Randomised, double-blind, multicentre, mixed-methods, dose-escalation feasibility trial of mirtazapine for better treatment of severe breathlessness in advanced lung disease (BETTER-B feasibility)

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. New treatments are required for severe breathlessness in advanced disease. We conducted a randomised feasibility trial of mirtazapine over 28 days in adults with a modified medical research council breathlessness scale score ≥3. Sixty-four patients were randomised (409 screened), achieving our primary feasibility endpoint of recruitment. Most patients had COPD or interstitial lung disease; 52 (81%) completed the trial. There were no differences between placebo and mirtazapine in tolerability or safety, and blinding was maintained. Worst breathlessness ratings at day 28 (primary clinical activity endpoint) were, 7.1 (SD 2.3, placebo) and 6.3 (SD 1.8, mirtazapine). A phase III trial of mirtazapine is indicated. Trial registration: ISRCTN 32236160; European Clinical Trials Database (EudraCT no: 2015-004064-11)

Homeless drug users' awareness and risk perception of peer "Take Home Naloxone" use – a qualitative study

BACKGROUND Peer use of take home naloxone has the potential to reduce drug related deaths. There appears to be a paucity of research amongst homeless drug users on the topic. This study explores the acceptability and potential risk of peer use of naloxone amongst homeless drug users. From the findings the most feasible model for future treatment provision is suggested. METHODS In depth face-to-face interviews conducted in one primary care centre and two voluntary organisation centres providing services to homeless drug users in a large UK cosmopolitan city. Interviews recorded, transcribed and analysed thematically by framework techniques. RESULTS Homeless people recognise signs of a heroin overdose and many are prepared to take responsibility to give naloxone, providing prior training and support is provided. Previous reports of the theoretical potential for abuse and malicious use may have been overplayed. CONCLUSION There is insufficient evidence to recommend providing "over the counter" take home naloxone" to UK homeless injecting drug users. However a programme of peer use of take home naloxone amongst homeless drug users could be feasible providing prior training is provided. Peer education within a health promotion framework will optimise success as current professionally led health promotion initiatives are failing to have a positive impact amongst homeless drug users

Diagnosis and aetiology of congenital muscular dystrophy: we are halfway there

OBJECTIVES: To evaluate the diagnostic outcomes in a large cohort of congenital muscular dystrophy (CMD) patients using traditional and Next Generation Sequencing (NGS) technologies. METHODS: 123 CMD patients were investigated using the traditional approaches of histology, immunohistochemical analysis of muscle biopsy and candidate gene sequencing. Undiagnosed patients available for further testing were investigated using NGS. RESULTS: Muscle biopsy and immunohistochemical analysis found deficiencies of laminin α2, α-dystroglycan or collagen VI in 50% of patients. Candidate gene sequencing and chromosomal microarray established a genetic diagnosis in 32% (39/123). Of 85 patients presenting in the last 20 years, 28 of 51 who lacked a confirmed genetic diagnosis (55%) consented to NGS studies, leading to confirmed diagnoses in a further 11 patients. Using the combination of approaches, a confirmed genetic diagnosis was achieved in 51% (43/85). The diagnoses within the cohort were heterogeneous. 45/59 probands with confirmed or probable diagnoses had variants in genes known to cause CMD (76%), and 11/59 (19%) had variants in genes associated with congenital myopathies, reflecting overlapping features of these conditions. One patient had a congenital myasthenic syndrome and two had microdeletions. Within the cohort, five patients had variants in novel (PIGY and GMPPB) or recently published genes (GFPT1 and MICU1) and seven had variants in TTN or RYR1; large genes that are technically difficult to Sanger sequence. INTERPRETATION: These data support NGS as a first-line tool for genetic evaluation of patients with a clinical phenotype suggestive of CMD, with muscle biopsy reserved as a second-tier investigation. This article is protected by copyright. All rights reserved

Over 1200 drugs-related deaths and 190,000 opiate-user-years of follow-up : relative risks by sex and age-group

Heroin users/injectors' risk of drugs-related death by sex and current age is weakly estimated both in individual cohorts of under 1000 clients, 5000 person-years or 50 drugs-related deaths and when using cross-sectional data. A workshop in Cambridge analysed six cohorts who were recruited according to a common European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) protocol from drug treatment agencies in Barcelona, Denmark, Dublin, Lisbon, Rome and Vienna in the 1990s; and, as external reference, opiate-user arrestees in France and hepatitis C diagnosed ever-injectors in Scotland in 1993-2001, both followed by database linkage to December 2001. EMCDDA cohorts recorded approximately equal numbers of drugs-related deaths (864) and deaths from other non-HIV causes (865) during 106,152 person-years of follow-up. External cohorts contributed 376 drugs-related deaths (Scotland 195, France 181) and 418 deaths from non-HIV causes (Scotland 221, France 197) during 86,417 person-years of follow-up (Scotland 22,670, France 63,747). EMCDDA cohorts reported 707 drugs-related deaths in 81,367 man-years {8.7 per 1000 person-years, 95% CI: 8.1 to 9.4} but only 157 in 24,785 person-years for females {6.3 per 1000 person-years, 95% CI: 5.4 to 7.4}. Except in external cohorts, relative risks by current age-group were not particularly strong, and more modest in Poisson regression than in cross-sectional analyses: relative risk was 1.2 (95% CI: 1.0-1.4) for 35-44 year olds compared to 15-24 year 3 olds, but 1.4 for males (95%CI: 1.2-1.6), and dramatically lower at 0.44 after the first year of follow-up (95% CI: 0.37-0.52)

Hysterectomy at a Canadian tertiary care facility: results of a one year retrospective review

BACKGROUND: The purpose of this study was to investigate the indications for and approach to hysterectomy at Kingston General Hospital (KGH), a teaching hospital affiliated with Queen's University at Kingston, Ontario. In particular, in light of current literature and government standards suggesting the superiority of vaginal versus abdominal approaches and a high number of concurrent oophorectomies, the aim was to examine the circumstances in which concurrent oophorectomies were performed and to compare abdominal and vaginal hysterectomy outcomes. METHODS: A retrospective chart audit of 372 consecutive hysterectomies performed in 2001 was completed. Data regarding patient characteristics, process of care and outcomes were collected. Data were analyzed using descriptive statistics, t-tests and linear and logistic regression. RESULTS: Average age was 48.5 years, mean body mass index (BMI) was 28.6, the mean length of stay (LOS) was 5.2 days using an abdominal approach and 3.0 days using a vaginal approach without laparoscopy. 14% of hysterectomies were performed vaginally, 5.9% were laparoscopically assisted vaginal hysterectomies and the rest were abdominal hysterectomies. The most common indication was dysfunctional or abnormal uterine bleeding (37%). The average age of those that had an oophorectomy (removal of both ovaries) was 50.8 years versus 44.3 years for those that did not (p < .05). Factors associated with LOS included surgical approach, age and the number of concurrent procedures. CONCLUSIONS: A significant reduction in LOS was found using the vaginal approach. Both the patient and the health care system may benefit from the tendency towards an increased use of vaginal hysterectomies. The audit process demonstrated the usefulness of an on-going review mechanism to examine trends associated with common surgical procedures

How organic farmers view their own practice: results from the Czech Republic

This paper addresses the development of organic agriculture in the Czech Republic, which is seen as a success story among post-communist countries. The relatively short history of organic farming and specific contextual factors raises questions about the nature and meaning of Czech organic farming. The goal of this study was to find out how farmers view their own practice, interpret its symbolic value, and construct its content. This empirical study uses Q methodology aimed at the identification of the collectively-shared perspectives belonging engaged actors. Data were gathered through semi-standardized interviews with Czech farmers registered in official organic scheme. The analysis emphasized three components, which are considered as three distinct perspectives possessed by organic farmers; that is, (1) organic farming as a way of life, (2) as an occupation, and (3) as a production of food of an alternative quality compared to conventional food. Each viewpoint entails a different understanding of what organic farming means; each then—when considered together—comprises the meaning of organic agriculture in the Czech Republic. The presented classification of the farmers holding the viewpoints contributes to the ongoing theoretical discussion regarding the nature of the current organic sector, its development and potential conventionalization

Sero-survey of rubella IgM antibodies among children in Jos, Nigeria

Sero-survey of rubella IgM antibodies was carried out among children aged 0-10 years in Jos, Nigeria. Blood samples were collected from the subjects and sera extracted. Of the 93(100%) assayed for the rubella IgM antibody, 42(45.2%) were seropositive for rubella IgM antibody while 51(54.8%) were seronegative. A breakdown of the seropositive subjects reveals that 14(15.1%) of the infected children were males while 28(30.1%) were females. Those subjects within the age groups of 1-2, 3-4 and 5-6 years had the highest prevalence of 8(8.6%) followed by those within the age groups of 7-8, 9-10 years with 7(7.5%). Blood transfusion as a risk factor did not show any significant influence on the status of the subjects. The demographic data of the mothers of the subjects were also linked with the seropositivity of the children

Glutamine Acts as a Neuroprotectant against DNA Damage, Beta-Amyloid and H2O2-Induced Stress

Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD

B Lymphocyte intestinal homing in inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Inflammatory bowel disease (IBD) is thought to be due to an abnormal interaction between the host immune system and commensal microflora. Within the intestinal immune system, B cells produce physiologically natural antibodies but pathologically atypical anti-neutrophil antibodies (xANCAs) are frequently observed in patients with IBD. The objective is to investigate the localisation of immunoglobulin-producing cells (IPCs) in samples of inflamed intestinal tissue taken from patients with IBD, and their possible relationship with clinical features.</p> <p>Methods</p> <p>The IPCs in small intestinal, colonic and rectal biopsy specimens of patients with IBD were analysed by means of immunofluorescence using polyclonal rabbit anti-human Ig and goat anti-human IgM. The B cell phenotype of the IPC-positive samples was assessed using monoclonal antibodies specific for CD79, CD20, CD23, CD21, CD5, λ and κ chains. Statistical correlations were sought between the histological findings and clinical expression.</p> <p>Results</p> <p>The study involved 96 patients (64 with ulcerative colitis and 32 with Crohn's disease). Two different patterns of B lymphocyte infiltrates were found in the intestinal tissue: one was characterised by a strong to moderate stromal localisation of small IgM⁺/CD79⁺/CD20^-/CD21^-/CD23^-/CD5^±IPCs (42.7% of cases); in the other (57.3%) no such small IPCs were detected in stromal or epithelial tissues. <it>IPCs </it>were significantly less frequent in the patients with Crohn's disease than in those with ulcerative colitis (p = 0.004).</p> <p>Conclusion</p> <p>Our findings suggest that different immunopathogenetic pathways underlie chronic intestinal inflammation with different clinical expressions. The presence of small B lymphocytes resembling B-1 cells also seemed to be negatively associated with Crohn's disease. It can therefore be inferred that the gut contains an alternative population of B cells that have a regulatory function.</p