of a policy or future triggers does not substitute for verification of follow-up material or completed public release.",
      "basis": "Material collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed; M04 §4.5, §4.6.3; limits on the current material conversion follow the user's scope and are internally designed",
      "condition_origin": "An internally developed condition written individually with knowledge of the currently retained materials. This is not clinical preregistration, blinding, or official methodological certification.",
      "proposed_research": "When follow-up material is received, preserve existing results and historical access records, and review only the relevant rows; handle condition changes separately through freeze→apply."
    }
  ],
  "language": "en",
  "translation_date": "2026-11-03"
}