Cannabidiol interactions with voltage-gated sodium channels

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high-resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels

Cannabidiol interactions with voltage-gated sodium channels

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels

KH domains with impaired nucleic acid binding as a tool for functional analysis

In eukaryotes, RNA-binding proteins that contain multiple K homology (KH) domains play a key role in coordinating the different steps of RNA synthesis, metabolism and localization. Understanding how the different KH modules participate in the recognition of the RNA targets is necessary to dissect the way these proteins operate. We have designed a KH mutant with impaired RNA-binding capability for general use in exploring the role of individual KH domains in the combinatorial functional recognition of RNA targets. A double mutation in the hallmark GxxG loop (GxxG-to-GDDG) impairs nucleic acid binding without compromising the stability of the domain. We analysed the impact of the GDDG mutations in individual KH domains on the functional properties of KSRP as a prototype of multiple KH domain-containing proteins. We show how the GDDG mutant can be used to directly link biophysical information on the sequence specificity of the different KH domains of KSRP and their role in mRNA recognition and decay. This work defines a general molecular biology tool for the investigation of the function of individual KH domains in nucleic acid binding proteins

Randomized clinical trial of postoperative chewing gum versus standard care after colorectal resection

Background Chewing gum may stimulate gastrointestinal motility, with beneficial effects on postoperative ileus suggested in small studies. The primary aim of this trial was to determine whether chewing gum reduces length of hospital stay (LOS) after colorectal resection. Secondary aims included examining bowel habit symptoms, complications and healthcare costs. Methods This clinical trial allocated patients randomly to standard postoperative care with or without chewing gum (sugar-free gum for at least 10 min, four times per day on days 1–5) in five UK hospitals. The primary outcome was LOS. Cox regression was used to calculate hazard ratios for LOS. Results Data from 402 of 412 patients, of whom 199 (49·5 per cent) were allocated to chewing gum, were available for analysis. Some 40 per cent of patients in both groups had laparoscopic surgery, and all study sites used enhanced recovery programmes. Median (i.q.r.) LOS was 7 (5–11) days in both groups (P = 0·962); the hazard ratio for use of gum was 0·94 (95 per cent c.i. 0·77 to 1·15; P = 0·557). Participants allocated to gum had worse quality of life, measured using the EuroQoL 5D-3L, than controls at 6 and 12 weeks after operation (but not on day 4). They also had more complications graded III or above according to the Dindo–Demartines–Clavien classification (16 versus 6 in the group that received standard care) and deaths (11 versus 0), but none was classed as related to gum. No other differences were observed. Conclusion Chewing gum did not alter the return of bowel function or LOS after colorectal resection

Cholinesterase inhibitor to prevent falls in Parkinson's disease (CHIEF-PD) trial:a phase 3 randomised, double-blind placebo-controlled trial of rivastigmine to prevent falls in Parkinson's disease

Abstract Background Falls are a common complication of Parkinson’s disease. There is a need for new therapeutic options to target this debilitating aspect of the disease. Cholinergic deficit has been shown to contribute to both gait and cognitive dysfunction seen in the condition. Potential benefits of using cholinesterase inhibitors were shown during a single centre phase 2 trial. The aim of this trial is to evaluate the effectiveness of a cholinesterase inhibitor on fall rate in people with idiopathic Parkinson’s disease. Methods This is a multi-centre, double-blind, randomised placebo-controlled trial in 600 people with idiopathic Parkinson’s disease (Hoehn and Yahr stages 1 to 4) with a history of a fall in the past year. Participants will be randomised to two groups, receiving either transdermal rivastigmine or identical placebo for 12 months. The primary outcome is the fall rate over 12 months follow-up. Secondary outcome measures, collected at baseline and 12 months either face-to-face or via remote video/telephone assessments, include gait and balance measures, neuropsychiatric indices, Parkinson’s motor and non-motor symptoms, quality of life and cost-effectiveness. Discussion This trial will establish whether cholinesterase inhibitor therapy is effective in preventing falls in Parkinson’s disease. If cost-effective, it will alter current management guidelines by offering a new therapeutic option in this high-risk population. Trial registration REC reference: 19/SW/0043. EudraCT: 2018–003219-23. ISCRTN: 41639809 (registered 16/04/2019). ClinicalTrials.gov Identifier: NCT04226248 Protocol at time of publication Version 7.0, 20th January 2021

Protocol for a cluster randomised controlled trial of an intervention to improve the mental health support and training available to secondary school teachers – the WISE (Wellbeing in Secondary Education) study

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Teachers are reported to be at increased risk of common mental health disorders compared to other occupations. Failure to support teachers adequately may lead to serious long-term mental disorders, poor performance at work (presenteeism), sickness absence and health-related exit from the profession. It also jeopardises student mental health, as distressed staff struggle to develop supportive relationships with students, and such relationships are protective against student depression. A number of school-based trials have attempted to improve student mental health, but these have mostly focused on classroom based approaches and have failed to establish effectiveness. Only a few studies have introduced training for teachers in supporting students, and none to date have included a focus on improving teacher mental health. This paper sets out the protocol (version 4.4 20/07/16) for a study aiming to address this gap. METHODS: Cluster randomised controlled trial with secondary schools as the unit of randomisation. Intervention schools will receive: i) Mental Health First Aid (MHFA) training for a group of staff nominated by their colleagues, after which they will set up a confidential peer support service for colleagues ii) training in MHFA for schools and colleges for a further group of teachers, which will equip them to more effectively support student mental health iii) a short mental health awareness raising session and promotion of the peer support service for all teachers. Comparison schools will continue with usual practice. The primary outcome is teacher wellbeing measured using the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS). Secondary outcomes are teacher depression, absence and presenteeism, and student wellbeing, mental health difficulties, attendance and attainment. Measures will be taken at baseline, one year follow up (teachers only) and two year follow up. Economic and process evaluations will be embedded within the study. DISCUSSION: This study will establish the effectiveness and cost-effectiveness of an intervention that supports secondary school teachers’ wellbeing and mental health, and improves their skills in supporting students. It will also provide information regarding intervention implementation and sustainability.This research study is funded by the National Institute for Health Research Public Health Research (NIHR PHR) Programme (project number 13/164/06). The views and opinions expressed in the paper are those of the authors and do not necessarily reflect those of the NIHR PHR Programme or the Department of Health. The intervention is jointly funded by Public Health Wales, Public Health England and Bristol City Council. The pilot study that led to this RCT was funded by the National Institute for Health Research’s School for Public Health Research (NIHR SPHR)

The impact of clozapine on hospital use: a systematic review and meta-analysis

Objective: The objective of this study was to perform a systematic review and meta-analysis of studies reporting the impact of clozapine on hospital use in people with a psychotic illness. Method: PubMed, EMBASE, PsycINFO and the Cochrane Schizophrenia Group Trials Register were systematically searched from inception to 12 October 2016. We included all trials and observational studies, except case reports. Results: Thirty-seven studies were included. Clozapine significantly reduced the proportion of people hospitalised compared to control medicines (RR = 0.74; 95% CI: 0.69–0.80, P < 0.001, 22 studies, n = 44 718). There were significantly fewer bed days after clozapine treatment compared to before clozapine treatment in both controlled (MD = −34.41 days; 95% CI: −68.22 to −0.60 days, P = 0.046, n = 162) and uncontrolled studies (MD = −52.86 days; 95% CI: −79.86 days to −25.86 days, P < 0.001, n = 2917). Clozapine and control medicines had a similar time to rehospitalisation (−19.90 days; 95% CI: −62.42 to 22.63 days, P = 0.36). Conclusion: Clozapine treatment reduced the number of people hospitalised and the number of bed days after treatment compared with before treatment. Clozapine has the potential to reduce acute hospital use among people with treatment refractory schizophrenia

A randomised feasibility trial comparing needle fasciotomy with limited fasciectomy treatment for Dupuytren’s contractures

© 2020 The Author(s). Purpose: The purpose of this study is to assess the feasibility of conducting a large, multicentre randomised controlled trial (RCT) comparing needle fasciotomy with limited fasciectomy for treatment of Dupuytren's contractures. Design: The design of this study is a parallel, two-arm, multicentre, randomised feasibility trial with embedded QuinteT Recruitment Intervention. Participants: Patients aged 18 years or over who were referred from primary to secondary care for treatment of a hand with Dupuytren's contractures of one or more fingers of more than 30° at the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints and well-defined cord(s). Patients were excluded if they had undergone previous Dupuytren's contracture surgery on the same hand. Methods: Potential participants were screened for eligibility. Recruited participants randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy and followed-up for up to 6 months after treatment. Data on recruitment rates, completion of follow-up, and procedure costs were collected. Four patient reported outcome measures (PROMs) and objective outcome measures were collected before intervention and 6 weeks and 6 months afterwards. Results: One hundred and fifty-three of 267 (57%) primary-care referrals for Dupuytren's contractures met the eligibility criteria for the study. Seventy-one of the 153 (46%) agreed to participate and were randomly allocated to treatment with needle fasciotomy or limited fasciectomy. Sixty-seven of these underwent their allocated treatment, two were crossovers from limited fasciectomy to needle fasciotomy, and two (both allocated limited fasciectomy) received no treatment. Fifty-nine participants (85%) completed 6-month follow-up PROMs. Participants felt the MYMOP, PEM and URAM PROMs allowed them to better describe how their treatment affected their hand function than the DASH PROM. The estimated costs of limited fasciectomy (in an operating theatre) and needle fasciotomy (in a clinic room) were £777 and £111 respectively. Conclusion: A large RCT comparing treatment of Dupuytren's contractures by needle fasciotomy and limited fasciectomy is feasible. Data from this study will help determine the number of sites and duration of recruitment required to complete an adequately powered RCT and will assist the selection of PROMs in future studies on the treatment of Dupuytren's contractures. (Level 1 feasibility study)

Optimising recruitment to the HAND-1 RCT feasibility study:integration 1 of the QuinteT Recruitment Intervention (QRI)

© 2020, The Author(s). Background: Recruitment to randomised controlled trials (RCTs) can be challenging, with most trials not reaching recruitment targets. Randomised feasibility studies can be set up prior to a main trial to identify and overcome recruitment obstacles. This paper reports on an intervention—the QuinteT Recruitment Intervention (QRI)—to optimise recruitment within a randomised feasibility study of surgical treatments for patients with Dupuytren’s contracture (the HAND-1 study). Methods: The QRI was introduced in 2-phases: phase 1 sought to understand the recruitment challenges by interviewing trial staff, scrutinising screening logs and analysing audio-recorded patient consultations; in phase 2 a tailored plan of action consisting of recruiter feedback and training was delivered to address the identified challenges. Results: Two key recruitment obstacles emerged: (1) issues with the recruitment pathway, in particular methods to identify potentially eligible patients and (2) equipoise of recruiters and patients. These were addressed by liaising with centres to share good practice and refine their pathway and by providing bespoke feedback and training on consent discussions to individual recruiters and centres whilst recruitment was ongoing. The HAND-1 study subsequently achieved its recruitment target. Conclusions: Transferable lessons learnt from the QRI in the feasibility study will be implemented in the definitive RCT, enabling a “head start” in the tackling of wider issues around screening methods and consent discussions in the set up/early recruitment study phases, with ongoing QRI addressing specific issues with new centres and recruiters. Findings from this study are likely to be relevant to other surgical and similar trials that are anticipated to encounter issues around patient and recruiter equipoise of treatments and variation in recruitment pathways across centres. The study also highlights the value of feasibility studies in fine-tuning design and conduct issues for definitive RCTs. Embedding a QRI in an RCT, at feasibility or main stage, offers an opportunity for a detailed and nuanced understanding of key recruitment challenges and the chance to address them in “real-time” as recruitment proceeds