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Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.

Abstract Peptide drugs have seen rapid advancement in biopharmaceutical development, with over 80 candidates approved globally. Despite their therapeutic potential, the clinical translation of peptide drugs is hampered by challenges in production yields and stability. Engineered bacterial therapeutics is a unique approach being explored to overcome these issues by using bacteria to produce and deliver therapeutic compounds at the body site of use. A key advantage of this technology is the possibility to control drug delivery within the body in real time using genetic switches. However, the performance of such genetic switches suffers when used to control drugs that require post-translational modifications or are toxic to the host. In this study, these challenges were experienced when attempting to establish a thermal switch for the production of a ribosomally synthesized and post-translationally modified peptide antibiotic, darobactin, in probiotic E. coli. These challenges were overcome by developing a thermo-amplifier circuit that combined the thermal switch with a T7 RNA Polymerase. Due to the orthogonality of the Polymerase, this strategy overcame limitations imposed by the host transcriptional machinery. This circuit enabled production of pathogen-inhibitory levels of darobactin at 40 °C while maintaining leakiness below the detection limit at 37 °C. Furthermore, the thermo-amplifier circuit sustained gene expression beyond the thermal induction duration such that with only 2 h of induction, the bacteria were able to produce pathogen-inhibitory levels of darobactin. This performance was maintained even in physiologically relevant simulated conditions of the intestines that include bile salts and low nutrient levels. Graphical Abstract

AIMS: The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known. METHODS AND RESULTS: Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001]. CONCLUSIONS: Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment. REGISTRATION: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

BACKGROUND: As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease. OBJECTIVES: In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. METHODS: We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants. RESULTS: Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores. CONCLUSIONS: Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.

Abstract Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.

This article sheds light on the emergence of private tutoring in Denmark. Written from the perspective of a tutoring entrepreneur, it discusses the challenges and opportunities faced by a fledgling tutoring company in present-day Danish society. The article is a personal narrative of the author's experience with establishing the first major Danish tutoring company. The enthusiastic response by parents to the services offered by the author's company shows that there has long existed a hitherto unmet need for private tutoring in Denmark. However, the author also argues that the political turmoil surrounding the 2013 Danish school reform made parents increasingly sceptical that mainstream schools could effectively address the needs of their children. It thereby prepared the ground for launching a private tutoring concept. It is only in the last decade that private tutoring has emerged in Denmark. The article provides a unique insider's perspective on this largely unexplored development.

IntroductionDevelopment of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood.MethodsIn this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93+GLA-SE vaccination.ResultsAnalyses revealed several distinct modules of co-varying genes that were either up- or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response.DiscussionThe results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses.

Abstract Background Workers in the field of radiation therapy are exposed to radiation hazards, and it is necessary to take precautions to limit the radiation dose to nursing staff and physicists. Objective To evaluate the external dose rate (EDR), effective whole-body dose (EHD) and hand equivalent dose (HED) for facilitating staff from radioiodine-131 (RAI-131) ablation therapy patients. Methods One hundred and eighty patients were selected from two radiotherapy centers in Cairo, Egypt in this study and divided into three groups, Group-A, Group-B and Group-C according to administered activities of (RAI-131) of 3700 MBq, 4440 MBq and 5550 MBq for ablation therapy patients respectively. The EDR, EHD and HED were measured using electronic dosimeters. Results The average EDR were 79.1 ± 12.1, 22.7 ± 8.5, 7.0 ± 4.0, 2.9 ± 1.3 and 1.9 ± .9.0 μSv h−1 for group-A, and about 87.8 ± 14.0, 25.6 ± 9.0, 8.1 ± 5.0, 3.4 ± 2.0 and 2.4 ± 1.0 μSv h−1 for group-B and were 93.5 ± 17.0, 31.6 ± 11.0, 10.1 ± 7.0, 4.7 ± 3.0 and 3.4 ± 1.5 μSv h−1 for group-C at 2 h, second, third, fourth and fifth days, respectively after administration of RAI-131. The average annual effective doses were 2.76 ± 0.09 and 1.55 ± 0.05 mSv at center 1, and were about 2.96 ± 0.09 and 1.71 ± 0.06 mSv at center 2 for physicists and nurses, respectively. Conclusion The EDR as well as the EHD and the HED received by radiation therapy workers up to the fifth day of administered activity RAI-131 were within the limits of values recommended by the International Commission on Radiation Protection (ICRP).

Abstract Groundnuts are mostly contaminated with the mold Aspergillus flavus which produces a carcinogenic mycotoxin called as aflatoxin. It is very important to understand the genetic factors underlying its pathogenicity, regulation, and biosynthesis of secondary metabolites and animal toxicities, but it still lacks useful information due to certain gaps in the era of modern technology. Therefore, the present study was considered to determine the key genes and metabolites involved in the biosynthesis of aflatoxin by using a molecular approach in a virulent strain of Aspergillus. The whole genome sequence of highly toxic and virulent Aspergillus isolates JAM-JKB-B HA-GG20 revealed 3,73,54,834 bp genome size, 2, 26, 257 number of contigs with N50 value of 49,272 bp, 12,400 genes and 48.1% of GC contained respectively. The genome sequence was compared with other known aflatoxin producing and non-producing genome of Aspergillus spp. and 61 secondary metabolite (SM) gene clusters were annotated with the toxic strain JAM-JKB-BHA-GG20 which showed similarity with other Aspergillus spp. A total number of eight genes (ver-1, AflR, pksA, uvm8, omt1, nor-1, Vha and aflP) were identified related to biosynthesis of aflatoxin and ochratoxin. Also, 69 SSR with forward and reverse primers and 137 di and tri nucleotide motifs were identified in the nucleotide sequence region related to aflatoxin gene pathway. The genes and putative metabolites identified in this study are potentially involved in host invasion and pathogenicity. As such, the genomic information obtained in this study is helpful in understanding aflatoxin gene producing pathway in comparison to other Aspergillus spp. and predicted presence of other secondary metabolites clusters viz. Nrps, T1pks etc. genes associated with a biosynthesis of OTA mycotoxin.

Purpose To determine, from a sizable cohort of reverse shoulder arthroplasty (RSA), whether the deltopectoral (DP) or anterosuperior (AS) approach grant better outcomes at a minimum follow-up of 24 months. Methods The authors reviewed 743 RSAs in patients with primary osteoarthritis (OA) with or without rotator cuff lesions and secondary OA due to rotator cuff tears. The DP approach was used in 540 and the AS approach in 203. Pre- and post-operative constant scores (CSs) and shoulder range of motion were recorded. Results Of the initial cohort of 743 shoulders, 193 (25.7%) were lost to follow-up, 16 (2.1%) died, and 33 (4.4%) were revised; 540 shoulders were operated using DP approach (73%), of which 22 were revised (4.1%), while 203 were operated using the AS approach (27%), of which 11 were revised (5.4%). Propensity score matching resulted in two groups: 172 shoulders operated by DP approach, and 88 shoulders operated by AS approach. Comparing outcomes of the matched groups at 2 or more years also revealed that, compared to the AS approach, the DP approach resulted in significantly better post-operative CSs (67.3 ± 14.0° vs 60.8 ± 18.3, P = 0.017), active forward elevation (137° ± 27.4° vs 129° ± 29.8; P = 0.031). Conclusion At 2 or more years following RSA, the DP approach granted significantly better CS (by 6.5 points) and active forward elevation (by 8°) compared to the AS approach. The differences observed are clinically relevant and must be considered to manage patient expectations following RSA and for selecting surgical approach depending on their functional needs. Level of evidence III, comparative study

Introduction: Development of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood. Methods: In this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93 +GLA-SE vaccination. Results: Analyses revealed several distinct modules of co-varying genes that were either up-or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response. vDiscussion: The results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses. [ABSTRACT FROM AUTHOR]

AbstractThe agricultural system that incorporates eucalyptus is used by 75% of the agricultural producers in the east of DR Congo (Walungu and Kabare). However, the latter’s perception and results from some studies on the effect of eucalyptus exploitation on soil quality bring out a negative balance. This study characterized the state of soils by determining the soil quality index (SQI) in three land-use types to guide soil fertility management policies. A survey was conducted to collect preliminary data on the historical effect of eucalyptus on the soil from 300 producers. Subsequently, the soils were sampled in the three land-use types and analyzed to assess SQI through a statistical approach based on principal component analysis (PCA). Using R 4.05 package software and crop exploitation as the baseline, the three land-use types were compared using analysis of variance. Out of the 13 considered crucial for SQI assessment, findings highlighted nine soil quality indicators (Al3+, pH, silt, SOC, CEC, H2O, sand, clay, and BD). Soils with eucalyptus (SQI = 0.486 0.07) and crops (0.539 ± 0.034) alone had low SQIs, suggesting unfavorable soils for better production, whereas soils with crop-eucalyptus association had SQI equals to 0.655 ± 0.034, indicating moderate soils. The calculated SQI highlighted soils’ acidity, their ability to maintain plants’ chemical nutrients equilibrium, and clay and sand content as soil quality determinants. To further improve soil conditions, we raised the need to understand the long-term effects of eucalyptus on soils and the appropriate soil management as a result of the aforesaid results.