AbstractRoutine full characterization of Mycobacterium tuberculosis (TB) is culture-based, taking many weeks. Whole-genome sequencing (WGS) can generate antibiotic susceptibility profiles to inform treatment, augmented with strain information for global surveillance; such data could be transformative if provided at or near point of care.We demonstrate a low-cost DNA extraction method for TB WGS direct from patient samples. We initially evaluated the method using the Illumina MiSeq sequencer (40 smear-positive respiratory samples, obtained after routine clinical testing, and 27 matched liquid cultures). M. tuberculosis was identified in all 39 samples from which DNA was successfully extracted. Sufficient data for antibiotic susceptibility prediction was obtained from 24 (62%) samples; all results were concordant with reference laboratory phenotypes. Phylogenetic placement was concordant between direct and cultured samples. Using an Illumina MiSeq/MiniSeq the workflow from patient sample to results can be completed in 44/16 hours at a cost of \u00a396/\u00a3198 per sample.We then employed a non-specific PCR-based library preparation method for sequencing on an Oxford Nanopore Technologies MinION sequencer. We applied this to cultured Mycobacterium bovis BCG strain (BCG), and to combined culture-negative sputum DNA and BCG DNA. For the latest flowcell, the estimated turnaround time from patient to identification of BCG was 6 hours, with full susceptibility and surveillance results 2 hours later. Antibiotic susceptibility predictions were fully concordant. A critical advantage of the MinION is the ability to continue sequencing until sufficient coverage is obtained, providing a potential solution to the problem of variable amounts of M. tuberculosis in direct samples.
\n \n\n \n \nBackground: Global efforts to strengthen health research capacity in low- and middle-income countries (LMICs) have intensified in the past few decades, and these efforts are often implemented by consortia. Our review of the literature indicated that reports on health research capacity strengthening (HRCS) consortia have primarily focused on programme outputs and outcomes while management processes and their contributions to consortia goals have received little attention. This qualitative study sought to identify the consortium management processes employed by 10 DELTAS Africa consortia, factors influencing these processes, and leaders' consortium management experiences. Methods: We conducted 24 key informant interviews with the directors and programme managers of all the 10 DELTAS Africa consortia, and funding actors who worked closely with the consortia. The interviews were supplemented by reviews of DELTAS and consortium-specific documents. Data were analysed using the content analysis approach. Results: The consortia studied employed similar management processes but adopted different strategies in executing these processes. Study results indicate that decision-making in consortia is not always a straightforward process as leaders were often faced with dilemmas when determining management strategies to adopt, and often tried to balance multiple factors which were not always aligned. This was demonstrated as consortia selected partners, determined goals and activities, assigned roles and responsibilities, allocated resources, established governance and partner management systems, and coordinated and monitored consortia activities. Factors that influenced the choice of processes and approaches included previous experiences, funders expectations, and the pressure to deliver research outputs. Consortia's unique approaches to management were due to varying contexts and influences and indicate that management decisions are nuanced and cannot easily be formularized. Conclusion: The study has highlighted the importance of flexibility in consortium management and the need to generate research capacity strengthening (RCS)-specific guidance that can assist consortia in resolving dilemmas and making appropriate management decisions.
\n \n\n \n \n\nBackground\nEarly access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant.\n\n\nMethods\nDuring 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis.\n\n\nResults\nVMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities.\n\n\nConclusions\nThe transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs.\n
\n \n\n \n \nDeep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.
\n \n\n \n \nThe majority of deaths from malaria are in young African children. Parenteral artesunate is the first\u2010line treatment for severe falciparum malaria. Since 2015 the World Health Organization has recommended individual doses of 3 mg/kg for children weighing less than 20 kg. Recently, the US Food and Drug Administration (FDA) has challenged this recommendation, based on a simulated pediatric population, and argued for a lower dose in younger children (2.4 mg/kg). In this study, we performed population pharmacokinetic modeling of plasma concentration data from 80 children with severe falciparum malaria in the Democratic Republic of Congo who were given 2.4 mg/kg of artesunate intravenously. Bayesian hierarchical modeling and a two\u2010compartment parent drug\u2010metabolite pharmacokinetic model for artesunate were used to describe the population pharmacokinetics of artesunate and its main biologically active metabolite dihydroartemisinin. We then generated a virtual population representative of the target population in which the drug is used and simulated the total first\u2010dose exposures. Our study shows that the majority of younger children given the lower 2.4 mg/kg dose of intravenous artesunate do not reach the same drug exposures as older children above 20 kg. This finding supports withdrawal of the FDA's recent lower artesunate dose recommendation as parenteral artesunate is an extremely safe and well\u2010tolerated drug and there is potential for harm from underdosing in this rapidly lethal infection.
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