Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (gt;99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMOdependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness

Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: an overview

Public Health and primary carePrevention and community carePrevention, Population and Disease management (PrePoD

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Psychosocial Strategies for Athletic Training

Psychosocial Strategies for Athletic Training provides a user-friendly introduction to the application and practical use of psychosocial theories and techniques. Featuring contributions from an expert team of authors, all specialists in the field, readers will develop an understanding of the research that underlies practice and will see how sports psychology is applied in clinical practice. With activities to help apply theory to practice, including case studies with critical-thinking questions, directed role-play activities with follow-up reflection questions, development of psychological skill ‘scripts’ for use with injured athletes/patients, and out-of-class activities, the text addresses a wide range of psychological interventions such as mental imagery, positive self-talk, and relaxation techniques and offers information about not only the physical rehabilitation regimen injured athletes need, but also the psychological and psychosocial support they need to recover from injuries.https://digitalcommons.linfield.edu/linfauth/1053/thumbnail.jp

Athletes’ expectations about sport injury rehabilitation: A cross-cultural study

Context: Athletes enter injury rehabilitation with certain expectations about the recovery process, outcomes, and the professional providing treatment. Their expectations influence the effectiveness of the assistance received and affect the overall rehabilitation process. Expectations may vary depending on numerous factors such as sport experience, gender, sport-type and cultural background. Unfortunately, limited information is available on athletes’ expectations about sport injury rehabilitation. Objective: To examine possible differences in athletes’ expectations about sport injury rehabilitation based on their country of residence and type of sport (physical contact versus non-physical contact). Design: A cross-sectional design. Setting: Recreational, collegiate, and professional athletes from the United States (US), United Kingdom (UK) and Finland were surveyed. Participants: Of the 1209 athletes ranging from 12 to 80 years of age (Mage = 23.46 ± 7.91), of which 529 US [80%], 253 UK [86%], and 199 Finnish [82%] provided details of their geographical location, were included in the final analyses. Main Outcome Measures: The Expectations about Athletic Training (EAAT) questionnaire was used to determine athletes’ expectations about personal commitment, facilitative conditions, and the expertise of the sports medicine professional (Clement et al., 2012). Results: 3x2 MANCOVA revealed significant main effects for country (p = .0001, ηp2 = .055) and sport type (p = .0001, ηp2 = .023). Specifically, US athletes were found to have higher expectations of personal commitment and facilitative conditions than their UK and Finnish counterparts. Athletes participating in physical contact sports had higher expectations of facilitative conditions and the expertise of the sports medicine professional (SMP) as compared to athletes participating in non-physical contact sports. Conclusions: SMPs, especially those in the US, should consider the sport and environment when providing services. In addition, SMPs need to highlight and demonstrate their expertise durin