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Abstract Background Quality smoking data is crucial for assessing smoking-related health risk and eligibility for interventions related to that risk. Smoking information collected in primary care practices (PCPs) is a major data source; however, little is known about the PCP smoking data quality. This project compared PCP smoking data to that collected in the Māori and Pacific Abdominal Aortic Aneurysm (AAA) screening programme. Methods A two stage review was conducted. In Stage 1, data quality was assessed by comparing the PCP smoking data recorded close to AAA screening episodes with the data collected from participants at the AAA screening session. Inter-rater reliability was analysed using Cohen’s kappa scores. In Stage 2, an audit of longitudinal smoking status was conducted, of a subset of participants potentially misclassified in Stage 1. Data were compared in three groups: current smoker (smoke at least monthly), ex-smoker (stopped > 1 month ago) and never smoker (smoked

Abstract Background HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. Methods This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Discussion Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. Trial registration ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986

Abstract Background Functional neurological disorder (FND) is a common neurological diagnosis that encapsulates a range of incapacitating clinical presentations. These include functional seizures, movement disorders, and sensory disturbances. Safe driving requires both cognitive skills and physical abilities, which may be impacted by FND symptoms. The primary objective of this study was to gain deeper insights into the challenges faced by people with FND when driving. Methods A qualitative study and interpretative phenomenological analysis were conducted. Individuals experiencing functional seizures and/or movement disorders completed both questionnaires and semi‐structured interviews about FND symptoms, driving behavior, and crashes. Results A total of 26 patients with FND participated in this study. Based on the interviews, four key themes were identified: (1) driving difficulties experienced by individuals with FND; (2) strategies utilized by people with FND to overcome difficulties experienced while driving; (3) barriers preventing driving challenges being addressed in this population; and (4) crashes and perceived dangerous driving events experienced by individuals with FND. All participants reported that driving a car provoked FND symptoms and this affected their driving ability. FND sufferers reported using a number of strategies such as limiting how far they drive and relying on advanced driver assistance system features to help manage their associated symptoms, such as fatigue and/or pain. Several participants reported crashes and perceived dangerous driving events since developing FND. Conclusion Individuals experiencing FND often employ self‐regulation techniques, yet the extent to which these methods enhance driving safety remains uncertain. The variable nature of the disorder makes judging an individual's driving risk particularly difficult. The themes emerging from the interviews highlighted the need for further empirical research to inform guidelines and best practice when determining the impact of FND on an individual's driving safety .

Abstract Background Severe mental ill health (SMI) includes schizophrenia, bipolar disorder and schizoaffective disorder and is associated with premature deaths when compared to people without SMI. Over 70% of those deaths are attributed to preventable health conditions, which have the potential to be positively affected by the adoption of healthy behaviours, such as physical activity. People with SMI are generally less active than those without and face unique barriers to being physically active. Physical activity interventions for those with SMI demonstrate promise, however, there are important questions remaining about the potential feasibility and acceptability of a physical activity intervention embedded within existing NHS pathways. Method This is a two-arm multi-site randomised controlled feasibility trial, assessing the feasibility and acceptability of a co-produced physical activity intervention for a full-scale trial across geographically dispersed NHS mental health trusts in England. Participants will be randomly allocated via block, 1:1 randomisation, into either the intervention arm or the usual care arm. The usual care arm will continue to receive usual care throughout the trial, whilst the intervention arm will receive usual care plus the offer of a weekly, 18-week, physical activity intervention comprising walking and indoor activity sessions and community taster sessions. Another main component of the intervention includes one-to-one support. The primary outcome is to investigate the feasibility and acceptability of the intervention and to scale it up to a full-scale trial, using a short proforma provided to all intervention participants at follow-up, qualitative interviews with approximately 15 intervention participants and 5 interventions delivery staff, and data on intervention uptake, attendance, and attrition. Usual care data will also include recruitment and follow-up retention. Secondary outcome measures include physical activity and sedentary behaviours, body mass index, depression, anxiety, health-related quality of life, healthcare resource use, and adverse events. Outcome measures will be taken at baseline, three, and six-months post randomisation. Discussion This study will determine if the physical activity intervention is feasible and acceptable to both participants receiving the intervention and NHS staff who deliver it. Results will inform the design of a larger randomised controlled trial assessing the clinical and cost effectiveness of the intervention. Trial registration ISRCTN: ISRCTN83877229. Registered on 09.09.2022.

Abstract Introduction Recent evidence has raised questions about whether newer HIV treatment regimens, including dolutegravir (DTG) and tenofovir alafenamide (TAF), are associated with increases in blood pressure (BP). Methods We assessed changes in BP by treatment regimen and evaluated the relative contribution of kidney function and weight gain to these changes among participants in the ADVANCE phase‐3 trial clinical trial in South Africa (study dates: January 2017–February 2022). Our primary outcome of interest was a change in systolic BP (SBP) at 96 and 192 weeks, among those not receiving antihypertensive medication. The secondary outcome was treatment‐emergent hypertension at these same time points, defined as BP ≥140/90 mmHg on two occasions, or initiation of antihypertensive medication after week 4 among individuals without hypertension at enrolment. We used linear regression to evaluate the relationship between change in estimated glomerular filtration rate (eGFR) and change in SBP; and Poisson regression to evaluate the relationship between change in eGFR and treatment‐emergent hypertension at each time point. All models were adjusted for age, sex, treatment group and change in body mass index (BMI). Results Over 96 weeks, the average changes in SBP were 1.7 mmHg (95% CI: 0.0−3.4), −0.5 mmHg (95% CI: −2.2 to 1.7) and −2.1 mmHg (95% CI: −3.8 to 0.4) in the TAF/emtricitabine (FTC)/DTG, tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz (EFV) groups, respectively. This difference was significant for the TAF/FTC/DTG compared to the TDF/FTC/EFV group (p = 0.002). Over 96 weeks, 18.2% (95% CI: 13.4–22.9), 15.4% (95% CI: 11.0–19.9) and 13.3% (95% CI: 8.9–17.6) of participants developed treatment‐emergent hypertension, respectively. In adjusted models, there was no significant relationship between change in eGFR and either outcome. Change in BMI was significantly associated with an increase in SBP, while age was associated with an increased risk of treatment‐emergent hypertension. Adjustment for BMI also mitigated the unadjusted relationship between HIV treatment regimen and SBP where present. Conclusions In the ADVANCE cohort, weight gain and age accounted for increases in BP and risk of treatment‐emergent hypertension. HIV treatment programmes may need to integrate the management of obesity and hypertension into routine care. Clinical Trial Number NCT03122262

Background Enhanced detection of large vessel occlusion (LVO) through machine learning (ML) for acute ischemic stroke appears promising. This systematic review explored the capabilities of ML models compared with prehospital stroke scales for LVO prediction. Methods and Results Six bibliographic databases were searched from inception until October 10, 2023. Meta‐analyses pooled the model performance using area under the curve (AUC), sensitivity, specificity, and summary receiver operating characteristic curve. Of 1544 studies screened, 8 retrospective studies were eligible, including 32 prehospital stroke scales and 21 ML models. Of the 9 prehospital scales meta‐analyzed, the Rapid Arterial Occlusion Evaluation had the highest pooled AUC (0.82 [95% CI, 0.79–0.84]). Support Vector Machine achieved the highest AUC of 9 ML models included (pooled AUC, 0.89 [95% CI, 0.88–0.89]). Six prehospital stroke scales and 10 ML models were eligible for summary receiver operating characteristic analysis. Pooled sensitivity and specificity for any prehospital stroke scale were 0.72 (95% CI, 0.68–0.75) and 0.77 (95% CI, 0.72–0.81), respectively; summary receiver operating characteristic curve AUC was 0.80 (95% CI, 0.76–0.83). Pooled sensitivity for any ML model for LVO was 0.73 (95% CI, 0.64–0.79), specificity was 0.85 (95% CI, 0.80–0.89), and summary receiver operating characteristic curve AUC was 0.87 (95% CI, 0.83–0.89). Conclusions Both prehospital stroke scales and ML models demonstrated varying accuracies in predicting LVO. Despite ML potential for improved LVO detection in the prehospital setting, application remains limited by the absence of prospective external validation, limited sample sizes, and lack of real‐world performance data in a prehospital setting.

Abstract Recent global events have drawn into focus the diversity of options for combatting disease across a spectrum of prophylactic and therapeutic approaches. The recent success of the mRNA-based COVID-19 vaccines has paved the way for RNA-based treatments to revolutionize the pharmaceutical industry. However, historical treatment options are continuously updated and reimagined in the context of novel technical developments, such as those facilitated through the application of synthetic biology. When it comes to the development of genetic forms of therapies and vaccines, synthetic biology offers diverse tools and approaches to influence the content, dosage, and breadth of treatment with the prospect of economic advantage provided in time and cost benefits. This can be achieved by utilizing the broad tools within this discipline to enhance the functionality and efficacy of pharmaceutical agent sequences. This review will describe how synthetic biology principles can augment RNA-based treatments through optimizing not only the vaccine antigen, therapeutic construct, therapeutic activity, and delivery vector. The enhancement of RNA vaccine technology through implementing synthetic biology has the potential to shape the next generation of vaccines and therapeutics.

Abstract Technologies to study localized host–pathogen interactions are urgently needed. Here, we present a spatial transcriptomics approach to simultaneously capture host and pathogen transcriptome-wide spatial gene expression information from human formalin-fixed paraffin-embedded (FFPE) tissue sections at a near single-cell resolution. We demonstrate this methodology in lung samples from COVID-19 patients and validate our spatial detection of SARS-CoV-2 against RNAScope and in situ sequencing. Host–pathogen colocalization analysis identified putative modulators of SARS-CoV-2 infection in human lung cells. Our approach provides new insights into host response to pathogen infection through the simultaneous, unbiased detection of two transcriptomes in FFPE samples.

IntroductionThe ADVANCE and NAMSAL trials evaluating antiretroviral drugs have both reported substantial levels of clinical obesity in participants. As one of the main risk factors for metabolic syndrome, growing rates of obesity may drive metabolic syndrome development. This study aims to evaluate the risk of metabolic syndrome in the ADVANCE and NAMSAL trials.MethodsThe number of participants with metabolic syndrome was calculated at baseline and week 192 as central obesity and any of the following two factors: raised triglycerides, reduced HDL-cholesterol, raised blood pressure and raised fasting glucose. Differences between the treatment arms were calculated using the χ2 test.ResultsAcross all visits to week 192, treatment-emergent metabolic syndrome was 15% (TAF/FTC + DTG), 10% (TDF/FTC + DTG) and 7% (TDF/FTC/EFV) in ADVANCE. The results were significantly higher in the TAF/FTC + DTG arm compared to the TDF/FTC/EFV arm (p

Objectives To develop consensus statements regarding the regional-level or district-level distribution of surgical services in low and middle-income countries (LMICs) and prioritisation of service scale-up.Design This work was conducted using a modified Delphi consensus process. Initial statements were developed by the International Standards and Guidelines for Quality Safe Surgery and Anesthesia Working Group of the Global Alliance for Surgical, Obstetric, Trauma and Anesthesia Care (G4 Alliance) and the International Society of Surgery based on previously published literature and clinical expertise. The Guidance on Conducting and REporting DElphi Studies framework was applied.Setting The Working Group convened in Suva, Fiji for a meeting hosted by the Ministry of Health and Medical Services to develop the initial statements. Local experts were invited to participate. The modified Delphi process was conducted through an electronically administered anonymised survey.Participants Expert LMIC surgeons were nominated for participation in the modified Delphi process based on criteria developed by the Working Group.Primary outcome measures The consensus panel voted on statements regarding the organisation of surgical services, principles for scale-up and prioritisation of scale-up. Statements reached consensus if there was ≥80% agreement among participants.Results Fifty-three nominated experts from 27 LMICs voted on 27 statements in two rounds. Ultimately, 26 statements reached consensus and comprise the current recommendations. The statements covered three major themes: which surgical services should be decentralised or regionalised; how the implementation of these services should be prioritised; and principles to guide LMIC governments and international visiting teams in scaling up safe, accessible and affordable surgical care.Conclusions These recommendations represent the first step towards the development of international guidelines for the scaling up of surgical services in LMICs. They constitute the best available basis for policymaking, planning and allocation of resources for strengthening surgical systems.

Summary: Background: This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19. Methods: This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18–65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population. Findings: The mITT population included 186 patients: mean age (SD) 34.9 (10.3) years, body weight 78.2 (17.1) kg. Day 7 SARS-CoV-2 clearance rates (n/N; risk ratio [95% CI]) were: SOC 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV + NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) and SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; SOF-DCV 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There were no deaths. Adverse events occurred in 55.3% (105/190) of patients, including one serious adverse event (pancytopenia; FPV + NTZ). Interpretation: There was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated. Funding: Medicines for Malaria Venture, with funding from the UK Foreign, Commonwealth and Development Office, within the Covid-19 Therapeutics Accelerator in partnership with Wellcome, the Bill and Melinda Gates Foundation, and Mastercard.

Introduction Diabetic foot ulcers contribute significantly to morbidity and mortality associated with diabetes, but are preventable with good foot self-care. This study sought to explore the perspectives of patients and healthcare professionals (HCPs) on barriers and/or facilitators to foot self-care behaviors in diabetes and areas of consensus and/or tension between patient and HCP perspectives.Research design and methods This was a sequential, qualitative study that used a hermeneutic phenomenological approach. Phase I involved nine in-depth, semi-structured patient interviews. Phase II involved seven in-depth semi-structured interviews with HCPs (podiatrists, diabetes nurses, foot health practitioners (FHPs) and general practitioners (GPs)). In phase III, findings from phases I and II were brought back to two patient interview groups (five patients in total) to try and identify any areas of consensus and tension between HCP and patient perspectives.Results Patient and HCP perspectives had several areas of alignment: concerns over consequences of diabetes complications; the importance of patient education and frustrations around aspects of health service delivery. There were also some notable tensions identified: mixed messaging from HCPs around whose responsibility patient foot health is; and who patients should initially consult following the development of a foot problem. Overall, patients expressed that motivation to undertake good foot self-care behaviors was generated from their lived experiences, and was enhanced when this aligned with the information they received from HCPs. HCPs appeared to attribute lack of patient motivation to lack of knowledge, which was not raised by patients.Conclusions This study has identified points of misalignment between the views of patients and practitioners that may help to explain why adherence to foot self-care among patients with diabetes is low. Our results suggest that better outcomes may stem from HCPs focusing on supporting autonomous motivation for self-care and enhancing the rationale through referencing patients’ own experience rather than focussing on increasing patient knowledge. Renewed focus on consistency of messaging by HCPs around the roles and responsibilities relating to foot health in diabetes, and the benefit of foot-specific training being provided to non-foot specialist HCPs may also help to improve uptake and adherence to foot self-care behaviors in diabetes.

An 81-year-old man, with a complex vascular surgical history, presents with sepsis from an infected Nellix stent-graft. He required an urgent laparotomy, explantation of the graft, and extra-anatomical repair. Although now widely used for this indication, the preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography was nondiagnostic for his stent-graft infection. We describe our management of a complicated Nellix graft infection and discuss the utility of positron emission tomography/computed tomography for stent-graft infections.

BackgroundIvermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing large-scale clinical trials to evaluate the effectiveness of this drug in the midst of the pandemic, while difficult, has been urgently needed.MethodsWe performed two large multicenter randomized, double-blind, placebo-controlled clinical trials evaluating the effectiveness of ivermectin in treating inpatients and outpatients with COVID-19 infection. The intervention group received ivermectin, 0.4mg/kg of body weight per day for 3 days. In the control group, placebo tablets were used for 3 days.ResultsData for 609 inpatients and 549 outpatients were analyzed. In hospitalized patients, complete recovery was significantly higher in the ivermectin group (37%) compared to placebo group (28%; RR, 1.32 [95% CI, 1.04–1.66]; p-value = 0.02). On the other hand, the length of hospital stay was significantly longer in the ivermectin group with a mean of 7.98 ± 4.4 days compared to the placebo receiving group with a mean of 7.16 ± 3.2 days (RR, 0.80 [95% CI, 0.15–1.45]; p-value = 0.02). In outpatients, the mean duration of fever was significantly shorter (2.02 ± 0.11 days) in the ivermectin group versus (2.41 ± 0.13 days) placebo group with p value = 0.020. On the day seventh of treatment, fever (p-value = 0.040), cough (p-value = 0.019), and weakness (p-value = 0.002) were significantly higher in the placebo group compared to the ivermectin group. Among all outpatients, 7% in ivermectin group and 5% in placebo group needed to be hospitalized (RR, 1.36 [95% CI, 0.65–2.84]; p-value = 0.41). Also, the result of RT-PCR on day five after treatment was negative for 26% of patients in the ivermectin group versus 32% in the placebo group (RR, 0.81 [95% CI, 0.60–1.09]; p-value = 0.16).ConclusionOur data showed, ivermectin, compared with placebo, did not have a significant potential effect on clinical improvement, reduced admission in ICU, need for invasive ventilation, and death in hospitalized patients; likewise, no evidence was found to support the prescription of ivermectin on recovery, reduced hospitalization and increased negative RT-PCR assay for SARS-CoV-2 5 days after treatment in outpatients. Our findings do not support the use of ivermectin to treat mild to severe forms of COVID-19.Clinical Trial Registrationwww.irct.ir IRCT20111224008507N5 and IRCT20111224008507N4.

BackgroundImpairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (

Here the authors combine next generation sequencing on plasma from participants of the ADVANCE clinical trial with virological and follow-up data to investigate the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second-generation integrase inhibitors and find an association between NNRTI resistance prior to treatment and long-term treatment.

Within the first year of distribution of vaccines against COVID-19, high-income countries (HICs) have achieved vaccination rates of 75-80%, whilst low-income countries (LICs) vaccinated

Abstract Background The rate at which COVID-19 has spread throughout the globe has been alarming. While the role of fomite transmission is not yet fully understood, precise data on the environmental stability of SARS-CoV-2 is required to determine the risks of fomite transmission from contaminated surfaces. Methods This study measured the survival rates of infectious SARS-CoV-2, suspended in a standard ASTM E2197 matrix, on several common surface types. All experiments were carried out in the dark, to negate any effects of UV light. Inoculated surfaces were incubated at 20 °C, 30 °C and 40 °C and sampled at various time points. Results Survival rates of SARS-CoV-2 were determined at different temperatures and D-values, Z-values and half-life were calculated. We obtained half lives of between 1.7 and 2.7 days at 20 °C, reducing to a few hours when temperature was elevated to 40 °C. With initial viral loads broadly equivalent to the highest titres excreted by infectious patients, viable virus was isolated for up to 28 days at 20 °C from common surfaces such as glass, stainless steel and both paper and polymer banknotes. Conversely, infectious virus survived less than 24 h at 40 °C on some surfaces. Conclusion These findings demonstrate SARS-CoV-2 can remain infectious for significantly longer time periods than generally considered possible. These results could be used to inform improved risk mitigation procedures to prevent the fomite spread of COVID-19.

Background: Repurposing broad-spectrum antivirals is an immediate treatment opportunity for 2019 coronavirus disease (COVID-19). Favipiravir is an antiviral previously indicated for influenza and Ebola, which has shown some promise in early trials for treatment of COVID-19. We aim to review existing favipiravir safety evidence, which is vital to informing the potential future use of favipiravir in COVID-19. Methods: A search was conducted across EMBASE and MEDLINE databases, supplemented by relevant grey-literature and ClinicalTrials.gov. All studies assessing the use of favipiravir in humans by 27 March 2020 were considered for inclusion. Further analysis of available safety data from phase 2 and 3 studies was undertaken. Data extracted were adverse events (AEs) grade 1–4, serious AEs and discontinuation for AEs. Specific AEs of interest highlighted in early-phase studies, including gastrointestinal AEs and hyperuricaemia, were also examined. Results: Twenty-nine studies were identified as potential sources of evidence of the clinical safety of favipiravir. Six were phase 2 and 3 studies reporting relevant safety data for statistical comparison, representing a total of 4299 participants, an estimated 175 person-years-of-follow-up (PYFU). Comparator drugs were oseltamivir, umifenovir, lopinavir/ritonavir or placebo. Study follow-up was between 5 and 21 days. The proportions of grade 1–4 AEs on favipiravir was 28.2% vs 28.4% (P = n.s.) in the comparison arms. The proportion of discontinuations due to AEs on favipiravir was 1.1% vs 1.2% (P = n.s.) in the comparison arms. For serious AEs the proportion was 0.4% in both arms (P = n.s.). There were significantly fewer gastrointestinal AEs occurring on favipiravir vs comparators [8.7% vs 11.5%; P = 0.003]. Favipiravir showed significantly more uric acid elevations than comparators [5.8% vs 1.3%; P

Introduction: People living with HIV (PLWH) are mainly African or Asian, the majority female. In contrast, pharmaceutical companies typically conduct phase 3 regulatory randomised controlled trials (RCTs) in high-income countries (HICs), where PLWH are mainly white males. Regulatory authorities can be conservative about including pregnant women in trials, discouraging female participation. Some adverse events occur more frequently by sex or by race because of differing pharmacokinetics. Most drugs have insufficient safety data in pregnancy and non-white people even after regulatory approval. The present study compared race and sex demographics of phase 3 RCTs of dolutegravir (DTG), bictegravir (BIC) and tenofovir alafenamide (TAF) with global HIV epidemic demography. Methods: National epidemic sizes by sex were extracted from UNAIDS 2018 data. National demographics were used to estimate prevalence by race. PLWH by national socio-economic status were calculated from World Bank data. Summary race and sex demographic data for 10 phase 3 trials of DTG (n = 7714), four of BIC (n = 2307), eight of TAF (n = 7573) and two of doravirine (DOR) (n = 1407) were extracted from ClinicalTrials.gov. Results: Black females (42%) and black males (30%) have highest prevalence globally. White males comprise 6% of PLWH. Over 60% of PLWH live in low or low-middle-income countries, 68% of whom are black and 23% Asian. Seventy-six per cent of DTG trial centres were in high-income countries (HICs) (5% global burden) and 23% in upper-middle-income countries (UMICs). DTG trials were not representative of PLWH even within the UMIC and HIC setting (49% white male vs 31% income band). White males were overrecruited by 44% to DTG, BIC, TAF and DOR trials in comparison with prevalence. Black females were underrepresented by 35%. Conclusion: Phase 3 RCT populations for new antiretrovirals comprised 51% white males, vastly disproportionate to the global HIV epidemic (6%). Females and non-white people are underrepresented. Female safety data are insufficient despite drug approval in Europe and USA. HIV trials should be located in regions representing the global epidemic with no sex-based selection. Trials should aim for at least 50% female and 50% non-white recruitment to properly provide safety information.

Introduction: ‘Repurposing’ existing drugs to treat COVID-19 is vital to reducing mortality and controlling the pandemic. Several promising drugs have been identified and are in various stages of clinical trials globally. If efficacy of these drugs is demonstrated, rapid, mass availability at an affordable cost would be essential to ensuring equity and access especially amongst low- and middle-income economies. Methods: Minimum costs of production were estimated from the costs of active pharmaceutical ingredients using established methodology, which had good predictive accuracy for medicines for hepatitis C and HIV amongst others. Data were extracted from global export shipment records or analysis of the route of chemical synthesis. The estimated costs were compared with list prices from a range of countries where pricing data were available. Results: Minimum estimated costs of production were US $0.93/day for remdesivir, $1.45/day for favipiravir, $0.08/day for hydroxychloroquine, $0.02/day for chloroquine, $0.10/day for azithromycin, $0.28/day for lopinavir/ritonavir, $0.39/day for sofosbuvir/daclatasvir and $1.09/day for pirfenidone. Costs of production ranged between $0.30 and $31 per treatment course (10–28 days). Current prices of these drugs were far higher than the costs of production, particularly in the US. Conclusions: Should repurposed drugs demonstrate efficacy against COVID-19, they could be manufactured profitably at very low costs, for much less than current list prices. Estimations for the minimum production costs can strengthen price negotiations and help ensure affordable access to vital treatment for COVID-19 at low prices globally.

IntroductionDepression is a leading mental health problem worldwide. People with long-term conditions are at increased risk of experiencing depression. The COVID-19 pandemic led to strict social restrictions being imposed across the UK population. Social isolation can have negative consequences on the physical and mental wellbeing of older adults. In the Behavioural Activation in Social IsoLation (BASIL+) trial we will test whether a brief psychological intervention (based on Behavioural Activation), delivered remotely, can mitigate depression and loneliness in older adults with long-term conditions during isolation.MethodsWe will conduct a two-arm, parallel-group, randomised controlled trial across several research sites, to evaluate the clinical and cost-effectiveness of the BASIL+ intervention. Participants will be recruited via participating general practices across England and Wales. Participants must be aged ≥65 with two or more long-term conditions, or a condition that may indicate they are within a 'clinically extremely vulnerable' group in relation to COVID-19, and have scored ≥5 on the Patient Health Questionnaire (PHQ9), to be eligible for inclusion. Randomisation will be 1:1, stratified by research site. Intervention participants will receive up to eight intervention sessions delivered remotely by trained BASIL+ Support Workers and supported by a self-help booklet. Control participants will receive usual care, with additional signposting to reputable sources of self-help and information, including advice on keeping mentally and physically well. A qualitative process evaluation will also be undertaken to explore the acceptability of the BASIL+ intervention, as well as barriers and enablers to integrating the intervention into participants' existing health and care support, and the impact of the intervention on participants' mood and general wellbeing in the context of the COVID-19 restrictions. Semi-structured interviews will be conducted with intervention participants, participant's caregivers/supportive others and BASIL+ Support Workers. Outcome data will be collected at one, three, and 12 months post-randomisation. Clinical and cost-effectiveness will be evaluated. The primary outcome is depressive symptoms at the three-month follow up, measured by the PHQ9. Secondary outcomes include loneliness, social isolation, anxiety, quality of life, and a bespoke health services use questionnaire.DiscussionThis study is the first large-scale trial evaluating a brief Behavioural Activation intervention in this population, and builds upon the results of a successful external pilot trial.Trial registrationClinicalTrials.Gov identifier ISRCTN63034289, registered on 5th February 2021.

With the proliferation of tobacco products, there might be a need for more complex models than current two-product models. We have developed a three-product model able to represent interactions between three products in the marketplace. We also investigate if using several implementations of two-product models could provide sufficient information to assess 3 coexisting products. Italy is used as case-study with THPs and e-cigarettes as the products under investigation. We use transitions rates estimated for THPs in Japan and e-cigarettes in the USA to project what could happen if the Italian population were to behave as the Japanese for THP or USA for e-cigarettes. Results suggest that three-product models may be hindered by data availability while two product models could miss potential synergies between products. Both, THP and E-Cigarette scenarios, led to reduction in life-years lost although the Japanese THP scenario reductions were 3 times larger than the USA e-cigarette projections.

Human gait analysis presents an opportunity to study complex spatiotemporal data transpiring as co-movement patterns of multiple moving objects (i.e., human joints). Such patterns are acknowledged as movement signatures specific to an individual, offering the possibility to identify each individual based on unique gait patterns. We present a spatiotemporal deep learning model, dubbed ST-DeepGait, to featurize spatiotemporal co-movement patterns of human joints, and accordingly classify such patterns to enable human gait recognition. To this end, the ST-DeepGait model architecture is designed according to the spatiotemporal human skeletal graph in order to impose learning the salient local spatial dynamics of gait as they occur over time. Moreover, we employ a multi-layer RNN architecture to induce a sequential notion of gait cycles in the model. Our experimental results show that ST-DeepGait can achieve recognition accuracy rates over 90%. Furthermore, we qualitatively evaluate the model with the class embeddings to show interpretable separability of the features in geometric latent space. Finally, to evaluate the generalizability of our proposed model, we perform a zero-shot detection on 10 classes of data completely unseen during training and achieve a recognition accuracy rate of 88% overall. With this paper, we also contribute our gait dataset captured with an RGB-D sensor containing approximately 30 video samples of each subject for 100 subjects totaling 3087 samples. While we use human gait analysis as a motivating application to evaluate ST-DeepGait, we believe that this model can be simply adopted and adapted to study co-movement patterns of multiple moving objects in other applications such as in sports analytics and traffic pattern analysis.

Objectives: The Joint United Nations Programme on HIV/AIDS (UNAIDS) targets aim to reduce new HIV infections below 500,000 per year by 2020. Despite targeted prevention programmes, total new infections remained in 2016 and 2017 at 1,800,000 cases. We have aimed to analyse data from 2017 and to compare HIV incidence, AIDS-related deaths and provision of antiretroviral therapy (ART) to adults, pregnant women and children living with HIV in lower- and higher-prevalence countries. Vertical or mother-to-child transmission (MTCT) and early infant diagnosis (EID) rates were also investigated. Methods: UNAIDSinfo data use the Spectrum model to represent country-level HIV data. Countries with epidemics over 40,000 HIV cases were separated into higher prevalence (≥4.5%) and lower prevalence (

Iatrogenic arteriovenous fistulae are rare occurrences after venepuncture, line placement or trauma. Presentations and symptoms can vary but they are usually identified soon after the causative injury due to the development of a visible, palpable, and pulsatile lump that can be concerning for patients. We describe the presentation and management of an unusual case of delayed presentation of an iatrogenic, traumatic brachio-brachial fistula.

Background: Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE). Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load

Dolutegravir, a second-generation integrase strand transfer inhibitor (InSTI), is replacing efavirenz as first-line antiretroviral therapy (ART) in low middle-income countries (LMICs). Tuberculosis remains the leading cause of HIV-related morbidity and mortality in LMICs. Rifampicin is a key agent in the treatment of tuberculosis but induces genes involved in dolutegravir metabolism and efflux. The resulting drug-drug interaction (DDI) reduces the exposure of dolutegravir. However, this can be overcome by supplying a supplemental dose of 50 mg dolutegravir 12 hours after the standard daily dose, which is difficult to implement in LMICs. Four lines of evidence suggest that the supplemental dose may not be necessary: 1) a phase 2 study showed 10 mg of dolutegravir as effective as 50 mg; 2) the prolonged dissociative half-life of dolutegravir after binding to its receptor; 3) a DDI study reported dolutegravir trough concentrations were maintained above its minimum effective concentration when using 50 mg dolutegravir with rifampicin; and 4) virologic outcomes were similar between standard and double dose of raltegravir (a first-generation InSTI) in participants with HIV-associated tuberculosis treated with rifampicin. We hypothesise that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based antituberculosis therapy. Here we outline the protocol for a phase 2, non-comparative, randomised, double-blind, placebo-controlled trial of standard versus double dose dolutegravir among adults living with HIV (ART naïve or first-line interrupted) on rifampicin-based antituberculosis therapy. A total of 108 participants will be enrolled from Khayelitsha in Cape Town, South Africa. Follow up will occur over 48 weeks. The primary objective is to assess proportion virological suppression at 24 weeks between groups analysed by modified intention to treat. Participant safety and the emergence of antiretroviral resistance mutations among those with virologic failure will be assessed throughout. Trial registrations: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).

Chronic obstructive pulmonary disease (COPD) is a disease with marked metabolic disturbance. Previous studies have shown the association between single metabolites and lung function for COPD, but whether a combination of metabolites could predict phenotype is unknown. We developed metabolomic severity scores using plasma metabolomics from the Metabolon platform from two US cohorts of ever-smokers: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) (n = 648; training/testing cohort; 72% non-Hispanic, white; average age 63 years) and the COPDGene Study (n = 1120; validation cohort; 92% non-Hispanic, white; average age 67 years). Separate adaptive LASSO (adaLASSO) models were used to model forced expiratory volume at one second (FEV1) and MESA-adjusted lung density using 762 metabolites common between studies. Metabolite coefficients selected by the adaLASSO procedure were used to create a metabolomic severity score (metSS) for each outcome. A total of 132 metabolites were selected to create a metSS for FEV1. The metSS-only models explained 64.8% and 31.7% of the variability in FEV1 in the training and validation cohorts, respectively. For MESA-adjusted lung density, 129 metabolites were selected, and metSS-only models explained 59.0% of the variability in the training cohort and 17.4% in the validation cohort. Regression models including both clinical covariates and the metSS explained more variability than either the clinical covariate or metSS-only models (53.4% vs. 46.4% and 31.6%) in the validation dataset. The metabolomic pathways for arginine biosynthesis; aminoacyl-tRNA biosynthesis; and glycine, serine, and threonine pathway were enriched by adaLASSO metabolites for FEV1. This is the first demonstration of a respiratory metabolomic severity score, which shows how a metSS can add explanation of variance to clinical predictors of FEV1 and MESA-adjusted lung density. The advantage of a comprehensive metSS is that it explains more disease than individual metabolites and can account for substantial collinearity among classes of metabolites. Future studies should be performed to determine whether metSSs are similar in younger, and more racially and ethnically diverse populations as well as whether a metabolomic severity score can predict disease development in individuals who do not yet have COPD.

Objectives: Seven years after the introduction of direct-acting antivirals (DAAs) for the treatment of hepatitis C, high prices remain a barrier for treatment programs worldwide. This study seeks to describe current prices for originator DAAs in 50 countries and evaluate the relationship between prices and GDP per capita. Methods: Data on prices of sofosbuvir, daclatasvir, sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir were collected from national databases for 50 countries. Cost-based generic prices were estimated using an established algorithm, which accounts for costs of the active pharmaceutical ingredient (API), excipients, conversion costs of API to finished pharmaceutical product, taxes assuming manufacture in India, and a 10% profit margin. Correlation between current market prices and GDP per capita was assessed by Spearman rank-order correlation. Results: Median originator prices per standard course were US$40,502 for sofosbuvir, US$26,928 for daclatasvir, US$46,812 for sofosbuvir/ledipasvir, US$34,381 for sofosbuvir/velpatasvir, and US$30,710 for glecaprevir/pibrentasvir (G/P). The estimated cost-based generic prices for a 12-week course were US$28 for sofosbuvir, US$31 for ledipasvir, US$58 for velpatasvir, US$4 for daclatasvir. For fixed-dose combinations, estimated cost-based prices were US$58 for sofosbuvir/ledipasvir, US$85 for sofosbuvir/velpatasvir, and US$31 for sofosbuvir/daclatasvir (API cost data were insufficient to calculate an estimate for G/P). Cumulative originator sales of WHO-recommended DAAs reached US$82 billion by the end of 2019. Across the 50 countries, there was no correlation between GDP per capita and DAA price, nor between estimated viraemic population and DAA price. Sub-analyses within World Bank income groups found a significant negative correlation between price and GDP per capita for all DAAs within the high-income countries group. Conclusions: Prices of DAAs vary widely across countries. The lack of correlation between DAA price and GDP per capita and viraemic population suggests that prices for DAAs are not adjusted based on country income level or potential patient population. Among high-income countries, DAA prices fall as income levels rise, possibly due to greater negotiating power of wealthier countries. DAA prices in most countries remain many times higher than estimated cost-based generic prices.

Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.