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.

Methodological and Reporting Quality of Noninferiority Randomized Controlled Trials Comparing Antiretroviral Therapies: A Systematic Review.

BACKGROUND: It is unclear whether the reporting quality of antiretroviral (ARV) noninferiority (NI) randomized controlled trials (RCTs) has improved since the CONSORT guideline release in 2006. The primary objective of this systematic review was assessing the methodological and reporting quality of ARV NI-RCTs. We also assessed reporting quality by funding source and publication year. METHODS: We searched Medline, Embase, and Cochrane Central from inception to 14 November 2022. We included NI-RCTs comparing ≥2 ARV regimens used for human immunodeficiency virus treatment or prophylaxis. We used the Cochrane Risk of Bias 2.0 tool to assess risk of bias. Screening and data extraction were performed blinded and in duplicate. Descriptive statistics were used to summarize data; statistical tests were 2 sided, with significance defined as P < .05. The systematic review was prospectively registered (PROSPERO CRD42022328586), and not funded. RESULTS: We included 160 articles reporting 171 trials. Of these articles, 101 (63.1%) did not justify the NI margin used, and 28 (17.5%) did not provide sufficient information for sample size calculation. Eighty-nine of 160 (55.6%) reported both intention-to-treat and per-protocol analyses, while 118 (73.8%) described missing data handling. Ten of 171 trials (5.9%) reported potentially misleading results. Pharmaceutical industry-funded trials were more likely to be double-blinded (28.1% vs 10.3%; P = .03) and to describe missing data handling (78.5% vs 59.0%; P = .02). The overall risk of bias was low in 96 of 160 studies (60.0%). CONCLUSIONS: ARV NI-RCTs should improve NI margin justification, reporting of intention-to-treat and per-protocol analyses, and missing data handling to increase CONSORT adherence.

Measures of Retention in HIV Care: A Study Within a Review.

People living with HIV (PLHIV) need lifelong medical care. However, retention in HIV care is not measured uniformly, making it challenging to compare or pool data. The objective of this study within a review (SWAR) is to describe the assortment of definitions used for retention in HIV care in randomized controlled trials (RCTs). We conducted a SWAR, drawing data from an overview of systematic reviews on interventions to improve the HIV care cascade. Ethics review was not required for this analysis of secondary data. We identified RCTs of interventions used to improve retention in care for PLHIV, including all age groups and extracted the definitions used and their characteristics. We identified 50 trials that measured retention published between 2007 and 2021 and provided 59 definitions for retention in care. The definitions consisted of nine different characteristics with follow-up time (n = 47), and clinical visits (n = 36) most used. The definitions of retention in HIV care are highly heterogeneous. In this study, we present the pros and cons of characteristics used to measure retention in HIV care.

A first case of prosthetic joint infection with Actinomyces radingae.

Prosthetic joint infection is a common clinical orthopedic problem but infections caused by Actinomyces species have been rarely reported. An increasing number of reports identifying Actinomyces in cases of prosthetic joint infection suggest it may be an emerging pathogen. We describe here the first known case of a prosthetic joint infection caused by Actinomyces radingae.

A pilot model of a public-private partnership for implementation of a coronavirus disease 2019 (COVID-19) diagnostic testing program to facilitate a safe school reopening.

Objective: We developed an implementation plan to integrate diagnostic testing for coronavirus disease 2019 (COVID-19) into a public school system. Implementation barriers were identified and strategies were mapped to overcome them. Design: A COVID-19 diagnostic testing program leveraging a public-private partnership was developed for a public school system. Setting: A suburban school district and a local hospital during the 2020-2021 academic year. Methods: Using Consolidated Framework for Implementation Research (CFIR) constructs and evidenced-based implementation strategies, the program was designed as a "closed system" and was adapted based on stakeholder feedback. Implementation barriers and facilitators were identified and mapped to CFIR constructs to provide insights into factors influencing program adoption. Results: Preimplementation stages of engagement, feasibility, and readiness planning were completed. The program did not progress to implementation due to multiple factors, including changes in school leadership (inner setting and process-level constructs), improved access to outside testing, and lack of an existing paradigm for in-school testing (external constructs). Limited support from key stakeholders and opinion leaders was also a barrier (process-level construct). Conclusions: Although this locally initiated program did not progress beyond the preimplementation stage, the processes developed and barriers identified may be useful to inform planning efforts in other testing programs within public school systems. Future programs may consider incorporating multiplex diagnostic testing for influenza in addition to COVID-19. With relaxation of infection control measures, the prevalence of other respiratory viruses will increase. Actionable results will be needed to inform decisions about closures and quarantines.

Cross-sectional trends in HIV prevalence among pregnant women in Botswana: an opportunity for PrEP?

INTRODUCTION: Young women in sub-Saharan Africa are at particularly high risk of HIV acquisition. Recent shifts towards "test and treat" strategies have potential to reduce transmission in this age group but have not been widely studied outside of clinical trials. Using data from nationwide surveillance among pregnant women in Botswana, where a "test and treat" program was implemented in 2016, we describe trends in HIV prevalence over time and highlight opportunities for targeted prevention. METHODS: The Tsepamo study abstracted data from obstetric records of all women delivering at eight government hospitals in Botswana between 2015 and 2019, accounting for 45% of all births in the country (n = 120,755). We used a stratified analysis to identify prevalence trends and evaluated decreases in HIV prevalence over time using the Cochrane-Armitage test for linear trend. A multivariable logistic regression analysis was also performed to identify factors associated with declines in HIV prevalence. RESULTS: Overall HIV prevalence was 24.1% among 120,755 women who delivered during the study period. Prevalence differed by site of delivery, ranging from 16.1% to 28.2%, and increased markedly with age. Lower educational attainment (adjusted odds ratio [aOR] = 3.28; 95% confidence interval [CI] 3.07-3.50) and being unmarried (aOR = 1.98; 95% CI 1.88-2.08) were associated with HIV infection. HIV prevalence was 10.0% with a first pregnancy, 21.0% with a second and 39.2% with a third or greater (aOR = 2.20; for any prior pregnancy; 95% CI 2.10-2.29). The same age-adjusted trends were seen when data were limited to women aged 15-24, with a two- to three-fold increase in HIV prevalence between a first and third pregnancy. Prevalence decreased linearly during the 5-year study period from 25.8% to 22.7% (p <0.001). Among age-specific strata, the greatest absolute decline occurred in those aged 35-39, with an 8.7% absolute decrease in HIV prevalence from 2015 to 2019. Minimal declines were seen in those 15-24, with a decrease of only 1.5% over the same period. CONCLUSIONS: While overall trends in Botswana show HIV prevalence declining among pregnant women, prevalence among the youngest age group has remained stagnant. Preventative interventions utilizing pre-exposure prophylaxis should be prioritized during the high-risk period surrounding a woman's first pregnancy.

Preventability of 30-Day Hospital Revisits Following Admission with COVID-19 at an Academic Medical Center.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic may have affected the preventability of 30-day hospital revisits, including readmissions and emergency department (ED) visits without admission. This study was conducted to examine the preventability of 30-day revisits for patients admitted with COVID-19 in order to inform the design of interventions that may decrease preventable revisits in the future. METHODS: The study team retrospectively reviewed a cohort of adults admitted to an academic medical center with COVID-19 between March 21 and June 29, 2020, and discharged alive. Patients with a 30-day revisit following hospital discharge were identified. Two-physician review was used to determine revisit preventability, identify factors contributing to preventable revisits, assess potential preventive interventions, and establish the influence of pandemic-related conditions on the revisit. RESULTS: Seventy-six of 576 COVID-19 hospitalizations resulted in a 30-day revisit (13.2%), including 21 ED visits without admission (3.6%) and 55 readmissions (9.5%). Of these 76 revisits, 20 (26.3%) were potentially preventable. The most frequently identified factors contributing to preventable revisits were related to the choice of postdischarge location and to patient/caregiver understanding of the discharge medication regimen, each occurring in 25.0% of cases. The most frequently cited potentially preventive intervention was "improved self-management plan at discharge," occurring in 65.0% of cases. Five of the 20 preventable revisits (25.0%) had contributing factors that were thought to be directly related to the COVID-19 pandemic. CONCLUSION: Although only approximately one quarter of 30-day hospital revisits following admission with COVID-19 were potentially preventable, these results highlight opportunities for improvement to reduce revisits going forward.

Immunotherapeutics to Treat HIV in the Central Nervous System.

PURPOSE OF REVIEW: The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system (CNS). Here we review the most promising immunotherapeutic strategies that can be used to target HIV in the CNS and focus on identifying their potential benefits while exploring the challenges that remain in their application. RECENT FINDINGS: We have identified five immunotherapeutic strategies that hold potential in managing CNS disease among HIV-infected patients. These include broadly neutralizing antibodies, multi-affinity antibodies, CAR-T cell therapy, checkpoint inhibitors, and therapeutic vaccines. Each class of immunotherapy presents unique mechanisms by which CNS viremia and latency may be addressed but are faced with several challenges. CAR-T cell therapy and multi-affinity antibodies seem to hold promise, but combination therapy is likely to be most effective. However, more human trials are needed before the clinical benefits of these therapies are realized.

Feasibility of remote administration of the Fundamentals of Laparoscopic Surgery (FLS) skills test.

BACKGROUND: Fundamentals of Laparoscopic Surgery (FLS) certification testing currently is offered at accredited test centers or at select surgical conferences. Maintaining these test centers requires considerable investment in human and financial resources. Additionally, it can be challenging for individuals outside North America to become FLS certified. The objective of this pilot study was to assess the feasibility of remotely administering and scoring the FLS examination using live videoconferencing compared with standard onsite testing. METHODS: This parallel mixed-methods study used both FLS scoring data and participant feedback to determine the barriers to feasibility of remote proctoring for the FLS examination. Participants were tested at two accredited FLS testing centers. An official FLS proctor administered and scored the FLS exam remotely while another onsite proctor provided a live score of participants' performance. Participant feedback was collected during testing. Interrater reliabilities of onsite and remote FLS scoring data were compared using intraclass correlation coefficients (ICCs). Participant feedback was analyzed using modified grounded theory to identify themes for barriers to feasibility. RESULTS: The scores of the remote and onsite proctors showed excellent interrater reliability in the total FLS (ICC 0.995, CI [0.985-0.998]). Several barriers led to critical errors in remote scoring, but most were accompanied by a solution incorporated into the study protocol. The most common barrier was the chain of custody for exam accessories. CONCLUSION: The results of this pilot study suggest that remote administration of the FLS has the potential to decrease costs without altering test-taker scores or exam validity. Further research is required to validate protocols for remote and onsite proctors and to direct execution of these protocols in a controlled environment identical to current FLS test administration.

Health biotechnology innovation on a global stage.

With increasing globalization, infectious diseases are spreading faster than ever before, creating an urgent need for international collaboration. The rise of emerging economies has changed the traditional collaborative landscape and provided opportunities for more diverse models of collaboration involving developing countries, including North-South, South-South and North-South-South partnerships. Here, we discuss how developing countries can partner with other nations to address their shared health problems and to promote innovation. We look specifically at what drives collaborations and at the challenges that exist for them, and we propose actions that can strengthen these partnerships.

The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan.

BACKGROUND: Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan - a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies. DISCUSSION: Building on the knowledge of a traditional medicine practitioner, Nigeria's National Institute for Pharmaceutical Research and Development (NIPRD) developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan's commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward. SUMMARY: Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due diligence, and recruiting entrepreneurial leaders capable of holding dual scientific and business responsibilities should be incorporated into future drug development initiatives based on traditional medicines. Country-level supporting policies and conditions are also important. With more experience and support, and an improved environment for innovation, developing new drugs from traditional medicines may be an attractive approach to addressing diseases in sub-Saharan Africa and other regions.