Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V).

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for β-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, β-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting β-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown

Can One-Run-Fixed-Arrhenius Kerogen Analysis Provide Comparable Organofacies Results to Detailed Palynological Analysis? A Case Study from a Prospective Mississippian Source Rock Reservoir (Bowland Shale, UK)

Organofacies analysis, a fundamental component within source rock appraisal based on the study of kerogen within a source rock, is typically produced from microscopy (palynological) and geochemical (kerogen kinetic) data, both of which are costly to acquire. One-Run-Fixed-Arrhenius (ORFA) kerogen kinetic analysis based on Rock–Eval pyrolysis offers a substantially cheaper kinetic dataset. Here, ORFA and palynological analyses are compared in organofacies characterization of a prospective Mississippian source rock reservoir (Bowland Shale, UK). Two-end-member organofacies were determined based on the abundance of the 56 kcal/mol activation energy peak derived from ORFA data: absence ( 15%) indicating ‘organofacies B’ containing the highest proportion of sporomorphs (Type II kerogen). A mud-dominated slope setting for the rock reservoir was also used to test the accuracy of organofacies analysis in determining depositional environment. Organofacies A found within lithofacies deposited from dilute waning density flows and hemipelagic suspension settling occurred between shelf edge, slope and basin. Organofacies B found within lithofacies deposited from dilute waning density flows, and low-strength cohesive debrites occurred only within the lower slope. This study demonstrates that ORFA kerogen kinetic analysis provides comparable net results to palynological analysis, enabling cheaper and faster organic characterization during initial source rock appraisal. However, caution must be exercised in drawing interpretations as to biological source(s), organic matter mixing and preservation state(s) without additional investigation using data from detailed palynological analysis

Where are the paediatricians? An international survey to understand the global paediatric workforce

Objective: Our primary objective was to examine the global paediatric workforce and to better understand geographic differences in the number of paediatricians globally. Secondary objectives were to describe paediatric workforce expectations, who provides children with preventative care and when children transition out of paediatric care. Design: Survey of identified paediatric leaders in each country. Setting: Paediatric association leaders worldwide. Main outcome measures: Paediatrician numbers, provision of primary care for children, age of transition to adult care. Results: Responses were obtained from 121 countries (73% of countries approached). The number of paediatricians per 100 000 children ranged from a median of 0.5 (IQR 0.3–1.4) in low-income countries to 72 (IQR 4–118) in high-income countries. Africa and South-East Asia reported the lowest paediatrician density (median of 0.8 paediatricians per 100 000 children, IQR 0.4–2.6 and median of 4, IQR 3–9, respectively) and fewest paediatricians entering the workforce. 82% of countries reported transition to adult care by age 18% and 39% by age 15. Most countries (91%) but only 64% of low-income countries reported provision of paediatric preventative care (p\u3c0.001, Cochran-Armitage trend test). Systems of primary care provision varied widely. A majority of countries (63%) anticipated increases in their paediatric workforce in the next decade. Conclusions: Paediatrician density mirrors known inequities in health provider distribution. Fewer paediatricians are entering the workforce in areas with already low paediatrician density, which may exacerbate disparities in child health outcomes. In some regions, children transition to adult care during adolescence, with implications for healthcare training and delivery. Paediatrician roles are heterogeneous worldwide, and country-specific strategies should be used to address inequity in child health provisio

Phase space density and chiral symmetry restoration in relativistic heavy ion collisions

The effect of altered hadron masses is studied for its effect with regard to final-state hadronic observables. It is shown that the final phase space densities of pions and kaons, which can be inferred experimentally, are sensitive to in-medium properties of the excited matter at earlier stages of the collision, but that the sensitivity is significantly moderated by interactions that change the effective numbers of pions and kaons during the latter part of the collision.Comment: 5 pages, 4 fig.

918-7 Limitations of Percutaneous Interventions in the Treatment of Bifurcation Lesions Involving the Left Anterior Descending Coronary Artery

Serious complications may occur when intervention is unsuccessful in bifurcation lesions involving the left anterior descending (LAD) and first major diagonal (D), because of the large amount of involved myocardium. To determine this complication rate, we reviewed 82 consecutive cases, over a 3 year period, in which these lesions were attempted. Sixty-six percent of the subjects were male, and 37% had unstable angina. The mean age was 59 and the mean ejection fraction was 56%. Digital calipers were used to measure vessel minimum lumen (MLD) and reference diameters. For the LAD the final MLD was 1.81mm and for the 0 1.32mm. The final percent mean diameter stenoses for the LAD and D were 41% and 45%, respectively. There were no significant differences in the rates of success or complication between groups treated with angioplasty only (N=68) or directional atherectomy (N=14). The in-hospital event-free success rate was 55%. The in-hospital complication rates were:Recurrent Ischemia16%Ventricular Tachycardia2%Myocardial Infarction14%Stroke2%Bypass Surgery12%Death1%Repeat Procedure4%Composite34%ConclusionLAD bifurcation lesion intervention is associated with a high in-hospital complication rate. Since these lesions are not amenable to stent placement or atherectomy with simultaneous protection of both vessels, these cases should be carefully evaluated before intervention, and bypass surgery should be considered as a treatment option

The Role of Public Health Institutions in Global Health System Strengthening Efforts: The US CDC's Perspective

Peter Bloland and colleagues from the US CDC lay out the agency's priorities for health systems strengthening efforts

An implementation research agenda.

In October 2006, the Chief Medical Officer (CMO) of England asked Professor Sir John Tooke to chair a High Level Group on Clinical Effectiveness in response to the chapter 'Waste not, want not' in the CMOs 2005 annual report 'On the State of the Public Health'. The high level group made recommendations to the CMO to address possible ways forward to improve clinical effectiveness in the UK National Health Service (NHS) and promote clinical engagement to deliver this. The report contained a short section on research needs that emerged from the process of writing the report, but in order to more fully identify the relevant research agenda Professor Sir John Tooke asked Professor Martin Eccles to convene an expert group - the Clinical Effectiveness Research Agenda Group (CERAG) - to define the research agenda. The CERAG's terms of reference were 'to further elaborate the research agenda in relation to pursuing clinically effective practice within the (UK) National Health Service'. This editorial presents the summary of the CERAG report and recommendations

Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial

Aim Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial. Methods and results Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73m2. Baseline standard of HF care was very good: 60% received triple therapy. Their N-terminal pro-B-type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992-6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization Conclusions VICTORIA comprises a broadly generalizable high-risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF

Reliability of physical examination of the upper extremity among keyboard operators

Background Physical examination is a traditional outcome measure in epidemiological research. Its value as a reliable measure depends, in part, on the prevalence of positive findings. The purpose of this paper is to determine the empirical reliability of physical examination and anthropometry in a field study of upper extremity disorders among keyboard operators. Methods Two experienced examiners independently performed common provocative tests and procedures in physical examinations of the neck and upper extremity among 160 keyboard operators. Two additional examiners conducted anthropometric surveys among 137 workers. Inter-examiner reliability was assessed with observed agreement, kappa statistics, and intra-class correlations (ICC). Results Observed agreement was between 96% and 100% for neck and upper extremity signs, muscle stretch reflexes, and muscle strength, however, with the exception of provocative tests, reliability statistics were unstable. Among the provocative tests, Phalen and Tinel tests had modest agreement after adjusting for chance (Κ range: 0.20–0.43). The carpal compression test had the best reliability (Κ=0.60 and Κ=0.67, left and right side, respectively). The ICCs for anthropometry ranged from 0.36–0.91. Conclusions Results from the study showed that statistically, except for the carpal compression test, physical examination contributed minimal reliable information. This was attributed mainly to the low prevalence of positive findings, and generally mild nature of upper extremity disorders in this population. The results are the best estimate of what would be found in a field study with experienced examiners. While it may reduce bias, separating physical examination from medical history may contribute to the poor reliability of findings. With a shift toward reliable measures, resources can be allocated to more effective tools, like questionnaires, in epidemiological research of upper extremity disorders among keyboard operators. Am. J. Ind. Med. 37:423–430, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34820/1/12_ftp.pd

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation