Derivation and validation of a novel risk score to predict need for haemostatic intervention in acute upper gastrointestinal bleeding (London Haemostat Score)

Background: Acute Upper Gastrointestinal Bleeding (AUGIB) is a common medical emergency which takes up considerable healthcare resources. However, only approximately 20-30% of bleeds require urgent haemostatic intervention. Current standard of care is for all patients admitted to hospital to undergo endoscopy within 24 hours for risk stratification, but this is difficult to achieve in practice, invasive and costly. Aim To develop a novel non-endoscopic risk stratification tool for AUGIB to predict the need for haemostatic intervention by endoscopic, radiological or surgical treatments. We compared this with the Glasgow-Blatchford Score (GBS). Design: Model development was carried out using a derivation (n=466) and prospectively collected validation cohort (n=404) of patients who were admitted with AUGIB to three large hospitals in London, UK (2015-2020). Univariable and multivariable logistic regression analysis was used to identify variables that were associated with increased or decreased chances of requiring haemostatic intervention. This model was converted into a risk scoring system, the London Haemostat Score (LHS). Results: The LHS was more accurate at predicting need for haemostatic intervention than the GBS, in the derivation cohort (Area Under the Receiver Operating Curve [AUROC] 0.82; 95% Confidence Interval (CI), 0.78-0.86 vs 0.72; 95% CI, 0.67-0.77; p<0.001) and validation cohort (AUROC 0.80; 95% CI, 0.75-0.85 vs 0.72; 95% CI, 0.67-0.78; p<0.001). At cut-off scores at which LHS and GBS identified patients who required haemostatic intervention with 98% sensitivity, the specificity of the LHS was 41% vs 18% with the GBS (p<0.001). This could translate to 32% of inpatient endoscopies for AUGIB being avoided at a cost of only a 0.5% false negative rate. Conclusions: The London Haemostat score is accurate at predicting the need for haemostatic intervention in AUGIB and could be used identify a proportion of low-risk patients who can undergo delayed or outpatient endoscopy. Validation in other geographical settings is required before routine clinical use

Barriers to women entering surgical careers: a global study into medical student perceptions

Background Barriers to female surgeons entering the field are well documented in Australia, the USA and the UK, but how generalizable these problems are to other regions remains unknown. Methods A cross-sectional survey was developed by the International Federation of Medical Students' Associations (IFMSA)'s Global Surgery Working Group assessing medical students' desire to pursue a surgical career at different stages of their medical degree. The questionnaire also included questions on students' perceptions of their education, resources and professional life. The survey was distributed via IFMSA mailing lists, conferences and social media. Univariate analysis was performed, and statistically significant exposures were added to a multivariate model. This model was then tested in male and female medical students, before a further subset analysis by country World Bank income strata. Results 639 medical students from 75 countries completed the survey. Mentorship [OR 3.42 (CI 2.29–5.12) p = 0.00], the acute element of the surgical specialties [OR 2.22 (CI 1.49–3.29) p = 0.00], academic competitiveness [OR 1.61 (CI 1.07–2.42) p = 0.02] and being from a high or upper-middle-income country (HIC and UMIC) [OR 1.56 (CI 1.021–2.369) p = 0.04] all increased likelihood to be considering a surgical career, whereas perceived access to postgraduate training [OR 0.63 (CI 0.417–0.943) p = 0.03], increased year of study [OR 0.68 (CI 0.57–0.81) p = 0.00] and perceived heavy workload [OR 0.47 (CI 0.31–0.73) p = 0.00] all decreased likelihood to consider a surgical career. Perceived quality of surgical teaching and quality of surgical services in country overall did not affect students' decision to pursue surgery. On subset analysis, perceived poor access to postgraduate training made women 60% less likely to consider a surgical career [OR 0.381 (CI 0.217–0.671) p = 0.00], whilst not showing an effect in the men [OR 1.13 (CI 0.61–2.12) p = 0.70. Concerns about high cost of training halve the likelihood of students from low and low-middle-income countries (LICs and LMICs) considering a surgical career [OR 0.45 (CI 0.25–0.82) p = 0.00] whilst not demonstrating a significant relationship in HIC or UMIC countries. Women from LICs and LMICs were 40% less likely to consider surgical careers than men, when controlling for other factors [OR 0.59 CI (0.342–1.01 p = 0.053]. Conclusion Perceived poor access to postgraduate training and heavy workload dissuade students worldwide from considering surgical careers. Postgraduate training in particular appears to be most significant for women and cost of training an additional factor in both women and men from LMICs and LICs. Mentorship remains an important and modifiable factor in influencing student's decision to pursue surgery. Quality of surgical education showed no effect on student decision-making

The influence of pre-radiation salivary flow rates and radiation dose on parotid salivary gland dysfunction in patients receiving radiotherapy for head and neck cancers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72238/1/j.1754-4505.1998.tb00913.x.pd

‘When Birds of a Feather Flock Together’: Synesthetic Correspondences Modulate Audiovisual Integration in Non-Synesthetes

Parise C, Spence C. ‘When Birds of a Feather Flock Together’: Synesthetic Correspondences Modulate Audiovisual Integration in Non-Synesthetes. Presented at the 10th International Multisensory Research Forum (IMRF 2009), New York, NY

Morphological characterization of the blood cells in the endangered Sicilian endemic pond turtle,Emys trinacris(Testudines: Emydidae)

In this study, measurements of morphological parameters, sizes and frequencies of peripheral blood cells (erythrocytes, leukocytes, thrombocytes) on blood smear preparation devices stained with May-Grünwald stain were evaluated for both sexes in 20 Emys trinacris (Testudines: Emydidae) specimens. Erythrocytes were higher in male than in female specimens. The leukocyte of E. trinacris contains eosinophil, basophil, monocyte, heterophil and lymphocyte. The eosinophil was higher in males than in females whereas lymphocytes were higher in females than in males. The erythrocyte morphological parameters (EL [erythrocyte length], EW [erythrocyte width], L/W [length/width], ES [erythrocyte size]) were compared with the same data from Emys orbicularis s.l, and from species belonging to other chelonian genera. The erythrocyte size did not vary within the studied Palearctic Emys taxa, whereas it proved to differ from that observed in other chelonians

Onset dynamics of type A botulinum neurotoxin-induced paralysis

Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized by receptor-mediated endocytosis. Subsequently its zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves a vesicle-docking protein, SNAP-25, to block neurally evoked cholinergic neurotransmission. We tested the hypothesis that mathematical models having a minimal number of reactions and reactants can simulate published data concerning the onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction (NMJ) and in other systems. Experimental data from several laboratories were simulated with two different models that were represented by sets of coupled, first-order differential equations. In this study, the 3-step sequential model developed by Simpson (J Pharmacol Exp Ther 212:16–21,1980) was used to estimate upper limits of the times during which anti-toxins and other impermeable inhibitors of BoNT/A can exert an effect. The experimentally determined binding reaction rate was verified to be consistent with published estimates for the rate constants for BoNT/A binding to and dissociating from its receptors. Because this 3-step model was not designed to reproduce temporal changes in paralysis with different toxin concentrations, a new BoNT/A species and rate (kS) were added at the beginning of the reaction sequence to create a 4-step scheme. This unbound initial species is transformed at a rate determined by kS to a free species that is capable of binding. By systematically adjusting the values of kS, the 4-step model simulated the rapid decline in NMJ function (kS ≥0.01), the less rapid onset of paralysis in mice following i.m. injections (kS = 0.001), and the slow onset of the therapeutic effects of BoNT/A (kS < 0.001) in man. This minimal modeling approach was not only verified by simulating experimental results, it helped to quantitatively define the time available for an inhibitor to have some effect (tinhib) and the relation between this time and the rate of paralysis onset. The 4-step model predicted that as the rate of paralysis becomes slower, the estimated upper limits of (tinhib) for impermeable inhibitors become longer. More generally, this modeling approach may be useful in studying the kinetics of other toxins or viruses that invade host cells by similar mechanisms, e.g., receptor-mediated endocytosis

Calcium Handling in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

BACKGROUND: The ability to establish human induced pluripotent stem cells (hiPSCs) by reprogramming of adult fibroblasts and to coax their differentiation into cardiomyocytes opens unique opportunities for cardiovascular regenerative and personalized medicine. In the current study, we investigated the Ca(2+)-handling properties of hiPSCs derived-cardiomyocytes (hiPSC-CMs). METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and immunocytochemistry experiments identified the expression of key Ca(2+)-handling proteins. Detailed laser confocal Ca(2+) imaging demonstrated spontaneous whole-cell [Ca(2+)](i) transients. These transients required Ca(2+) influx via L-type Ca(2+) channels, as demonstrated by their elimination in the absence of extracellular Ca(2+) or by administration of the L-type Ca(2+) channel blocker nifedipine. The presence of a functional ryanodine receptor (RyR)-mediated sarcoplasmic reticulum (SR) Ca(2+) store, contributing to [Ca(2+)](i) transients, was established by application of caffeine (triggering a rapid increase in cytosolic Ca(2+)) and ryanodine (decreasing [Ca(2+)](i)). Similarly, the importance of Ca(2+) reuptake into the SR via the SR Ca(2+) ATPase (SERCA) pump was demonstrated by the inhibiting effect of its blocker (thapsigargin), which led to [Ca(2+)](i) transients elimination. Finally, the presence of an IP3-releasable Ca(2+) pool in hiPSC-CMs and its contribution to whole-cell [Ca(2+)](i) transients was demonstrated by the inhibitory effects induced by the IP3-receptor blocker 2-Aminoethoxydiphenyl borate (2-APB) and the phospholipase C inhibitor U73122. CONCLUSIONS/SIGNIFICANCE: Our study establishes the presence of a functional, SERCA-sequestering, RyR-mediated SR Ca(2+) store in hiPSC-CMs. Furthermore, it demonstrates the dependency of whole-cell [Ca(2+)](i) transients in hiPSC-CMs on both sarcolemmal Ca(2+) entry via L-type Ca(2+) channels and intracellular store Ca(2+) release

Panel 4 : Report of the Microbiology Panel

Objective. To perform a comprehensive review of the literature from July 2011 until June 2015 on the virology and bacteriology of otitis media in children. Data Sources. PubMed database of the National Library of Medicine. Review Methods. Two subpanels comprising experts in the virology and bacteriology of otitis media were created. Each panel reviewed the relevant literature in the fields of virology and bacteriology and generated draft reviews. These initial reviews were distributed to all panel members prior to meeting together at the Post-symposium Research Conference of the 18th International Symposium on Recent Advances in Otitis Media, National Harbor, Maryland, in June 2015. A final draft was created, circulated, and approved by all panel members. Conclusions. Excellent progress has been made in the past 4 years in advancing our understanding of the microbiology of otitis media. Numerous advances were made in basic laboratory studies, in animal models of otitis media, in better understanding the epidemiology of disease, and in clinical practice. Implications for Practice. (1) Many viruses cause acute otitis media without bacterial coinfection, and such cases do not require antibiotic treatment. (2) When respiratory syncytial virus, metapneumovirus, and influenza virus peak in the community, practitioners can expect to see an increase in clinical otitis media cases. (3) Biomarkers that predict which children with upper respiratory tract infections will develop otitis media may be available in the future. (4) Compounds that target newly identified bacterial virulence determinants may be available as future treatment options for children with otitis media.Peer reviewe