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The authors reflect on the benefits of adaptive sport and adventure training in Great Britain. They revealed that the growth in access of adaptive sports and adventure training has embraced the social model of disability in which the goal is to improve participation of athletes with disabilities. The authors also believe that disabled participants will experience improvements in impairment brought on by novel stimuli, challenges, and social interactions.

Background and Aims: Given the costs of alcohol to society, it is important to evaluate whether local alcohol licensing decisions can mitigate the effects of alcohol misuse. Robust natural experiment evaluations of the impact of individual licensing decisions could potentially inform and improve local decision‐making. We aimed to assess whether alcohol licensing decisions could be evaluated at small spatial scale by using a causal inference framework. Design Three natural experiments. Setting and participants: Three English local areas of 1000–15 000 people each. Intervention and comparator: The case study interventions were (i) the closure of a nightclub following reviews; (ii) closure of a restaurant/nightclub following reviews and (iii) implementation of new local licensing guidance (LLG). Trends in outcomes were compared with synthetic counterfactuals created using Bayesian structural time–series. Measurements Time–series data were obtained on emergency department admissions, ambulance call‐outs and alcohol‐related crime at the Lower or Middle Super Output geographical aggregation level. Findings Closure of the nightclub led to temporary 4‐month reductions in antisocial behaviour (−18%; 95% credible interval − 37%, −4%), with no change in other outcomes. Closure of the restaurant/nightclub did not lead to measurable changes in outcomes. The new licensing guidance led to small reductions in drunk and disorderly behaviour (nine of a predicted 21 events averted), and the unplanned end of the LLG coincided with an increase in domestic violence of two incidents per month. Conclusions: The impact of local alcohol policy, even at the level of individual premises, can be evaluated using a causal inference framework. Local government actions such as closure or restriction of alcohol venues and alcohol licensing may have a positive impact on health and crime in the immediate surrounding area. [ABSTRACT FROM AUTHOR]

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/μg mL-1) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization. [ABSTRACT FROM AUTHOR]

Background Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. Methods In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged >16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100 000 per µL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose- 6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single- dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (µ7500 and >7500 per µL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01376167. Findings Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57.7% (95% CI 43-70) with tafenoquine 50 mg, 54.1% (40-66) with tafenoquine 100 mg, 89.2% (77-95) with tafenoquine 300 mg, 91.9% (80-97) with tafenoquine 600 mg, 77.3% (63-87) with primaquine, and 37.5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51.7% [95% CI 35-69], p<0-0001, with tafenoquine 300 mg and 54.5% [38-71], p<0-0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39.9% [21-59], p=0.0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration. Interpretation Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3. INSET: Research in context. [ABSTRACT FROM AUTHOR]

Background. Treatment strategies that would induce durable virological control of human immunodeficiency virus (HIV)-1 in the absence of continued antiretroviral therapy (ART) are highly desirable. Methods. We assessed, in a randomized, double-blind, placebo-controlled trial, whether the addition of therapeutic vaccines (ALVAC-HIV [vCP1452] or ALVAC-HIV and Remune) to ART initiated during acute infection could increase the probability of having a plasma viral load ⩽1000 HIV-1 RNA copies/mL 24 weeks after planned discontinuation of ART. Results. All 79 randomized subjects completed the immunization schedule, and 78 discontinued ART with no major safety concerns. After immunization, subjects in the vaccine study arms had significantly increased HIV-1-specific CD4+ and CD8+ T cell responses, by interferon-γ enzyme-linked immunospot assay, compared with those in the placebo study arm. Overall, 17.7% of subjects had ⩽1000 HIV-1 RNA copies/mL 24 weeks after discontinuation of ART, with no significant difference between the vaccine study arms and the placebo study arm (15.4% vs. 22.2%; difference, -6.8% [95% confidence interval, -26.8% to 10.0%]; P = .54). Conclusion. Therapeutic immunization and ART, compared with ART alone, generated HIV-1-specific cellular immunity but did not lead to better virological control of HIV-1 24 weeks after discontinuation of ART. Our trial design appears to be feasible and safe for testing future immune-boosting strategies. [ABSTRACT FROM AUTHOR]

Background: Fracture risk is determined by both bone health and fall risk. Evidence suggests that older women with osteoporosis may have a greater risk of falling compared with their age-matched counterparts without osteoporosis ( 1). To determine whether fall risk screening should be a routine part of medical assessment in older women with osteoporosis, a comparison of fall risk between those with osteoporosis and healthy age-matched counterparts is needed. The purpose of this study was to compare 3 established fall risk factors between these 2 groups of women.Methods: 42 women between the ages of 64 and 75 years old participated in this study. 21 women with osteoporosis were matched by age and current physical activity level to 21 women without osteoporosis. The performance on 3 fall risk factors (quadriceps strength, balance, and functional mobility) was compared between the 2 groups using multivariate analysis of variance. The level of significance was set at p Results: There was an overall difference between the 2 groups on the fall risk factors (Wilk's lambda = 0.769, p =.018). Dominant quadriceps strength and composite balance score were, respectively, 18% significantly less and 11% worse in women with osteoporosis than those without. Functional mobility was not significantly different between the 2 groups.Conclusions: This study highlights older women with osteoporosis as a high fracture risk group due to having both lower bone density, and possibly, higher fall risk compared with their age-matched counterparts without osteoporosis. Both fall risk screening and fall risk reduction may be prudent to prevent fractures in women with osteoporosis. [ABSTRACT FROM AUTHOR]

Laparoscopic cholecystectomy has become the standard of care for the treatment of symptomatic gallstone disease. In the context of the increasing uptake of robotic surgery, robotic cholecystectomy has seen a substantial growth over the past decades. Despite this, a formal assessment of the evidence for this practice remains elusive and a randomised controlled trial is yet to be performed. This paper reviews the evidence to date for robotic multiport cholecystectomy compared to conventional multiport cholecystectomy. This systematic review was performed conducted using the Medline, Embase and Cochrane databases; in line with the PRISMA guideline. All articles that compared robotic and conventional laparoscopic cholecystectomy were included. The studies were assessed with regards to operative outcomes, postoperative recovery and complications. Fourteen studies were included, describing a total of 3002 patients. There was no difference in operative blood loss, complication rates, incidence of bile duct injury or length of hospital stay between the robotic and laparoscopic groups. The operative time for robotic cholecystectomy was longer, whereas the risk of conversion to open surgery was lower. There was marked variation in definitions of measured outcomes, and most studies lacked data on training and quality assessment, leading to substantial heterogeneity of the data. Available evidence on multiport robotic cholecystectomy compared to conventional laparoscopic cholecystectomy is scarce and the quality of the available studies is generally poor. Results suggest longer operating time for robotic cholecystectomy, although many studies included the learning curve period. Postoperative recovery and complications were similar in both groups., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Robot-assisted minimally invasive esophagectomy (RAMIE) is gaining increasing popularity as an operative approach. Learning curves to achieve surgical competency in robotic-assisted techniques have shown significant variation in learning curve lengths and outcomes. This study aimed to summarize the current literature on learning curves for RAMIE., Methods: A systematic review was conducted in line with PRISMA guidelines. Electronic databases PubMed, MEDLINE, and Cochrane Library were searched, and articles reporting on learning curves in RAMIE were identified and scrutinized. Studies were eligible if they reported changes in operative outcomes over time, or learning curves, for surgeons newly adopting RAMIE., Results: Fifteen studies reporting on 1767 patients were included. Nine studies reported on surgeons with prior experience of robot-assisted surgery prior to adopting RAMIE, with only four studies outlining a specified RAMIE adoption pathway. Learning curves were most commonly analyzed using cumulative sum control chart (CUSUM) and were typically reported for lymph node yields and operative times, with significant variation in learning curve lengths (18-73 cases and 20-80 cases, respectively). Most studies reported adoption without significant impact on clinical outcomes such as anastomotic leak; significant learning curves were more likely in studies, which did not report a formal learning or adoption pathway., Conclusion: Reported RAMIE adoption phases are variable, with some authors suggesting significant impact to patients. With robust training through formal programmes or proctorship, however, others report RAMIE adoption without impact on clinical outcomes. A formalized adoption curriculum appears critical to prevent adverse effects on operative efficiency and patient care., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Given the costs of alcohol to society, it is important to evaluate whether local alcohol licensing decisions can mitigate the effects of alcohol misuse. Robust natural experiment evaluations of the impact of individual licensing decisions could potentially inform and improve local decision-making. We aimed to assess whether alcohol licensing decisions could be evaluated at small spatial scale by using a causal inference framework., Design: Three natural experiments., Setting and Participants: Three English local areas of 1000-15 000 people each., Intervention and Comparator: The case study interventions were (i) the closure of a nightclub following reviews; (ii) closure of a restaurant/nightclub following reviews and (iii) implementation of new local licensing guidance (LLG). Trends in outcomes were compared with synthetic counterfactuals created using Bayesian structural time-series., Measurements: Time-series data were obtained on emergency department admissions, ambulance call-outs and alcohol-related crime at the Lower or Middle Super Output geographical aggregation level., Findings: Closure of the nightclub led to temporary 4-month reductions in antisocial behaviour (-18%; 95% credible interval - 37%, -4%), with no change in other outcomes. Closure of the restaurant/nightclub did not lead to measurable changes in outcomes. The new licensing guidance led to small reductions in drunk and disorderly behaviour (nine of a predicted 21 events averted), and the unplanned end of the LLG coincided with an increase in domestic violence of two incidents per month., Conclusions: The impact of local alcohol policy, even at the level of individual premises, can be evaluated using a causal inference framework. Local government actions such as closure or restriction of alcohol venues and alcohol licensing may have a positive impact on health and crime in the immediate surrounding area., (© 2020 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Unlabelled: Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse., Clinical Trials Registration: NCT01376167., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria. PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication. Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ. Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial. The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored. A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy., Methods: The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM). The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC). In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes. Metabolite identification experiments were performed using liquid chromatography-mass spectrometry., Results: Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57). In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %). Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems., Conclusion: Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ. As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs. These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.