Autoantibodies to truncated GAD(96-585) antigen stratify risk of early insulin requirement in adult-onset diabetes

We investigated whether characterisation of full-length (f-)GADA responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed associations of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement

Safe prescribing training provision for junior doctors: is this optimal?

Background The aim of this study was to determine the training provisions in practical safe prescribing for foundation doctors in NHS hospitals located in the South Thames region. Methods A web-based questionnaire was distributed by e-mail to all 1762 foundation doctors in the South Thames Foundation School (STFS) region. In addition, a separate questionnaire was distributed to prescribing training Leads at 15 NHS Hospital Trusts. Quantitative data were analysed using descriptive statistics and thematic analysis was performed on qualitative data. Results Trainers: 10 Prescribing Leads (67 %) responded. Of the 9 NHS Trusts that offered safe prescribing training in their induction programme, 5 included a practical prescribing session. By the end of the foundation year, 6 NHS Trusts had provided at least one dedicated practical prescribing session for F1s compared with 2 NHS Trusts for F2s. Trainees: A total of 124 foundation trainees (7.2 %) responded (69 F1s and 55 F2s). 87 % of F1s received dedicated training in safe prescribing at their Trust induction (n = 60) in comparison to 49 % of F2s (n = 27). 80 % of F1s (n = 55) had a practical prescribing session during induction versus 27 % of F2s (n = 15). The difference was significant, X2 (1, N = 124) = 34.23, p <0.0001. Emerging themes from qualitative data included, recognition of medical education as a continuum, importance of working relationships with pharmacists and neglect of F2s. Conclusions There appears to be a lack of emphasis on the training of F2 doctors in practical safe prescribing compared with F1 doctors. There should be standardisation of safe prescribing training provisions, particularly in the induction period and for F2 doctors

Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis

Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac developmen

Temperature surpasses the effects of velocity and turbulence on swimming performance of two invasive non-native fish species

Global climate change continues to impact fish habitat quality and biodiversity, especially in regard to the dynamics of invasive non-native species. Using individual aquaria and an open channel flume, this study evaluated the effects of water temperature, flow velocity and turbulence interactions on swimming performance of two lentic, invasive non-native fish in the UK, pumpkinseed (Lepomis gibbosus) and topmouth gudgeon (Pseudorasbora parva). Burst and sustained swimming tests were conducted at 15, 20 and 25°C. Acoustic Doppler velocimetry was used to measure the flume hydrodynamic flow characteristics. Both L. gibbosus and P. parva occupied the near-bed regions of the flume, conserving energy and seeking refuge in the low mean velocities flow areas despite the relatively elevated turbulent fluctuations, a behaviour which depended on temperature. Burst swimming performance and sustained swimming increased by up to 53% as temperature increased from 15 to 20°C and 71% between 15 and 25°C. Furthermore, fish test area occupancy was dependent on thermal conditions, as well as on time-averaged velocities and turbulent fluctuations. This study suggests that invasive species can benefit from the raised temperatures predicted under climate change forecasts by improving swimming performance in flowing water potentially facilitating their further dispersal and subsequent establishment in lotic environments

Flower-visitor communities of an arcto-alpine plant-Global patterns in species richness, phylogenetic diversity and ecological functioning

Pollination is an ecosystem function of global importance. Yet, who visits the flower of specific plants, how the composition of these visitors varies in space and time and how such variation translates into pollination services are hard to establish. The use of DNA barcodes allows us to address ecological patterns involving thousands of taxa that are difficult to identify. To clarify the regional variation in the visitor community of a widespread flower resource, we compared the composition of the arthropod community visiting species in the genus Dryas (mountain avens, family Rosaceae), throughout Arctic and high-alpine areas. At each of 15 sites, we sampled Dryas visitors with 100 sticky flower mimics and identified specimens to Barcode Index Numbers (BINs) using a partial sequence of the mitochondrial COI gene. As a measure of ecosystem functioning, we quantified variation in the seed set of Dryas. To test for an association between phylogenetic and functional diversity, we characterized the structure of local visitor communities with both taxonomic and phylogenetic descriptors. In total, we detected 1,360 different BINs, dominated by Diptera and Hymenoptera. The richness of visitors at each site appeared to be driven by local temperature and precipitation. Phylogeographic structure seemed reflective of geological history and mirrored trans-Arctic patterns detected in plants. Seed set success varied widely among sites, with little variation attributable to pollinator species richness. This pattern suggests idiosyncratic associations, with function dominated by few and potentially different taxa at each site. Taken together, our findings illustrate the role of post-glacial history in the assembly of flower-visitor communities in the Arctic and offer insights for understanding how diversity translates into ecosystem functioning.Peer reviewe

An exploration of the views of paramedics regarding airway management

© 2016 Brandling et al. Background: Paramedics are a skilled group of clinicians with expertise in airway management. Our research group has completed a trial comparing supraglottic airway devices with tracheal intubation during out of hospital cardiac arrest. This is a contentious topic amongst paramedics in the United Kingdom (UK). We explored the customs and beliefs of UK paramedics in relation to airway management, and whether tracheal intubation contributes to and sustains paramedic professional identity. Methods: The study took place within South Western Ambulance Service NHS Foundation Trust. We used a qualitative approach, conducting interviews and focus groups with paramedics. The themes arising from interviews were discussed in focus groups, developing a deeper understanding and providing insight and recommendations for future research and policy. Purposive sampling accounted for differing training and for participation in the main trial. There were 17interviews and five focus groups with a further 17 participants. Data saturation was achieved. Results: Four domains were identified. Pride - The ability to use a life-saving skill in austere conditions. Utility - Different training routes and experience have led to different attitudes towards airway management. Inconsistent expectations - Paramedics felt that there were different perceptions of their abilities amongst hospital staff and the general public. Professionalization - Debate over airway management is not founded on good evidence. Conclusion: We have demonstrated that UK paramedics have a wide range of views regarding airway management, and that these are based on evidence and experience rather than dogma. Airway management contributes to paramedics' professional identity, but is not reliant on this

Prostate-Specific Antigen Screening and 15-year Prostate Cancer Mortality:A Secondary Analysis of the CAP Randomized Clinical Trial

Key PointsQuestion  In men aged 50 to 69 years, does a single invitation for a prostate-specific antigen (PSA) screening test reduce prostate cancer mortality at 15-year follow-up compared with no invitation for testing?Findings  In this secondary analysis of a randomized clinical trial of 415 357 men aged 50 to 69 years randomized to a single invitation for PSA screening (n = 195 912) or a control group without PSA screening (n = 219 445) and followed up for a median of 15 years, risk of death from prostate cancer was lower in the group invited to screening (0.69% vs 0.78%; mean difference, 0.09%) compared with the control group.Meaning  Compared with no invitation for routine PSA testing, a single invitation for a PSA screening test reduced prostate cancer mortality at a median follow-up of 15 years, but the absolute mortality benefit was small.AbstractIMPORTANCE The Cluster randomized trial of PSA testing for Prostate cancer (CAP) reported no effect of prostate specific antigen (PSA) screening on prostate cancer mortality at median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear.OBJECTIVE To evaluate the effect of a single invitation for PSA screening on the pre-specified secondary outcome of prostate cancer-specific mortality at a median of 15 years’ follow-up, compared to a control group not invited for screening. DESIGN, SETTING, PARTICIPANTS Cluster randomized trial of men aged 50-69 identified from 573 primary-care practices in England and Wales. Primary-care practices were randomized between 09/25/2001 and 08/24/2007 and men were enrolled between 01/08/2002 and 01/20/2009. Follow-up was completed on 03/31/2021. INTERVENTION A single invitation for a PSA screening test with subsequent diagnostic tests if PSA≥3.0ng/ml, compared to standard practice (control). MAIN OUTCOMES AND MEASURES The primary outcome was reported previously. Of eight prespecified secondary outcomes, results of four were reported previously. The four remaining pre-specified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis.RESULTS Of 415,357 randomized men (mean [SD] age: 59.0 [5.6] years), 98% were analyzed in these analyses. Overall, 12,013 and 12,958 men with prostate cancers were diagnosed in the intervention and control groups (15-year cumulative risks 7.1% and 6.9% respectively). At a median 15-year follow-up, 1,199 (0.69%) men in the intervention group and 1,451 (0.78%) men in the control group died of prostate cancer (rate ratio [RR] 0.92 [95% CI 0.85, 0.99]; p=0.03). Compared to the control group, the PSA screening intervention increased detection of low-grade (Gleason score [GS]≤6; 2.2% versus 1.6%;p&lt;0.001) and localized (T1/T2; 3.6% versus 3.1%;p&lt;0.001) disease, but not intermediate (GS=7), high-grade (GS≥8), locally-advanced (T3) or distally-advanced (T4/N1/M1) tumors. There were 45,084 all-cause deaths (23.2%) in the intervention group and 50,336 deaths (23.3%) in the control group respectively (RR 0.97 [95% CI 0.94, 1.01]; p=0.11). Eight deaths in the intervention and seven deaths in the control group were related to a diagnostic biopsy or prostate cancer treatment.CONCLUSIONS AND RELEVANCE A single invitation for PSA screening, compared to standard practice without routine screening, reduced the secondary outcome of prostate cancer deaths at a median follow-up of 15-years. However, the absolute reduction in deaths was small.<br/