Initial clinical validation of a hybrid in silico—in vitro cardiorespiratory simulator for comprehensive testing of mechanical circulatory support systems

Simulators are expected to assume a prominent role in the process of design—development and testing of cardiovascular medical devices. For this purpose, simulators should capture the complexity of human cardiorespiratory physiology in a realistic way. High fidelity simulations of pathophysiology do not only allow to test the medical device itself, but also to advance practically relevant monitoring and control features while the device acts under realistic conditions. We propose a physiologically controlled cardiorespiratory simulator developed in a mixed in silico-in vitro simulation environment. As inherent to this approach, most of the physiological model complexity is implemented in silico while the in vitro system acts as an interface to connect a medical device. As case scenarios, severe heart failure was modeled, at rest and at exercise and as medical device a left ventricular assist device (LVAD) was connected to the simulator. As initial validation, the simulator output was compared against clinical data from chronic heart failure patients supported by an LVAD, that underwent different levels of exercise tests with concomitant increase in LVAD speed. Simulations were conducted reproducing the same protocol as applied in patients, in terms of exercise intensity and related LVAD speed titration. Results show that the simulator allows to capture the principal parameters of the main adaptative cardiovascular and respiratory processes within the human body occurring from rest to exercise. The simulated functional interaction with the LVAD is comparable to the one clinically observed concerning ventricular unloading, cardiac output, and pump flow. Overall, the proposed simulation system offers a high fidelity in silico-in vitro representation of the human cardiorespiratory pathophysiology. It can be used as a test bench to comprehensively analyze the performance of physically connected medical devices simulating clinically realistic, critical scenarios, thus aiding in the future the development of physiologically responding, patient-adjustable medical devices. Further validation studies will be conducted to assess the performance of the simulator in other pathophysiological conditions

Novel intervention to promote COVID-19 protective behaviours among Black and South Asian communities in the UK: protocol for a mixed-methods pilot evaluation

INTRODUCTION: Culturally appropriate interventions to promote COVID-19 health protective measures among Black and South Asian communities in the UK are needed. We aim to carry out a preliminary evaluation of an intervention to reduce risk of COVID-19 comprising a short film and electronic leaflet. METHODS AND ANALYSIS: This mixed methods study comprises (1) a focus group to understand how people from the relevant communities interpret and understand the intervention's messages, (2) a before-and-after questionnaire study examining the extent to which the intervention changes intentions and confidence to carry out COVID-19 protective behaviours and (3) a further qualitative study exploring the views of Black and South Asian people of the intervention and the experiences of health professionals offering the intervention. Participants will be recruited through general practices. Data collection will be carried out in the community. ETHICS AND DISSEMINATION: The study received Health Research Authority approval in June 2021 (Research Ethics Committee Reference 21/LO/0452). All participants provided informed consent. As well as publishing the findings in peer-reviewed journals, we will disseminate the findings through the UK Health Security Agency, NHS England and the Office for Health Improvement and Disparities and ensure culturally appropriate messaging for participants and other members of the target groups

UNMASC: Tumor-only variant calling with unmatched normal controls

Despite years of progress, mutation detection in cancer samples continues to require significant manual review as a final step. Expert review is particularly challenging in cases where tumors are sequenced without matched normal control DNA. Attempts have been made to call somatic point mutations without a matched normal sample by removing well-known germline variants, utilizing unmatched normal controls, and constructing decision rules to classify sequencing errors and private germline variants. With budgetary constraints related to computational and sequencing costs, finding the appropriate number of controls is a crucial step to identifying somatic variants. Our approach utilizes public databases for canonical somatic variants as well as germline variants and leverages information gathered about nearby positions in the normal controls. Drawing from our cohort of targeted capture panel sequencing of tumor and normal samples with varying tumortypes and demographics, these served as a benchmark for our tumor-only variant calling pipeline to observe the relationship between our ability to correctly classify variants against a number of unmatched normals. With our benchmarked samples, approximately ten normal controls were needed to maintain 94% sensitivity, 99% specificity and 76% positive predictive value, far outperforming comparable methods. Our approach, called UNMASC, also serves as a supplement to traditional tumor with matched normal variant calling workflows and can potentially extend to other concerns arising from analyzing next generation sequencing data

Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis

SCISSOR: a framework for identifying structural changes in RNA transcripts

High-throughput sequencing protocols such as RNA-seq have made it possible to interrogate the sequence, structure and abundance of RNA transcripts at higher resolution than previous microarray and other molecular techniques. While many computational tools have been proposed for identifying mRNA variation through differential splicing/alternative exon usage, challenges in its analysis remain. Here, we propose a framework for unbiased and robust discovery of aberrant RNA transcript structures using short read sequencing data based on shape changes in an RNA-seq coverage profile. Shape changes in selecting sample outliers in RNA-seq, SCISSOR, is a series of procedures for transforming and normalizing base-level RNA sequencing coverage data in a transcript independent manner, followed by a statistical framework for its analysis (https://github.com/hyochoi/SCISSOR). The resulting high dimensional object is amenable to unsupervised screening of structural alterations across RNA-seq cohorts with nearly no assumption on the mutational mechanisms underlying abnormalities. This enables SCISSOR to independently recapture known variants such as splice site mutations in tumor suppressor genes as well as novel variants that are previously unrecognized or difficult to identify by any existing methods including recurrent alternate transcription start sites and recurrent complex deletions in 3′ UTRs

Symptom profiles and accuracy of clinical case definitions for COVID-19 in a community cohort: results from the Virus Watch study

Background: Understanding symptomatology and accuracy of clinical case definitions for community COVID-19 cases is important for Test, Trace and Isolate (TTI) and future targeting of early antiviral treatment. Methods: Community cohort participants prospectively recorded daily symptoms and swab results (mainly undertaken through the UK TTI system). We compared symptom frequency, severity, timing, and duration in test positive and negative illnesses. We compared the test performance of the current UK TTI case definition (cough, high temperature, or loss of or altered sense of smell or taste) with a wider definition adding muscle aches, chills, headache, or loss of appetite. Results: Among 9706 swabbed illnesses, including 973 SARS-CoV-2 positives, symptoms were more common, severe and longer lasting in swab positive than negative illnesses. Cough, headache, fatigue, and muscle aches were the most common symptoms in positive illnesses but also common in negative illnesses. Conversely, high temperature, loss or altered sense of smell or taste and loss of appetite were less frequent in positive illnesses, but comparatively even less frequent in negative illnesses. The current UK definition had 81% sensitivity and 47% specificity versus 93% and 27% respectively for the broader definition. 1.7-fold more illnesses met the broader case definition than the current definition. Conclusions: Symptoms alone cannot reliably distinguish COVID-19 from other respiratory illnesses. Adding additional symptoms to case definitions could identify more infections, but with a large increase in the number needing testing and the number of unwell individuals and contacts self-isolating whilst awaiting results

The effects of corporate and country sustainability characteristics on the cost of debt: an international investigation

We investigate the relationship between corporate and country sustainability on the cost of bank loans. We look into 470 loan agreements signed between 2005 and 2012 with borrowers based in 28 different countries across the world and operating in all major industries. Our principal findings reveal that country sustainability, relating to both social and environmental frameworks, has a statistically and economically impactful effect on direct financing of economic activity. An increase of one unit in a country's sustainability score is associated with an average decrease in the cost of debt by 64 basis points. Our international analysis shows that the environmental dimension of a country's institutional framework is approximately twice as impactful as the social dimension, when it comes to determining the cost of corporate loans. On the other hand, we find no conclusive evidence that firm-level sustainability influences the interest rates charged to borrowing firms by banks. Our main findings survive a battery of robustness tests and additional analyses concerning subsamples, alternative sustainability metrics and the effects of financial crisis