Reducing alcohol harms whilst minimising impact on hospitality businesses: 'Sweetspot' policy options.

BACKGROUND: During COVID-19, hospitality businesses (e.g. bars, restaurants) were closed/restricted whilst off-sales of alcohol increased, with health consequences. Post-covid, governments face lobbying to support such businesses, but many health services remain under pressure. We appraised 'sweetspot' policy options: those with potential to benefit public services and health, whilst avoiding or minimising negative impact on the hospitality sector. METHODS: We conducted rapid non-systematic evidence reviews using index papers, citation searches and team knowledge to summarise the literature relating to four possible 'sweetspot' policy areas: pricing interventions (9 systematic reviews (SR); 14 papers/reports); regulation of online sales (1 SR; 1 paper); place-shaping (2 SRs; 18 papers/reports); and violence reduction initiatives (9 SRs; 24 papers/reports); and led two expert workshops (n = 11). RESULTS: Interventions that raise the price of cheaper shop-bought alcohol appear promising as 'sweetspot' policies; any impact on hospitality is likely small and potentially positive. Restrictions on online sales such as speed or timing of delivery may reduce harm and diversion of consumption from on-trade to home settings. Place-shaping is not well-supported by evidence and experts were sceptical. Reduced late-night trading hours likely reduce violence; evidence of impact on hospitality is scant. Other violence reduction initiatives may modestly reduce harms whilst supporting hospitality, but require resources to deliver multiple measures simultaneously in partnership. CONCLUSIONS: Available evidence and expert views point to regulation of pricing and online sales as having greatest potential as 'sweetspot' alcohol policies, reducing alcohol harm whilst minimising negative impact on hospitality businesses.

Localized Liver Injury During Normothermic Ex Situ Liver Perfusion Has No Impact on Short-term Liver Transplant Outcomes.

BACKGROUND: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized. METHODS: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant. The primary study outcome was 1-y graft survival. RESULTS: Seventy livers (63%) were included in the analysis. Radiological evidence of cradle compression was observed in 21 of 70 (30%). There was no difference in rate of cradle compression between donor after circulatory death and donated after brain death donors ( P  = 0.37) or with duration of NESLiP. Univariate analysis demonstrated younger (area under the receiver operating characteristic, 0.68; P = 0.008; 95% confidence interval [CI], 0.55-0.82) and heavier (area under the receiver operating characteristic, 0.80; P  < 0.001; 95% CI, 0.69-0.91) livers to be at risk of cradle compression. Only liver weight was associated with cradle compression on multivariate analysis (odds ratio, 1.003; P  = 0.005; 95% CI, 1.001-1.005). There was no difference in 1-y graft survival (16/17 [94.1%] versus 44/48 [91.6%]; odds ratio, 0.69; P  = 0.75; 95% CI, 0.07-6.62). CONCLUSIONS: This is the first study assessing the impact of cradle compression on outcome. We have identified increased donor liver weight and younger age as risk factors for the development of this phenomenon. Increasing utilization of NESLiP will result in the increased incidence of cradle compression but the apparent absence of long-term sequelae is reassuring. Routine postoperative axial imaging may be warranted.

Achilles Tendon Loading during Running Estimated Via Shear Wave Tensiometry: A Step Toward Wearable Kinetic Analysis.

PURPOSE: Understanding muscle-tendon forces (e.g., triceps surae and Achilles tendon) during locomotion may aid in the assessment of human performance, injury risk, and rehabilitation progress. Shear wave tensiometry is a noninvasive technique for assessing in vivo tendon forces that has been recently adapted to a wearable technology. However, previous laboratory-based and outdoor tensiometry studies have not evaluated running. This study was undertaken to assess the capacity for shear wave tensiometry to produce valid measures of Achilles tendon loading during running at a range of speeds. METHODS: Participants walked (1.34 m·s -1 ) and ran (2.68, 3.35, and 4.47 m·s -1 ) on an instrumented treadmill while shear wave tensiometers recorded Achilles tendon wave speeds simultaneously with whole-body kinematic and ground reaction force data. A simple isometric task allowed for the participant-specific conversion of Achilles tendon wave speeds to forces. Achilles tendon forces were compared with ankle torque measures obtained independently via inverse dynamics analyses. Differences in Achilles tendon wave speed, Achilles tendon force, and ankle torque across walking and running speeds were analyzed with linear mixed-effects models. RESULTS: Achilles tendon wave speed, Achilles tendon force, and ankle torque exhibited similar temporal patterns across the stance phase of walking and running. Significant monotonic increases in peak Achilles tendon wave speed (56.0-83.8 m·s -1 ), Achilles tendon force (44.0-98.7 N·kg -1 ), and ankle torque (1.72-3.68 N·m·(kg -1 )) were observed with increasing locomotion speed (1.34-4.47 m·s -1 ). Tensiometry estimates of peak Achilles tendon force during running (8.2-10.1 body weights) were within the range of those estimated previously via indirect methods. CONCLUSIONS: These results set the stage for using tensiometry to evaluate Achilles tendon loading during unobstructed athletic movements, such as running, performed in the field.

A hierarchical clustering approach for examining the relationship between pelvis-proximal femur geometry and bone stress injury in runners.

Bone stress injury (BSI) risk in runners is multifactorial and not well understood. Unsupervised machine learning approaches can potentially elucidate risk factors for BSI by identifying groups of similar runners within a population which differ in BSI incidence. Here, a hierarchical clustering approach is used to identify groups of collegiate cross country runners based on 2-dimensional frontal plane pelvis and proximal femur geometry, which was extracted from dual-energy X-ray absorptiometry scans and dimensionally reduced by principal component analysis. Seven distinct groups were identified using the cluster tree, with the initial split being highly related to female-male differences. Visual inspection revealed clear differences between groups in pelvis and proximal femur geometry, and groups were found to differ in lower body BSI incidence during the subsequent academic year (Rand index = 0.53; adjusted Rand index = 0.07). Linear models showed between-cluster differences in visually identified geometric measures. Geometric measures were aggregated into a pelvis shape factor based on trends with BSI incidence, and the resulting shape factor was significantly different between clusters (p < 0.001). Lower shape factor values, corresponding with lower pelvis height and ischial span, and greater iliac span and trochanteric span, appeared to be related to increased BSI incidence. This trend was dominated by the effect observed across clusters of male runners, indicating that geometric effects may be more relevant to BSI risk in males, or that other factors masked the relationship in females. More broadly, this work outlines a methodological approach for distilling complex geometric differences into simple metrics that relate to injury risk.

A trained neural network model accurately predicts Achilles tendon stress during walking and running based on shear wave propagation.

Shear wave tensiometry is a noninvasive technique for measuring tendon loading during activity based on the speed of a shear wave traveling along the tendon. Shear wave speed has been shown to modulate with axial stress, but calibration is required to obtain absolute measures of tendon loading. However, the current technique only makes use of wave speed, whereas other characteristics of the wave (e.g., amplitude, frequency content) may also vary with tendon loading. It is possible that these data could be used in addition to wave speed to circumvent the need for calibration. Given the potential complex relationships to tendon loading, and the lack of an analytical model to guide the use of these data, it is sensible to use a machine learning approach. Here, we used an ensemble neural network approach to predict inverse dynamics estimates of Achilles tendon stress from shear wave tensiometry data collected in a prior study. Neural network-predicted stresses were highly correlated with stance phase inverse dynamics estimates for walking (R2 = 0.89 ± 0.06) and running (R2 = 0.87 ± 0.11) data reserved for neural network model testing and not included in model training. Additionally, error between neural network-predicted and inverse dynamics-estimated stress was reasonable (walking: RMSD = 11 ± 2% of peak load; running: 25 ± 14%). Results of this pilot analysis suggest that a machine learning approach could reduce the reliance of shear wave tensiometry on calibration and expand its usability in many settings.

The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition.

Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly susceptible to cisplatin. We hypothesised that cisplatin ototoxicity might be caused by cisplatin-protein interactions rather than cisplatin-DNA interactions. Two known cisplatin-binding proteins are involved in the stress granule (SG) response. SGs are a pro-survival mechanism involving formation of transient ribonucleoprotein complexes during stress. We examined the effects of cisplatin on SG dynamics and composition in cell lines derived from the cochlea and retinal pigment epithelium. Cisplatin-induced SGs are significantly diminished in size and quantity compared to arsenite-induced SGs and are persistent after 24 h recovery. Additionally, cisplatin pre-treated cells were unable to form a typical SG response to subsequent arsenite stress. Cisplatin-induced SGs had significant reductions in the sequestration of eIF4G and the proteins RACK1 and DDX3X. Live-cell imaging of Texas Red-conjugated cisplatin revealed its localisation to SGs and retention for at least 24 h. We show cisplatin-induced SGs have impaired assembly, altered composition and are persistent, providing evidence of an alternate mechanism for cisplatin-induced ototoxicity via an impaired SG response.

Persistent mortality and heart failure burden of anterior ST-segment elevation myocardial infarction following primary percutaneous coronary intervention: real-world evidence from the US Medicare Data Set.

OBJECTIVES: We sought to compare the temporal trends in the incidence of death and rehospitalisation for congestive heart failure (CHF) following anterior ST-elevation myocardial infarction (STEMI) in a Medicare cohort of beneficiaries treated with primary percutaneous coronary intervention (PCI) in 2005 (n=1479) with those treated in 2016 through quarter (Q) 2 of 2017 (n=22 432). DESIGN: This retrospective analysis examined outcomes using both descriptive and regression analysis to control for differences in patient clinical characteristics over time. PRIMARY OUTCOME MEASURES: The primary outcomes are 1 year and 2 year rates of mortality and re-hospitalisation for CHF. RESULTS: The 1 year mortality rate was numerically higher in the 2016 cohort at 10.3% (95% CI 9.9 to 10.7) versus 8.9% (CI 7.4 to 10.3; p=0.068). The 2 year mortality rate was significantly higher in the 2016 cohort at 14.5% (CI 13.9 to 15.1) versus 11.4% (CI 9.2 to 13.6; p<0.01). The 1 year rehospitalisation for CHF was lower in the 2016 cohort at 10.6% (CI 10.0 to 11.2) versus 16.7% (CI 14.0 to 19.4; p<0.001), but the 2 year rate was not significantly different at 19.3% (CI 17.7 to 20.9) versus 20.7% (CI 16.4 to 24.9; p=0.55). After adjustment for covariates with two models, the 1 year mortality increased by 2.3% (CI 0.8 to 3.7; p<0.01) and 4.1% (CI 2.6 to 5.6; p<0.001) in the 2016 cohort. The 2 year adjusted mortality also increased by 4.2% (CI 2.0 to 6.4; p<0.001) and 6.5% (CI 4.2 to 8.7; p<0.001) in the 2016 cohort. The risk adjusted trends for rehospitalisation for CHF were similar to the unadjusted findings. CONCLUSIONS: Despite prior improvements in STEMI outcomes in the reperfusion era related to the broad adoption of timely PCI, there is a persistent high mortality and CHF burden in Medicare beneficiaries with anterior STEMI. New strategies that address reperfusion injury and enhance myocardial salvage are needed.

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study.

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding: Cambridge Hepatopancreatobiliary Department Research Fund.

American Society of Biomechanics Clinical Biomechanics Award 2021: Redistribution of muscle-tendon work in children with cerebral palsy who walk in crouch.

BACKGROUND: Previous study showed the triceps surae exhibits spring-like behavior about the ankle during walking in children with cerebral palsy. Thus, the work generated by the triceps surae is diminished relative to typically developing children. This study investigated whether the quadriceps offset the lack of triceps surae work production in children with cerebral palsy who walk in crouch. METHODS: Seven children with cerebral palsy (8-16 yrs) and 14 typically developing controls (8-17 yrs) walked overground at their preferred speed in a motion analysis laboratory. Shear wave tensiometers were used to track patellar and Achilles tendon loading throughout the gait cycle. Tendon force measures were coupled with muscle-tendon kinematic estimates to characterize the net work generated by the quadriceps and triceps surae about the knee and ankle, respectively. FINDINGS: Children with cerebral palsy generated significantly less triceps surae work when compared to controls (P < 0.001). The reverse was true at the knee. Children with cerebral palsy generated positive net work from the quadriceps about the knee, which exceeded the net quadriceps work generated by controls (P = 0.028). INTERPRETATION: There was a marked difference in functional behavior of the triceps surae and quadriceps in children with cerebral palsy who walk in crouch. In particular, the triceps surae of children with cerebral palsy exhibited spring-like behavior about the ankle while the quadriceps exhibited more motor-like behavior about the knee. This redistribution in work could partly be associated with the elevated energetic cost of walking in children with cerebral palsy and is relevant to consider when planning treatments to correct crouch gait.

Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease.

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

An emerging role for stress granules in neurodegenerative disease and hearing loss.

Stress granules (SGs) are membrane-less cytosolic assemblies that form in response to stress (e.g., heat, oxidative stress, hypoxia, viral infection and UV). Composed of mRNA, RNA binding proteins and signalling proteins, SGs minimise stress-related damage and promote cell survival. Recent research has shown that the stress granule response is vital to the cochlea's response to stress. However, emerging evidence suggests stress granule dysfunction plays a key role in the pathophysiology of multiple neurodegenerative diseases, several of which present with hearing loss as a symptom. Hearing loss has been identified as the largest potentially modifiable risk factor for dementia. The underlying reason for the link between hearing loss and dementia remains to be established. However, several possible mechanisms have been proposed including a common pathological mechanism. Here we will review the role of SGs in the pathophysiology of neurodegenerative diseases and explore possible links and emerging evidence that they may play an important role in maintenance of hearing and may be a common mechanism underlying age-related hearing loss and dementia.

" Exercise opportunities became very important": Scottish older adults' changes in physical activity during Covid19'.

BACKGROUND: The purpose of this study was to explore perceived changes in physical activity (PA) due to Covid19 stay-at-home and social distancing guidance among older adults. METHODS: Participants (n = 1429, 77% female, 84% ≥60 years) living in Scotland completed an online survey in Summer 2020 measuring PA and wellbeing (indexed through loneliness, and health-related quality of life). The survey included open- and closed-ended questions about how these variables changed in response to Covid19 social distancing and 'shielding' guidelines. RESULTS: From the International Physical Activity Questionnaire (IPAQ), the majority reported high volumes of PA, indicative of being 'moderately' or 'highly' active. When asked specifically about strength training, 12% reported engagement on ≥2d/wk. Most participants reported that PA had changed during this time, citing reduced use of exercise facilities, increased active travel, and online PA classes; although only 16% reported engaging in PA online. CONCLUSIONS: Higher levels of PA were found to be associated with better health-related quality of life. Additional efforts should be made to support PA engagement in older adults, including strength training and other tailored approaches to support individual needs.

Stakeholder views of current laws surrounding alcohol at UK football matches: Is it a case of using a "sledgehammer to crack a nut"?

BACKGROUND: In 2021, a fan-led review of football governance in England recommended that legislation surrounding alcohol and football be reviewed to determine whether it is still fit for purpose, the first such review since the mid-1980s. Restricting football fans' alcohol consumption has been debated in the UK for over 40 years. However, more research is needed into the current attitudes of fans and influential stakeholders on this matter. METHODS: Focus groups with football supporters (n=79) and semi-structured interviews (n=15) with key organisational stakeholders were conducted between November 2019 and February 2021. Focus groups included fans who regularly attended matches and supported various teams from professional leagues in Scotland and England, casual fans who usually watched games at home or in bars, and fans who followed the Scotland and England national teams. Stakeholders were selected to represent organisations likely to be instrumental in any regulatory change, such as the UK and Scottish Governments, Police, football supporters' groups and safety organisations. RESULTS: The current law does not allow for alcohol to be consumed within view of the pitch. Participants from England suggested this could be changed. While in Scotland, where the legislation only allows alcohol to be sold in hospitality, most participants were in favour of allowing the general sale of alcohol at football stadia via a pilot scheme. The reasons for these changes included: reducing unhealthy drinking behaviours; minimising the health and safety risk of fans arriving at the stadium just before kick-off; and a potential increase in much needed revenue for clubs. CONCLUSION: Our data suggests an evidence-based review of current laws regarding alcohol and football may be appropriate. However, any discussion regarding changes to the law regarding alcohol at football stadia, including potential pilot schemes, should be evaluated and monitored in terms of both financial impact and the impact on public health and safety.

A hierarchical clustering approach for examining potential risk factors for bone stress injury in runners.

Bone stress injuries (BSI) are overuse injuries that commonly occur in runners. BSI risk is multifactorial and not well understood. Unsupervised machine learning approaches can potentially elucidate risk factors for BSI by looking for groups of similar runners within a population that differ in BSI incidence. Here, a hierarchical clustering approach is used to identify groups of collegiate cross country runners (32 females, 21 males) based on healthy pre-season running (4.47 m·s-1) gait data which were aggregated and dimensionally reduced by principal component analysis. Five distinct groups were identified using the cluster tree. Visual inspection revealed clear differences between groups in kinematics and kinetics, and linear mixed effects models showed between-group differences in metrics potentially related to BSI risk. The groups also differed in BSI incidence during the subsequent academic year (Rand index = 0.49; adjusted Rand index = -0.02). Groups ranged from those including runners spending less time contacting the ground and generating higher peak ground reaction forces and joint moments to those including runners spending more time on the ground with lower loads. The former groups showed higher BSI incidence, indicating that short stance phases and high peak loads may be risk factors for BSI. Since ground contact duration may itself account for differences in peak loading metrics, we hypothesize that the percentage of time a runner is in contact with the ground may be a useful metric to include in machine learning models for predicting BSI risk.

High-Throughput Screening of Microbial Isolates with Impact on Caenorhabditis elegans Health.

With its small size, short lifespan, and easy genetics, Caenorhabditis elegans offers a convenient platform to study the impact of microbial isolates on host physiology. It also fluoresces in blue when dying, providing a convenient means of pinpointing death. This property has been exploited to develop high-throughput label-free C. elegans survival assays (LFASS). These involve time-lapse fluorescence recording of worm populations set in multiwell plates, from which population median time of death can be derived. The present study adopts the LFASS approach to screen multiple microbial isolates at once for the effects on C. elegans susceptibility to severe heat and oxidative stresses. Such microbial screening pipeline, which can notably be used to prescreen probiotics, using severe stress resistance as a proxy for host health is reported here. The protocol describes how to grow both C. elegans gut microbiota isolate collections and synchronous worm populations in multiwell arrays before combining them for the assays. The example provided covers the testing of 47 bacterial isolates and one control strain on two worm strains, in two stress assays in parallel. However, the approach pipeline is readily scalable and applicable to the screening of many other modalities. Thus, it provides a versatile setup to rapidly survey a multiparametric landscape of biological and biochemical conditions that impact C. elegans health.

Atypical triceps surae force and work patterns underlying gait in children with cerebral palsy.

The purpose of this study was to quantitatively assess Achilles tendon mechanical behavior during gait in children with cerebral palsy (CP). We used a newly designed noninvasive sensor to measure Achilles tendon force in 11 children with CP (4F, 8-16 years old) and 15 typically developing children (controls) (9F, 8-17 years old) during overground walking. Mechanical work loop plots (force-displacement plots) were generated by combining muscle-tendon kinetics, kinematics, and EMG activity to evaluate the Achilles tendon work generated about the ankle. Work loop patterns in children with CP were substantially different than those seen in controls. Notably, children with CP showed significantly diminished work production at their preferred speed compared to controls at their preferred speed and slower speeds. Despite testing a heterogeneous population of children with CP, we observed a homogenous spring-like muscle-tendon behavior in these participants. This is in contrast with control participants who used their plantar flexors like a motor during gait. Statement of Clinical Significance: These data demonstrate the potential for using skin-mounted sensors to objectively evaluate muscle contributions to work production in pathological gait.

Testing the feasibility of operationalizing a prospective, randomized trial with remote cardiac safety EKG monitoring during a pandemic.

BACKGROUND: The coronavirus SARS-CoV-2 is highly contagious. Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2. The FDA authorized emergency use of HCQ against COVID-19. HCQ may have dose-related cardiotoxicity. This clinical trial received ethical approval on May 15, 2020, operationalized in June to evaluate a low prophylaxis dose of HCQ (200mg BID) in household contacts of COVID-19-positive patients without physical contact between investigators and participants. It represents the first report of the FDA approved 6-lead EKGs with a smartphone KardiaMobile® 6L application. METHODS: To reach a sample size of 170, household members were contacted by telephone, emailed consent forms with electronic signature capability, and randomized 2:1 to HCQ or observation for 10 days with follow-up of 14 days. Home saliva PCR tests recorded COVID status on days 1 and 14. Symptoms and 6-lead EKGs were obtained daily. RESULTS: Fifty-one participants were randomized with 42 evaluable at day 14. Remote monitoring of 407 EKGs revealed no QTc prolongation or other ECG changes in either group. At time of consent, no participants were symptomatic or COVID+. On days 1 and 14, COVID tests were positive in 4 and 2 in the HCQ group and 4 and 0 in the observation group. No tests converted to positive. There were no deaths or hospitalizations. CONCLUSIONS: A clinical trial without personal contact, rapidly initiated and operationalized to exclude cardiac toxicity using daily remote 6-lead EKG monitoring, is feasible. Of 407 EKGs from 42 participants, there was no evidence of cardiac toxicity. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov : NCT04652648 registration date: December 3, 2020.

Lockdown and licensed premises: COVID-19 lessons for alcohol policy.

INTRODUCTION: The COVID-19 pandemic necessitated unprecedented changes in alcohol availability, including closures, curfews and restrictions. We draw on new data from three UK studies exploring these issues to identify implications for premises licensing and wider policy. METHODS: (i) Semi-structured interviews (n = 17) with licensing stakeholders in Scotland and England reporting how COVID-19 has reshaped local licensing and alcohol-related harms; (ii) semi-structured interviews (n = 15) with ambulance clinicians reporting experiences with alcohol during the pandemic; and (iii) descriptive and time series analyses of alcohol-related ambulance callouts in Scotland before and during the first UK lockdown (1 January 2019 to 30 June 2020). RESULTS: COVID-19 restrictions (closures, curfews) affected on-trade premises only and licensing stakeholders highlighted the relaxation of some laws (e.g. on takeaway alcohol) and a rise in home drinking as having long-term risks for public health. Ambulance clinicians described a welcome break from pre-pandemic mass public intoxication and huge reductions in alcohol-related callouts at night-time. They also highlighted potential long-term risks of increased home drinking. The national lockdown was associated with an absolute fall of 2.14 percentage points [95% confidence interval (CI) -3.54, -0.74; P = 0.003] in alcohol-related callouts as a percentage of total callouts, followed by a daily increase of +0.03% (95% CI 0.010, 0.05; P = 0.004). DISCUSSION AND CONCLUSIONS: COVID-19 gave rise to both restrictions on premises and relaxations of licensing, with initial reductions in alcohol-related ambulance callouts, a rise in home drinking and diverse impacts on businesses. Policies which may protect on-trade businesses, while reshaping the night-time economy away from alcohol-related harms, could offer a 'win-win' for policymakers and health advocates.

The future is now: our experience starting a remote clinical trial during the beginning of the COVID-19 pandemic.

BACKGROUND: The World Health Organization declared the outbreak of SARS-CoV-2 a pandemic on February 11, 2020. This organism causes COVID-19 disease and the rapid rise in cases and geographic spread strained healthcare systems. Clinical research trials were hindered by infection control measures discouraging physical contact and diversion of resources to meet emergent requirements. The need for effective treatment and prevention of COVID-19 prompted an untested investigational response. Trial groups adapted approaches using remote enrolment and consenting, newly developed diagnostic tests, delivery of study medications and devices to participants' homes, and remote monitoring to ensure investigator/enrollee safety while preserving ethical integrity, confidentiality, and data accuracy. METHODS: Clinical researchers at our community health system in the USA undertook an outpatient randomized open-label study of hydroxychloroquine (HCQ) prophylaxis versus observation of SARS-CoV-2 infection in household COVID-19 contacts. Designed in March 2020, challenges included COVID-19 infection in the research group, HCQ shortage, and lack of well-established home SARS-CoV-2 tests and remote ECG monitoring protocols in populations naive to these procedures. The study was written, funded, and received ethical committee approval in 4 months and was completed by September 2020 during a period of fluctuating infection rates and conflicting political opinions on HCQ use; results have been published. Singular methodology included the use of a new RNA PCR saliva SARS-CoV-2 home diagnostic test and a remote smartphone-based 6-lead ECG recording system. RESULTS: Of 483 households contacted regarding trial participation, 209 (43.3%) did not respond to telephone calls/e-mails and 90 (18.6%) declined; others were not eligible by inclusion or exclusion criteria. Ultimately, 54 individuals were enrolled and 42 completed the study. Numbers were too small to determine the efficacy of HCQ prophylaxis. No serious treatment-related adverse events were encountered. CONCLUSIONS: Flexibility in design, a multidisciplinary research team, prompt cooperation among research, funding, ethics review groups, and finding innovative study approaches enabled this work. Concerns were balancing study recruitment against unduly influencing individuals anxious for protection from the pandemic and exclusion of groups based on lack of Internet access and technology. An issue to address going forward is establishing research cooperation across community health systems before emergencies develop. TRIAL REGISTRATION: ClinicalTrials.gov NCT04652648 . Registered on December 3, 2020.

Normative Achilles and patellar tendon shear wave speeds and loading patterns during walking in typically developing children.

BACKGROUND: Motion analysis is commonly used to evaluate joint kinetics in children with cerebral palsy who exhibit gait disorders. However, one cannot readily infer muscle-tendon forces from joint kinetics. This study investigates the use of shear wave tensiometry to characterize Achilles and patellar tendon forces during gait. RESEARCH QUESTION: How do Achilles and patellar tendon wave speed and loading modulate with walking speed in typically developing children? METHODS: Twelve typically developing children (9-16 years old) walked on an instrumented treadmill with shear wave tensiometers over their Achilles (n = 11) and patellar (n = 9) tendons. Wave speeds were recorded at five leg length-normalized walking speeds (very slow to very fast). Achilles and patellar tendon moment arms were measured with synchronized ultrasound and motion capture. The tendon wave speed-load relationship was calibrated at the typical walking speed and used to estimate tendon loading at other walking speeds. RESULTS: Characteristic Achilles and patellar tendon wave speed trajectories exhibited two peaks over a gait cycle. Peak Achilles tendon force closely aligned with peak ankle plantarflexor moment during pushoff, though force exhibited less modulation with walking speed. A second peak in late swing Achilles loading, which was not evident from the ankle moment, increased significantly with walking speed (p < 0.001). The two peaks in patellar tendon loading occurred at 12 ± 1% and 68 ± 6% of the gait cycle, matching the timing of peak knee extension moment in early stance and early swing. Both patellar tendon load peaks increased significantly with walking speed (p < 0.05). SIGNIFICANCE: This is the first study to use shear wave tensiometry to characterize Achilles and patellar tendon loading during gait in children. These data could serve as a normative comparison when using tensiometry to identify abnormal tendon loading patterns in individuals who exhibit equinus and/or crouch gait.