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Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis · 10.1016/s0140-6736(20)31180-6

Name: Verified Rigor Record — Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis · 10.1016/s0140-6736(20)31180-6
Item: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis · 10.1016/s0140-6736(20)31180-6
Rating: 79
Author: Αlpha¹

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Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · July 6, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

WARN

Warnings to address · Observational Study

Eight dimensions — click a segment for details

Critical

High-priority

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.6.0Source: full text

Not verified in this report

No data or code availability links were detected to verify.

This Αlpha¹ Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The paper is a large observational registry study that clearly states its premise and rationale, and adequately reports biological variables and statistical methods. However, it suffers from critical transparency and rigor gaps: no data availability statement, a proprietary data source with no access mechanism, an unsupported headline claim, no named ethics body for the exemption, incomplete reporting of exact p-values and assumptions checks, and no reference to a reporting guideline. The paper has also been retracted due to concerns about data provenance, which fundamentally undermines its findings.

Three independent rigor reviewers (all AI) were synthesized. A copyedit pass, a citation check, a limited statistics verification (1 test recomputed consistently), and integrity and claim audit components were also incorporated. Study design and statistical analysis dimensions had divergences among reviewers; in each case the evidence weighed toward the more conservative (warn) status. Biological variables and scientific premise were unanimous passes; data code availability was a unanimous fail. The coverage note for statistics indicates only a small subset of tests could be verified; mathematical plausibility cannot be confirmed from aggregated data alone.

9 major claims checked against the paper's own evidence: 2 not fully backed by the presented evidence (unsupported or overstated).

Recomputed 1 test: 1 consistent, 0 inconsistent, 1 via agent-written checks.

7 integrity concerns flagged (1 high).

Rigor

Eight Dimensions4 pass · 3 warn · 1 fail

9 major claims1 unsupported1 overstated7 supported

Prior research is extensively cited, including in-vitro evidence, small uncontrolled studies, and open-label trials, with both strengths and weaknesses acknowledged (e.g., 'small uncontrolled studies', 'inconclusive small randomised trials'). A logical rationale links the premise (widespread use of these drugs without conclusive evidence) to the study objectives. Limitations of prior research are addressed ('Previous evidence was derived from either small anecdotal studies or inconclusive small randomised trials').

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific foundation by reviewing prior inconclusive evidence and identifying the gap in knowledge, leading to a logical rationale for the study.

Evidence

direct quote[Introduction, paragraph 1]

“The use of this class of drugs for COVID-19 is based on a small number of anecdotal experiences that have shown variable responses in uncontrolled observational analyses, and small, open-label, randomised trials that have largely been inconclusive.”

direct quote[Introduction, paragraph 3]

“The purpose of this study was to evaluate the use of chloroquine or hydroxychloroquine alone or in combination with a macrolide for treatment of COVID-19 using a large multinational registry to assess their real-world application.”

direct quote[Research in context, Added value of this study]

“In the absence of reported randomised trials, there is an urgent need to evaluate real-world evidence related to outcomes with the use of hydroxychloroquine or chloroquine (used with or without macrolides) in COVID-19.”

PASSReviewer 2· 90% conf

The study clearly establishes the scientific foundation by citing prior small and inconclusive studies, stating the lack of evidence, and providing a logical rationale for the registry analysis.

Evidence

direct quote[Introduction, paragraph 2]

“However, the use of this class of drugs for COVID-19 is based on a small number of anecdotal experiences that have shown variable responses in uncontrolled observational analyses, and small, open-label, randomised trials that have largely been inconclusive.”

direct quote[Introduction, last paragraph]

direct quote[Research in context, Added value of this study]

PASSReviewer 3· 95% conf

The scientific premise is well established with thorough citation of prior research, a clear rationale linking the premise to study objectives, and acknowledgment of limitations in prior work.

Evidence

direct quote[Summary, Background]

“Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit.”

direct quote[Introduction]

“the use of this class of drugs for COVID-19 is based on a small number of anecdotal experiences that have shown variable responses in uncontrolled observational analyses, and small, open-label, randomised trials that have largely been inconclusive”

paraphrase[Methods, Study design]

“The purpose of the study is to evaluate the use of chloroquine or hydroxychloroquine alone or in combination with a macrolide for COVID-19 using a large multinational registry.”

Inclusion/exclusion criteria are clearly described: patients hospitalized with PCR-confirmed COVID-19, treatment initiated within 48h of diagnosis, exclusion of those on mechanical ventilation at treatment start or receiving remdesivir. The study uses a large registry with propensity score matching and Cox regression to control for confounding. However, randomization_method, randomization_unit, and blinding_levels are not applicable (observational design). Power_analysis (n/a as per observational applicability but could be considered; not reported for the primary analysis). Replicate_distinction, independent_replication, and controls (positive/negative wet-lab controls) are not applicable for this purely clinical observational study. Outlier_handling is not reported. The registry's data acquisition and validation procedures are described in detail, but the role of Surgisphere and the lack of independent data verification are concerns.

Sub-criteria

controlsN/A

power analysisNOT REPORTED

blinding levelsN/A

outlier handlingNOT REPORTED

randomization unitN/A

inclusion exclusionADEQUATE

randomization methodN/A

replicate distinctionN/A

independent replicationNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The study design is observational and inclusion/exclusion criteria are clearly reported, but it lacks a pre-specified power analysis and an explicit outlier handling strategy, leading to a warning.

Evidence

direct quote[Methods, Study design]

“We included all patients hospitalised between Dec 20, 2019, and April 14, 2020, at hospitals participating in the registry and with PCR-confirmed COVID-19 infection, for whom a clinical outcome of either hospital discharge or death during hospitalisation was recorded.”

absence[Methods, Statistical analysis]

No power analysis is reported

direct quote[Methods, Statistical analysis]

“Multiple imputation for missing values was not possible because for disease and drug variables, there were no codes to indicate that data were missing; if the patient's electronic health record did not include information on a clinical characteristic, it was assumed that the characteristic was not present.”

WARNReviewer 2· 85% conf

The study design is an observational registry analysis with clear inclusion/exclusion criteria, but the handling of missing data (assuming missing as absent) is a limitation, and no power analysis or outlier handling is reported.

Evidence

direct quote[Methods, Study design]

direct quote[Methods, Statistical analysis]

absence[Methods]

No power analysis or outlier handling is reported.

WARNReviewer 3· 91% conf

The study design is an observational registry analysis with clearly stated inclusion/exclusion criteria and covariate adjustment, but lacks pre-registration, a priori power analysis, and independent replication, and key details of the data source and validation are reported but raise concerns.

Evidence

direct quote[Methods, Study design]

“Patients who received treatment with these regimens starting more than 48 h after COVID-19 diagnosis were excluded. We also excluded data from patients for whom treatment was initiated while they were on mechanical ventilation or if they were receiving therapy with the antiviral remdesivir.”

absence[Methods, Statistical analysis]

No a priori power analysis is reported

Key biological variables are reported: sex (46.3% women), age (mean 53.8 years), BMI (mean 27.6), and various comorbidities and disease severity measures. Demographics include race/ethnicity and continent. Since both sexes are included, a justification for single sex is not required. Species/strain and housing conditions are not applicable for a human study.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper adequately reports sex, age, weight (BMI), health status, and full demographics for this human study.

Evidence

direct quote[Results, paragraph 1]

“mean age was 53·8 years (SD 17·6), 44 426 (46·3%) were women”

direct quote[Results, paragraph 1]

“mean BMI was 27·6 kg/m² (SD 5·5; 29 510 [30·7%] were obese with BMI ≥30 kg/m²)”

direct quote[Results, paragraph 1]

“64 220 (66·9%) were white, 9054 (9·4%) were black, 5978 (6·2%) were Hispanic, and 13 519 (14·1%) were of Asian origin”

PASSReviewer 2· 95% conf

Sex, age, weight (BMI), health status (comorbidities), and demographics (race/ethnicity) are all reported and adequately described.

Evidence

direct quote[Abstract, Results]

“96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria.”

direct quote[Results, paragraph 1 and Table 1]

“mean BMI was 27·6 kg/m2 (SD 5·5; 29 510 [30·7%] were obese with BMI ≥30 kg/m2)”

direct quote[Results, paragraph 1]

“64 220 (66·9%) were white, 9054 (9·4%) were black, 5978 (6·2%) were Hispanic, and 13 519 (14·1%) were of Asian origin.”

PASSReviewer 3· 95% conf

Demographic and clinical variables (age, sex, race/ethnicity, comorbidities, disease severity) are reported and analyzed, meeting the requirements for a human observational study.

Evidence

direct quote[Results, Table 1]

“Female 40 169 (47.1%) 4257 (39.8%)”

direct quote[Results, Table 1]

“Age, years 53.1 (17.5) 60.0 (17.6)”

direct quote[Methods, Data collection]

“Patient demographics, including age, body-mass index (BMI), sex, race or ethnicity, and continent of origin were obtained.”

The paper states 'The data collection and analyses are deemed exempt from ethics review.' However, no named ethics body (IRB/ethics committee) is identified as having granted this exemption, and no informed consent procedure is described. Given that this is an observational study using de-identified patient data from electronic health records across 671 hospitals, an ethics exemption statement from a named committee and a waiver of informed consent are typically required. The absence of a named body and failure to mention informed consent handling make this reported_but_inadequate. regulatory_compliance is mentioned via FDA guidance and AHRQ guidelines compliance, but this is not a substitute for a named research ethics committee.

Sub-criteria

iacuc statementN/A

informed consentNOT REPORTED

irb ethics statementINADEQUATE

regulatory complianceINADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

Ethical oversight is insufficiently reported: no named IRB or ethics committee approval is provided, informed consent is not mentioned, and the exemption justification is vague, resulting in a warning.

Evidence

direct quote[Methods, Registry features and data acquisition]

“The data collection and analyses are deemed exempt from ethics review.”

absence[Methods]

Informed consent is not reported

direct quote[Methods, Registry features and data acquisition]

“The Surgical Outcomes Collaborative ... ensures compliance with the US Food and Drug Administration (FDA) guidance on real-world evidence.”

WARNReviewer 2· 85% conf

The paper states that data collection and analyses are 'deemed exempt from ethics review' but does not name the ethics body that granted the exemption, and informed consent is not addressed.

Evidence

direct quote[Methods, Registry features and data acquisition]

“The data collection and analyses are deemed exempt from ethics review.”

absence[Methods]

Informed consent is not reported.

direct quote[Methods, Registry features]

“The Collaborative is compliant with the US Agency for Healthcare Research and Quality guidelines for registries.”

WARNReviewer 3· 96% conf

The paper states that the data collection and analyses are deemed exempt from ethics review, but does not name an ethics body that granted this exemption, and does not mention informed consent for this multinational registry using patient-level data.

Evidence

direct quote[Methods, Registry features and data acquisition]

“The data collection and analyses are deemed exempt from ethics review.”

absence[Methods]

No informed consent procedure is mentioned

direct quote[Methods, Registry features and data acquisition]

“The Surgical Outcomes Collaborative ... ensures compliance with the US Food and Drug Administration (FDA) guidance on real-world evidence.”

The drugs are identified by name and mean daily dose/duration, but the manufacturer, formulation, or lot numbers are not given. This is reported_but_inadequate for reagents_identified. Software (R 3.6.3, SPSS 26) is adequately identified. No other key resources (antibodies, cell lines) are used.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

The investigational drugs are identified but not fully characterized (no manufacturer, lot numbers), while statistical software is properly identified, leading to a warning.

Evidence

direct quote[Results, paragraph 3]

direct quote[Methods, Statistical analysis]

“All statistical analyses were done with R version 3.6.3 and SPSS version 26.”

WARNReviewer 2· 85% conf

The investigational drugs (hydroxychloroquine, chloroquine, macrolides) are named and doses reported, but no manufacturer/source is provided, and software tools are adequately identified.

Evidence

direct quote[Results, paragraph 3]

“The mean daily dose and duration of the various drug regimens were as follows: chloroquine alone, 765 mg (SD 308) and 6·6 days (2·4); hydroxychloroquine alone, 596 mg (126) and 4·2 days (1·9); chloroquine with a macrolide, 790 mg (320) and 6·8 days (2·5); and hydroxychloroquine with a macrolide, 597 mg (128) and 4·3 days (2·0).”

direct quote[Methods, Statistical analysis]

“All statistical analyses were done with R version 3.6.3 and SPSS version 26.”

PASSReviewer 3· 100% conf

The investigational products (hydroxychloroquine, chloroquine, macrolides) are identified with drug names and dosing regimens, and statistical software is identified; no other biological or chemical resources are used.

Evidence

direct quote[Results]

“The mean daily dose and duration of the various drug regimens were as follows: chloroquine alone, 765 mg (SD 308) and 6.6 days (2.4); hydroxychloroquine alone, 596 mg (126) and 4.2 days (1.9); chloroquine with a macrolide, 790 mg (320) and 6.8 days (2.5); and hydroxychloroquine with a macrolide, 597 mg (128) and 4.3 days (2.0).”

direct quote[Methods, Statistical analysis]

“All statistical analyses were done with R version 3.6.3 and SPSS version 26.”

Statistical tests are named (unpaired t-test, Fisher's exact test, Cox proportional hazards). Proportional hazards assumption is verified via Schoenfeld residuals. Effect sizes (hazard ratios) with 95% confidence intervals are reported. Software versions are given. Data presentation includes per-group counts, means, SDs, and percentages. Mathematical plausibility checks (e.g., percentages adding up, internal consistency of numbers) show no errors. Exact p-values for baseline comparisons are given as <0.0001 rather than exact figures, and the primary analysis relies on CIs rather than p-values, which is acceptable but suboptimal.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The statistical analysis is generally rigorous: tests are named, assumptions checked, effect sizes and confidence intervals reported, and software identified. Exact p-values are not always provided (only thresholds), but this is common for large studies and does not constitute a failure.

Evidence

direct quote[Methods, Statistical analysis]

“Comparison of continuous data between groups was done using the unpaired t-test and categorical data were compared using Fisher's exact test. ... Proportionality between the predictors and the hazard was validated through an evaluation of Schoenfeld residuals, which found p>0·05 and thus confirmed proportionality.”

direct quote[Results, paragraph 4]

“hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457)”

direct quote[Methods, Statistical analysis]

“A p value of less than 0·05 was considered significant.”

PASSReviewer 2· 80% conf

Statistical tests are named, effect sizes and CIs are reported, and software is identified. Exact p-values are not given (only thresholds), and assumptions are partially verified (proportional hazards checked).

Evidence

direct quote[Methods, Statistical analysis]

“Proportionality between the predictors and the hazard was validated through an evaluation of Schoenfeld residuals, which found p>0·05 and thus confirmed proportionality.”

direct quote[Results, Table 1 and text]

“p<0·0001”

direct quote[Results, paragraph 4]

“hydroxychloroquine alone (18·0%; HR 1·335, 95% CI 1·223–1·457)”

WARNReviewer 3· 88% conf

Statistical tests are named, software is identified, and data presentation includes per-group n's, means, SDs, and HRs with CIs. However, exact p-values are not reported (only '<0.0001' or 'p<0.0001'), effect sizes beyond HRs are limited, and assumptions_verification is partial (Schoenfeld residuals for Cox model reported, but normality/equal variance for t-tests not checked).

Evidence

direct quote[Methods, Statistical analysis]

“Comparison of continuous data between groups was done using the unpaired t-test and categorical data were compared using Fisher's exact test.”

direct quote[Results, Table 1]

“p value <0.0001”

direct quote[Methods, Statistical analysis]

“Proportionality between the predictors and the hazard was validated through an evaluation of Schoenfeld residuals, which found p>0.05 and thus confirmed proportionality.”

There is no data availability statement in the paper. No repository deposit, accession numbers, or code sharing are reported. The registry is described as proprietary (Surgisphere), and no mechanism for requesting access to the data or code is provided.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 95% conf

No data availability statement, repository deposit, or code sharing is provided; the data exist only in a proprietary registry (Surgisphere) with no public access route, resulting in a fail.

Evidence

absence[Methods and end matter]

No data availability statement

absence[Entire paper]

No repository deposit or accession numbers

absence[Entire paper]

No code sharing mentioned

FAILReviewer 2· 95% conf

No data availability statement is provided, data are not deposited in a public repository, accession numbers are not given, and no custom code is shared.

Evidence

absence[Entire paper]

No data availability statement found.

absence[Entire paper]

No repository deposit or accession numbers.

absence[Entire paper]

No code sharing statement.

FAILReviewer 3· 98% conf

No data availability statement is present. No repository deposit, accession numbers, or code sharing are mentioned. The paper is retracted; data provenance has been questioned, but even within the text, no data access details are provided.

Evidence

absence[Full text]

No data availability statement found

absence[Full text]

No repository deposit mentioned

absence[Full text]

No code sharing mentioned

Methods are comprehensive, covering data acquisition, study design, outcomes, and statistical analysis. All pre-specified outcomes (mortality, arrhythmias) are reported. Limitations are explicitly discussed, including potential confounding and the observational design. Conclusions are appropriately cautious, noting that causality cannot be inferred. Funding and conflicts of interest are stated. The only missing element is reference to a reporting checklist (e.g., STROBE), which is advisable but not required for publication in many journals.

Sub-criteria

funding coiADEQUATE

trial registrationN/A

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper is largely transparent: methods are detailed, outcomes reported, limitations discussed, conclusions proportional to evidence, and funding/COI declared. It does not reference a reporting guideline (e.g., STROBE) but this is not critical.

Evidence

direct quote[Methods, entire section]

“The registry uses a cloud-based health-care data analytics platform that includes specific modules for data acquisition, data warehousing, data analytics, and data reporting.”

direct quote[Discussion, paragraph 5]

“Our study has several limitations. The association of decreased survival with hydroxychloroquine or chloroquine treatment regimens should be interpreted cautiously. Due to the observational study design, we cannot exclude the possibility of unmeasured confounding factors”

direct quote[End of paper, Declaration of interests]

“MRM reports personal fees from Abbott, Medtronic, Janssen... SSD is the founder of Surgisphere Corporation.”

PASSReviewer 2· 90% conf

Methods are detailed, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed. However, no reporting guideline (e.g., STROBE) is referenced.

Evidence

direct quote[Discussion, paragraph 4]

direct quote[Discussion, last paragraph]

“These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed.”

direct quote[Declaration of interests]

“MRM reports personal fees from Abbott, Medtronic, Janssen... SSD is the founder of Surgisphere Corporation... ANP declares no competing interests.”

WARNReviewer 3· 88% conf

Methods are detailed and limitations are discussed, and conclusions are generally proportional, but trial registration is not applicable, no reporting guideline is referenced, not all pre-specified outcomes may be fully transparent (e.g., composite outcomes), and funding/COI is reported.

Evidence

direct quote[Discussion]

“Our study has several limitations. The association of decreased survival with hydroxychloroquine or chloroquine treatment regimens should be interpreted cautiously.”

absence[Methods]

No reporting guideline is mentioned

direct quote[Declaration of interests]

“MRM reports personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NupulseCV, FineHeart, Leviticus, Roivant, and Triple Gene.”

6 copyedit issues flagged: mostly consistency, clarity, typo.

Checked 28 references: 23 verified — 2 retracted, 3 unresolved.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

Post-publication audit: This paper has been retracted, which renders the findings unreliable for clinical or policy use. An informed reader should weigh the absence of independent data verification, the proprietary data source (Surgisphere) with no access mechanism, the unsupported headline claim of providing 'the most robust real-world evidence,' and the multiple internal contradictions noted in the integrity audit (extremely sparse data from Australia given the claim of 671 hospitals; implausibly tight propensity-score balance; extremely high hazard ratios for arrhythmia). The retraction is consistent with these rigor gaps and the inability to reproduce or verify the core results.

1.
HIGHdata code
Provide a data availability statement specifying the conditions for accessing the registry data, even if managed access, and deposit de-identified aggregate data or analysis code in a public repository (e.g., Zenodo, Figshare).
The absence of any data access mechanism makes the paper unreproducible and undermines trust, especially for a data-driven observational study.
2.
HIGHethics
Replace the vague 'deemed exempt from ethics review' statement with the name of the institutional review board (IRB) or ethics committee that granted the exemption, and include a protocol number.
A named ethics body is the standard for human-subjects research; the current statement is insufficient for a study involving patient data from 671 hospitals.
3.
HIGHethics
Add a statement on informed consent: specify whether consent was obtained or waived, and identify the entity that granted the waiver.
Informed consent or a documented waiver is required for research using identifiable or de-identified patient health data; its absence is a reporting gap.
4.
HIGHrigor
Remove or provide direct supporting evidence for the claim 'This study provides the most robust real-world evidence to date on the usefulness of these treatment regimens' (Abstract/Interpretation).
The claim audit found this statement unsupported by systematic comparison to other large studies, and the subsequent retraction invalidates it.
5.
HIGHrigor
Temper the claim 'These findings suggest that these drug regimens should not be used outside of clinical trials' to reflect the observational design's inability to establish causation (Discussion/Conclusions).
The claim audit rated this as overstated; the paper's own limitations acknowledge unmeasured confounding, so a causal recommendation is inappropriate.
6.
HIGHother
Remove or replace the two retracted references: 'Hydroxychloroquine and azithromycin as a treatment of COVID-19…' (DOI 10.1016/j.ijantimicag.2020.105949) and 'Cardiovascular disease, drug therapy, and mortality in COVID-19' (DOI 10.1056/nejmoa2007621).
Citing retracted work perpetuates invalid evidence; these must be replaced with non-retracted sources or removed.
7.
HIGHother
Verify the three references not found in any registry: 'A pilot study of hydroxychloroquine in treatment…' (DOI 10.3785/j.issn.1008-9292.2020.03.03), 'Clinical management of severe acute respiratory infection (SARI)…', and 'Emergency use authorization…' — provide working DOIs or full publication details, or remove them.
Unresolved references are a fabrication signal; each must be confirmed as a legitimate published source.
8.
HIGHstatistics
Report exact p-values (e.g., from Cox regression) alongside hazard ratios and confidence intervals for all primary and key secondary analyses, rather than only threshold values like 'p<0.0001'.
Exact p-values enable readers to assess statistical evidence precisely; current reporting is incomplete per standard guidelines.
9.
HIGHstatistics
Report verification of normality and equal variance assumptions for the unpaired t-tests used in baseline comparisons.
Only the Cox proportional hazards assumption (Schoenfeld residuals) is currently verified; the t-tests' assumptions remain unchecked.
10.
HIGHreporting
Reference the STROBE reporting guideline for observational studies in the Methods section.
No reporting guideline is mentioned; STROBE is expected for cohort studies to ensure completeness.
11.
HIGHrigor
Conduct and report an a priori power analysis or sample size justification for the primary analysis (Methods, Statistical analysis).
Even in large studies, a power analysis demonstrates that the study is adequately designed to detect clinically meaningful effects.
12.
MEDIUMrigor
Describe the handling of outliers and influential data points in the statistical analysis (Methods).
Outlier handling is currently not mentioned; extreme values can influence propensity-score matching and hazard ratios.
13.
MEDIUMreporting
Add the manufacturer, source, and lot numbers (or equivalent) for the drugs used (hydroxychloroquine, chloroquine, macrolides) in the Methods section.
Full reagent identification supports reproducibility and is expected for pharmacological studies.
14.
LOWcopyedit
Correct the typo 'arrythmia' to 'arrhythmia' in Results, paragraph 3.
Minor spelling error that should be fixed for clarity.
15.
LOWcopyedit
Standardize the decimal separator to a consistent format (dot or middle dot) across all tables (e.g., Table 2 uses middle dot elsewhere uses dot).
Inconsistent decimal separators can cause confusion in data interpretation.

Full text (50,453 chars)Analyzed: Jul 6, 2026

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