Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals

Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P \u3c 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals

Insights into the Influence of Priors in Posterior Mapping of Discrete Morphological Characters: A Case Study in Annonaceae

Background - Posterior mapping is an increasingly popular hierarchical Bayesian based method used to infer character histories and reconstruct ancestral states at nodes of molecular phylogenies, notably of morphological characters. As for all Bayesian analyses specification of prior values is an integrative and important part of the analysis. He we provide an example of how alternative prior choices can seriously influence results and mislead interpretations. Methods/Principal Findings - For two contrasting discrete morphological characters, namely a slow and a fast evolving character found in the plant family Annonaceae, we specified a total of eight different prior distributions per character. We investigated how these prior settings affected important summary statistics. Our analyses showed that the different prior distributions had marked effects on the results in terms of average number of character state changes. These differences arise because priors play a crucial role in determining which areas of parameter space the values of the simulation will be drawn from, independent of the data at hand. However, priors seemed to fit the data better if they would result in a more even sampling of parameter space (normal posterior distribution), in which case alternative standard deviation values had little effect on the results. The most probable character history for each character was affected differently by the prior. For the slower evolving character, the same character history always had the highest posterior probability independent of the priors used. In contrast, the faster evolving character showed different most probable character histories depending on the prior. These differences could be related to the level of homoplasy exhibited by each character. Conclusions - Although our analyses were restricted to two morphological characters within a single family, our results underline the importance of carefully choosing prior values for posterior mapping. Prior specification will be of crucial importance when interpreting the results in a meaningful way. It is hard to suggest a statistically sound method for prior specification without more detailed studies. Meanwhile, we propose that the data could be used to estimate the prior value of the gamma distribution placed on the transformation rate in posterior mappin

“Structural Transformations in Ceramics: Perovskite-like Oxides and Group III, IV, and V Nitrides”

1 Overview of Results and their Significance Ceramic perovskite-like oxides with the general formula (A. A0. ...)(B. B0. ...)O3and titanium-based oxides are of great technological interest because of their large piezoelectric and dielectric response characteristics.[1] In doped and nanoengineered forms, titantium dioxide finds increasing application as an organic and hydrolytic photocatalyst. The binary main-group-metal nitride compounds have undergone recent advancements of in-situ heating technology in diamond anvil cells leading to a burst of experimental and theoretical interest. In our DOE proposal, we discussed our unique theoretical approach which applies ab initio electronic calculations in conjunction with systematic group-theoretical analysis of lattice distortions to study two representative phase transitions in ceramic materials: (1) displacive phase transitions in primarily titanium-based perovskite-like oxide ceramics, and (2) reconstructive phase transitions in main-group nitride ceramics. A sub area which we have explored in depth is doped titanium dioxide electrical/optical properties

Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio

Miscellaneous Rheumatic Diseases [73-83]: 73. Is There a Delay in Specialist Referral of Hot Swollen Joint?

Background: Patients with acute, hot, swollen joints commonly present to general practitioners, emergency departments and/or acute admitting teams rather than directly to rheumatology. It is imperative to consider septic arthritis in the differential diagnosis of these patients. The British Society of Rheumatology (BSR) has produced guidelines for the management of this condition, which include recommendations for early specialist referral and joint aspiration of all patients with suspected septic arthritis. We examined whether the initial management of patients with acute hot swollen joint(s) at University College London Hospital (UCLH) follows BSR guidelines. Methods: For the period Feb to Nov 2009, appropriate patients were identified by searching the UCLH database using the diagnostic terms, "pyogenic arthritis”, "septic arthritis” and "gout”; and from all joint aspirate requests sent to microbiology. Medical notes were obtained and any patients who had elective arthroscopies or chronic (> 6 weeks) symptoms were excluded. Data were collected on the time taken from the onset of symptoms to specialist (orthopaedic/rheumatology) referral and joint aspiration, collection of blood cultures and antibiotic treatment with or without microbiology advice. Results: Twenty patients were identified with hot swollen (18 monoarticular, 3 prosthetic) joint(s) of < 2 weeks duration. Of whom, 3/20 (15%) were admitted directly to rheumatology, 7/20 (35%) to the acute admissions unit, 3/20 (15%) to orthopaedic, 4/20 (20%) to a medical team and 1/20 (5%) to general surgery. In 19 (95%) cases, specialist (rheumatology/orthopaedic) advice was sought. Of 14 cases not seen directly by specialists 9 (64%) were referred at 24-48 h and 5 (36%) at 48-192 h. All 20 patients had joint aspiration. In 9/20 (45%) of cases, joint aspiration was performed in less than 6 h, 3/20 (15%) cases at 6-24h and 6/20 (30%) cases at 24-192 h and was not recorded in two patients. Of these, crystals were identified in two and one was culture positive. Blood cultures were received for only 6/20 (30%) of cases and only clearly documented to have been taken prior to antibiotic therapy and none were positive. Of 14/20 (70%) started on antibiotic treatment empirically, only 6 (42%) were preceded by joint aspiration. In the 6 patients not treated with antibiotics due to low index of suspicion of septic arthritis, synovial fluid and blood cultures were negative. Microbiology advice was sought in 10/20 (50%) of cases by the admitting teams but the timing of this advice is unclear. Conclusions: Despite the provision of 24 h rheumatology and orthopaedic cover at UCLH, we found a significant delay in acute medical firms seeking specialist advice on the management of patients with acute, hot swollen joints with subsequent deviation from BSR guidelines. Consequently, we plan to increase awareness of these guidelines amongst medical firms at UCLH. Disclosure statement: All authors have declared no conflicts of interes

Self-Administered Intranasal Etripamil Using a Symptom-Prompted, Repeat-Dose Regimen for Atrioventricular-Nodal-Dependent Supraventricular Tachycardia (RAPID): A Multicentre, Randomised Trial

BACKGROUND: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min. METHODS: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes (≥20 min) as documented by electrocardiogram. Patients were administered two test doses of intranasal etripamil (each 70 mg, 10 min apart) during sinus rhythm; those who tolerated the test doses were randomly assigned (1:1) using an interactive response technology system to receive either etripamil or placebo. Prompted by symptoms of paroxysmal supraventricular tachycardia, patients self-administered a first dose of intranasal 70 mg etripamil or placebo and, if symptoms persisted beyond 10 min, a repeat dose. Continuously recorded electrocardiographic data were adjudicated, by individuals masked to patient assignment, for the primary endpoint of time to conversion of paroxysmal supraventricular tachycardia to sinus rhythm for at least 30 s within 30 min after the first dose, which was measured in all patients who administered blinded study drug for a confirmed atrioventricular-nodal-dependent event. Safety outcomes were assessed in all patients who self-administered blinded study drug for an episode of perceived paroxysmal supraventricular tachycardia. This trial is registered at ClinicalTrials.gov, NCT03464019, and is complete. FINDINGS: Between Oct 13, 2020, and July 20, 2022, among 692 patients randomly assigned, 184 (99 from the etripamil group and 85 from the placebo group) self-administered study drug for atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia, with diagnosis and timing confirmed. Kaplan-Meier estimates of conversion rates by 30 min were 64% (63/99) with etripamil and 31% (26/85) with placebo (hazard ratio 2·62; 95% CI 1·66-4·15; p INTERPRETATION: Using a symptom-prompted, self-administered, initial and optional-repeat-dosing regimen, intranasal etripamil was well tolerated, safe, and superior to placebo for the rapid conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm. This approach could empower patients to treat paroxysmal supraventricular tachycardia themselves outside of a health-care setting, and has the potential to reduce the need for additional medical interventions, such as intravenous medications given in an acute-care setting. FUNDING: Milestone Pharmaceuticals

Variation of Maximum Tree Height and Annual Shoot Growth of Smith Fir at Various Elevations in the Sygera Mountains, Southeastern Tibetan Plateau

Little is known about tree height and height growth (as annual shoot elongation of the apical part of vertical stems) of coniferous trees growing at various altitudes on the Tibetan Plateau, which provides a high-elevation natural platform for assessing tree growth performance in relation to future climate change. We here investigated the variation of maximum tree height and annual height increment of Smith fir (Abies georgei var. smithii) in seven forest plots (30 m×40 m) along two altitudinal transects between 3,800 m and 4,200/4,390 m above sea level (a.s.l.) in the Sygera Mountains, southeastern Tibetan Plateau. Four plots were located on north-facing slopes and three plots on southeast-facing slopes. At each site, annual shoot growth was obtained by measuring the distance between successive terminal bud scars along the main stem of 25 trees that were between 2 and 4 m high. Maximum/mean tree height and mean annual height increment of Smith fir decreased with increasing altitude up to the tree line, indicative of a stress gradient (the dominant temperature gradient) along the altitudinal transect. Above-average mean minimum summer (particularly July) temperatures affected height increment positively, whereas precipitation had no significant effect on shoot growth. The time series of annual height increments of Smith fir can be used for the reconstruction of past climate on the southeastern Tibetan Plateau. In addition, it can be expected that the rising summer temperatures observed in the recent past and anticipated for the future will enhance Smith fir's growth throughout its altitudinal distribution range

A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest

Background The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest. Methods We compared the use of an active ITD with that of a sham ITD in patients with out-ofhospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability). Results Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, −0.1 percentage points; 95% confidence interval, −1.1 to 0.8; P=0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge. Conclusions Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments