Rumour as Information: British Forces, Control, and Communication on the Indian North-West Frontier

India during the nineteenth century was a rumour rich-society. For the British authorities these rumours were difficult to control and had the ability to weaken their prestige. This point was highlighted during the Frontier ‘Uprising’ of 1897 when a British official ignored a report he had received because it contradicted his own information. The report of potential trouble proved to be correct. Rumours were also misunderstood with these misunderstandings connected to the authorities’ sources of information being inadequate. However, despite the inadequacy of information gathering, rumours were the only sources available for the authorities to make decisions. This illustrates the fragility of rule and the challenges that the officials on the Frontier encountered. The consequence of these shortfalls was that the British had to respond to events reactively and miscalculations were made. The paper will exemplify the importance of rumour on the Frontier through two case studies: The First Afghan War (1838–42) and the 1897 Frontier Uprising. These two examples, by setting original archival documents in their historical context, illustrate the extent to which rumours were free to circulate leading to responsive and ill-prepared actions by the British

Physical loading in professional soccer players:Implications for contemporary guidelines to encompass carbohydrate periodization

Despite more than four decades of research examining the physical demands of match-play, quantification of the customary training loads of adult male professional soccer players is comparatively recent. The training loads experienced by players during weekly micro-cycles are influenced by phase of season, player position, frequency of games, player starting status, player-specific training goals and club coaching philosophy. From a macronutrient perspective, the periodization of physical loading within (i.e., match versus training days) and between contrasting micro-cycles (e.g., 1, 2 or 3 games per week schedules) has implications for daily carbohydrate (CHO) requirements. Indeed, aside from the well-recognised role of muscle glycogen as the predominant energy source during match-play, it is now recognised that the glycogen granule may exert regulatory roles in activating or attenuating the molecular machinery that modulate skeletal muscle adaptations to training. With this in mind, the concept of CHO periodization is gaining in popularity, whereby CHO intake is adjusted day-by-day and meal-by-meal according to the fuelling demands and specific goals of the upcoming session. On this basis, the present paper provides a contemporary overview and theoretical framework for which to periodize CHO availability for the professional soccer player according to the “fuel for the work” paradigm.</p

Artificial intelligence-ready skin cancer alchemy:transforming routine teledermatology data into metadata-embedded DICOM files

Most skin artificial intelligence (AI) classifiers are trained only on images with diagnostic labels. However, the addition of clinical information can improve predictive accuracy. Recent interest has been stimulated in incorporating clinical data into image files, using the well-established international Digital Imaging and Communication in Medicine (DICOM) standards (Caffery L, Weber J, Kurtansky N et al. DICOM in dermoscopic research: experience report and a way forward. J Digit Imaging 2021; 34: 967–73). We have developed an automated process of creating metadata-embedded DICOM files, directly from a live teledermatology system, described below. Through our Community and Locality Imaging Centre (CLIC) model, patients referred from primary care are triaged to CLIC for high-quality image capture. There, trained health professionals use a mobile application to capture standardized DICOM information for each lesion. Each lesion dataset contains images (macroscopic, dermoscopic) and clinical metadata (patient and lesion information). Datasets are transferred to an image management system, for teledermatology and verification of ground-truth diagnoses by a consultant dermatologist. On completion of diagnoses, datasets are flagged for conversion into DICOM format, where metadata are embedded in the image files. Flagged datasets are cleaned and clinical metadata are mapped to DICOM attributes. Datasets are converted into metadata-embedded DICOM files, and reviewed for conformance to the DICOM standard using the open-source fo-dicom library (v5). These files are further tested for conformance to DICOM standard using the dciodvfy validator tool. Compliant DICOM files are then transferred to a trusted research environment for research. To test whether these DICOM files are usable for AI research, they are examined using the DICOM viewing software 3D Slicer (https://www.slicer.org/), ensuring images are usable and metadata are correctly translated. Image pixel data and clinical metadata are extracted using pydicom, into a format suitable for AI algorithm development. In our pilot work, 658 lesion datasets have been converted into metadata-embedded DICOM files. Conversion on existing hardware [virtual Intel central processing units with 2.60 GHz (two processors) and 8 GB of memory] took &lt; 1 s per image. Metadata-embedded DICOM files were approximately 0.2 kB bigger than the original JPEG files. For 3-MB images, this represented a negligible 0.003% increase in storage requirement. Testing has shown that these files can be successfully handled by algorithms within an AI research environment. In summary, we have demonstrated the feasibility of automating the conversion of routine teledermatology data into AI-ready image files encoded with clinical metadata. Future work is planned to evaluate the utility of this output on the performance of AI classifiers

Case Study : Muscle Atrophy, Hypertrophy, and Energy Expenditure of a Premier League Soccer Player During Rehabilitation From Anterior Cruciate Ligament Injury

Peer reviewedPostprin

OpenSAFELY: a platform for analysing electronic health records designed for reproducible research

Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY’s reproducibility-by-design approach in detail

Quantification of training load during one-, two- and three-game week schedules in professional soccer players from the English Premier League: implications for carbohydrate periodisation.

Muscle glycogen is the predominant energy source for soccer match play, though its importance for soccer training (where lower loads are observed) is not well known. In an attempt to better inform carbohydrate (CHO) guidelines, we quantified training load in English Premier League soccer players (n = 12) during a one-, two- and three-game week schedule (weekly training frequency was four, four and two, respectively). In a one-game week, training load was progressively reduced (P 14.4 km · h(-1) (14%, 18% and 23% in the one-, two- and three-game weeks, respectively). Considering that high CHO availability improves physical match performance but high CHO availability attenuates molecular pathways regulating training adaptation (especially considering the low daily customary loads reported here, e.g., 3-5 km per day), we suggest daily CHO intake should be periodised according to weekly training and match schedules

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

BACKGROUND: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. METHODS: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. FINDINGS: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. INTERPRETATION: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. FUNDING: Medical Research Council

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values &lt;10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies. </p