Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus

Aim: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. Results: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14–5.0 μM. Additionally a quantitative structure–property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. Conclusion: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified

Fitting to the UK COVID-19 outbreak, short-term forecasts and estimating the reproductive number

The COVID-19 pandemic has brought to the fore the need for policy makers to receive timely and ongoing scientific guidance in response to this recently emerged human infectious disease. Fitting mathematical models of infectious disease transmission to the available epidemiological data provides a key statistical tool for understanding the many quantities of interest that are not explicit in the underlying epidemiological data streams. Of these, the effective reproduction number, R, has taken on special significance in terms of the general understanding of whether the epidemic is under control (R < 1). Unfortunately, none of the epidemiological data streams are designed for modelling, hence assimilating information from multiple (often changing) sources of data is a major challenge that is particularly stark in novel disease outbreaks. Here, focusing on the dynamics of the first-wave (March-June 2020), we present in some detail the inference scheme employed for calibrating the Warwick COVID-19 model to the available public health data streams, which span hospitalisations, critical care occupancy, mortality and serological testing. We then perform computational simulations, making use of the acquired parameter posterior distributions, to assess how the accuracy of short-term predictions varied over the timecourse of the outbreak. To conclude, we compare how refinements to data streams and model structure impact estimates of epidemiological measures, including the estimated growth rate and daily incidence

PROPEL: implementation of an evidence based pelvic floor muscle training intervention for women with pelvic organ prolapse: a realist evaluation and outcomes study protocol

Abstract Background Pelvic Organ Prolapse (POP) is estimated to affect 41%–50% of women aged over 40. Findings from the multi-centre randomised controlled “Pelvic Organ Prolapse PhysiotherapY” (POPPY) trial showed that individualised pelvic floor muscle training (PFMT) was effective in reducing symptoms of prolapse, improved quality of life and showed clear potential to be cost-effective. However, provision of PFMT for prolapse continues to vary across the UK, with limited numbers of women’s health physiotherapists specialising in its delivery. Implementation of this robust evidence from the POPPY trial will require attention to different models of delivery (e.g. staff skill mix) to fit with differing care environments. Methods A Realist Evaluation (RE) of implementation and outcomes of PFMT delivery in contrasting NHS settings will be conducted using multiple case study sites. Involving substantial local stakeholder engagement will permit a detailed exploration of how local sites make decisions on how to deliver PFMT and how these lead to service change. The RE will track how implementation is working; identify what influences outcomes; and, guided by the RE-AIM framework, will collect robust outcomes data. This will require mixed methods data collection and analysis. Qualitative data will be collected at four time-points across each site to understand local contexts and decisions regarding options for intervention delivery and to monitor implementation, uptake, adherence and outcomes. Patient outcome data will be collected at baseline, six months and one year follow-up for 120 women. Primary outcome will be the Pelvic Organ Prolapse Symptom Score (POP-SS). An economic evaluation will assess the costs and benefits associated with different delivery models taking account of further health care resource use by the women. Cost data will be combined with the primary outcome in a cost effectiveness analysis, and the EQ-5D-5L data in a cost utility analysis for each of the different models of delivery. Discussion Study of the implementation of varying models of service delivery of PFMT across contrasting sites combined with outcomes data and a cost effectiveness analysis will provide insight into the implementation and value of different models of PFMT service delivery and the cost benefits to the NHS in the longer term

Design Considerations for Fire Safety

ERAF: 48415Papers presented at the Symposium on Design Considerations for Fire Safety at the Semiannual Meeting of The American Society of Heating, Refrigerating and Air-conditioning Engineer

Stabilized Polymer Micelles for the Development of IT-147, an Epothilone D Drug-Loaded Formulation

Epothilones have demonstrated promising potential for oncology applications but suffer from a narrow therapeutic window. Epothilone D stabilizes microtubules leading to apoptosis, is active against multidrug-resistant cells, and is efficacious in animal tumor models despite lack of stability in rodent plasma. Clinical development was terminated in phase II due to dose limiting toxicities near the efficacious dose. Taken together, this made epothilone D attractive for encapsulation in a stabilized polymer micelle for improved safety and efficacy. We have designed a library of triblock copolymers to develop IT-147, a lead formulation of epothilone D that extends plasma circulation for accumulation in the tumor environment, and potentially decrease systemic exposure to reduce dose limiting toxicities. The drug loading efficiency for IT-147 exceeds 90%, is 75 nm in diameter, and demonstrates pH-dependent release of epothilone D without chemical conjugation or enzymatic activation. Administration of IT-147 at 20 mg/kg increases exposure of epothilone D to the plasma compartment over 6-fold compared to free drug. At the same dose, 20 mg/kg epothilone D from IT-147 is considered the no observed adverse effect level (NOAEL) but is the maximum tolerated dose for free drug. Consequently, IT-147 is positioned to be a safer, more effective means to deliver epothilone D

Women’s experiences of receiving care for pelvic organ prolapse: a qualitative study

Background Pelvic organ prolapse is a common urogenital condition affecting 41–50% of women over the age of 40. To achieve early diagnosis and appropriate treatment, it is important that care is sensitive to and meets women’s needs, throughout their patient journey. This study explored women’s experiences of seeking diagnosis and treatment for prolapse and their needs and priorities for improving person-centred care. Methods Twenty-two women receiving prolapse care through urogynaecology services across three purposefully selected NHS UK sites took part in three focus groups and four telephone interviews. A topic guide facilitated discussions about women’s experiences of prolapse, diagnosis, treatment, follow-up, interactions with healthcare professionals, overall service delivery, and ideals for future services to meet their needs. Data were analysed thematically. Results Three themes emerged relating to women’s experiences of a) Evaluating what is normal b) Hobson’s choice of treatment decisions, and c) The trial and error of treatment and technique. Women often delayed seeking help for their symptoms due to lack of awareness, embarrassment and stigma. When presented to GPs, their symptoms were often dismissed and unaddressed until they became more severe. Women reported receiving little or no choice in treatment decisions. Choices were often influenced by health professionals’ preferences which were subtly reflected through the framing of the offer. Women’s embodied knowledge of their condition and treatment was largely unheeded, resulting in decisions that were inconsistent with women’s preferences and needs. Physiotherapy based interventions were reported as helping women regain control over their symptoms and life. A need for greater awareness of prolapse and physiotherapy interventions among women, GPs and consultants was identified alongside greater focus on prevention, early diagnosis and regular follow-up. Greater choice and involvement in treatment decision making was desired. Conclusions As prolapse treatment options expand to include more conservative choices, greater awareness and education is needed among women and professionals about these as a first line treatment and preventive measure, alongside a multi-professional team approach to treatment decision making. Women presenting with prolapse symptoms need to be listened to by the health care team, offered better information about treatment choices, and supported to make a decision that is right for them

Beta-defensin genomic copy number is not a modifier locus for cystic fibrosis

Human beta-defensin 2 (DEFB4, also known as DEFB2 or hBD-2) is a salt-sensitive antimicrobial protein that is expressed in lung epithelia. Previous work has shown that it is encoded in a cluster of beta-defensin genes at 8p23.1, which varies in copy number between 2 and 12 in different individuals. We determined the copy number of this locus in 355 patients with cystic fibrosis (CF), and tested for correlation between beta-defensin cluster genomic copy number and lung disease associated with CF. No significant association was found

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Determination of Beta-Defensin Genomic Copy Number in Different Populations: A Comparison of Three Methods

There have been conflicting reports in the literature on association of gene copy number with disease, including CCL3L1 and HIV susceptibility, and β-defensins and Crohn's disease. Quantification of precise gene copy numbers is important in order to define any association of gene copy number with disease. At present, real-time quantitative PCR (QPCR) is the most commonly used method to determine gene copy number, however the Paralogue Ratio Test (PRT) is being used in more and more laboratories.In this study we compare a Pyrosequencing-based Paralogue Ratio Test (PPRT) for determining beta-defensin gene copy number with two currently used methods for gene copy number determination, QPCR and triplex PRT by typing five different cohorts (UK, Danish, Portuguese, Ghanaian and Czech) of DNA from a total of 576 healthy individuals. We found a systematic measurement bias between DNA cohorts revealed by QPCR, but not by the PRT-based methods. Using PRT, copy number ranged from 2 to 9 copies, with a modal copy number of 4 in all populations.QPCR is very sensitive to quality of the template DNA, generating systematic biases that could produce false-positive or negative disease associations. Both triplex PRT and PPRT do not show this systematic bias, and type copy number within the correct range, although triplex PRT appears to be a more precise and accurate method to type beta-defensin copy number

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe