Project description:The COVID-19 pandemic threatens to disrupt the provision of mental health services. In response, policymakers, administrators, and providers have taken bold steps toward enabling telepsychiatry to bridge this sudden gap in care for our most vulnerable populations. With rapid deregulation and adoption of this modality of care, careful consideration of issues related to policy and implementation is essential to maximize its effectiveness and mitigate unintended consequences. Though the crisis places the healthcare system under strain, it sets the stage for a lasting shift in not only how care is delivered, but also our beliefs around the system's capacity for rapid, innovative change.
Project description:BackgroundTo date different vaginal gel microbicides have been evaluated in phase 2b/3 trials, but none have demonstrated effectiveness for preventing HIV infection. Failure to demonstrate effectiveness however does not necessarily indicate that a product is truly inefficacious, as several sources of efficacy dilution may compromise our ability to identify products that may have been truly efficacious.MethodsFor four individual sources of dilution, we describe the dilution mechanisms and quantify the expected effectiveness. An overall expected effectiveness that combines all sources of dilution in a trial is derived as well.ResultsUnder conditions that have been observed in recent microbicide trials, the overall expected effectiveness assuming an active gel with true efficacy of 50% and 75% are in the range of [16%; 33%] and [28%; 50%], respectively, when considering the four major sources of dilution. In contrast the diluting effect due to adherence alone (assuming an adherence of 80%) leads to higher expected effectiveness, 40% and 60% assuming an active gel with true efficacy of 50% and 75%, respectively. Individual sources of dilution may demonstrate a small effect when evaluated independently, but the overall dilution effect in a trial with several sources of dilution can be quite substantial.ConclusionCurrently planned phase 2b/3 microbicide trials of new candidate vaginal microbicides are not immune from these shortcomings. A good understanding of dilution effects is necessary to properly interpret microbicide trial results and to identify products worthy of further development and evaluation. Greater attention should be devoted to reducing and assessing the impact of efficacy dilution and to carefully selecting the effect size in the design of future trials.
Project description:Adherence optimization and measurement have emerged as critically challenging issues for clinical trials of topical microbicides. Although microbicide trials have routinely collected adherence data, their utilization in trial design, implementation, and interpretation has been inconsistent. Drawing on data-driven presentations from several focused meetings, this paper synthesizes lessons from past microbicide trials and provides recommendations for future trials of microbicide and other HIV prevention technologies. First, it describes four purposes for adherence data collection, with particular attention to intention-to-treat versus adherence-adjusted analyses for determining effectiveness. Second, the microbicide field's experiences with adherence measures and data collection modes are discussed, including the strengths and weaknesses of various options and approaches for improving measurement. Then, several approaches to optimizing trial participants' adherence are presented. The paper concludes with a set of recommendations for immediate use or further research.
Project description:BackgroundConsiderable heterogeneity exists in treatment response to first-line posttraumatic stress disorder (PTSD) treatments, such as Cognitive Processing Therapy (CPT). Relatively little is known about the timing of when during a course of care the treatment response becomes apparent. Novel machine learning methods, especially continuously updating prediction models, have the potential to address these gaps in our understanding of response and optimize PTSD treatment.MethodsUsing data from a 3-week (n = 362) CPT-based intensive PTSD treatment program (ITP), we explored three methods for generating continuously updating prediction models to predict endpoint PTSD severity. These included Mixed Effects Bayesian Additive Regression Trees (MixedBART), Mixed Effects Random Forest (MERF) machine learning models, and Linear Mixed Effects models (LMM). Models used baseline and self-reported PTSD symptom severity data collected every other day during treatment. We then validated our findings by examining model performances in a separate, equally established, 2-week CPT-based ITP (n = 108).ResultsResults across approaches were very similar and indicated modest prediction accuracy at baseline (R2 ~ 0.18), with increasing accuracy of predictions of final PTSD severity across program timepoints (e.g. mid-program R2 ~ 0.62). Similar findings were obtained when the models were applied to the 2-week ITP. Neither the MERF nor the MixedBART machine learning approach outperformed LMM prediction, though benefits of each may differ based on the application.ConclusionsUtilizing continuously updating models in PTSD treatments may be beneficial for clinicians in determining whether an individual is responding, and when this determination can be made.
Project description:BACKGROUND: Access to affordable inhaled medicines for chronic respiratory diseases (CRDs) is severely limited in low- and middle-income countries (LMICs), causing avoidable morbidity and mortality. The International Union Against Tuberculosis and Lung Disease convened a stakeholder meeting on this topic in February 2022.METHODS: Focused group discussions were informed by literature and presentations summarising experiences of obtaining inhaled medicines in LMICs. The virtual meeting was moderated using a topic guide around barriers and solutions to improve access. The thematic framework approach was used for analysis.RESULTS: A total of 58 key stakeholders, including patients, healthcare practitioners, members of national and international organisations, industry and WHO representatives attended the meeting. There were 20 pre-meeting material submissions. The main barriers identified were 1) low awareness of CRDs; 2) limited data on CRD burden and treatments in LMICs; 3) ineffective procurement and distribution networks; and 4) poor communication of the needs of people with CRDs. Solutions discussed were 1) generation of data to inform policy and practice; 2) capacity building; 3) improved procurement mechanisms; 4) strengthened advocacy practices; and 5) a World Health Assembly Resolution.CONCLUSION: There are opportunities to achieve improved access to affordable, quality-assured inhaled medicines in LMICs through coordinated, multi-stakeholder, collaborative efforts.
Project description:The introduction of novel agents, characterized by favorable toxicity profiles and higher manageability compared to conventional drugs employed in the past, has considerably changed the treatment paradigm for multiple myeloma. Continuous therapy currently represents the standard approach for myeloma patients both at diagnosis and at relapse. In younger patients, long-term maintenance after autologous transplantation significantly improved progression-free survival and overall survival compared to observation. Also in transplant-ineligible patients, continuous treatment with combinations of newer agents and maintenance treatment following a more intense induction phase proved to be superior as compared to fixed-duration therapy. Maintenance and continuous therapy at diagnosis have shown to deepen responses and suppress minimal residual disease. At relapse, continuous therapy allowed better disease control over time. This review covers the main evidence supporting the use of continuous therapy in multiple myeloma as well as the open issues, such as the optimal agents to be used and the optimal candidates for receiving them.
Project description:Uterine leiomyomas are common and life-altering for many women. Despite a wide range of symptoms, varying characteristics of the uterus and the leiomyomas themselves, and many alternatives, hysterectomy accounts for almost three fourths of all surgical therapy, yet there is increasing evidence for a variety of procedural therapies for symptomatic leiomyomas and a new generation of medical therapies under development. With increasing evidence of long-term risk from hysterectomy and new data regarding leiomyoma biology, individualized medical approaches to leiomyomas are likely in the near future. Key biological attributes that influence this disease process are common driver mutations and the new appreciation of the interaction of smooth muscle cells and fibroblasts. Additionally, the interaction between cell types and steroid hormone responsiveness likely plays a role in pathogenesis that can be leveraged in individualized therapy. However, given the independent clonal nature of leiomyomas within the same uterus, moving in the direction of biopsies for individual leiomyomas to understand the biology is unlikely to be fruitful. Use of advanced imaging will likely continue to evolve not only to accurately predict malignant disease, including sarcomas, but to predict leiomyoma subtypes, response to therapy, or both. We predict the continued evolution of therapy from excisional or interventional therapies to medical therapies and ultimately prediction of at-risk individuals. Ideally, individualized therapies will offer primary prevention for women at high risk of leiomyomas and secondary prevention after initial treatment.