Enhancing global access to cancer medicines.

Globally, cancer is the second leading cause of death, with numbers greatly exceeding those for human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria combined. Limited access to timely diagnosis, to affordable, effective treatment, and to high-quality care are just some of the factors that lead to disparities in cancer survival between countries and within countries. In this article, the authors consider various factors that prevent access to cancer medicines (particularly access to essential cancer medicines). Even if an essential cancer medicine is included on a national medicines list, cost might preclude its use, it might be prescribed or used inappropriately, weak infrastructure might prevent it being accessed by those who could benefit, or quality might not be guaranteed. Potential strategies to address the access problems are discussed, including universal health coverage for essential cancer medicines, fairer methods for pricing cancer medicines, reducing development costs, optimizing regulation, and improving reliability in the global supply chain. Optimizing schedules for cancer therapy could reduce not only costs, but also adverse events, and improve access. More and better biomarkers are required to target patients who are most likely to benefit from cancer medicines. The optimum use of cancer medicines depends on the effective delivery of several services allied to oncology (including laboratory, imaging, surgery, and radiotherapy). Investment is necessary in all aspects of cancer care, from these supportive services to technologies, and the training of health care workers and other staff.

Studying the impact of translational genomic research: Lessons from eMERGE.

Two major goals of the Electronic Medical Record and Genomics (eMERGE) Network are to learn how best to return research results to patient/participants and the clinicians who care for them and also to assess the impact of placing these results in clinical care. Yet since its inception, the Network has confronted a host of challenges in achieving these goals, many of which had ethical, legal, or social implications (ELSIs) that required consideration. Here, we share impediments we encountered in recruiting participants, returning results, and assessing their impact, all of which affected our ability to achieve the goals of eMERGE, as well as the steps we took to attempt to address these obstacles. We divide the domains in which we experienced challenges into four broad categories: (1) study design, including recruitment of more diverse groups; (2) consent; (3) returning results to participants and their health care providers (HCPs); and (4) assessment of follow-up care of participants and measuring the impact of research on participants and their families. Since most phases of eMERGE have included children as well as adults, we also address the particular ELSI posed by including pediatric populations in this research. We make specific suggestions for improving translational genomic research to ensure that future projects can effectively return results and assess their impact on patient/participants and providers if the goals of genomic-informed medicine are to be achieved.

The association between playing professional American football and longevity.

Recent research concludes that professional American football players (hereafter, "football players") live longer than American men in general, despite experiencing higher rates of chronic traumatic encephalopathy (CTE) and cardiovascular disease (CVD). This suggests that the longevity-enhancing benefits of playing football (e.g., physical fitness, money) outweigh the costs associated with CTE, CVD, and other longevity detriments of playing football. However, these surprising results may be the consequence of flawed research design. To investigate, we conducted two analyses. In analysis 1, we compared a) all professional American football players whose first season was 1986 or between 1988 and 1995 to b) a random sample of same-age American men observed as part of the National Health Interview Surveys in those same years selected on good health, at least 3 y of college, and not being poor. The exposure consists of playing one or more games of professional football; the outcome is risk of death within 25 y. In analysis 2, we use data on 1,365 men drafted to play in the (American) National Football League in the 1950s-906 of whom ultimately played professional football, and 459 of whom never played a game in any professional league. We estimate the association between playing football and survival through early 2023. In both analyses, we investigate differences between linemen and other position players. In contrast to most prior research, in both analyses, we find that linemen died earlier than otherwise similar men; men who played other positions died no earlier (or later).

Re-Imagining Hospital Patient Room Design for People After stroke: A Randomized Controlled Study Using Virtual Reality.

BACKGROUND: The hospital's physical environment can impact health and well-being. Patients spend most of their time in their hospital rooms. However, little experimental evidence supports specific physical design variables in these rooms, particularly for people poststroke. The study aimed to explore the influence of patient room design variables modeled in virtual reality using a controlled experimental design. METHODS: Adults within 3 years of stroke who had spent >2 nights in hospital for stroke and were able to consent were included (Melbourne, Australia). Using a factorial design, we immersed participants in 16 different virtual hospital patient rooms in both daytime and nighttime conditions, systematically varying design attributes: patient room occupancy, social connectivity, room size (spaciousness), noise (nighttime), greenery outlook (daytime). While immersed, participants rated their affect (Pick-A-Mood Scale) and preference. Mixed-effect regression analyses were used to explore participant responses to design variables in both daytime and nighttime conditions. Feasibility and safety were monitored throughout. Australian New Zealand Clinical Trials Registry, Trial ID: ACTRN12620000375954. RESULTS: Forty-four adults (median age, 67 [interquartile range, 57.3-73.8] years, 61.4% male, and a third with stroke in the prior 3-6 months) completed the study in 2019-2020. We recorded and analyzed 701 observations of affective responses (Pick-A-Mood Scale) in the daytime (686 at night) and 698 observations of preference responses in the daytime (685 nighttime) while continuously immersed in the virtual reality scenarios. Although single rooms were most preferred overall (daytime and nighttime), the relationship between affective responses differed in response to different combinations of nighttime noise, social connectivity, and greenery outlook (daytime). The virtual reality scenario intervention was feasible and safe for stroke participants. CONCLUSIONS: Immediate affective responses can be influenced by exposure to physical design variables other than room occupancy alone. Virtual reality testing of how the physical environment influences patient responses and, ultimately, outcomes could inform how we design new interventions for people recovering after stroke. REGISTRATION: URL: https://anzctr.org.au; Unique identifier: ACTRN12620000375954.

Changing Landscape of Randomized Clinical Trials in Stroke: Explaining Contemporary Trial Designs and Methods.

Evidence generated from randomized clinical trials (RCTs) plays an indispensable role in advancing clinical stroke care. Although the number of stroke-related RCTs published every year has grown exponentially over the past 25 years, the execution and completion of RCTs, particularly those conducted in a hyperacute setting, have grown more complicated and challenging over the years. In addition to the practical challenges associated with conducting a clinical trial, like obtaining human subjects approval, identifying clinical sites, training trial personnel, and enrolling the target number of patients within the available funding and timeline, the complexity of contemporary RCT designs and analyses has become much more exacting. It is no longer sufficient to have a decent understanding of the 2-arm, placebo-controlled RCT, combined with a rudimentary grasp of the P value; things are now much more complicated. Innovations in trial design and analysis, including adaptive, Bayesian, platform, and noninferiority designs, have occurred to address the problems of poor trial efficiency. However, these advances require the end user to have a much greater level of understanding regarding the rationale, conduct, analysis, and interpretation of each design. While these newer designs seek greater efficiency, there are inevitably tradeoffs that need to be understood. In this month's edition of Stroke, we introduce a new series designed to help fill in these knowledge gaps. Over the next few months, 4 papers will be published that address major design innovations (adaptive, Bayesian, platform, and noninferiority) with the aim of illustrating how these approaches can make trials more efficient (where efficiency is defined as getting to the right answer, sooner, with a potentially lower sample size). In addition to introducing this series, this current article also reviews traditional hypothesis testing and the common misinterpretations of the P value; fortunately, new philosophical schools of inference are beginning to vanquish the overreliance on the P value. We are excited about the opportunity to educate the Stroke readership about these new trial designs and the profound implications that they bring.

More Than a Decade Since the Latest CONSORT Non-inferiority Trials Extension: Do Infectious Diseases Trials Do Enough?

More than a decade after the Consolidated Standards of Reporting Trials group released a reporting items checklist for non-inferiority randomized controlled trials, the infectious diseases literature continues to underreport these items. Trialists, journals, and peer reviewers should redouble their efforts to ensure infectious diseases studies meet these minimum reporting standards.

A practical guide to cross-cultural and multi-sited data collection in the biological and behavioural sciences.

Researchers in the biological and behavioural sciences are increasingly conducting collaborative, multi-sited projects to address how phenomena vary across ecologies. These types of projects, however, pose additional workflow challenges beyond those typically encountered in single-sited projects. Through specific attention to cross-cultural research projects, we highlight four key aspects of multi-sited projects that must be considered during the design phase to ensure success: (1) project and team management; (2) protocol and instrument development; (3) data management and documentation; and (4) equitable and collaborative practices. Our recommendations are supported by examples from our experiences collaborating on the Evolutionary Demography of Religion project, a mixed-methods project collecting data across five countries in collaboration with research partners in each host country. To existing discourse, we contribute new recommendations around team and project management, introduce practical recommendations for exploring the validity of instruments through qualitative techniques during piloting, highlight the importance of good documentation at all steps of the project, and demonstrate how data management workflows can be strengthened through open science practices. While this project was rooted in cross-cultural human behavioural ecology and evolutionary anthropology, lessons learned from this project are applicable to multi-sited research across the biological and behavioural sciences.

An evaluation of untargeted metabolomics methods to characterize inborn errors of metabolism.

Inborn errors of metabolism (IEMs) encompass a diverse group of disorders that can be difficult to classify due to heterogenous clinical, molecular, and biochemical manifestations. Untargeted metabolomics platforms have become a popular approach to analyze IEM patient samples because of their ability to detect many metabolites at once, accelerating discovery of novel biomarkers, and metabolic mechanisms of disease. However, there are concerns about the reproducibility of untargeted metabolomics research due to the absence of uniform reporting practices, data analyses, and experimental design guidelines. Therefore, we critically evaluated published untargeted metabolomic platforms used to characterize IEMs to summarize the strengths and areas for improvement of this technology as it progresses towards the clinical laboratory. A total of 96 distinct IEMs were collectively evaluated by the included studies. However, most of these IEMs were evaluated by a single untargeted metabolomic method, in a single study, with a limited cohort size (55/96, 57%). The goals of the included studies generally fell into two, often overlapping, categories: detecting known biomarkers from many biochemically distinct IEMs using a single platform, and detecting novel metabolites or metabolic pathways. There was notable diversity in the design of the untargeted metabolomic platforms. Importantly, the majority of studies reported adherence to quality metrics, including the use of quality control samples and internal standards in their experiments, as well as confirmation of at least some of their feature annotations with commercial reference standards. Future applications of untargeted metabolomics platforms to the study of IEMs should move beyond single-subject analyses, and evaluate reproducibility using a prospective, or validation cohort.

Knowledge gaps in health-related quality of life research performed in children with bleeding disorders - A scoping review.

INTRODUCTION: Bleeding disorders (BDs) may influence health-related quality of life (HRQoL) in children and caregivers. Measuring HRQoL gives insight into domains requiring support and provides an opportunity to evaluate the effects of novel therapies. AIM: To gain insight in the current body of literature on HRQoL in children with BDs in order to identify knowledge gaps for research and further development of this field. METHODS: Scoping review. RESULTS: We included 53 articles, describing studies mainly performed in Europe and North-America (60.4%) and mostly within the last ten years. Only 32% studies included children <4 years. Almost all studies (47/53, 88.7%) were performed in boys with haemophilia, pooling haemophilia A and B (n = 21) and different disease severities (n = 20). Thirteen different generic and five disease-specific HRQoL-questionnaires were applied; all questionnaires were validated for haemophilia specifically. Six (11,3%) combined generic and disease-specific questionnaires. Self-reports were most frequently applied (40/53, 75.5%), sometimes combined with proxy and/or parent-reports (17/53, 32.1%). Eleven studies used a reference group (20.8%). Statistical analyses mostly consisted of mean and SD (77.4%). CONCLUSION: HRQoL-research is mainly performed in school-aged boys with haemophilia, treated in developed countries. Pitfalls encountered are the pooling of various BDs, subtypes and severities, as well as the application of multiple generic questionnaires prohibiting comparison of results. More attention is needed for broader study populations including other BDs, young children, feminine bleeding issues and platelet disorders, as well as the use of HRQoL as an effect-measurement tool for medical interventions, and more thorough statistical analysis.

Kids SIPsmartER reduces sugar-sweetened beverages among Appalachian middle-school students and their caregivers: a cluster randomized controlled trial.

BACKGROUND: High consumption of sugar-sweetened beverages (SSB) is a global health concern. Additionally, sugar-sweetened beverage (SSB) consumption is disproportionately high among adolescents and adults in rural Appalachia. The primary study objective is to determine the intervention effects of Kids SIPsmartER on students' SSB consumption. Secondary objectives focus on caregivers' SSB consumption and secondary student and caregiver outcomes [e.g, body mass index (BMI), quality of life (QOL)]. METHODS: This Type 1 hybrid, cluster randomized controlled trial includes 12 Appalachian middle schools (6 randomized to Kids SIPsmartER and 6 to control). Kids SIPsmartER is a 6-month, 12 lesson, multi-level, school-based, behavior and health literacy program aimed at reducing SSB among 7th grade middle school students. The program also incorporates a two-way text message strategy for caregivers. In this primary prevention intervention, all 7th grade students and their caregivers from participating schools were eligible to participate, regardless of baseline SSB consumption. Validated instruments were used to assess SSB behaviors and QOL. Height and weight were objectively measured in students and self-reported by caregivers. Analyses included modified two-part models with time fixed effects that controlled for relevant demographics and included school cluster robust standard errors. RESULTS: Of the 526 students and 220 caregivers, mean (SD) ages were 12.7 (0.5) and 40.6 (6.7) years, respectively. Students were 55% female. Caregivers were mostly female (95%) and White (93%); 25% had a high school education or less and 33% had an annual household income less than $50,000. Regardless of SSB intake at baseline and relative to control participants, SSB significantly decreased among students [-7.2 ounces/day (95% CI = -10.7, -3.7); p < 0.001, effect size (ES) = 0.35] and caregivers [-6.3 ounces/day (95% CI = -11.3, -1.3); p = 0.014, ES = 0.33]. Among students (42%) and caregivers (28%) who consumed > 24 SSB ounces/day at baseline (i.e., high consumers), the ES increased to 0.45 and 0.95, respectively. There were no significant effects for student or caregiver QOL indicators or objectively measured student BMI; however, caregiver self-reported BMI significantly decreased in the intervention versus control schools (p = 0.001). CONCLUSIONS: Kids SIPsmartER was effective at reducing SSB consumption among students and their caregivers in the rural, medically underserved Appalachian region. Importantly, SSB effects were even stronger among students and caregivers who were high consumers at baseline. TRIAL REGISTRATION: Clincialtrials.gov: NCT03740113. Registered 14 November 2018- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03740113 .

Time to STEP UP: methods and findings from the development of guidance to help researchers design inclusive clinical trials.

BACKGROUND: It is important to design clinical trials to include all those who may benefit from the intervention being tested. Several frameworks have been developed to help researchers think about the barriers to inclusion of particular under-served groups when designing a trial, but there is a lack of practical guidance on how to implement these frameworks. This paper describes the ACCESS project, the findings from each phase of the project and the guidance we developed (STEP UP) on how to design more inclusive trials. METHODS: Development of the STEP UP guidance had five phases: (1) Scoping literature review, (2) 'roundtable' discussion meetings, (3) redesign of trials, (4) interviews and (5) guidance document development, with input from public contributors and the ACCESS team. RESULTS: Over 40 experts contributed to the ACCESS project-patients and the public, clinicians, NHS research staff, trialists and other academics. The scoping review identified several strategies being used to improve inclusion, mostly around recruitment settings, but there was little evaluation of these strategies. The 'roundtable' discussions identified additional strategies being used across the UK and Ireland to improve inclusion, which were grouped into: Communication, Community engagement, Recruitment sites, Patient information, Flexibility, Recruitment settings, Consent process, Monitoring, Training for researchers and Incentives. These strategies were used to redesign three existing trials by applying one of the three INCLUDE frameworks (ethnicity, socioeconomic disadvantage, impaired capacity to consent) to one trial each, to produce the key recommendations for the guidance. Issues around implementation were explored in stakeholder interviews and key facilitators were identified: funders requesting information on inclusion, having the time and funding to implement strategies, dedicated staff, flexibility in trial protocols, and considering inclusion of under-served groups at the design stages. The STEP UP guidance is freely available at http://step-up-clinical-trials.co.uk . CONCLUSION: Researchers should consider inclusivity to shape initial trial design decisions. Trial teams and funders need to ensure that trials are given both the resources and time needed to implement the STEP UP guidance and increase the opportunities to recruit a diverse population.

Randomised clinical trials compare one or more treatments to another to see which ones work best. Trials don't always include people or groups who might benefit from the results: those excluded are sometimes called 'under- served groups'. Recent work has shone a light on this and now researchers are being asked by the public, trial funders and others to design their research so that under-served groups are more able to take part.We worked on a project to find out how to make sure everyone can be part of clinical trials. We looked at published work and held five online meetings with researchers, doctors, and patients to see what was being done already, and to think of other things that could help under-served groups take part in trials. Three groups of people, including scientists, patients, doctors and other NHS workers then  used this information to redesign three older trials using some existing inclusivity frameworks to think through the barriers for under-served groups in these trials. The three groups then talked through these trials at a 2-hour meeting, suggesting changes to the original trial plan, and discussed whether the suggestions were practical and useful. From this we came up with recommendations for how to design trials so that they have fewer barriers for under-served groups.We interviewed people to find out the best way to put these things into practice and talk through any practical issues. Using all of this information: the recommendations and what came out of the interviews, the study team created some guidance ­ 'STEP UP (Strategies for Trialists to promote Equal Participation in clinical trials for Under-served Populations)' ­ for people working in trials.

From complexity to clarity: how directed acyclic graphs enhance the study design of systematic reviews and meta-analyses.

While frameworks to systematically assess bias in systematic reviews and meta-analyses (SRMAs) and frameworks on causal inference are well established, they are less frequently integrated beyond the data analysis stages. This paper proposes the use of Directed Acyclic Graphs (DAGs) in the design stage of SRMAs. We hypothesize that DAGs created and registered a priori can offer a useful approach to more effective and efficient evidence synthesis. DAGs provide a visual representation of the complex assumed relationships between variables within and beyond individual studies prior to data analysis, facilitating discussion among researchers, guiding data analysis, and may lead to more targeted inclusion criteria or set of data extraction items. We illustrate this argument through both experimental and observational case examples.

Statistically significant differences versus convincing evidence of real treatment effects: an analysis of the false positive risk for single-centre trials in anaesthesia.

BACKGROUND: The American Statistical Association has highlighted problems with null hypothesis significance testing and outlined alternative approaches that may 'supplement or even replace P-values'. One alternative is to report the false positive risk (FPR), which quantifies the chance the null hypothesis is true when the result is statistically significant. METHODS: We reviewed single-centre, randomised trials in 10 anaesthesia journals over 6 yr where differences in a primary binary outcome were statistically significant. We calculated a Bayes factor by two methods (Gunel, Kass). From the Bayes factor we calculated the FPR for different prior beliefs for a real treatment effect. Prior beliefs were quantified by assigning pretest probabilities to the null and alternative hypotheses. RESULTS: For equal pretest probabilities of 0.5, the median (inter-quartile range [IQR]) FPR was 6% (1-22%) by the Gunel method and 6% (1-19%) by the Kass method. One in five trials had an FPR ≥20%. For trials reporting P-values 0.01-0.05, the median (IQR) FPR was 25% (16-30%) by the Gunel method and 20% (16-25%) by the Kass method. More than 90% of trials reporting P-values 0.01-0.05 required a pretest probability >0.5 to achieve an FPR of 5%. The median (IQR) difference in the FPR calculated by the two methods was 0% (0-2%). CONCLUSIONS: Our findings suggest that a substantial proportion of single-centre trials in anaesthesia reporting statistically significant differences provide limited evidence of real treatment effects, or, alternatively, required an implausibly high prior belief in a real treatment effect. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42023350783).

Trends in authorship in the Journal of Cutaneous Pathology, 1981-2020.

BACKGROUND: The increase in authors per scientific article in many different medical and scientific disciplines has raised concerns over ethical authorship. Trends in authorship in dermatopathology are unknown. METHODS: Cross-sectional study of a random sample of 200 articles from the Journal of Cutaneous Pathology (1981-2020). RESULTS: The number of authors per article increased by an estimated 96% between 1981 and 2020 (2.7-5.3), while the relative citation ratio decreased by an estimated 56% during the same period (1.19-0.52). Higher author counts were not associated with higher relative citation ratios (p = 0.2349) or analytic study designs (p = 0.2987). Higher relative citation ratios were associated with analytic study designs (p = 0.0374). CONCLUSIONS: There has been significant growth in authorship credit at the journal without a corresponding increase in research impact or study rigor. Remedial measures to stem authorship inflation and promote more impactful studies may be necessary.

The study of psychosocial outcomes of parents bereaved by pediatric illness: a scoping review of methodology and sample composition.

OBJECTIVE: Parents of children who died of a medical condition experience a range of psychosocial outcomes. The current scoping review aims to summarize the outcomes assessed, methodology, and sample characteristics of recent psychosocial research conducted with this population. METHODS: Included studies were limited to peer-reviewed, psychosocial outcomes research published between August 2011 and August 2022, written in English, and including caregiver study participants of children who died of a medical condition. Data sources were scholarly journal articles from 9 electronic databases, including Scopus, Web of Science, Academic Search Primer, ProQuest Research Library, PubMed, Embase, PsycINFO, Psychology & Behavioral Sciences Collection, and Health Source: Nursing/Academic Edition. The Mixed Methods Appraisal Tool-2018 evaluated methodological quality. RESULTS: The study sample included 106 studies, most of which were either qualitative (60%) or quantitative (29%). Mixed-methods studies (8%) and randomized clinical trials (2%) were also identified. Study quality was variable, but most studies met all quality criteria (73%). Studies primarily represented cancer populations (58%), White participants (71%), and mothers (66%). Risk-based psychosocial outcomes (e.g., grief) were more commonly assessed than resilience-based outcomes. CONCLUSIONS: The current scoping review revealed that recent research assessing the psychosocial outcomes of bereaved parents is limited in the representation of diverse populations, primarily qualitative, of broadly strong methodological quality, and oriented to psychosocial risk. To enhance the state of the science and inform evidence-based psychosocial services, future research should consider varied methodologies to comprehensively assess processes of risk and resilience with demographically and medically diverse populations.

Employing user-centered design to develop a remote technology kit for studying young children's social communication skills.

OBJECTIVE: The COVID-19 pandemic required behavioral researchers to rapidly pivot to the implementation of remote study protocols to facilitate data collection. Remote implementation required robust and flexible research protocols including reliable audio/visual technology that met all the quality, security, and privacy hallmarks of lab-based equipment, while also being portable and usable by nontechnical staff and participants. The project's primary purpose was to develop a technology kit that could be deployed for data collection in homes with young children. The secondary objective was to determine the feasibility of the kit for use longitudinally across four disparate sites. METHOD: User-centered design principles were employed in the development and implementation of a technology kit deployed across urban, suburban, and rural participant locations in four states. Preliminary feasibility and usability data were gathered to determine the reliability of the kit across three timepoints. RESULTS: In study 1, a technology kit was constructed addressing all project needs including the provision of the internet to connect remotely with participants. Staff training protocols and participant-facing materials were developed to accompany deployment procedures. In study 2, data gathered in technology logs demonstrated successful capturing of video footage in 96% of opportunities with most technology challenges mitigated. Subsequent behavioral coding indicated 100% of captured assessment footage has been successfully coded to date. Moreover, participants needed less support for technology setup at their later timepoints, and staff rated the kit as highly usable. CONCLUSION: This study offers a model for future development of technology use in remote community- and home-based pediatric research.

Public involvement in Australian clinical trials: A systematic review.

BACKGROUND: Public involvement enhances the relevance, quality, and impact of research. There is some evidence that public involvement in Australian research lags other countries, such as the United Kingdom. The purpose of the systematic review was to establish the rates and describe the characteristics of public involvement in Australian clinical trials. METHODS: We reviewed evidence of public involvement in all Australian randomised controlled trials published in the first 6 months of 2021. To determine the quality of public involvement, we used the five-item short-form version of the Guidance of Reporting Involvement Patients and the Public, version 2. RESULTS: In total, 325 randomised controlled trials were included, of which 17 (5%) reported any public involvement. Six trials reported public involvement in setting the research aim and seven in developing study methods. The authors of one study reflected on the overall role and influence of public involvement in the research. CONCLUSION: Rate of public involvement in Australian clinical trials is seemingly substantially lower than those reported in countries with similar advanced public health care systems, notably the United Kingdom. Our observations may be explained by a lack of researcher skills in how to involve the public and the failure by major funding agencies in Australia to mandate public involvement when deciding on how to award grant funding.

A case study evaluating the effect of clustering, publication bias, and heterogeneity on the meta-analysis estimates in implant dentistry.

Meta-analyses may provide imprecise estimates when important meta-analysis parameters are not considered during the synthesis. The aim of this case study was to highlight the influence of meta-analysis parameters that can affect reported estimates using as an example pre-existing meta-analyses on the association between implant survival and sinus membrane perforation. PubMed was searched on 7 July 2021 for meta-analyses comparing implant failure in perforated and non-perforated sinus membranes. Primary studies identified in these meta-analyses were combined in a new random-effects model with odds ratios (ORs), confidence intervals (CIs), and prediction intervals reported. Using this new meta-analysis, further meta-analyses were then undertaken considering the clinical, methodological, and statistical heterogeneity of the primary studies, publication bias, and clustering effects. The meta-analyses with the greatest number and more homogeneous studies provided lower odds of implant failure in non-perforated sites (OR 0.49, 95 % CI = [0.26, 0.92]). However, when considering heterogeneity, publication bias, and clustering (number of implants), the confidence in these results was reduced. Interpretation of estimates reported in systematic reviews can vary depending on the assumptions made in the meta-analysis. Users of these analyses need to carefully consider the impact of heterogeneity, publication bias, and clustering, which can affect the size, direction, and interpretation of the reported estimates.

Accounting for Competing Events When Evaluating Long-Term Outcomes in Survivors of Critical Illness.

The clinical trajectory of survivors of critical illness after hospital discharge can be complex and highly unpredictable. Assessing long-term outcomes after critical illness can be challenging because of possible competing events, such as all-cause death during follow-up (which precludes the occurrence of an event of particular interest). In this perspective, we explore challenges and methodological implications of competing events during the assessment of long-term outcomes in survivors of critical illness. In the absence of competing events, researchers evaluating long-term outcomes commonly use the Kaplan-Meier method and the Cox proportional hazards model to analyze time-to-event (survival) data. However, traditional analytical and modeling techniques can yield biased estimates in the presence of competing events. We present different estimands of interest and the use of different analytical approaches, including changes to the outcome of interest, Fine and Gray regression models, cause-specific Cox proportional hazards models, and generalized methods (such as inverse probability weighting). Finally, we provide code and a simulated dataset to exemplify the application of the different analytical strategies in addition to overall reporting recommendations.

Learning outcomes from a systematic review workshop series for junior doctors.

BACKGROUND: Systematic reviews provide the highest level of evidence about a topic. Ten-week workshops in conducting systematic reviews were held with hospital doctors in 2019 and 2020. AIM: This study analysed participants' feedback about the systematic review workshops to improve how we teach clinicians about conducting systematic reviews. METHODS: Attendees completed a post-workshop survey (with multiple-choice and free-text items) to assess knowledge and skills gained. We compared the responses of senior and junior doctors. We used descriptive statistics for the quantitative data and compared groups using Χ2 testing. Qualitative data were analysed using conceptual content analysis. RESULTS: Of 81 attendees, 52% completed the survey. Of those, 69% had no prior experience with systematic reviews, 93% reported increased knowledge and ability to conduct research and 69% reported increased ability to conduct systematic reviews. More senior than junior clinicians reported gaining knowledge about writing and publishing (37% vs 11%, P = 0.047) and making greater use of skills gained to conduct research (56% vs 23%, P = 0.029). Five themes were identified: learning through course structure; learning through course organisation; teaching style; flexible learning; and suggestions for progression and improvement. Respondents suggested running the workshops during protected teaching time, more time for some sessions, conducting the workshop series more often and making clinicians aware of the workshop series at hospital orientation. CONCLUSION: The skills learnt from the systematic review workshop series impacted not only participants' research knowledge and skills, and plans to conduct future research, but also facilitated looking up medical literature in daily clinical work, supporting evidence-based clinical practice.