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The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) was designed to build tuberculosis (TB) trial capacity whilst conducting clinical trials on novel and existing agents to shorten and simplify TB treatment. PanACEA has now established a dynamic network of 11 sub-Saharan clinical trial sites and four European research institutions.In 2011, a capacity development program, funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), was launched with four objectives, aiming at strengthening collaborating TB research sites to reach the ultimate goal of becoming self-sustainable institutions: networking; training; conducting clinical trials; and infrastructure scaling-up of sites.Assessment in six sub-Saharan TB-endemic countries (Gabon, Kenya, South Africa, Tanzania, Uganda and Zambia) were performed through a structured questionnaire, site visits, discussion with the PanACEA consortium, setting of milestones and identification of priorities and followed-up with evaluations of each site. The results of this needs-based assessment was then translated into capacity development measures.In the initial phase, over a four-year period (March 2011 - June 2014), the programme scaled-up six sites; conducted a monitoring training program for 11 participants; funded five MSc and four PhD students, fostering gender balance; conducted four epidemiological studies; supported sites to conduct five Phase II studies and formed a sustainable platform for TB research (panacea-tb.net).Our experience of conducting TB clinical trials within the PanACEA programme environment of mentoring, networking and training has provided a sound platform for establishing future sustainable research centres. Our goal of facilitating emergent clinical TB trial sites to better initiate and lead research activities has been mostly successful.

Ethanol impairs cognitive and psychomotor performance, although the precise reasons for this remain unclear. We investigated the effect of ethanol on individuals' judgment of their performance. Eighteen healthy volunteers (19–22 years) received a high dose of ethanol (0.8 g/kg for males and 0.7 g/kg, for females), a medium dose (75% of the high dose) and a placebo in counterbalanced order on three study days. A general knowledge (GK) test was administered on a pen computer 75 min after the drink. An adaptive algorithm adjusted the difficulty of questions so that scores were similar on all three study days. Volunteers then rated how well they believed they had performed the GK task using a visual analogue scale. A battery of other performance tests and mood ratings was also completed both before and after the GK test. These showed the expected effects of ethanol. There were no significant differences in scores on the GK test between treatment sessions. There was a highly significant dose‐dependent increase with ethanol on volunteers' ratings of their performance on this test. These findings suggest that ethanol leads to an overoptimistic assessment of ability which may contribute to ethanol's impairment of performance.

Abstract Aims Minimum unit price (MUP) of 50 pence per unit of alcohol was introduced in Scotland on the 1 May 2018. We assessed alcohol-related liver disease (ArLD) discharges from Glasgow Royal Infirmary (GRI) before and after the introduction of MUP. Methods Medical records of all patients discharged from Gastroenterology wards at GRI in the fourth quarter (Q4) of the years 2015–2019 were reviewed. All patients with ArLD were identified, and detailed hospitalization data were collected retrospectively. Active drinking, severity scores, presence of alcoholic hepatitis (AH) and 90-day mortality and readmission rates were assessed. Results There were fewer ArLD discharges per quarter after MUP than before (mean 80.3 pre-MUP; mean 68 post-MUP), and the proportion of active drinkers was lower post-MUP (64.7 vs. 70.5%). There was a significant fall in the mean number of weekly discharges of individual patients who were actively drinking (4.0 ± 2.0 pre-MUP, 2.8 ± 1.5 post-MUP, P = 0.01). There were no differences in the proportion of patients presenting with ascites, encephalopathy or AH; however, there was a reduction in presentations with acute upper gastrointestinal bleeding from 15.8% pre-MUP to 7.4% post-MUP (P = 0.02; odds ratio 0.42). Severity of liver disease remained unchanged. The 90-day mortality and readmission rates were not significantly different. Conclusion Since the introduction of MUP there has been a reduction in the absolute numbers of patients discharged with ArLD and the number of individual patients involved at GRI. The pattern of clinical presentation was largely unaffected with overall ArLD severity, readmission rates and 90-day mortality similar pre- and post-MUP.

The relative biological effectiveness (RBE) varies along the treatment field. However, in clinical practice, a constant RBE of 1.1 is assumed, which can result in undesirable side effects. This study provides an accurate overview of current clinical practice for considering proton RBE in Europe.A survey was devised and sent to all proton therapy centres in Europe that treat patients. The online questionnaire consisted of 39 questions addressing various aspects of RBE consideration in clinical practice, including treatment planning, patient follow-up and future demands.All 25 proton therapy centres responded. All centres prescribed a constant RBE of 1.1, but also applied measures (except for one eye treatment centre) to counteract variable RBE effects such as avoiding beams stopping inside or in front of an organ at risk and putting restrictions on the minimum number and opening angle of incident beams for certain treatment sites. For the future, most centres (16) asked for more retrospective or prospective outcome studies investigating the potential effect of the effect of a variable RBE. To perform such studies, 18 centres asked for LET and RBE calculation and visualisation tools developed by treatment planning system vendors.All European proton centres are aware of RBE variability but comply with current guidelines of prescribing a constant RBE. However, they actively mitigate uncertainty and risk of side effects resulting from increased RBE by applying measures and restrictions during treatment planning. To change RBE-related clinical guidelines in the future more clinical data on RBE are explicitly demanded.

Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3–3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6–68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites ( n = 3–66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. Trial registration: ClinicalTrials.gov Identifier: NCT04648423

Effects of nicotine, administered by continuous infusion via osmotic minipumps, were studied on the operant self-administration of alcohol by rats, using a variable interval (15 s) schedule, and measuring the acquisition, maintenance, extinction and reinstatement of responding for alcohol. Doses of nicotine of 0.25, 1.25 and 7.5 mg/kg/24 h had no significant effects on the maintenance of responding for alcohol, but 5 mg/kg/24 h nicotine resulted in a significant increase in responding on the lever delivering the reward when water was substituted for the alcohol, indicating delayed extinction of responding. During infusion of 2.5 mg/kg/24 h nicotine, responding was significantly greater over the "sucrose-fading" training sessions, during acquisition of responding, when mixtures of alcohol and sucrose were provided as reward. When minipumps infusing 2.5 mg/kg/24 h nicotine were implanted after the alcohol responding had been acquired, the responding for alcohol increase during the first week of nicotine infusion, but corresponding nicotine infusion doses of 0.25, 1.25 and 7.5 had no significant effects. The results indicate that nicotine can increase operant responding for alcohol and this is crucially dependent on the dose of nicotine and the time of testing. The results have implications for the frequently encountered dependence on the combination of alcohol and nicotine.

Some tendons, such as the human Achilles and equine superficial digital flexor tendon (SDFT), act as energy stores, stretching and recoiling to increase efficiency during locomotion. Our previous observations of rotation in response to applied strain in SDFT fascicles suggest a helical structure, which may provide energy-storing tendons with a greater ability to extend and recoil efficiently. Despite this specialization, energy-storing tendons are prone to age-related tendinopathy. The aim of this study was to assess the effect of cyclic fatigue loading (FL) on the microstructural strain response of SDFT fascicles from young and old horses. The data demonstrate two independent age-related mechanisms of fatigue failure; in young horses, FL caused low levels of matrix damage and decreased rotation. This suggests that loading causes alterations to the helix substructure, which may reduce their ability to recoil and recover. By contrast, fascicles from old horses, in which the helix is already compromised, showed greater evidence of matrix damage and suffer increased fibre sliding after FL, which may partially explain the age-related increase in tendinopathy. Elucidation of helix structure and the precise alterations occurring owing to both ageing and FL will help to develop appropriate preventative and repair strategies for tendinopathy.