Beyond the Biography of a Gene

Collins approaches the ethical nuances of Cal’s intersex narrative in Middlesex, drawing comparisons with current debates in North Carolina concerning gender-normative bathroom use and trans rights, in order to advocate for more ethical practices of relation and responsibility outside of mere knowledge creation and policy

Pneumocystis pneumonia, a COVID-19 mimic, reminds us of the importance of HIV testing in COVID-19

While clinical environments are highly focused on COVID-19, reports of missed or delayed treatment for conditions that imitate COVID-19, such as pneumonia caused by the fungus Pneumocystis jirovecii, are emerging. Given the uncertain spectrum of COVID-19 presentations and variable sensitivity of laboratory tests for SARS-CoV-2, there is a risk that, without a high index of suspicion, alternative aetiologies may be overlooked while pursuing a diagnosis of COVID-19. The British HIV Association has been calling for the inclusion of HIV testing in all patients admitted to hospital with suspected COVID-19. In this article we reflect on the importance of including HIV testing to prevent avoidable morbidity and mortality in our patients.Publisher PDFPeer reviewe

Evaluation of clinical prediction models (part 2): how to undertake an external validation study

External validation studies are an important but often neglected part of prediction model research. In this article, the second in a series on model evaluation, Riley and colleagues explain what an external validation study entails and describe the key steps involved, from establishing a high quality dataset to evaluating a model’s predictive performance and clinical usefulness

Real-Time Feedback of Air Quality in Children’s Bedrooms Reduces Exposure to Secondhand Smoke

Introduction:Secondhand smoke (SHS) exposure creates health risks for nonsmokers and is especially detrimental to children. This study evaluated whether immediate feedback in response to poor indoor air quality in children’s bedrooms can reduce the potential for SHS exposure, as measured by adherence to a World Health Organization (WHO) indoor air standard.Methods:Homes that contained children and an adult who regularly smoked inside (n=298) had an air particle monitor installed in the child’s bedroom. These devices measured the concentration of particulate matter (PM2.5) for approximately three months and, for half of the participants, immediately provided aversive feedback in response to elevated PM2.5. Hierarchical linear models were fit to the data to assess whether the intervention increased the probability that: 1) a given day was below the WHO guideline for daily exposure, and 2) a household established and maintained a smoke-free home (SFH), operationalized as achieving 30 consecutive days below the WHO guideline. The intervention’s impact was calculated as groupby- time effects.Results:The likelihood that a child’s bedroom met the WHO indoor air quality standard on a given day increased such that the baseline versus post-baseline odds ratio (OR) of maintaining indoor PM2.5 levels below the WHO guideline was 2.38 times larger for participants who received the intervention. Similarly, the baseline versus post-baseline OR associated with achieving an SFH was 3.49 times larger for participants in the intervention group.Conclusions:The real-time intervention successfully drove clinically meaningful changes in smoking behavior that mitigated indoor PM2.5 levels in children’s bedrooms and thereby reduced SHS exposure. These results demonstrate the effectiveness of targeting sensitive microenvironments by giving caregivers actionable information about children’s SHS risks. Future extensions should examine additional microenvironments and focus on identifying the potential for SHS exposure before it occurs

Evaluation of clinical prediction models (part 2):how to undertake an external validation study

External validation studies are an important but often neglected part of prediction model research. In this article, the second in a series on model evaluation, Riley and colleagues explain what an external validation study entails and describe the key steps involved, from establishing a high quality dataset to evaluating a model’s predictive performance and clinical usefulness.</p

Northward propagation of the Inter Tropical Convergence Zone and strengthening of Indian summer monsoon rainfall

Since 2002, there has been a clear increase in Indian summer monsoon rainfall (ISMR). We demonstrate that this increase is associated with a change in the dynamics of the Intertropical Convergence Zone (ITCZ). Using a recently‐released reanalysis product from 1980‐2016, we show that the ITCZ has strengthened and propagated northward since 2002. Analysis of the total energy‐budget reveals an increase in energy divergence and atmospheric diabatic heating, which is consistent with the changes in the ITCZ. Although global aerosol optical depth shows a significant positive trend during 1980‐2016, it has declined over many parts of India since 2002. We put forward the hypothesis that this is the driver of the changing characteristics of the ITCZ. Our results suggest that changes in the dynamics of the ITCZ, together with changes in the energy/moisture‐budget, are responsible for the strengthening of ISMR since 2002, consistent with the emergence of a greenhouse‐gas induced signal

External validation of clinical prediction models:simulation-based sample size calculations were more reliable than rules-of-thumb

INTRODUCTION: Sample size "rules-of-thumb" for external validation of clinical prediction models suggest at least 100 events and 100 non-events. Such blanket guidance is imprecise, and not specific to the model or validation setting. We investigate factors affecting precision of model performance estimates upon external validation, and propose a more tailored sample size approach.METHODS: Simulation of logistic regression prediction models to investigate factors associated with precision of performance estimates. Then, explanation and illustration of a simulation-based approach to calculate the minimum sample size required to precisely estimate a model's calibration, discrimination and clinical utility.RESULTS: Precision is affected by the model's linear predictor (LP) distribution, in addition to number of events and total sample size. Sample sizes of 100 (or even 200) events and non-events can give imprecise estimates, especially for calibration. The simulation-based calculation accounts for the LP distribution and (mis)calibration in the validation sample. Application identifies 2430 required participants (531 events) for external validation of a deep vein thrombosis diagnostic model.CONCLUSION: Where researchers can anticipate the distribution of the model's LP (eg, based on development sample, or a pilot study), a simulation-based approach for calculating sample size for external validation offers more flexibility and reliability than rules-of-thumb.</p

Human PrimPol is a highly error-prone polymerase regulated by single-stranded DNA binding proteins

PrimPol is a recently identified polymerase involved in eukaryotic DNA damage tolerance, employed in both re-priming and translesion synthesis mechanisms to bypass nuclear and mitochondrial DNA lesions. In this report, we investigate how the enzymatic activities of human PrimPol are regulated. We show that, unlike other TLS polymerases, PrimPol is not stimulated by PCNA and does not interact with it in vivo. We identify that PrimPol interacts with both of the major single-strand binding proteins, RPA and mtSSB in vivo. Using NMR spectroscopy, we characterize the domains responsible for the PrimPol-RPA interaction, revealing that PrimPol binds directly to the N-terminal domain of RPA70. In contrast to the established role of SSBs in stimulating replicative polymerases, we find that SSBs significantly limit the primase and polymerase activities of PrimPol. To identify the requirement for this regulation, we employed two forward mutation assays to characterize PrimPol's replication fidelity. We find that PrimPol is a mutagenic polymerase, with a unique error specificity that is highly biased towards insertion-deletion errors. Given the error-prone disposition of PrimPol, we propose a mechanism whereby SSBs greatly restrict the contribution of this enzyme to DNA replication at stalled forks, thus reducing the mutagenic potential of PrimPol during genome replication

Guide to presenting clinical prediction models for use in clinical settings

For permission to use (where not already granted under a licence) please go to. Clinical prediction models estimate the risk of existing disease or future outcome for an individual, which is conditional on the values of multiple predictors such as age, sex, and biomarkers. In this article, Bonnett and colleagues provide a guide to presenting clinical prediction models so that they can be implemented in practice, if appropriate. They describe how to create four presentation formats and discuss the advantages and disadvantages of each format. A key message is the need for stakeholder engagement to determine the best presentation option in relation to the clinical context of use and the intended users