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Diverse drug-resistant subpopulations of Mycobacterium tuberculosis are sustained in continuous culture
<jats:p> Drug resistance to tuberculosis (TB) has become more widespread over the past decade. As such, understanding the emergence and fitness of antibiotic-resistant subpopulations is crucial for the development of new interventions. Here we use a simple mathematical model to explain the differences in the response to isoniazid (INH) of <jats:italic>Mycobacterium tuberculosis</jats:italic> cells cultured under two growth rates in a chemostat. We obtain posterior distributions of model parameters consistent with data using a Markov chain Monte Carlo (MCMC) method. We explore the dynamics of diverse INH-resistant subpopulations consistent with these data in a multi-population model. We find that the simple model captures the qualitative behaviour of the cultures under both dilution rates and also present testable predictions about how diversity is maintained in such cultures. </jats:p>
Study protocol for an exploratory interventional study investigating the feasibility of video-based non-contact physiological monitoring in healthy volunteers by Mapping Of Lower Limb skIn pErfusion (MOLLIE).
INTRODUCTION:Skin perfusion varies in response to changes in the circulatory status. Blood flow to skin is reduced during haemodynamic collapse secondary to peripheral vasoconstriction, whereas increased skin perfusion is frequently observed when haemodynamics improve with resuscitation. These changes in perfusion may be monitored using non-contact image-based methods. Previous camera-derived physiological measurements have focused on accurate vital signs monitoring and extraction of physiological signals from environmental noise. One of the biggest challenges of camera-derived monitoring is artefacts from motion, which limits our understanding of what parameters may be derived from skin. In this study, we use phenylephrine and glyceryl trinitrate (GTN) to cause vasoconstriction and vasodilation in stationary healthy volunteers to describe directional changes in skin perfusion pattern. METHODS AND ANALYSIS:We aim to recruit 30 healthy volunteers who will undergo protocolised infusions of phenylephrine and GTN, followed by the monitored and timed release of a thigh tourniquet. The experimental timeline will be identical for all participants. Measurements of traditionally used haemodynamic markers (heart rate, blood pressure and stroke volume) and camera-derived measurements will be taken concurrently throughout the experimental period. The parameters of interest from the image data are skin colour and pattern, skin surface temperature, pulsatile signal detected at the skin surface and skin perfusion index. ETHICS AND DISSEMINATION:This study was reviewed and approved by the Oxford University Research and Ethics Committee and Clinical Trials and Research Governance teams (R63796/RE001). The results of this study will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:ISRCTN10417167.
Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.
Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.
Insights from quantitative and mathematical modelling on the proposed WHO 2030 goal for schistosomiasis
Schistosomiasis remains one of the neglected tropical diseases (NTDs) impacting millions of people around the world. The World Health Organization (WHO) recently proposed a goal of elimination as a public health problem (EPHP) for schistosomiasis to be reached by 2030. Current WHO treatment guidelines for achieving EPHP focus on targeting school-aged children. The NTD Modelling Consortium has developed mathematical models to study schistosomiasis transmission dynamics and the impact of control measures. Our modelling insights on Schistosoma mansoni have shown that EPHP is likely to be attainable in low to moderate prevalence settings using the current guidelines. However, as prevalence rises within higher settings, EPHP is less likely to be achieved unless both school-aged children and adults are treated (with coverage levels increasing with the adult burden of infection). We highlight the challenges that are faced by treatment programmes, such as non-adherence to treatment and resurgence, which can hinder progress towards achieving and maintaining EPHP. Additionally, even though EPHP may be reached, prevalence can still be high due to persisting infections. Therefore, without elimination of transmission, treatment will likely have to continue to maintain EPHP. Further modelling work is being carried out, including extending our results to S. haematobium . By providing these modelling insights, we aim to inform discussions on the goals and treatment guidelines for schistosomiasis.
Discovering correlates of age-related decline in a healthy late-midlife male birth cohort.
Studies exploring age-related brain and cognitive change have identified substantial heterogeneity among individuals, but the underlying reasons for the differential trajectories remain largely unknown. We investigated cross-sectional and longitudinal associations between brain-imaging phenotypes (IDPs) and cognitive ability, and how these relations may be modified by common risk and protective factors. Participants were recruited from the 1953 Danish Male Birth Cohort (N=123), a longitudinal study of cognitive and brain ageing. Childhood IQ and socio-demographic factors are available for these participants who have been assessed regularly on multiple IDPs and behavioural factors in midlife. Using Pearson correlations and canonical correlation analysis (CCA), we explored the relation between 454 IDPs and 114 behavioural variables. CCA identified a single mode of population covariation coupling cross-subject longitudinal changes in brain structure to changes in cognitive performance and to a range of age-related covariates (r=0.92, Pcorrected < 0.001). Specifically, this CCA-mode indicated that; decreases in IQ and speed assessed tasks, higher rates of familial myocardial infarct, less physical activity, and poorer mental health are associated with larger decreases in whole brain grey matter and white matter. We found no evidence supporting the role of baseline scores as predictors of impending brain and behavioural change in late-midlife.
Artificial intelligence driven assessment of routinely collected healthcare data is an effective screening test for COVID-19 in patients presenting to hospital
The early clinical course of SARS-CoV-2 infection can be difficult to distinguish from other undifferentiated medical presentations to hospital, however viral specific real- time polymerase chain reaction (RT-PCR) testing has limited sensitivity and can take up to 48 hours for operational reasons. In this study, we develop two early-detection models to identify COVID-19 using routinely collected data typically available within one hour (laboratory tests, blood gas and vital signs) during 115,394 emergency presentations and 72,310 admissions to hospital. Our emergency department (ED) model achieved 77.4% sensitivity and 95.7% specificity (AUROC 0.939) for COVID- 19 amongst all patients attending hospital, and Admissions model achieved 77.4% sensitivity and 94.8% specificity (AUROC 0.940) for the subset admitted to hospital. Both models achieve high negative predictive values (>99%) across a range of prevalences (<5%), facilitating rapid exclusion during triage to guide infection control. We prospectively validated our models across all patients presenting and admitted to a large UK teaching hospital group in a two-week test period, achieving 92.3% (n= 3,326, NPV: 97.6%, AUROC: 0.881) and 92.5% accuracy (n=1,715, NPV: 97.7%, AUROC: 0.871) in comparison to RT-PCR results. Sensitivity analyses to account for uncertainty in negative PCR results improves apparent accuracy (95.1% and 94.1%) and NPV (99.0% and 98.5%). Our artificial intelligence models perform effectively as a screening test for COVID-19 in emergency departments and hospital admission units, offering high impact in settings where rapid testing is unavailable.
Number of HIV-1 founder variants is determined by the recency of the source partner infection.
During sexual transmission, the high genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to developing effective infection control strategies. Little is known about the importance of the source partner during this bottleneck. To test the hypothesis that the source partner affects the number of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results suggest that acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple-founder variant transmission compared with acquiring infection from someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple-founder strain infections.
Efficacy of self-monitored blood pressure, with or without telemonitoring, for titration of antihypertensive medication (TASMINH4): an unmasked randomised controlled trial.
BACKGROUND:Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care. METHODS:This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self-monitor their blood pressure. Patients were randomly assigned (1:1:1) to self-monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care (clinic blood pressure; usual care group). Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366. FINDINGS:1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137·0 [SD 16·7] mm Hg and telemonitoring, 136·0 [16·1] mm Hg vs usual care, 140·4 [16·5]; adjusted mean differences vs usual care: self-monitoring alone, -3·5 mm Hg [95% CI -5·8 to -1·2]; telemonitoring, -4·7 mm Hg [-7·0 to -2·4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference -1·2 mm Hg [95% CI -3·5 to 1·2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups. INTERPRETATION:Self-monitoring, with or without telemonitoring, when used by general practitioners to titrate antihypertensive medication in individuals with poorly controlled blood pressure, leads to significantly lower blood pressure than titration guided by clinic readings. With most general practitioners and many patients using self-monitoring, it could become the cornerstone of hypertension management in primary care. FUNDING:National Institute for Health Research via Programme Grant for Applied Health Research (RP-PG-1209-10051), Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK.
Erratum: The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.
[This corrects the article DOI: 10.1093/ckj/sfy090.].
Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank.
BACKGROUND:Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank. METHODS:A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure. RESULTS:After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death. CONCLUSION:We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.