Non-Inferiority Trials: A Systematic Review on Methodological Quality and Reporting Standards.

BACKGROUND: Non-inferiority (NI) trials require unique trial design and methods, which pose challenges in their interpretation and applicability, risking introduction of inferior therapies in clinical practice. With the abundance of novel therapies, NI trials are increasing in publication. Prior studies found inadequate quality of reporting of NI studies, but were limited to certain specialties/journals, lacked NI margin evaluation, and did not examine temporal changes in quality. We conducted a systematic review without restriction to journal type, journal impact factor, disease state or intervention to evaluate the quality of NI trials, including a comprehensive risk of bias assessment and comparison of quality over time. METHODOLOGY: We searched PubMed and Cochrane Library databases for NI trials published in English in 2014 and 2019. They were assessed for: study design and NI margin characteristics, primary results, and risk of bias for blinding, concealment, analysis method and missing outcome data. RESULTS: We included 823 studies. Between 2014 and 2019, a shift from publication in specialty to general journals (15% vs 28%, p < 0.001) and from pharmacological to non-pharmacological interventions (25% vs 38%, p = 0.025) was observed. The NI margin was specified in most trials for both years (94% vs 95%). Rationale for the NI margin increased (36% vs 57%, p < 0.001), but remained low, with clinical judgement the most common rationale (30% vs 23%), but more 2019 articles incorporating patient values (0.3% vs 21%, p < 0.001). Over 50% of studies were open-label for both years. Gold standard method of analyses (both per protocol + (modified) intention to treat) declined over time (43% vs 36%, p < 0.001). DISCUSSION: The methodological quality and reporting of NI trials remains inadequate although improving in some areas. Improved methods for NI margin justification, blinding, and analysis method are warranted to facilitate clinical decision-making.

Safety and Efficacy of Influenza Vaccination in Patients Receiving Immune Checkpoint Inhibitors. Systematic Review with Meta-Analysis.

The potential increased risk of immune-related adverse events (irAEs) post-influenza vaccine is a concern in patients receiving immune checkpoint inhibitors (ICI). We conducted a systematic review with meta-analysis of studies reporting the effects of influenza vaccination in patients with cancer during ICI treatment. We searched five electronic databases until 01/2022. Two authors independently selected studies, appraised their quality, and collected data. The primary outcome was the determination of pooled irAE rates. Secondary outcomes included determination of immunogenicity and influenza infection rates and cancer-related outcomes. Nineteen studies (26 publications, n = 4705) were included; 89.5% were observational. Vaccinated patients reported slighter lower rates of irAEs compared to unvaccinated patients (32% versus 41%, respectively). Seroprotection for influenza type A was 78%-79%, and for type B was 75%. Influenza and irAE-related death rates were similar between groups. The pooled proportion of participants reporting a laboratory-confirmed infection was 2% (95% CI 0% to 6%), and influenza-like illness was 14% (95% CI 2% to 32%). No differences were reported on the rates of laboratory-confirmed infection between vaccinated and unvaccinated patients. Longer progression-free and overall survival was also observed in vaccinated compared with unvaccinated patients. Current evidence suggests that influenza vaccination is safe in patients receiving ICIs, does not increase the risk of irAEs, and may improve survival.

Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia.

A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.

Systematic review of recommendations on the use of methotrexate in rheumatoid arthritis.

OBJECTIVE: Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries. It is unknown whether they are relevant globally. We reviewed existing recommendations on the use of MTX for the treatment of RA and summarized areas of agreement that could be relevant for least developed countries (LDCs). METHODS: Electronic databases and registries were searched for recommendations on MTX use in RA, duplicates were eliminated, and the most updated version adopted when there were several versions on the same recommendation. Reviewers used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for study quality assessment. Similarities and discrepancies of recommendations are reported. RESULTS: After deduplication, 1693 unique citations were found; 25 full texts were screened and 12 included in the narrative synthesis. Average scores for the AGREE II domains ranged from 33.3 to 83.3%. Recommendations targeted rheumatologists and health care providers involved in RA care. Most covered some but not all of the following areas: baseline "pre-MTX" assessment (7/12;58%), prescription of MTX (10/12;83.3%), management of MTX side effects (6/12;50%), and special considerations (e.g., peri-operative management) (8/12; 66.7%). Recommendations agreed on baseline tests prior to starting MTX, monitoring, and need for folic acid supplementation. These aspects can serve as the foundation for the development of MTX recommendations relevant to LDCs. Recommendations disagreed on the MTX starting dose, optimal route, titration, and intervals to monitor toxicity. CONCLUSION: Existing recommendations do not uniformly address all aspects related to the use of MTX and disagree in relevant aspects of MTX use. Adaptations to these recommendations are needed to facilitate their implementation in LDCs. Key Points • This paper summarizes current recommendations on the use of methotrexate for the treatment of rheumatoid arthritis. • Areas of agreement between recommendations include the following: pre-methotrexate patient assessment, need for folic acid supplementation, and toxicity monitoring. • Areas of disagreement relate to methotrexate starting and maximal dose, titration, and frequency of assessments.

Adherence to Discounting Guidelines: Evidence from Over 2000 Published Cost-Effectiveness Analyses.

Previous studies have shown that not all cost-effectiveness analyses (CEAs) adhere to recommended guidelines on intertemporal discounting. This analysis investigates adherence in a sample of over 2000 CEAs from seven countries. Guideline discount rates were retrieved for Australia, Belgium, Canada, Ireland, The Netherlands, New Zealand and the UK. Data on the rates applied in published CEAs were retrieved from the Tufts CEA Registry from the sample countries within the periods covered by the discounting guidelines. The relationship between adherence and candidate explanatory factors were assessed using logistic regression. The analysis appraised 2270 CEAs. The overall rate of adherence to discounting recommendations was 79%. Country-specific adherence ranged from 28% in New Zealand to 87% in Belgium and the UK. Adherence in Australia and Canada was 73% and 66%, respectively. Adherence is statistically significantly higher in more recent studies, countries currently applying differential discounting and manufacturer-sponsored studies. Relative to the reference case of Australia, adherence is statistically significantly higher in the UK and lower in Canada and New Zealand. There is notable variation in the rates of adherence to discounting recommendations between countries and over time. Incomplete adherence raises concerns regarding the comparability of evidence between studies. In turn, this raises concerns regarding equity of access to scarce healthcare resources. Journal editors should ensure that adherence to discounting recommendations is assessed as part of the peer review process.

The Impact of Vocal and Laryngeal Pathologies Among Professional Singers: A Meta-analysis.

OBJECTIVE: Professional singers are more likely to develop laryngeal pathologies and symptoms associated with misuse and overuse of the voice. However, different studies have shown conflicting evidence. We aim to perform a systematic review and quantitative meta-analysis to determine the prevalence and risk of laryngeal pathologies and symptoms among professional singers. METHODS: Four electronic databases (MEDLINE, PubMed, EMBASE, and CINAHL) were searched, with no language restrictions. From 3368 potential studies, a total of 21 studies met our inclusion criteria. A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. All cohort, case-control, or cross-sectional studies that reported the risk of laryngeal pathologies in singers were included. Data were pooled by a random effects model and the pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: There was a positive relationship between singing and laryngeal pathologies. There was an increased risk of hoarseness (OR: 2.00, 95% CI: 1.61-2.49), gastroesophageal reflux disease (GERD) (OR: 1.45, 95% CI: 1.19-1.77), Reinke edema (OR: 2.15, 95% CI: 1.08-4.30), and polyps (OR: 2.10, 95% CI: 1.06-4.14) in professional singers. CONCLUSION: Professional singers are at an increased risk of laryngeal pathologies and symptoms associated with vocal misuse and overuse, particularly hoarseness, GERD, edema, and polyps.