Heterosexist Harassment and Rejection, Emotional Social Support and Perceived Stress in a Lesbian, Gay and Bisexual Sample

The minority stress theory suggests LGBs experience greater stress levels due to their sexual minority identities; thus, they are more prone to psychological distress. Poor mental health is linked to internalized homophobia and heterosexism. However, affirmative social support may mitigate the stress response via the buffering hypothesis. My model posits that LGBs are more likely to report perceived stress; however, affirmative social support can mitigate stress. I investigated the relationship between perceived stress and sexual minority identity. I explored the relationship between heterosexism, emotional support and perceived stress and the moderating role of social support in my LGB sample. I conducted a hierarchical linear regression to test my model, which accounted for 29% of the variance in perceived stress. Heterosexism and emotional support were significantly associated with perceived stress. I failed to find a moderating role of emotional support. Limitations, strengths, future research and implications are discussed

Impact of Parenteral Nutrition Versus Fasting on Hepatic Bile Acid Production and Transport in a Rabbit Model of Prolonged Critical Illness

Cholestatic liver dysfunction frequently occurs during critical illness. Administration of parenteral nutrition (PN) is thought to aggravate this. Underlying mechanisms are not clear.status: publishe

Prescriber commitment posters to increase prudent antibiotic prescribing in English general practice: a cluster randomized controlled trial

Unnecessary antibiotic prescribing contributes to Antimicrobial Resistance posing a major public health risk. Estimates suggest as many as half of antibiotics prescribed for respiratory infections may be unnecessary. We conducted a three-armed unblinded cluster randomized controlled trial (ISRCTN trial registry 83322985). Interventions were a commitment poster (CP) advocating safe antibiotic prescribing or a CP plus an antimicrobial stewardship message (AM) on telephone appointment booking lines, tested against a usual care control group. The primary outcome measure was antibiotic item dispensing rates per 1000 population adjusted for practice demographics. The outcome measures for post-hoc analysis were dispensing rates of antibiotics usually prescribed for upper respiratory tract infections and broad spectrum antibiotics. In total, 196 practice units were randomized to usual care (n = 60), CP (n = 66), and CP&AM (n = 70). There was no effect on the overall dispensing rates for either interventions compared to usual care (CP 5.673, 95%CI −9.768 to 21.113, p = 0.458; CP&AM, −12.575, 95%CI −30.726 to 5.576, p = 0.167). Secondary analysis, which included pooling the data into one model, showed a significant effect of the AM (−18.444, 95%CI −32.596 to −4.292, p = 0.012). Fewer penicillins and macrolides were prescribed in the CP&AM intervention compared to usual care (−12.996, 95% CI −34.585 to −4.913, p = 0.018). Commitment posters did not reduce antibiotic prescribing. An automated patient antimicrobial stewardship message showed effects and requires further testing

Spatially heterogeneous argon-isotope systematics and apparent ⁴⁰Ar/³⁹Ar ages in perlitised obsidian

In situ laser ablation Ar-isotope analyses of variably hydrated and devitrified obsidian from the ~ 27 Ma Cochetopa Dome, San Juan, USA, reveal complex interplay between degassing of initial Ar and absorption of atmospheric Ar. These processes have locally modified the Ar-isotope composition of the obsidian and led to spurious, spatially-heterogeneous Ar-isotope and 40Ar/39Ar age data. Small perlite beads exhibit older apparent Ar-ages at the rims than the cores. This is interpreted as an apparent excess of 40Ar at the rims, produced either by a) diffusion of excess 40Ar into the bead during flushing of the lava with excess 40Ar-bearing volcanic gas, or by b) isotopic fractionation during degassing of initial Ar, causing preferential loss of 36Ar over 40Ar at the bead rims. The second interpretation is favoured by a relative enrichment of 36Ar in the core of a perlite bead along a microlite-free (poorly degassed) flow band, and by a lack of age variation in a larger, fresh, well-degassed perlite bead. These isotopic gradients were later overprinted during glass hydration by absorption of Ar with near-atmospheric composition, resulting in elevated 36Ar and reduced radiogenic 40Ar* yields at the rims of perlite beads. These complex interactions essentially represent the mixing of three distinct Ar reservoirs: initial trapped Ar that may or may not be fractionated, an isotopically atmospheric Ar component introduced during hydration, and radiogenic 40Ar*. Such reservoir mixing is the underlying reason for poor correlations on isotope correlation diagrams and the difficulties in validating the composition of the non-radiogenic Ar component. We thus suggest that high 36Ar yields are a combination of the incomplete degassing of initial (possibly magmatic) Ar and the gain of Ar during interaction between the obsidian and meteoric/atmospheric fluids. Our analyses emphasise the challenging nature of 40Ar/39Ar dating obsidian samples, but also point to possible solutions by careful sample characterisation and selection of highly degassed samples

Reduced Cortisol Metabolism during Critical Illness

Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.status: publishe

Screening and brief intervention for obesity in primary care:cost-effectiveness analysis in the BWeL trial

This paper is closed access until 31 July 2019.Background: The Brief Intervention for Weight Loss Trial enrolled 1882 consecutively attending primary care patients who were obese and participants were randomised to physicians opportunistically endorsing, offering, and facilitating a referral to a weight loss programme (support) or recommending weight loss (advice). After one year, the support group lost 1.4 kg more (95%CI 0.9 to 2.0): 2.4 kg versus 1.0 kg. We use a cohort simulation to predict effects on disease incidence, quality of life, and healthcare costs over 20 years. Methods: Randomly sampling from the trial population, we created a virtual cohort of 20 million adults and assigned baseline morbidity. We applied the weight loss observed in the trial and assumed weight regain over four years. Using epidemiological data, we assigned the incidence of 12 weight-related diseases depending on baseline disease status, age, gender, body mass index. From a healthcare perspective, we calculated the quality adjusted life years (QALYs) accruing and calculated the incremental difference between trial arms in costs expended in delivering the intervention and healthcare costs accruing. We discounted future costs and benefits at 1.5% over 20 years. Results: Compared with advice, the support intervention reduced the cumulative incidence of weight-related disease by 722/100,000 people, 0.33% of all weight-related disease. The incremental cost of support over advice was £2.01million/100,000. However, the support intervention reduced health service costs by £5.86 million/100,000 leading to a net saving of £3.85 million/100,000. The support intervention produced 992 QALYs/100,000 people relative to advice. Conclusions: A brief intervention in which physicians opportunistically endorse, offer, and facilitate a referral to a behavioural weight management service to patients with a BMI of at least 30 kg/m2 reduces healthcare costs and improves health more than advising weight loss

The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia

PURPOSE: Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF).METHODS: We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape.RESULTS: IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients (P &lt; .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P &lt; .0001) and who should therefore be considered for experimental agents.CONCLUSION: The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.</p

The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia

PURPOSE: Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF). METHODS: We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape. RESULTS: IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients (P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents. CONCLUSION: The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed

Early phase clinical trials extension to the guidelines for the content of statistical analysis plans

This paper reports guidelines for the content of statistical analysis plans for early phase clinical trials, ensuring specification of the minimum reporting analysis requirements, by detailing extensions (11 new items) and modifications (25 items) to existing guidance after a review by various stakeholders

Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not INCOL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg, reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis