TGFb2 induces the soluble isoform of CTLA-4 – implications for CTLA-4 based checkpoint inhibitor antibodies in malignant melanoma

FUNDING This work was funded by the Chief Scientist’s office, Scotland grant no. ETM/280. Acknowledgments Microscopy was performed in the Microscopy and Histology Core Facility at the University of Aberdeen. Flow cytometry was performed in the Iain Fraser Cytometry Centre. We are very grateful to our lab manager Ms. Gill Moir for her assistance with this work and also to the many BSc/MSc project students who worked on this project. We are extremely grateful for all of the volunteer melanoma patient donors and healthy donors that supported this work. FA-F received an Elphinstone PhD scholarship funded by the School of Medicine, Medical Sciences & Nutrition at the University of Aberdeen.Peer reviewedPublisher PD

The first OSCE; Does students' experience of performing in public affect their results? Assessment and evaluation of admissions, knowledge, skills and attitudes

Background: Personal qualities have been shown to affect students' exam results. We studied the effect of experience, and level, of public performance in music, drama, dance, sport, and debate at the time of admission to medical school as a predictor of student achievement in their first objective structured clinical examination (OSCE). Methods: A single medical school cohort (n=265) sitting their first clinical exam in 2011 as third year students were studied. Pre-admission statements made at the time of application were coded for their stated achievements in the level of public performance; participation in each activity was scored 0-3, where 0 was no record, 1=leisure time activity, 2=activity at school or local level, 3=activity at district, regional or national level. These scores were correlated to OSCE results by linear regression and t-test. Comparison was made between the highest scoring students in each area, and students scoring zero by t-test. Results: There was a bell shaped distribution in public performance score in this cohort. There was no significant linear regression relationship between OSCE results and overall performance score, or between any subgroups. There was a significant difference between students with high scores in theatre, debate and vocal music areas, grouped together as verbal performance, and students scoring zero in these areas. (p<0.05, t-test) with an effect size of 0.4. Conclusions: We found modest effects from pre-admission experience of verbal performance on students' scores in the OSCE examination. As these data are taken from students' admission statements, we call into question the received wisdom that such statements are unreliable

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation

Abdominal compartment syndrome in trauma patients: New insights for predicting outcomes

Context: Abdominal compartment syndrome (ACS) is associated with high morbidity and mortality among trauma patients. Several clinical and laboratory findings have been suggested as markers for ACS, and these may point to different types of ACS and complications. Aims: This study aims to identify the strength of association of clinical and laboratory variables with specific adverse outcomes in trauma patients with ACS. Settings and Design: A 5-year retrospective chart review was conducted at three Level I Trauma Centers in the City of Chicago, IL, USA. Subjects and Methods:A complete set of demographic, pre-, intra- and post-operative variables were collected from 28 patient charts. Statistical Analysis:Pearson's correlation coefficient was used to determine the strength of association between 29 studied variables and eight end outcomes. Results: Thirty-day mortality was associated strongly with the finding of an initial intra-abdominal pressure >20 mmHg and moderately with blunt injury mechanism. A lactic acid >5 mmol/L on admission was moderately associated with increased blood transfusion requirements and with acute renal failure during the hospitalization. Developing ACS within 48 h of admission was moderately associated with increased length of stay in the Intensive Care Unit (ICU), more ventilator days, and longer hospital stay. Initial operative intervention lasting more than 2 h was moderately associated with risk of developing multi-organ failure. Hemoglobin level 7 days were moderately associated with a disposition to long-term support facility. Conclusions: Clinical and lab variables can predict specific adverse outcomes in trauma patients with ACS. These findings may be used to guide patient management, improve resource utilization, and build capacity within trauma centers