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Neurosurgery has experienced significant growth over the past century, but much of that development has been centralized in Europe and North America. Despite their high burden of neurosurgical conditions, African countries like The Gambia continue to face barriers in accessing neurosurgical care. We intend to accentuate the barriers to neurosurgical care in The Gambia, elucidate pragmatic ways of improving this issue, and highlight models of sustainable neurosurgical development that have been used in similar lower- and middle-income countries. Our study analyzed the limited literature available on The Gambia's neurosurgical capabilities, disease burden, and outcomes. The keywords "Gambia" and "Neurosurgery" were searched on PubMed, from inception to July 1, 2024. Then, a complementary search was performed on Google using the keywords "The Gambia," "Healthcare," "Neurosurgery," and "Africa." The pertinent data from our search were collected and composed into a review. Neurosurgery in The Gambia is still in its infancy. Although several domestic general surgeons and a few visiting neurosurgeons have performed neurosurgical procedures in the past, the country did not have a designated neurosurgical department until 2018. Although neurosurgical activity has ramped up in The Gambia recently, the country continues to trail behind both regionally and internationally in neurosurgical care capacity. While the shortage of a neurosurgical workforce is the core of this issue, paucity of neurosurgical research and training and the limited availability of neuroimaging also amplify this problem. Neurosurgery in The Gambia is plodding because of workforce shortage, paucity of research, and inadequate neuroimaging. Eradicating these barriers would be salient in attaining sustainable neurosurgical development. With the devotion of the local team and the philanthropic efforts of international partners, The Gambia can experience similar advances seen in other lower- and middle-income countries., Competing Interests: The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article., (© The Author(s) 2024. Published by Wolters Kluwer Health, Inc. on behalf of Congress of Neurological Surgeons.)

Deep brain stimulation (DBS) has emerged as a crucial therapeutic strategy for various neurological and psychiatric disorders. Precise target localization is essential for optimizing therapeutic outcomes, necessitating advanced neuroimaging techniques. Normative atlases provide standardized references for accurate electrode placement, enhancing treatment customization and efficacy. This comprehensive review explores the application of normative atlases in DBS, emphasizing their role in target identification, patient-specific electrode placement, and predicting stimulation outcomes. Challenges, such as variability across atlases and technical complexities, are addressed alongside future directions and innovations, including advancements in neuroimaging technologies and the integration of machine learning (ML) and artificial intelligence (AI). Normative atlases play a pivotal role in enhancing DBS precision and patient outcomes, promising a future of personalized and effective therapies in neurology and psychiatry., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Streptococcus pneumoniae (Spn) has been a leading cause of bacterial meningitis in children. The most recent estimation of the global burden of Spn meningitis indicates a positive trajectory in eliminating Spn through the implementation of pneumococcal conjugate vaccines. However, continuous monitoring and assessment of the disease burden are necessary due to the evidence of serotype replacement, antibiotic resistance, and the impact of the recent COVID-19 pandemic., Objective: The aim of this systematic review is to provide an updated and focused assessment of the global and regional burden of Spn meningitis in children, which can guide policies and strategies to reduce the disease burden., Methods: Population-based studies published from January 1, 2000, to January 1, 2022, were preliminarily searched from the electronic databases PubMed, Embase, Global Health (CABI), and CINAHL Plus without any language restrictions. Studies were included if they reported the incidence, prevalence, mortality, or case-fatality ratio (CFR) for Spn meningitis in children aged 0-4 years; meningitis was confirmed by cerebrospinal fluid culture; the study period was a minimum of 1 year; the number of reported cases was at least 10; and the study had no methodological ambiguities. The article screening process follows the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Characteristics including study period, setting, World Health Organization region, income level, vaccination information, and participant data (age, number of cases, deaths, sequelae, and risk factors) will be extracted from the included studies. Search results will be updated and incorporated into our review prior to finalizing the extraction of data. Generalized linear mixed models meta-analysis will be performed to estimate the pooled incidence and CFR. We will further assess the risk of bias and heterogeneity, and will perform subgroup and sensitivity analyses to provide a meaningful interpretation of the current burden and literature for pneumococcal meningitis., Results: Our preliminary search in December 2021 yielded 9295 articles. Out of 275 studies that were assessed with our eligibility criteria, 117 articles were included. Data extraction and analysis are expected to be complete by January 2025. We plan to publish the results from the full study, including an updated search in 2024, by March 2025., Conclusions: Given that the major burden of Spn meningitis affects children under the age of 5 years, this systematic review will provide a thorough understanding of the global burden of Spn meningitis in this vulnerable population over a span of 2 decades. Insights into incidence trends, geospatial distribution, risk factors, and sequelae will be valuable for stakeholders, policy makers, and the academic community. This information will aid in the ongoing monitoring of the disease and in enhancing targeted vaccine programs to further mitigate the impact of the disease on children worldwide., Trial Registration: PROSPERO CRD42021293110; https://tinyurl.com/kc3j5k4m., International Registered Report Identifier (irrid): DERR1-10.2196/50678., (©Jay J Park, Jakov Tiefenbach, Mohammed Ma'arij Anwar, Sandhya Narayanan, Beatrice Ope, Selene Seo Bin Han, Boni Maxime Ale, Davies Adeloye, Igor Rudan. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.07.2024.)

It is well known that medication adherence is critical to patient outcomes and can decrease patient mortality. The Pharmacy Quality Alliance (PQA) has recognized and identified medication adherence as an important indicator of medication-use quality. Hence, there is a need to use the right methods to assess medication adherence. The PQA has endorsed the proportion of days covered (PDC) as the primary method of measuring adherence. Although easy to calculate, the PDC has however several drawbacks as a method of measuring adherence. PDC is a deterministic approach that cannot capture the complexity of a dynamic phenomenon. Group-based trajectory modeling (GBTM) is increasingly proposed as an alternative to capture heterogeneity in medication adherence. The main goal of this paper is to demonstrate, through a simulation study, the ability of GBTM to capture treatment adherence when compared to its deterministic PDC analogue and to the nonparametric longitudinal K-means. A time-varying treatment was generated as a quadratic function of time, baseline, and time-varying covariates. Three trajectory models are considered combining a cat's cradle effect, and a rainbow effect. The performance of GBTM was compared to the PDC and longitudinal K-means using the absolute bias, the variance, the c-statistics, the relative bias, and the relative variance. For all explored scenarios, we find that GBTM performed better in capturing different patterns of medication adherence with lower relative bias and variance even under model misspecification than PDC and longitudinal K-means., (© 2024 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Clinical trials in public health-particularly those conducted in low- and middle-income countries-often involve communicable and non-communicable diseases with high disease burden and unmet needs. Trials conducted in these regions often are faced with resource limitations, so improving the efficiencies of these trials is critical. Adaptive trial designs have the potential to save trial time and resources and reduce the number of patients receiving ineffective interventions. In this paper, we provide a detailed account of the implementation of vaccine and cluster randomized trials within the framework of Bayesian adaptive trials, with emphasis on computational efficiency and flexibility with regard to stopping rules and allocation ratios. We offer an educated approach to selecting prior distributions and a data-driven empirical Bayes method for plug-in estimates for nuisance parameters., (© 2024 John Wiley & Sons Ltd.)

Importance: Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease., Objective: To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19., Design, Setting, and Participants: In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs., Exposures: Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point., Main Outcomes and Measures: Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores., Results: A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences., Conclusions and Relevance: In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

Primitive myxoid mesenchymal tumour of infancy (PMMTI) is a rare mesenchymal tumour that typically appears in those under 6 months of age and preferentially affects the deep soft tissues of the trunk and paravertebral spinal regions. PMMTI has only recently been described, and there is scarce literature reporting cases regarding the management paradigm of the tumour. We report the case of an 11-week-old male who presented with bilaterally reduced movement and brisk reflexes in his lower limbs, and irritability. Despite numerous radiological investigations, including MRI, PMMTI was only diagnosed upon biopsy and histopathology. Although PMMTI is known to be relatively unresponsive to chemotherapy, we observed a notable decrease in tumour size after a series of chemotherapy sessions. After two-staged surgical resection of the tumour, the patient is currently stable and under close follow-up. In this article, we aim to report on the patient's clinical presentation, investigations, diagnosis, and treatment, while also discussing the findings from a review of the literature pertaining to future approaches in managing PMMTI. Overall, this case highlights the importance of considering PMMTI in the differential diagnosis of deep soft tissue tumours in young infants and the potential for a combination of chemotherapy and surgical resection to be effective in treating this rare tumour., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Clinical neuroscience training programmes are becoming increasingly competitive to enter. UK university neuroscience societies act as a local environment for students to develop their career interests and provide portfolio building opportunities through hosting events such as annual conferences. Recently there has been a transition to more of these events being held online yet the impact of this, if any, remains unclear. This prospective study aimed to identify the impact of student-led neuroscience conferences on delegates and examine attitudes towards an online delivery approach., Methods: Multi-centre prospective survey study using pre-conference, post-conference, and 6-month post-conference online questionnaires distributed at 6 virtual student-led neuroscience conferences in 2021. The questionnaires had five-domains: demographics, career aspirations, academic skillsets, an educational manipulation check (EMC) and mode of delivery preference., Results: Nine hundred twenty-four surveys were completed across 559 conference attendances. 79.9% of delegates were medical students. Interest in a neuroscience career (p < 0.001), preparedness to undertake research (p < 0.001) and presentation (p < 0.001), as well as EMC scores (p < 0.001) increased immediately post conference. Most participants at 6 months post-attendance had completed an academic project (71.9%) or presentation (50.9%), although 88.8% were lost to follow up. Online format was preferred (65%) with reasons including elimination of travel and access to home facilities whilst lack of face-to-face interaction and engagement were recognised limitations., Conclusion: UK student-led online neuroscience conferences play a role in developing knowledge and may facilitate career interest, academic skillset and longer term portfolio building. A hybrid virtual and in-person experience would offer an ideal solution to future conferencing, providing options promoting engagement and interactivity whilst advocating sustainability, accessibility and widening participation., (© 2023. The Author(s).)

Introduction: The utilisation of artificial intelligence (AI) augments intraoperative safety, surgical training, and patient outcomes. We introduce the term Surgeon-Machine Interface (SMI) to describe this innovative intersection between surgeons and machine inference. A custom deep computer vision (CV) architecture within a sparse labelling paradigm was developed, specifically tailored to conceptualise the SMI. This platform demonstrates the ability to perform instance segmentation on anatomical landmarks and tools from a single open spinal dural arteriovenous fistula (dAVF) surgery video dataset., Methods: Our custom deep convolutional neural network was based on SOLOv2 architecture for precise, instance-level segmentation of surgical video data. Test video consisted of 8520 frames, with sparse labelling of only 133 frames annotated for training. Accuracy and inference time, assessed using F1-score and mean Average Precision (mAP), were compared against current state-of-the-art architectures on a separate test set of 85 additionally annotated frames., Results: Our SMI demonstrated superior accuracy and computing speed compared to these frameworks. The F1-score and mAP achieved by our platform were 17% and 15.2% respectively, surpassing MaskRCNN (15.2%, 13.9%), YOLOv3 (5.4%, 11.9%), and SOLOv2 (3.1%, 10.4%). Considering detections that exceeded the Intersection over Union threshold of 50%, our platform achieved an impressive F1-score of 44.2% and mAP of 46.3%, outperforming MaskRCNN (41.3%, 43.5%), YOLOv3 (15%, 34.1%), and SOLOv2 (9%, 32.3%). Our platform demonstrated the fastest inference time (88ms), compared to MaskRCNN (90ms), SOLOV2 (100ms), and YOLOv3 (106ms). Finally, the minimal amount of training set demonstrated a good generalisation performance -our architecture successfully identified objects in a frame that were not included in the training or validation frames, indicating its ability to handle out-of-domain scenarios., Discussion: We present our development of an innovative intraoperative SMI to demonstrate the future promise of advanced CV in the surgical domain. Through successful implementation in a microscopic dAVF surgery, our framework demonstrates superior performance over current state-of-the-art segmentation architectures in intraoperative landmark guidance with high sample efficiency, representing the most advanced AI-enabled surgical inference platform to date. Our future goals include transfer learning paradigms for scaling to additional surgery types, addressing clinical and technical limitations for performing real-time decoding, and ultimate enablement of a real-time neurosurgical guidance platform., Competing Interests: VB and JS filed intellectual property that initiated this work. VB has equity ownership in TAIRIS, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Park, Doiphode, Zhang, Pan, Blue, Shi and Buch.)

Purpose: Substandard quality across published randomized controlled trials (RCTs) is a major concern. Imperfect reporting has the potential to distort the evidence landscape and waste valuable health-care resources. In this study, we aim to assess the current quality of reporting in the field of spine using a modified version of the Consolidated Standards of Reporting Trials (CONSORT) checklist., Materials and Methods: A list of published RCTs in the field of spine disease from January 1, 2013, to December 31, 2020, was built. Two reviewers scored the published RCTs against a modified CONSORT checklist. The mean adjusted CONSORT scores for each study, reporting category, and checklist item were calculated., Results: The mean and median scores across all of the RCTs were 0.72 and 0.74 out of 1.00, respectively. The spectrum of scores was wide, ranging from 0.45 to 0.94. The reporting categories with the lowest score included randomization, blinding, and abstract. The items which were most under-reported included allocation sequence generation, type of randomization used, full trial protocol details, and abstract methodology. The inter-rater reliability between our reviewers was substantial (κ = 0.7, κ = 0.71)., Conclusion: Our findings correlate with only a moderate level of compliance to the CONSORT criteria on the quality of reporting for RCTs in spinal conditions. This is in line with previous reports on compliance, both within and outside the field of spinal conditions. Further continued and sustained efforts are still required to enhance the quality and consistency of RCT reporting, ultimately reducing health-care resource wastage and improving patient safety., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Craniovertebral Junction and Spine.)

Background: Current guidelines set clinical standards for the management of suspected first seizures and epilepsy. We aimed to assess if these standards are being met across first seizure clinics nationally, to describe variations in care and identify opportunities for service delivery improvement., Methods: Multicentre audit assessing the care of adults (≥16 years) referred to first seizure clinics from 31st December 2019 going backwards (30 consecutive patients per centre). Patients with pre-existing diagnosis of epilepsy were excluded. Anonymised referral, clinic, and follow-up data are reported with descriptive statistics., Results: Data provided for 727 patients from 25 hospitals in the UK and Ireland (median age 41 years [IQR 26-59], 52% males). Median time to review was 48 days (IQR 26-86), with 13.8% (IQR 3.3%-24.0%) of patients assessed within 2 weeks. Seizure recurrence was seen in 12.7% (IQR 6.6%-17.4%) of patients awaiting first appointment. Documentation for witness accounts and driving advice was evident in 85.0% (IQR 74.0%-100%) and 79.7% (IQR 71.2%-96.4%) of first seizure/epilepsy patients, respectively. At first appointment, discussion of sudden unexpected death in epilepsy was documented in 30.1% (IQR 0%-42.5%) of patients diagnosed with epilepsy. In epilepsy patients, median time to MRI neuroimaging was 37 days [IQR 22-56] and EEG was 30 days [IQR 19-47]. 30.4% ([IQR 0%-59.5%]) of epilepsy patients were referred to epilepsy nurse specialists., Conclusions: There is variability nationally in the documented care of patients referred to first seizure clinics. Many patients are facing delays to assessment with epilepsy specialists with likely subsequent impact on further management., Competing Interests: Declaration of Competing Interest None to declare. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: Improving the targeted use of drug regimens requires robust real-world evidence (RWE) to address the uncertainties that remain regarding their real-world performance following market entry. However, challenges in the current state of RWE production limit its impact on clinical decisions, as well as its operational scalability and sustainability. We propose an adaptive point-of-care (APoC) platform trial as an approach to RWE production that improves both clinical and operational efficiencies., Methods and Findings: We explored design innovations, operational challenges, and infrastructure needs within a multi-stakeholder consortium to evaluate the potential of an APoC platform trial for studying chronic disease treatment regimens using rheumatoid arthritis as a case study. The concept integrates elements from adaptive clinical trials (dynamic treatment regimen strategies) and point-of-care trials (research embedded into routine clinical care) under a perpetual platform infrastructure. The necessary components to implement an APoC platform trial within outpatient settings exist, and present an opportunity for a cross-disciplinary, multi-stakeholder approach. Effective engagement of key stakeholders involved in and impacted by the platform is critical to success. Our collaborative design process identified three high-impact stakeholder-engagement areas: (1) focus on research question(s), (2) design and implementation planning such that it is feasible and fit-for-purpose, and (3) measurement, or meaningful metrics for both clinical (patient outcomes) and system (operational efficiencies) impact., Conclusions: An APoC platform trial for rheumatoid arthritis integrating innovative design elements in a scalable infrastructure has the potential to reduce important uncertainties about the real-world performance of biomedical innovations and improve clinical decisions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Hirsch reported receiving support for the present manuscript from the NEWDIGS initiative under MIT's Center for Biomedical Innovation (CBI) and from the NEWDIGS initiative under Tufts Medical Center's Center for Biomedical System Design (CBSD). Dr. Velentgas reported receiving support for the present manuscript from IQVIA (past position). Dr. Curtis reported receiving grants from Abbvie, Amgen, GHLF, BMS, CorEvitas, GSK, Janssen, Lilly, Myriad, Novartis, Pfizer, Sanofi, UCB, consulting fees from Abbvie, Amgen, GHLF, BMS, CorEvitas, GSK, Illumination Health, Janssen, Lilly, Myriad, Novartis, Pfizer, Sanofi, Scipher, UCB, and other financial or non-financial interests in Illumination Health. Dr. Larholt reported receiving support for the present manuscript from the NEWDIGS initiative under MIT's Center for Biomedical Innovation (CBI) and reported receiving stock options from Johnson & Johnson. Dr. Park reported being an employee of Core Clinical Sciences, Inc. No other disclosures were reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Hydrocephalus and myelomeningocele (MMC) place disproportionate burdens of disease on low-income and middle-income countries (LMICs). MMC-associated hydrocephalus and its sequelae result in a spectrum of severely devastating clinical manifestations, for which LMICs are disproportionately unprepared in terms of human, capital and technological resources. This study aims to review and compare the management and outcomes of infant MMC-associated hydrocephalus in LMICs and high-income countries., Methods and Analysis: This systematic review and meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. The following databases will be searched without restrictions on language, publication date or country of origin: EMBASE, MEDLINE, The Cochrane Library, Global Index Medicus, African Journals Online and SciELO. All peer-reviewed studies of primary data reporting management and outcomes of infant MMC-associated hydrocephalus will be included. Where high-quality homogeneous studies exist, meta-analyses will be conducted to compare the management and outcomes of MMC-associated hydrocephalus across socioeconomic and geographical regions of the world. The primary outcome will be treatment failure of the first-line hydrocephalus treatment, which we defined operationally as the performance of a second intervention for the same reason as the first. Secondary outcomes include time to failure, rates of mortality and postoperative complications., Ethics and Dissemination: Ethical approval was not applicable because this study does not involve human participants. Dissemination strategies will include publication in a peer-reviewed journal, oral and poster presentations at conferences and an interactive web application to facilitate interaction with the findings and promote the discussion and sharing of findings on social media., Prospero Registration Number: CRD42021285850., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We describe a case of a young male patient with KRIT1-driven familial cavernous malformation syndrome who developed multiple brain cavernomas, intracranial bleeding, and persistent seizures. Due to the relentless growth of cavernous malformations and recurrent intracranial bleeds, it was decided to enrol the patient in the "Propranolol for Intracranial Cavernoma" (PICC) pilot trial at our institution. Over the 5-year treatment period with 20 to 40-mg oral propranolol three times daily (TDS), we noted the near-complete arrest of the growth of cavernous malformations with no further evidence of intracranial bleeding or any further seizures. The observed outcome is consistent with the extremely limited published literature on the topic; thus, this case provides important evidence that supports the use of propranolol as a prophylactic treatment for paediatric intracranial cavernomas. We strongly encourage and recommend future prospective randomised controlled trials to definitively assess and characterize the therapeutic utility of propranolol in this patient population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Artificial Intelligence (AI) plays an integral role in enhancing the quality of surgical simulation, which is increasingly becoming a popular tool for enriching the training experience of a surgeon. This spans the spectrum from facilitating preoperative planning, to intraoperative visualisation and guidance, ultimately with the aim of improving patient safety. Although arguably still in its early stages of widespread clinical application, AI technology enables personal evaluation and provides personalised feedback in surgical training simulations. Several forms of surgical visualisation technologies currently in use for anatomical education and presurgical assessment rely on different AI algorithms. However, while it is promising to see clinical examples and technological reports attesting to the efficacy of AI-supported surgical simulators, barriers to wide-spread commercialisation of such devices and software remain complex and multifactorial. High implementation and production costs, scarcity of reports evidencing the superiority of such technology, and intrinsic technological limitations remain at the forefront. As AI technology is key to driving the future of surgical simulation, this paper will review the literature delineating its current state, challenges, and prospects. In addition, a consolidated list of FDA/CE approved AI-powered medical devices for surgical simulation is presented, in order to shed light on the existing gap between academic achievements and the universal commercialisation of AI-enabled simulators. We call for further clinical assessment of AI-supported surgical simulators to support novel regulatory body approved devices and usher surgery into a new era of surgical education., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Park, Tiefenbach and Demetriades.)

This review discusses the potential significance of glymphatic system dysfunction in the pathophysiology of idiopathic intracranial hypertension (IIH). IIH is a clinical syndrome characterised by signs and symptoms which arise from raised intracranial pressure (ICP), in the absence of a clear primary cause of intracranial hypertension. The underlying pathophysiological mechanisms driving IIH remain unclear and raised cerebrospinal fluid (CSF) secretion, reduced fluid drainage, and elevated cerebral venous sinus pressure do not fully explain the condition's aetiology. There is a growing literature which implicates the glymphatic system, a mechanism by which fluid moves into the brain parenchyma via peri-arterial channels and out via perivenous spaces and brain lymphatics, in IIH pathogenesis. We propose that aquaporin-4 (AQP4) changes, neurogliovascular unit disruption, a pro-inflammatory CSF profile and impaired glymphatic outflow are the main mechanisms driving glymphatic dysfunction in IIH. However, it remains unclear which of these mechanisms are primary causes and which are secondary effects. Further studies using CSF tracers, electron microscopy, and immunohistochemistry are needed to better evaluate the cellular and molecular pathology associated with IIH at different timepoints in the disease course, which will help elucidate the mechanistic role of the glymphatic system in the condition's pathogenesis., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: The scale of waste in research funding systems is large and detrimental to research capacity. Both incompleteness and non-publication of Randomised Controlled Trials (RCTs) have been increasingly reported in the literature. This is a serious consequence as RCTs demand monumental amounts of healthcare resources leading to wastage. Most importantly, both under-reporting and non-publication can distort the evidence landscape and obscure rationale behind clinical decisions., Research Question: We, therefore, aimed at conducting the first systematic assessment of registered trial discontinuation and non-publication in the field of spinal disorders., Material and Methods: A list of RCTs was obtained from the U.S National Library of Medicine ClinicalTrials.gov database from January 1st, 2013, to December 31st, 2020. Two independent authors excluded all non-RCTs, trials unrelated to spinal diseases, and trials that are in or before the recruitment phase. We extracted the progress status, sources of funding, the number of centres, type of intervention, principal investigator's department affiliation, publication status, location, the reason for discontinuation, publication date, and subtopics., Results: 112 trials were included in the study. 25 (22%) trials were discontinued early, with slow recruitment being the major reason (38%). Only 56 (50%) of the trials were published in peer-reviewed journals. The publication rate amongst discontinued trials was significantly lower compared to completed trials ( P  ​< ​0·001). The trial discontinuation rate was much higher in trials registered in the United States (US) compared to other countries ( P  ​= ​0·009). Industry-sponsored studies had 11 trials (23·4%) that were discontinued whilst there was 20% of non-industry-sponsored studies that were unfinished. Only 20% of the trials were compliant with the FDA reporting requirements over the study period., Discussion and Conclusion: Nearly a quarter of all trials in spinal disorders were discontinued. Half of the trials were unpublished. There was over a third of trials that were completed but not published. These rates remain worrisome from an ethical and financial perspective. Both under-reporting and non-publication adversely affect efforts in evidence synthesis and can compromise clinical guideline development., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article., (© 2022 The Authors.)

Importance: Platform trial design allows the introduction of new interventions after the trial is initiated and offers efficiencies to clinical research. However, limited guidance exists on the economic resources required to establish and maintain platform trials., Objective: To compare cost (US dollars) and time requirements of conducting a platform trial vs a series of conventional (nonplatform) trials using a real-life example., Design, Setting, and Participants: For this economic evaluation, an online survey was administered to a group of international experts (146 participants) with publication records of platform trials to elicit their opinions on cost and time to set up and conduct platform, multigroup, and 2-group trials. Using the reported entry dates of 10 interventions into Systemic Therapy in Advancing Metastatic Prostate Cancer: Evaluation of Drug Efficacy, the longest ongoing platform trial, 3 scenarios were designed involving a single platform trial (scenario 1), 1 multigroup followed by 5 2-group trials (scenario 2), and a series of 10 2-group trials (scenario 3). All scenarios started with 5 interventions, then 5 more interventions were either added to the platform or evaluated independently. Simulations with the survey results as inputs were used to compare the platform vs conventional trial designs. Data were analyzed from July to September 2021., Exposure: Platform trial design., Main Outcomes and Measures: Total trial setup and conduct cost and cumulative duration., Results: Although setup time and cost requirements of a single trial were highest for the platform trial, cumulative requirements of setting up a series of multiple trials in scenarios 2 and 3 were larger. Compared with the platform trial, there was a median (IQR) increase of 216.7% (202.2%-242.5%) in cumulative setup costs for scenario 2 and 391.1% (365.3%-437.9%) for scenario 3. In terms of total cost, there was a median (IQR) increase of 17.4% (12.1%-22.5%) for scenario 2 and 57.5% (43.1%-69.9%) for scenario 3. There was a median (IQR) increase in cumulative trial duration of 171.1% (158.3%-184.3%) for scenario 2 and 311.9% (282.0%-349.1%) for scenario 3. Cost and time reductions in the platform trial were observed in both the initial and subsequently evaluated interventions., Conclusions and Relevance: Although setting up platform trials can take longer and be costly, the findings of this study suggest that having a single infrastructure can improve efficiencies with respect to costs and efforts.

Introduction: Healthcare students have played a significant role in the National Health Service during the COVID-19 pandemic. We captured data on the well-being of medical students during the acute phase of the pandemic with the Social and Psychological Impact of COVID-19 on medical students: a national survey Evaluation (SPICE-19) study. We will evaluate changes in mental health and well-being of medical and nursing students 1 year after SPICE-19, in a cross-sectional study, to understand the impact of the pandemic, and inform well-being policies., Methods and Analysis: This study will be a national, multi-institution, cross-discipline study. An online 53-item survey of demographics, mental health and well-being will be used to record responses. Students studying for a medical or nursing degree at any UK universities will be eligible to participate. The survey will be advertised through the Neurology and Neurosurgery Interest Group national network. Participation is anonymous and voluntary, with relevant mental health resources made available to participants., Ethics and Dissemination: Ethical approval was granted by the University of Oxford Central University Research Ethics Committee (R75719/RE001) on 21 May 2021. Study findings will be presented at national and international meetings, and submitted for publication in a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Collaboration and successful teamworking are important components of clinical practise, and these skills should be cultivated early in medical school. The breadth of current medical school curricula means that students often have limited exposure to clinical neurosciences. Since its inception in 2009, the Neurology and Neurosurgery Interest Group (NANSIG) has become a national (UK and Republic of Ireland) example of student and junior doctor synergistic collaboration to deliver educational materials, research, conferences, seminars and workshops, as well as advocating for diversity in this field. Recently, it has expanded to incorporate an international audience and cater for a larger group of young medical professionals. The organisation has overcome numerous challenges and is constantly innovating new approaches to harness the necessary knowledge, skills and network to succeed in a career in neurosciences, neurology and neurosurgery. This article summarises the initiatives undertaken by the group over its first 10 years of existence and its organisational structure, as well as its future plans., (© 2022. The Author(s).)

Background: Haemophilus influenzae Type B (Hib) meningitis caused significant public health concern for children. Recent assessment in 2015 suggests vaccination has virtually eliminated invasive Hib diseases. However, many countries launched their programs after 2010, and few are yet to establish routine Hib immunisations. We therefore aimed to update the most recent global burden of Hib meningitis before the impact of COVID-19 pandemic, from 2010 to 2020, in order to aid future public health policies on disease management and prevention., Methods: Epidemiological data regarding Hib meningitis in children <5 years old were systematically searched and evaluated from PubMed and Scopus in August, 2020. We included studies published between 2010 and 2019 that reported incidence, prevalence, mortality, or case-fatality-ratio (CFR), and confirmation of meningitis by cerebrospinal fluid culture, with a minimum one year study period and ten cases. Each data was stratified by one study-year. Median study-year was used if information was not available. Quality of all studies were assessed using our adapted assessment criteria from Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Study Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from National Heart, Lung and Blood Institute (NHLBI). We constructed and visually inspected a funnel plot of standard error by the incidence rate and performed an Egger's regression test to statistically assess publication bias. To ascertain incidence and CFR, we performed generalised linear mixed models on crude individual study estimates. Heterogeneity was assessed using I-squared statistics whilst further exploring heterogeneity by performing subgroup analysis., Results: 33 studies were identified. Pooled incidence of global Hib meningitis in children was 1.13 per 100 000-child-years (95% confidence interval (CI) = 0.80-1.59). Southeast Asian Region (SEAR) of World Health Organisation (WHO) region reported the highest incidence, and European Region (EUR) the lowest. Considering regions with three or more data, Western Pacific Region (WPR) had the highest incidence rate of 5.22 (95% CI = 3.12-8.72). Post-vaccination incidence (0.67 cases per 100 000-child-years, 95% CI = 0.48-0.94) was dramatically lower than Pre-vaccination incidence (4.84 cases per 100 000-child-years, 95% CI = 2.95-7.96). Pooled CFR in our meta-analysis was 11.21% (95% CI = 7.01-17.45). Eastern Mediterranean Region (EMR) had the highest CFR (26.92, 95% CI = 13.41-46.71) while EUR had the lowest (4.13, 95% CI = 1.73-9.54). However, considering regions with three or more data, African Region (AFR) had the highest CFR at 21.79% (95% CI = 13.65-32.92). Before the coronavirus disease 2019 (COVID-19) impact, the estimation for global Hib meningitis cases in 2020 is 7645 and 857 deaths., Conclusions: Global burden of Hib meningitis has markedly decreased, and most regions have implemented vaccination programs. Extrapolating population-at-risk from studies has possibly led to an underestimation. Continuous surveillance is necessary to monitor vaccination impact, resurgence, vaccine failures, strain variance, COVID-19 impact, and to track improvement of regional and global Hib meningitis mortality., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest. Igor Rudan is the Co-Editor in Chief of the Journal of Global Health. To ensure that any possible conflict of interest relevant to the journal has been addressed, this article was reviewed according to best practice guidelines of international editorial organisations., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Platform trials are a type of randomized clinical trial that allow simultaneous comparison of multiple intervention groups against a single control group that serves as a common control based on a prespecified interim analysis plan. The platform trial design enables introduction of new interventions after the trial is initiated to evaluate multiple interventions in an ongoing manner using a single overarching protocol called a master (or core) protocol. When multiple treatment candidates are available, rapid scientific therapeutic discoveries may be made. Platform trials have important potential advantages in creating an efficient trial infrastructure that can help address critical clinical questions as the evidence evolves. Platform trials have recently been used in investigations of evolving therapies for patients with COVID-19. The purpose of this Users' Guide to the Medical Literature is to describe fundamental concepts of platform trials and master protocols and review issues in the conduct and interpretation of these studies. This Users' Guide is intended to help clinicians and readers understand articles reporting on interventions evaluated using platform trial designs.

The global demand for coronavirus disease 2019 (COVID-19) vaccines currently far outweighs the available global supply and manufacturing capacity. As a result, securing doses of vaccines for low- and middle-income countries has been challenging, particularly for African countries. Clinical trial investigation for COVID-19 vaccines has been rare in Africa, with the only randomized clinical trials (RCTs) for COVID-19 vaccines having been conducted in South Africa. In addition to addressing the current inequities in the vaccine roll-out for low- and middle-income countries, there is a need to monitor the real-world effectiveness of COVID-19 vaccines in these regions. Although RCTs are the superior method for evaluating vaccine efficacy, the feasibility of conducting RCTs to monitor COVID-19 vaccine effectiveness during mass vaccine campaigns will likely be low. There is still a need to evaluate the effectiveness of mass COVID-19 vaccine distribution in a practical manner. We discuss how target trial emulation, the application of trial design principles from RCTs to the analysis of observational data, can be used as a practical, cost-effective way to evaluate real-world effectiveness for COVID-19 vaccines. There are several study design considerations that need to be made in the analyses of observational data, such as uncontrolled confounders and selection biases. Target trial emulation accounts for these considerations to improve the analyses of observational data. The framework of target trial emulation provides a practical way to monitor the effectiveness of mass vaccine campaigns for COVID-19 using observational data.

With billions of dollars in research and development (R&D) funding continuing to be invested, the novel coronavirus disease 2019 (COVID-19) has become into a singular focus for the scientific community. However, the collective response from the scientific communities have seen poor return on investment, particularly for therapeutic research for COVID-19, revealing the existing weaknesses and inefficiencies of the clinical trial enterprise. In this article, we argue for the importance of structural changes to existing research programs for clinical trials in light of the lessons learned from COVID-19., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Evaluating whether an intervention works when trialled in groups of individuals can pose complex challenges for clinical research. Cluster randomised controlled trials involve the random allocation of groups or clusters of individuals to receive an intervention, and they are commonly used in global health research. In this paper, we describe the potential reasons for the increasing popularity of cluster trials in low-income and middle-income countries. We also draw on key areas of global health research for an assessment of common trial planning practices, and we address their methodological shortcomings and pitfalls. Lastly, we discuss alternative approaches for population-level intervention trials that could be useful for research undertaken in low-income and middle-income countries for situations in which the use of cluster randomisation might not be appropriate., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

This paper shows the scale of global health research and the context in which we frame the subsequent papers in the Series. In this Series paper, we provide a historical perspective on clinical trial research by revisiting the 1948 streptomycin trial for pulmonary tuberculosis, which was the first documented randomised clinical trial in the English language, and we discuss its close connection with global health. We describe the current state of clinical trial research globally by providing an overview of clinical trials that have been registered in the WHO International Clinical Trial Registry since 2010. We discuss challenges with current trial planning and designs that are often used in clinical trial research undertaken in low-income and middle-income countries, as an overview of the global health trials landscape. Finally, we discuss the importance of collaborative work in global health research towards generating sustainable and culturally appropriate research environments., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

COVID-19 has had negative repercussions on the entire global population. Despite there being a common goal that should have unified resources and efforts, there have been an overwhelmingly large number of clinical trials that have been registered that are of questionable methodological quality. As the final paper of this Series, we discuss how the medical research community has responded to COVID-19. We recognise the incredible pressure that this pandemic has put on researchers, regulators, and policy makers, all of whom were doing their best to move quickly but safely in a time of tremendous uncertainty. However, the research community's response to the COVID-19 pandemic has prominently highlighted many fundamental issues that exist in clinical trial research under the current system and its incentive structures. The COVID-19 pandemic has not only re-emphasised the importance of well designed randomised clinical trials but also highlighted the need for large-scale clinical trials structured according to a master protocol in a coordinated and collaborative manner. There is also a need for structures and incentives to enable faster data sharing of anonymised datasets, and a need to provide similar opportunities to those in high-income countries for clinical trial research in low-resource regions where clinical trial research receives considerably less research funding., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In global health research, short-term, small-scale clinical trials with fixed, two-arm trial designs that generally do not allow for major changes throughout the trial are the most common study design. Building on the introductory paper of this Series, this paper discusses data-driven approaches to clinical trial research across several adaptive trial designs, as well as the master protocol framework that can help to harmonise clinical trial research efforts in global health research. We provide a general framework for more efficient trial research, and we discuss the importance of considering different study designs in the planning stage with statistical simulations. We conclude this second Series paper by discussing the methodological and operational complexity of adaptive trial designs and master protocols and the current funding challenges that could limit uptake of these approaches in global health research., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Medical students across the United Kingdom helped the National Health Service (NHS) with the increased workload caused by the COVID-19 pandemic. This study was conducted to better understand the implications of COVID-19 on the intricate relationship between the psychological wellbeing of students and working within the NHS., Method: This was a cross-sectional, national UK study analyzing the self-reported pandemic anxiety scale (PAS) of participants during the pandemic, using an online questionnaire., Results: 25.2% of participants worked within the NHS. Working significantly reduced anxiety levels of participants. Concerns around the training and information provided on personal protective equipment (PPE) (odds ratio [OR] 2.57, 95% confidence interval [CI] OR: 1.93, 3.43) (P < 0.001) and Ethnicity (OR 2.15, 95% CI OR: 1.54, 2.99) (P < 0.001) were the most significant covariates affecting the likelihood of working., Conclusion: Working during the pandemic was influenced by age, ethnicity, and information surrounding PPE. On average those who worked experienced less anxiety and were more cheerful and energetic., Competing Interests: Conflict of Interest: This research has received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed., Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting., Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020., Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo., Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events., Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group., Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic., Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.

This paper aims to provide a perspective on data sharing practices in the context of the COVID-19 pandemic. The scientific community has made several important inroads in the fight against COVID-19, and there are over 2500 clinical trials registered globally. Within the context of the rapidly changing pandemic, we are seeing a large number of trials conducted without results being made available. It is likely that a plethora of trials have stopped early, not for statistical reasons but due to lack of feasibility. Trials stopped early for feasibility are, by definition, statistically underpowered and thereby prone to inconclusive findings. Statistical power is not necessarily linear with the total sample size, and even small reductions in patient numbers or events can have a substantial impact on the research outcomes. Given the profusion of clinical trials investigating identical or similar treatments across different geographical and clinical contexts, one must also consider that the likelihood of a substantial number of false-positive and false-negative trials, emerging with the increasing overall number of trials, adds to public perceptions of uncertainty. This issue is complicated further by the evolving nature of the pandemic, wherein baseline assumptions on control group risk factors used to develop sample size calculations are far more challenging than those in the case of well-documented diseases. The standard answer to these challenges during nonpandemic settings is to assess each trial for statistical power and risk-of-bias and then pool the reported aggregated results using meta-analytic approaches. This solution simply will not suffice for COVID-19. Even with random-effects meta-analysis models, it will be difficult to adjust for the heterogeneity of different trials with aggregated reported data alone, especially given the absence of common data standards and outcome measures. To date, several groups have proposed structures and partnerships for data sharing. As COVID-19 has forced reconsideration of policies, processes, and interests, this is the time to advance scientific cooperation and shift the clinical research enterprise toward a data-sharing culture to maximize our response in the service of public health., (©Louis Dron, Alison Dillman, Michael J Zoratti, Jonas Haggstrom, Edward J Mills, Jay J H Park. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 12.03.2021.)

Background: The novel coronavirus 2019 (COVID-19) pandemic has mobilized global research at an unprecedented scale. While challenges associated with the COVID-19 trial landscape have been discussed previously, no comprehensive reviews have been conducted to assess the reporting, design, and data sharing practices of randomized controlled trials (RCTs)., Purpose: The purpose of this review was to gain insight into the current landscape of reporting, methodological design, and data sharing practices for COVID-19 RCTs., Data Sources: We conducted three searches to identify registered clinical trials, peer-reviewed publications, and pre-print publications., Study Selection: After screening eight major trial registries and 7844 records, we identified 178 registered trials and 38 publications describing 35 trials, including 25 peer-reviewed publications and 13 pre-prints., Data Extraction: Trial ID, registry, location, population, intervention, control, study design, recruitment target, actual recruitment, outcomes, data sharing statement, and time of data sharing were extracted., Data Synthesis: Of 178 registered trials, 112 (62.92%) were in hospital settings, median planned recruitment was 100 participants (IQR: 60, 168), and the majority (n = 166, 93.26%) did not report results in their respective registries. Of 35 published trials, 31 (88.57%) were in hospital settings, median actual recruitment was 86 participants (IQR: 55.5, 218), 10 (28.57%) did not reach recruitment targets, and 27 trials (77.14%) reported plans to share data., Conclusions: The findings of our study highlight limitations in the design and reporting practices of COVID-19 RCTs and provide guidance towards more efficient reporting of trial results, greater diversity in patient settings, and more robust data sharing., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: A multitude of randomized controlled trials (RCTs) have emerged in response to the novel coronavirus disease (COVID-19) pandemic. Understanding the distribution of trials among various settings is important to guide future research priorities and efforts. The purpose of this review was to describe the emerging evidence base of COVID-19 RCTs by stages of disease progression, from pre-exposure to hospitalization., Methods: We collated trial data across international registries: ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Registry; Chinese Clinical Trial Registry; Clinical Research Information Service; EU Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; German Clinical Trials Register (up to 7 October 2020). Active COVID-19 RCTs in international registries were eligible for inclusion. We extracted trial status, intervention(s), control, sample size, and clinical context to generate descriptive frequencies, network diagram illustrations, and statistical analyses including odds ratios and the Mann-Whitney U -test., Results: Our search identified 11503 clinical trials registered for COVID-19 and identified 2388 RCTs. After excluding 45 suspended RCTs and 480 trials with unclear or unreported disease stages, 1863 active RCTs were included and categorized into four broad disease stages: pre-exposure (n=107); post-exposure (n=208); outpatient treatment (n=266); hospitalization, including the intensive care unit (n=1376). Across all disease stages, most trials had two arms (n=1500/1863, 80.52%), most often included (hydroxy)chloroquine (n=271/1863, 14.55%) and were US-based (n=408/1863, 21.90%). US-based trials had lower odds of including (hydroxy)chloroquine than trials in other countries (OR: 0.63, 95% CI: 0.45-0.90) and similar odds of having two arms compared to other geographic regions (OR: 1.05, 95% CI: 0.80-1.38)., Conclusion: There is a marked difference in the number of trials across settings, with limited studies on non-hospitalized persons. Focus on pre- and post-exposure, and outpatients, is worthwhile as a means of reducing infections and lessening the health, social, and economic burden of COVID-19., Competing Interests: The authors report no conflicts of interest for this work., (© 2020 Dillman et al.)

Antivirals have demonstrated efficacy in treating other infectious diseases in early stages of disease, reducing morbidity, mortality, and the likelihood of onward transmission. At the time of writing, more than 1900 clinical trials are registered globally to assess the efficacy and safety of candidate therapeutics for COVID-19. The majority of these trials are designed to evaluate the comparative efficacy and safety of candidate therapeutics for the treatment of COVID-19 to prevent death among populations of hospitalized patients with advanced disease. Yet, emerging epidemiological evidence now indicates that the majority of those infected with the SARS-CoV-2, while still infectious, experience minimal or mild disease symptomology. Like HIV and hepatitis C that pioneered treatment as prevention, there is a missed opportunity for trials of early pharmaceutical intervention for COVID-19 disease evaluating not only reductions in morbidity and mortality but also transmissibility. We discuss this clinical research gap within an historical context of viral treatment as prevention for HIV and hepatitis C, and comment on the challenges and opportunities for clinical research of candidate therapeutics for early COVID-19 disease.

Competing Interests: Competing interests: The author completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declares no conflicts of interest.

The Bayesian paradigm provides an ideal platform to update uncertainties and carry them over into the future in the presence of data. Bayesian predictive power (BPP) reflects our belief in the eventual success of a clinical trial to meet its goals. In this paper we derive mathematical expressions for the most common types of outcomes, to make the BPP accessible to practitioners, facilitate fast computations in adaptive trial design simulations that use interim futility monitoring, and propose an organized BPP-based phase II-to-phase III design framework., (© 2020 John Wiley & Sons Ltd.)

As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.

Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) is critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness are currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ <-2SD) Methods: For this study, we searched for low- and middle-income country (LMIC)-based randomized clinical trials (RCTs) of aforementioned interventions provided to children during CFP. We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We performed random-effects network meta-analysis (NMA) for HAZ and stunting. Results: The evidence base for our NMA was based on 79 RCTs (96 papers) involving 81,786 children. Among the micronutrients, compared to standard-of-care, iron + folic acid (IFA) (mean difference =0.08; 95% credible interval [CrI]: 0.01, 0.15) and multiple micronutrients (MMN) (mean difference =0.06; 95%CrI: 0.01, 0.11) showed improvements for HAZ; MMN also reduced the risks for stunting (RR=0.86; 95%Crl: 0.73, 0.98), whereas IFA did not (RR=0.92; 95%Crl: 0.64, 1.23). For food supplements, flour in the caloric range of 270-340 kcal (RR=0.73; 95%Crl: 0.51, 1.00) and fortified lipid-based nutrient supplements (LNS) containing 220-285 kcal (RR=0.80; 95%Crl: 0.66, 0.97) decreased the risk of stunting compared to standard-of-care, but these interventions and other food supplements did not show improvements for HAZ. Deworming, maternal education, and WASH interventions did not show improvements for HAZ nor stunting. Conclusion: While we found micronutrient and food supplements to be effective for HAZ and/or stunting, the evidence base for other domains in this life stage was limited, highlighting the need for more investigation. Registration: PROSPERO CRD42018110449; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Exclusive breastfeeding (EBF) during the first six months of life is critical for child's linear growth. While there is strong evidence in favor of EBF, the evidence with regards to other interventions for linear growth is unclear. We evaluated intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care, for their comparative effectiveness on linear growth. Methods: For this review, we searched for randomized clinical trials (RCTs) of the interventions provided to infants aged 0-6 months and/or their breastfeeding mothers in low- and middle-income countries reporting on length-for-age z-score (LAZ), stunting, length, and head circumference. We searched for reports published until September 17 th , 2019 and hand-searched bibliographies of existing reviews. For LAZ and stunting, we used network meta-analysis (NMA) to compare the effects of all interventions except for kangaroo care, where we used pairwise meta-analysis to compare its effects versus standard-of-care. For length and head circumference, we qualitatively summarized our findings. Results: We found 29 RCTs (40 papers) involving 35,119 mother and infant pairs reporting on the effects of aforementioned interventions on linear growth outcomes. Our NMA on LAZ found that compared to standard-of-care, multiple micronutrients administered to infants (MMN-C) improved LAZ (mean difference: 0.20; 95% credible interval [CrI]: 0.03,0.35), whereas supplementing breastfeeding mothers with MMN did not (MMN-M, mean difference: -0.02, 95%CrI: -0.18,0.13). No interventions including MMN-C (relative risk: 0.74; 95%CrI: 0.36,1.44) reduced risk for stunting compared to standard-of-care. Kangaroo care, on the other hand, improved head circumference (mean difference: 0.20 cm/week; 95% confidence intervals [CI]: 0.09,0.31 cm/week) and length (mean difference: 0.23 cm/week; 95%CI: 0.10,0.35 cm/week) compared to standard-of-care.   Conclusion: Our study found important improvements for kangaroo care, but we did not find sufficient evidence for other interventions. Registration: PROSPERO CRD42018110450; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Improving the health of pregnant women is important to prevent adverse birth outcomes, such as preterm birth and low birthweight. We evaluated the comparative effectiveness of interventions under the domains of micronutrient, balanced energy protein, deworming, maternal education, and water sanitation and hygiene (WASH) for their effects on these adverse birth outcomes. Methods: For this network meta-analysis, we searched for randomized clinical trials (RCTs) of interventions provided to pregnant women in low- and middle-income countries (LMICs). We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We extracted data from eligible studies for study characteristics, interventions, participants' characteristics at baseline, and birth outcomes. We compared effects on preterm birth (<37 gestational week), low birthweight (LBW; <2500 g), and birthweight (continuous) using studies conducted in LMICs. Results: Our network meta-analyses were based on 101 RCTs (132 papers) pertaining to 206,531 participants. Several micronutrients and balanced energy food supplement interventions demonstrated effectiveness over standard-of-care. For instance, versus standard-of-care, micronutrient supplements for pregnant women, such as iron and calcium, decreased risks of preterm birth (iron: RR=0.70, 95% credible interval [Crl] 0.47, 1.01; calcium: RR=0.76, 95%Crl 0.56, 0.99). Daily intake of 1500kcal of local food decreased the risks of preterm birth (RR=0.36, 95%Crl 0.16, 0.77) and LBW (RR=0.17, 95%Crl 0.09, 0.29), respectively when compared to standard-of-care. Educational and deworming interventions did not show improvements in birth outcomes, and no WASH intervention trials reported on these adverse birth outcomes. Conclusion: We found several pregnancy interventions that improve birth outcomes. However, most clinical trials have only evaluated interventions under a single domain (e.g. micronutrients) even though the causes of adverse birth outcomes are multi-faceted. There is a need to combine interventions that of different domains as packages and test for their effectiveness. Registration: PROSPERO CRD42018110446; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Objectives: The objective of the study was to outline key considerations for general clinical readers when critically evaluating publications on platform trials and for researchers when designing these types of clinical trials., Study Design and Setting: In this review, we describe key concepts of platform trials with case study discussion of two hallmark platform trials in STAMPEDE and I-SPY2. We provide reader's guide to platform trials with a critical appraisal checklist., Results: Platform trials offer flexibilities of dropping ineffective arms early based on interim data and introducing new arms into the trial. For platform trials, it is important to consider how interventions are compared and evaluated throughout and how new interventions are introduced. For intervention comparisons, it is important to consider what the primary analysis is, what and how many interventions are active simultaneously, and allocation between different arms. Interim evaluation considerations should include the number and timing of interim evaluations and outcomes and statistical rules used to drop interventions. New interventions are usually introduced based on scientific merits, so consideration of these merits is important, together with the timing and mechanisms in which new interventions are added., Conclusion: More efforts are needed to improve the scientific literacy of platform trials. Our review provides an overview of the important concepts of platform trials., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)