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Effects of visfatin on brown adipose tissue energy regulation using T37i cells.
No full textThe role of brown adipose tissue (BAT) in pathological states of energy homeostasis and impaired adipocyte function, such as obesity has been a major area of research interest in recent years. Herein, we sought to determine the direct effects of adipokines, visfatin and leptin on BAT thermogenesis. The effects of mouse recombinant visfatin, nicotinamide mononucleotide (NMN) and leptin with or without FK866 were studied on differentiated T37i cells. Treated cells were analyzed for key genes and proteins regulating BAT [UCP-1, PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM-16), PPARgamma-coactivator-1alpha (PGC-1α) and receptor-interacting protein 140 (RIP-140)] using quantitative PCR and western blot analysis. Data is presented as mean P-values. Both visfatin and leptin had significant concentration dependent effects on thermogenesis in brown pre-adipocytes and at physiological levels, increased uncoupling protein-1 (UCP-1) levels in brown adipocytes. These effects of visfatin were similar to that of nicotinamide mononucleotide (NMN), further strengthening the enzymatic role of visfatin. We also showed that leptin induced UCP-1 mRNA expression and protein production appears to be mediated by visfatin. High concentrations of both visfatin and leptin led to a dramatic decrease in UCP-1 protein levels, supporting the notion that visfatin levels are raised in obesity and that obese people have reduced BAT activity, plausibly through a reduction in UCP-1 levels. Additionally, we found differential regulation of key brown adipogenic genes, specifically, PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM-16), PPARgamma-coactivator-1alpha (PGC-1α) and receptor-interacting protein 140 (RIP-140) by visfatin. Our observations provide novel insights in the potential actions of visfatin in BAT
Outcomes Following Percutaneous Coronary Intervention in Saphenous Vein Grafts With and Without Embolic Protection Devices.
No full textOBJECTIVES
The aim of this study was to describe the early (inpatient and 30-day) and late (1-year) outcomes of percutaneous coronary intervention (PCI) in saphenous vein grafts (SVGs), with and without the use of embolic protection devices (EPD), in a large, contemporary, unselected national cohort from the database of the British Cardiovascular Intervention Society.
BACKGROUND
There are limited, and discrepant, data on the clinical benefits of the adjunctive use of EPDs during PCI to SVGs in the contemporary era.
METHODS
A longitudinal cohort of patients (2007 to 2014, n = 20,642) who underwent PCI to SVGs in the British Cardiovascular Intervention Society database was formed. Clinical, demographic, procedural, and outcome data were analyzed by dividing into 2 groups: no EPD (PCI to SVGs without EPDs, n = 17,730) and EPD (PCI to SVGs with EPDs, n = 2,912).
RESULTS
Patients in the EPD group were older, had more comorbidities, and had a higher prevalence of moderate to severe left ventricular systolic dysfunction. Mortality was lower in the EPD group during hospital admission (0.70% vs. 1.29%; p = 0.008) and at 30 days (1.44% vs. 2.01%; p = 0.04) but similar at 1 year (6.22% vs. 6.01%; p = 0.67). Following multivariate analyses, no significant difference in mortality was observed during index admission (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.42 to 1.19; p = 0.19), at 30 days (OR: 0.87; 95% CI: 0.60 to 1.25; p = 0.45), and at 1 year (OR: 0.92; 95% CI: 0.77 to 1.11; p = 0.41), along with similar rates of in-hospital major adverse cardiovascular events (OR: 1.16; 95% CI: 0.83 to 1.62; p = 0.39) and stroke (OR: 0.68; 95% CI: 0.20 to 2.35; p = 0.54). In propensity score-matched analyses, lower inpatient mortality was observed in the EPD group (OR: 0.46; 95% CI: 0.13 to 0.80; p = 0.002), although the adjusted risk for the periprocedural no-reflow or slow-flow phenomenon was higher in patients in whom EPDs were used (OR: 2.16; 95% CI: 1.71 to 2.73; p < 0.001).
CONCLUSIONS
In this contemporary cohort, EPDs were used more commonly in higher risk patients but were associated with similar clinical outcomes in multivariate analyses. Lower inpatient mortality was observed in the EPD group in univariate and propensity score-matched analyses
STOP-Colitis pilot trial protocol: a prospective, open-label, randomised pilot study to assess two possible routes of faecal microbiota transplant delivery in patients with ulcerative colitis.
No full textINTRODUCTION
Imbalance of the gut microbiome is key to the pathogenesis of ulcerative colitis (UC). Faecal microbiota transplant (FMT) is the transfer of homogenised and filtered faeces from a healthy individual to the gastrointestinal tract of a patient with disease. Published datasets show a positive signal for the use of FMT to treat UC, but the optimal route and dose of FMT remain unanswered.
METHODS AND ANALYSIS
This prospective, multi-centre open-label, randomised pilot study will assess two possible routes of FMT delivery, via the nasogastric (NG) route or by delivery to the COLON, in 30 patients with active UC recruited from three sites in the UK. Stool will be collected from healthy screened donors, processed, frozen and stored under a Medicines and Healthcare products Regulatory Agency (MHRA) "specials" manufacturing licence held at the University of Birmingham Microbiome Treatment Centre. Thawed FMT samples will be administered to patients either via eight nasogastric infusions given initially over 4 days starting on the day of randomisation, and then again for 4 days in week 4 for foregut delivery (total of 240 g of stool) or via one colonoscopic infusion followed by seven weekly enemas according to the hindgut protocol (total of 360 g of stool). Patients will be followed up weekly for 8 weeks, and then at 12 weeks. The aims of this pilot study are (1) to determine which FMT administration route (NG or COLON) should be investigated in a randomised double-blind, placebo-controlled trial and (2) to determine if a full randomised controlled trial is feasible. The primary outcome will be a composite assessment of both qualitative and quantitative data based on efficacy (clinical response), acceptability and safety. At the end of the pilot study, decisions will be made regarding the feasibility of a full randomised double-blind, placebo-controlled trial and, if deemed feasible, which route of administration should be used in such a study.
ETHICS AND DISSEMINATION
Ethical approval for this study has been obtained from the East Midlands-Nottingham Research Ethics Committee (REC 17/EM/0274). At the end of the study, findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER
ISRCTN74072945
Grand round: Autoimmune hepatitis.
No full textAutoimmune hepatitis is a corticosteroid-responsive liver disease arising consequent to immunogenetic and environmental risk factors. The clinical course reflects relapsing and remitting, hepatocyte targeted immunologic damage, which is countered by reparative responses to cell injury. Appropriate and timely immunosuppressive therapy drives the disease into remission, albeit with inevitable side effects. Many challenges faced in the clinic reflect practice that must capture a heterogeneous disease presentation, course, and treatment response, as well as treatment tolerability. In this Grand Round we appraise the evidence supporting current treatment approaches, address the impact of autoimmune liver disease 'crossover or overlap' presentations, explore important clinical correlates to immune-serological classifiers, and discuss the factors influencing choice of alternative therapy in difficult-to-treat situations
Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study).
No full textINTRODUCTION
Observational studies have demonstrated an association between vitamin D deficiency and increased risk of morbidity and mortality in critically ill patients. Cohort studies and pilot trials have suggested promising beneficial effects of vitamin D replacement in the critical ill, at least in patients with severe vitamin D deficiency. As vitamin D is a simple, low-cost and safe intervention, it has potential to improve survival in critically ill patients.
METHODS AND ANALYSIS
In this randomised, placebo-controlled, double-blind, multicentre, international trial, 2400 adult patients with severe vitamin D deficiency (25-hydroxyvitamin D≤12 ng/mL) will be randomised in a 1:1 ratio by www.randomizer.at to receive a loading dose of 540 000 IU cholecalciferol within 72 hours after intensive care unit (ICU) admission, followed by 4000 IU daily for 90 days or placebo. Hypercalcaemia may occur as a side effect, but is monitored by regular checks of the calcium level. The primary outcome is all-cause mortality at 28 days after randomisation. Secondary outcomes are: ICU, hospital, 90-day and 1-year mortality; hospital and ICU length of stay, change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment (SOFA) score, number of organ failures; hospital and ICU readmission until day 90; discharge destination, self-reported infections requiring antibiotics until day 90 and health-related quality of life. Recruitment status is ongoing.
ETHICS AND DISSEMINATION
National ethical approval was obtained by the Ethics Committee of the University of Graz for Austria, Erasme University Brussels (Belgium) and University Hospital Frankfurt (Germany), and will further be gained according to individual national processes. On completion, results will be published in a peer-reviewed scientific journal. The study findings will be presented at national and international meetings with abstracts online.
TRIAL REGISTRATION
NCT03188796, EudraCT-No: 2016-002460-13
Perceptions and Factors Influencing Eating Behaviours and Physical Function in Community-Dwelling Ethnically Diverse Older Adults: A Longitudinal Qualitative Study.
No full textEthnic minorities have a high prevalence of non-communicable diseases relating to unhealthy lifestyle practices. Several factors have been identified as influencing unhealthy lifestyle practices among this population; however, there is little evidence about how these factors differ among a heterogeneous sample living in a super-diverse city. This study aimed to: (1) identify and compare factors influencing eating behaviours and physical function among ethnic older minorities living in Birmingham, United Kingdom; and (2) understand how these factors and their association with healthy eating and physical function changed over 8-months. An in-depth interviewing approach was used at baseline ( = 92) and after 8-months ( = 81). Interviews were transcribed verbatim and analysed using directed content analysis. Healthy eating was viewed as more important than, and unrelated to, physical function. Personal, social and cultural/environmental factors were identified as the main factors influencing eating behaviours and physical function, which differed by ethnicity, age, and sex. At 8-month interviews, more men than women reported adverse changes. The study provides unique and useful insights regarding perceived eating behaviours and physical function in a relatively large and diverse sample of older adults that can be used to design new, and adapt existing, culturally-tailored community interventions to support healthy ageing
Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.
No full textBACKGROUND
Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1β and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia.
METHODS
VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1β and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 10 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425.
FINDINGS
Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes.
INTERPRETATION
Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect.
FUNDING
UK Department of Health and the Wellcome Trust
Hyperprolactinaemia.
No full textHyperprolactinaemia is one of the most common problems in clinical endocrinology. It relates with various aetiologies (physiological, pharmacological, pathological), the clarification of which requires careful history taking and clinical assessment. Analytical issues (presence of macroprolactin or of the hook effect) need to be taken into account when interpreting the prolactin values. Medications and sellar/parasellar masses (prolactin secreting or acting through "stalk effect") are the most common causes of pathological hyperprolactinaemia. Hypogonadism and galactorrhoea are well-recognized manifestations of prolactin excess, although its implications on bone health, metabolism and immune system are also expanding. Treatment mainly aims at restoration and maintenance of normal gonadal function/fertility, and prevention of osteoporosis; further specific management strategies depend on the underlying cause. In this review, we provide an update on the diagnostic and management approaches for the patient with hyperprolactinaemia and on the current data looking at the impact of high prolactin on metabolism, cardiovascular and immune systems
Patterns and predictors of relapse following radical chemoradiotherapy delivered using intensity-modulated radiotherapy with a simultaneous integrated boost in anal squamous cell carcinoma.
No full textMultivariable analysis of predictors of unplanned hospital readmission after pancreaticoduodenectomy: development of a validated risk score.
No full textBACKGROUND
Unplanned hospital readmission after pancreaticoduodenectomy (PD) is usually due to surgical complications and has significant clinical and economic impact. This study developed a risk score to predict 30-day readmission after PD.
METHODS
Patients undergoing PD between 2009 and 2016 were reviewed from a prospective database. Predictors of readmission were identified using a multivariable logistic regression model, from which a points-based risk scoring system was derived.
RESULTS
81 of 518 patients (15.6%) were readmitted within 30 days. History of cardiac disease ([odds ratio] OR = 2.12; 95% CI: 1.12-4.56), CRP>140 mg/L on post-operative day 3 (OR = 2.34; 95% CI: 1.37-4.35) and comprehensive complication index >14 (OR = 1.74; 95% CI: 1.03-2.85) were independent predictors of readmission. The regression coefficients were used to generate a risk score with excellent calibration (p = 0.917) and good discrimination (c-index = 0.65; 95% CI: 0.58-0.71; p < 0.001). Patients were categorised as low, moderate and high risk, with readmission rates of 6.4%, 13.4% and 23.0% respectively (p < 0.001).
CONCLUSION
The risk score identifies patients at high risk of readmission after pancreaticoduodenectomy. Such patients may benefit from pre-discharge imaging and/or enhanced follow-up, which may potentially reduce the impact of readmissions