Genetically Predicted Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From Mendelian Randomization.

Inflammation contributes to atherosclerosis and coronary artery disease (CAD). In order to help identify therapeutic targets, it is important to ascertain whether biomarkers associated with CAD risk are causal. In a recent meta-analysis of clinical trials, neutrophil-to lymphocyte ratio (NLR) was associated with increased cardiovascular risk 1 . We investigate a potential causal nature of this relationship by performing Mendelian randomization (MR) analyse

Musculoskeletal foot problems in primary care: what influences older people to consult?

Objective. To estimate the incidence of, and factors associated with, consultation for musculoskeletal foot problems in primary care

'20 days protected learning' - students' experiences of an Overseas Nurses Programme - 4 years on: A retrospective survey

Background From September 2005 the Nursing and Midwifery Council (NMC) introduced new arrangements for the registration of non-EU overseas nurses which requires all applicants to undertake '20 days of protected learning' time in the UK and for some, a period of supervised practice. A survey was undertaken at Bournemouth University, which offers a '20 days protected learning only' programme, to elicit overseas nurses' demographic details, experiences in completing the programme and their 'final destinations' once registered. Methods An online survey was devised which contained a mixture of tick box and open ended questions which covered demographic details, views on the programme and final destinations This was uploaded to www.SurveyMonkey.com and sent out to nurses who had completed the Overseas Nurses Programme (ONP) with Bournemouth University (n=1050). Quantiative data were analysed using descriptive statistics and the qualitative data were coded and analysed using content analysis . Results There were 251 respondents (27.7% response rate). The typical 'profile' of a nurse who responded to the survey was female, aged 25-40 years and had been qualified for more than 5 years with a bachelors degree. The majority came from Australia on a 2 year working holiday visa and the key final destination in the UK, on registration with the NMC, was working for an agency. There were five key findings regarding experience of the programe. Of those surveyed 61.2% did not feel it necessary to undergo an ONP; 71.6% felt that they should be able to complete the programme on-line in their own country; 64.2% that the ONP should only contain information about delivery of healthcare in UK and Legal and professional (NMC) issues; 57% that European nurses should also undergo the same programme and sit an IELTS test; and 68.2% that the programme was too theory orientated; and should have links to practice (21%). Conclusions The NMC set the admissions criteria for entry to the register and Standards for an ONP. The findings of this survey raise issues regarding the percieved value and use of this approach for overseas nurses, and it may be helpful to take this into account when considering future policy

Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration

Structural evidence for the partially oxidized dipyrromethene and dipyrromethanone forms of the cofactor of porphobilinogen deaminase: structures of the Bacillus megaterium

The enzyme porphobilinogen deaminase (PBGD; hydroxymethylbilane synthase; EC 2.5.1.61) catalyses an early step of the tetrapyrrole-biosynthesis pathway in which four molecules of the monopyrrole porphobilinogen are condensed to form a linear tetrapyrrole. The enzyme possesses a dipyrromethane cofactor, which is covalently linked by a thioether bridge to an invariant cysteine residue (Cys241 in the Bacillus megaterium enzyme). The cofactor is extended during the reaction by the sequential addition of the four substrate molecules, which are released as a linear tetrapyrrole product. Expression in Escherichia coli of a His-tagged form of B. megaterium PBGD has permitted the X-ray analysis of the enzyme from this species at high resolution, showing that the cofactor becomes progressively oxidized to the dipyrromethene and dipyrromethanone forms. In previously solved PBGD structures, the oxidized cofactor is in the dipyromethenone form, in which both pyrrole rings are approximately coplanar. In contrast, the oxidized cofactor in the B. megaterium enzyme appears to be in the dipyrromethanone form, in which the C atom at the bridging α-position of the outer pyrrole ring is very clearly in a tetrahedral configuration. It is suggested that the pink colour of the freshly purified protein is owing to the presence of the dipyrromethene form of the cofactor which, in the structure reported here, adopts the same conformation as the fully reduced dipyrromethane form