A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo

Funded by Medical Research Council. Grant Number: 74804 NHS Grampian Endowments Research Trust. Grant Number: 12/16 Kidney Research UK. Grant Number: RP1/2012 Cunningham Trust. Grant Number: ACC/KWF/CT08/03Peer reviewedPublisher PD

Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5\u27-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P \u3c 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P \u3c 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities

Contractor tendering research: Going beyond bid/no-bid and markup models

Within a wider research programme into the effectiveness and efficiency of the tendering procedures of construction contractors (CCs), a content analysis of tender research published in 27 journals between 2010 and 2016 found that CC tendering procedure research remains a low-focus area. CC-related tender research commonly focuses on factors influencing ‘bid/no-bid’ and markup decisions, often combined with developed decision modelling. Comparing the content analysis results with semi-structured interviews with 20 Australian civil engineering CCs (including some of Australia’s largest contractors, and with eight involved in international operations), it was found that the industry remains largely unaware and unsupportive of such developed tender decision tools. Instead, CCs suggest tender research should focus on efficient tendering procedures, encouraging clients to use standard rather than bespoke contracts, and improved quality and risk transfer in tender documents. The combined semi-structured interview findings and content analysis results provide researchers with contemporary tender research themes that civil engineering CCs, and potentially more general contractors, are more likely to embrace, thereby advancing the efficiency of construction tendering and contractors’ work procurement management

Role of shear stress and tPA concentration in the fibrinolytic potential of thrombi

Funding: This research was funded by British Heart Foundation PG/08/127/26517 awarded to N.A.B. and D.E.N. C.S.W. and N.J.M. were supported by the British Heart Foundation project grants (PG/15/82/31721 and PG/20/17/35050). D.E.N. and A.J.L. were supported by the British Heart Foundation project grant PG/04/131/18118. D.E.N. is supported by the British Heart Foundation (CH/09/002, RE/18/5/34216, RG/16/10/32375) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA).Peer reviewedPublisher PD

Indigeneity and likelihood of discharge to psychiatric hospital in an Australian deliberate self-poisoning hospital-treated cohort

Hospital-treated self-harm rates for Aboriginal and Torres Strait Islander (Indigenous) people are at least double those for other Australians. Despite this, limited research has explored the relationship between Indigeneity and the clinical management of hospital-treated deliberate self-harm. A retrospective clinical cohort study (2003–2012) at a regional referral centre (NSW) for deliberate self-poisoning was used to explore the magnitude and direction of the relationship between Indigeneity and discharge destination (psychiatric hospital vs. other) using a series of logistic regressions. There were 149 (4%) Indigenous and 3697 (96%) non-Indigenous deliberate self-poisoning admissions during the study period. One-third (31%) were referred to the psychiatric hospital at discharge; Indigenous 21% (n = 32) vs. non-Indigenous 32% (n = 1175). Those who identified as Indigenous were less likely to be discharged to the psychiatric hospital, OR 0.59 (0.40–0.87) at the univariate level, with little change after sequential adjustment; and AOR 0.34 (0.21–0.73) in the fully adjusted model. The Indigenous cohort had a lower likelihood of psychiatric hospital discharge even after adjustment for variables associated with discharge to the psychiatric hospital highlighting the need for further investigation of the reasons accounting for this differential pattern of clinical management and the effectiveness of differential after-care allocation

The efficacy and mechanism evaluation of treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole (EME-TIPAC): study protocol for a randomised controlled trial

Background: We hypothesise, based upon the findings from our previous trial, that the addition of co-trimoxazole to standard therapy is beneficial to patients with moderate to severe idiopathic pulmonary fibrosis (IPF). We aim to investigate this by assessing unplanned hospitalisation-free survival (defined as time from randomisation to first non-elective hospitalisation, lung transplant or death) and to determine whether any effect relates to changes in infection and/or markers of disease control and neutrophil activity. Methods/design: The EME-TIPAC trial is a double-blind, placebo-controlled, randomised, multicentre clinical trial. A total of 330 symptomatic patients, aged 40 years old or older, with IPF diagnosed by a multidisciplinary team (MDT) according to international guidelines and a FVC ≤ 75% predicted will be enrolled. Patients are randomised equally to receive either two tablets of co-trimoxazole 480 mg or two placebo tablets twice daily over a median treatment period of 27 (range 12–42) months. All patients receive folic acid 5 mg daily whilst on the trial IMP to reduce the risk of bone marrow depression. The primary outcome for the trial is a composite endpoint consisting of the time to death, transplant or first nonelective hospital admission and will be determined from adverse event reporting, hospital databases and the Office of National Statistics with active tracing of patients missing appointments. Secondary outcomes include the individual components of the primary outcome, (1) King’s Brief Interstitial Lung Disease Questionnaire, (2) MRC Dyspnoea Score, (3) EQ5D, (4) spirometry, (5) total lung-diffusing capacity and (6) routine sputum microbiology. Blood will be taken for cell count, biochemistry and analysis of biomarkers including C-reactive protein and markers of disease. The trial will last for 4 years. Recruitment will take place in a network of approximately 40 sites throughout the UK (see Table 1 for a full list of participating sites). We expect recruitment for 30 months, follow-up for 12 months and trial analysis and reporting to take 4 months. Discussion: The trial is designed to test the hypothesis that treating IPF patients with co-trimoxazole will increase the time to death (all causes), lung transplant or first non-elective hospital admission compared to standard care (https://www.nice.org.uk/guidance/cg163), in patients with moderate to severe disease. The mechanistic aims are to investigate the effect on lung microbiota and other measures of infection, markers of epithelial injury and markers of neutrophil activity. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 17464641. Registered on 29 January 2015. Keywords: Idiopathic pulmonary fibrosis, Co-trimoxazole, Forced vital capacity, Mortalit

Personal and professional challenges in the management of deliberate self-poisoning patients in rural Sri Lanka: a qualitative study of rural hospital doctors' experiences and perceptions

Background. Deliberate self-poisoning is a major public heath issue in developing countries. In rural Sri Lanka deliberate self-poisoning is one of the leading causes of hospital death. The majority of patients with poisoning present to rural hospitals for initial treatment that are staffed by non-specialist and often relatively junior doctors. The treatment of self-poisoning patients poses numerous clinical challenges and further difficulties are experienced if patients are uncooperative and aggressive, intoxicated with alcohol or suffering mental illness. Previous research in developed countries has examined self-poisoning patients and their treatment but little is know about self-poisoning patient care in the context of rural health provision in developing countries. This study provides the first focused exploration of the experiences and perceptions of primary care rural hospital doctors in Sri Lanka toward the treatment of self-poisoning patients. Methods. Semi-structured in-depth interviews were conducted with fifteen doctors from rural hospitals in the North Central Province, Sri Lanka. All interviews were recorded and transcribed and subject to thematic analysis. Results. Participating doctors did perceive that treating self-poisoning patients in a primary care rural hospital as potentially confidence-building. However, resource issues such as the lack of medication, equipment and staffing were seen as important challenges to treating self-poisoning patients. Other challenges identified included disparity with community and other staff members regarding expectations of care, a sense of professional isolation and a lack of continuing education programs. Conclusion. Addressing professional isolation through educational and trainee programs for doctors and reducing the variance in expectations between professional groups and the community has the potential to improve delivery of care for self-poisoning patients

Correlations between fMRI activation and individual psychotic symptoms in un-medicated subjects at high genetic risk of schizophrenia

<p>Abstract</p> <p>Background:</p> <p>It has been proposed that different types of psychopathology in schizophrenia may reflect distinguishable pathological processes. In the current study we aimed to address such associations in the absence of confounders such as medication and disease chronicity by examining specific relationships between fMRI activation and individual symptom severity scores in un-medicated subjects at high genetic risk of schizophrenia.</p> <p>Methods:</p> <p>Associations were examined across two functional imaging paradigms: the Hayling sentence completion task, and an encoding/retrieval task, comprising encoding (at word classification) and retrieval (old word/new word judgement). Symptom severity was assessed using the positive and negative syndrome scale (PANSS). Items examined were hallucinations, delusions, and suspiciousness/persecution.</p> <p>Results:</p> <p>Associations were seen in the anterior middle temporal gyrus in relation to hallucination scores during the sentence completion task, and in the medial temporal lobe in association with suspiciousness/persecution scores in the encoding/retrieval task. Cerebellar activation was associated with delusions and suspiciousness/persecution scores across both tasks with differing patterns of laterality.</p> <p>Conclusion:</p> <p>These results support a role for the lateral temporal cortex in hallucinations and medial temporal lobe in positive psychotic symptoms. They also highlight the potential role of the cerebellum in the formation of delusions. That the current results are seen in un-medicated high risk subjects indicates these associations are not specific to the established illness and are not related to medication effects.</p

Trial protocol OPPTIMUM : does progesterone prophylaxis for the prevention of preterm labour improve outcome?

Background Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the “progesterone” group having a lower incidence of preterm birth. Methods/Design The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites. Discussion OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome