Search

In this article, ab initio calculations of unexplored Ti 2 PB 2 , Zr 2 PbB 2 , and Nb 2 AB 2 [A = P, S] were performed wherein Ti 2 PB 2 along with its 211 boride phase Ti 2 PB was predicted for the first time. The stability was confirmed by calculating the formation energy, phonon dispersion curve, and elastic stiffness constants. The obtained elastic constants, elastic moduli, and Vickers hardness values of Ti 2 PB 2 , Zr 2 PbB 2 , and Nb 2 AB 2 [A = P, S] were found to be significantly larger than those of their counterparts 211 borides and carbides. The studied compounds are brittle, like most MAX and MAB phases. The electronic band structure and density of states revealed the metallic nature of the titled borides. Several thermal parameters were explored, certifying the suitability of Ti 2 PB 2 , Zr 2 PbB 2 , and Nb 2 AB 2 [A = P, S] to be used as efficient thermal barrier coating materials. The response of Ti 2 PB 2 , Zr 2 PbB 2 , and Nb 2 AB 2 [A = P, S] to the incident photon was studied by computing the dielectric constant (real and imaginary parts), refractive index, absorption coefficient, photoconductivity, reflectivity, and energy loss function. In this work, we have explored the physical basis of the improved thermomechanical properties of 212 MAX phase borides compared to their existing carbide and boride counterparts., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

LaIr 3 Ga 2 is a kagome superconductor with a superconducting temperature ( T c ) of 5.16 K. Here, we present the physical properties of the LaIr 3 Ga 2 kagome superconductor computed via the DFT method wherein six different exchange-correlation functionals were used. The lattice parameters obtained using different functionals are reasonable, with a slight variation compared to experimental values. The bonding nature was explored. The elastic constants ( C ij ), moduli ( B , G , Y ), and Vickers hardness ( H v ) were computed to disclose the mechanical behavior. The H v values were estimated to be 2.56-3.16 GPa using various exchange-correlation functionals, indicating the softness of the kagome material. The Pugh ratio, Poisson's ratio, and Cauchy pressure revealed the ductile nature. In addition, mechanical stability was ensured based on the estimated elastic constants. The anisotropic mechanical behavior was confirmed via different anisotropic indices. The Debye temperature ( Θ D ), melting temperature ( T m ), and minimum thermal conductivity ( k min ) were calculated to characterize the thermal properties and predict the potential of LaIr 3 Ga 2 as a thermal barrier coating material. The electronic density of states was investigated in detail. The McMillan equation was used to estimate T c , and the electron-phonon coupling constant ( λ ) was calculated to explore the superconducting nature. The important optical constants were also calculated to explore its possible optoelectronic applications. The values of reflectivity in the IR-visible region are about 62% to 80%, indicating that the compound under study is suitable as a coating to reduce solar heating. The obtained parameters were compared with previously reported parameters, where available.

Smallholder farmers in Bangladesh often use low-density polyethylene (LDPE) bags contained within woven polypropylene bags to store wheat seed during the summer monsoon that precedes winter season planting. High humidity and temperature during this period can encourage increased seed moisture and pests, thereby lowering seed quality. Following a farm household survey conducted to inform trial design, eighty farmers were engaged in an action research process in which they participated in designing and conducting trials comparing traditional and alternative seed storage methods over 30 weeks. Factorial treatments included comparison of hermetic SuperGrainbags® (Premium RZ) against LDPE bags, both with and without the addition of dried neem tree leaves ( Azadirachta indica ). SuperGrainbags® were more effective in maintaining seed moisture at acceptable levels close to pre-storage conditions than LDPE bags. Both seed germination and seedling coleoptile length were significantly greater in hermetic than LDPE bags. Neem had no effect on seed moisture, germination, or coleoptile length. SuperGrainbags® were also more effective in abating seed damage during storage, although inclusion of neem within LDPE bags also had significant damage. Quantification of seed predating insects and diseases suggested that SuperGrainbags® also suppressed Coleopteran pests and blackspot, the latter indicative of Fusarium graminearum . Conversely, where farmers used LDPE bags, neem also had an additional though limited pest suppressive effect. Post-storage treatment scoring by farmers revealed a strong preference for SuperGrainbags® and no preference differences for or against neem. This study demonstrates a process by which farmers can be involved in the participatory co-design and testing of alternative wheat storage options, and stresses the need to develop SuperGrainbag® supply chains so hermetic storage can be made widely available., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Country bean is a grain legume extensively farmed for its multi-purpose uses, yet the traits related to yield are are poorly studied and yet unexplored. A study on the diversity of qualitative and quantitative morphological characteristics concerning yield among the country bean germplasms collected from Bangladesh identified considerable variation in the studied traits across the germplasms and identified a complex correlation between the qualitative and quantitative traits. Principal Component Analysis (PCA) detected five components that contributed 66.38% qualitative traits and six components contributed 74.49% quantitative traits to total variations. Eigenvalues indicated that a majority of color-related qualitative traits included cotyledon, leaf, vein, seed, flower, and petals contributed, in contrast,a majority of the seed, leaf, flower, and inflorescence-related quantitative traits contributed to the total diversity of the Lablab germplasms. Among the quantitative traits, the highest coefficient of variation (CV%) was found in average pod weight (50.98%), followed by the total number of spikes per plant (43.82%), while seed length, pod weight, length, width, thickness, number of flower/spike, spike length, and total no of spikes/plant all had more than 20.00 percent CV, suggesting suitability to use in the breeding of high yielding genotypes. The germplasms are grouped into four and three clusters based on quantitative and qualitative traits, suggesting quantitative characters offer better clustering of genotypes. Considering the above traits, our research found that the BD-10804, BD-10807, BD-11091, BD-10808, BD-10815, and BD-11089 and cultivar Goal Goda Lablab beans germplasms produced higher pod weight with corresponding higher pod length, width, and thickness suggesting to use them as high yielding genotypes for food and fodder purposes., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

High-hardness materials with ductile deformation behavior have recently piqued interest due to their prospective applications, particularly as hard and protective coatings. The crack formation, especially in metal and ceramic materials, is one of the biggest problems of the surface hard coatings on heavy-duty tools. In this regard, mechanical properties (Vickers hardness, fracture toughness, machinability index, index of brittleness, as well as Pugh's ratio) have been studied for the metallic boro-carbides of A 2 BC (A = Ti, Zr, Hf, and W) compounds using the state-of-the-art density functional theory in detail. The compounds under investigation are both thermodynamically and mechanically stable. The value of Vickers hardness (in GPa) for A 2 BC (A = Ti, Zr, Hf, and W) compounds are 28.20, 23.12, 12.44, and 35.70, respectively, which indicates the W 2 BC could be a member of the hard family ( H v > 30 GPa). Pugh's ratio suggests ductile deformation for the W 2 BC compound, whereas the other three (Ti 2 BC, Zr 2 BC, and Hf 2 BC) compounds exhibit brittle deformation behavior. The W 2 BC compounds have the highest ductility among the other metallic boro-carbides (M 2 BC; M = V, Nb, Mo and Ta) and some other benchmark coating materials (TiN, TiAlN, C-BN, and Cr 0.5 Al 0.5 N). The fracture toughness ( K IC ) values are in the following sequence: Zr 2 BC < Ti 2 BC < Hf 2 BC < W 2 BC, which indicates that, the highest resistance ( K IC = 4.96 MPam 1/2 ) found for W 2 BC is suitable to prevent the crack propagation within the solid. In addition, the structural, electronic, optical, and thermal properties are also investigated for the A 2 BC (A = Ti, Zr, Hf, and W) compounds. The Ti 2 BC (W 2 BC) reflectivity spectra never fall below 53 (45)% in the 0 to 10.3 eV (0 to 16.70 eV) photon energy range, suggesting that these compounds have promise for usage as coating materials to reduce solar heating. Hf 2 BC and W 2 BC compounds could also be exploited as promising thermal barrier coating materials, while Ti 2 BC could be used as heat sink material based on the results of Debye temperature, melting temperature, thermal conductivity, and thermal expansion coefficient. The electronic properties reveal the metallic behavior of these compounds. The results obtained here are compared with those of some commercially known compounds, where available., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Encapsulation of cells inside microfluidic droplets is central to several applications involving cellular analysis. Although, theoretically the encapsulation statistics are expected to follow a Poisson distribution, experimentally this may not be achieved due to lack of full control of the experimental variables and conditions. Therefore, there is a need for automatic detection of droplets and cell count enumeration within droplets so a process control feedback to adjust experimental conditions can be implemented. In this study, we use a deep learning object detector called You Only Look Once (YOLO), an influential class of object detectors with several benefits over traditional methods. This paper investigates the application of both YOLOv3 and YOLOv5 object detectors in the development of an automated droplet and cell detector. Experimental data was obtained from a microfluidic flow focusing device with a dispersed phase of cancer cells. The microfluidic device contained an expansion chamber downstream of the droplet generator, allowing for visualization and recording of cell-encapsulated droplet images. In the procedure, a droplet bounding box is predicted, then cropped from the original image for the individual cells to be detected through a separate model for further examination. The system includes a production set for additional performance analysis with Poisson statistics while providing an experimental workflow with both droplet and cell models. The training set is collected and preprocessed before labeling and applying image augmentations, allowing for a generalizable object detector. Precision and recall were utilized as a validation and test set metric, resulting in a high mean average precision (mAP) metric for an accurate droplet detector. To examine model limitations, the predictions were compared to ground truth labels, illustrating that the YOLO predictions closely matched with the droplet and cell labels. Furthermore, it is demonstrated that droplet enumeration from the YOLOv5 model is consistent with hand counted ratios and the Poisson distribution, confirming that the platform can be used in real-time experiments for cell encapsulation optimization.

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout., (© 2022 by The American Society of Hematology.)

Literature regarding recent trends, mortality outcomes of ST-elevation myocardial infarction (STEMI) in cardiac amyloidosis (CA) patients is limited.To study coronary interventions, and trends in prevalence and mortality outcomes among CA patients with STEMI.Data from the national readmissions database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the USA, representing more than 95% of the national population, were analyzed for hospitalizations associated with CA with STEMI. A linear p-trend was used to assess the trends.Out of the total 4252 adult patients (mean age 73.3 ± 11.7 years, 40.2% females) with diagnosis of CA, 439 (10.3%) had STEMI while 3813 (89.7%) had no STEMI. STEMI-CA patients had higher rates of multi-organ manifestations including VT/VF (12% vs 8.5%; p-value < 0.001), cardiogenic shock (12.7% vs 7.3%; p < 0.001), AKI requiring dialysis (5.3% vs 4%; p < 0.001), and ICU admissions (25.2% vs 15.3%; p < 0.001) compared to CA without STEMI. CA-STEMI had increased mortality rates (23.7% vs 16.1%, p < 0.001) compared to CA without STEMI. On multivariate logistic regression analysis, coronary interventions including PCI (OR 0.6, CI 0.4-1.1; p = 0.3) and CABG (OR 0.7, CI 0.3-1.8; p = 0.2) had no association with mortality among CA patients. The absolute yearly trends for prevalence and mortality associated with STEMI in CA patients remained steady over the study years (linear p-trends 0.2 and 0.6, respectively).CA-STEMI is associated with significant complications and mortality. Coronary interventions may not have significant mortality benefits. Thus, more research will be needed to improve mortality rates among these patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Expression of the immune checkpoint programmed death ligand-1 (PD-L1) is increased in ovarian cancer (OC) and correlates with poor prognosis. Interferon-γ (IFNγ) induces PD-L1 expression in OC cells, resulting in their increased proliferation and tumor growth, but the mechanisms that regulate the PD-L1 expression in OC remain unclear. Here, we show that the IFNγ-induced PD-L1 expression in OC cells is associated with increased levels of STAT1, Tyr-701 pSTAT1 and Ser-727 pSTAT1. Suppression of JAK1 and STAT1 significantly decreases the IFNγ-induced PD-L1 expression in OC cells, and STAT1 overexpression increases the IFNγ-induced PD-L1 expression. In addition, IFNγ induces expression of the transcription factor interferon regulatory factor 1 (IRF1) and IRF1 suppression attenuates the IFNγ-induced gene and protein levels of PD-L1. Chromatin immunoprecipitation results show that IFNγ induces PD-L1 promoter acetylation and recruitment of STAT1, Ser-727 pSTAT1 and IRF1 in OC cells. Together, these findings demonstrate that the IFNγ-induced PD-L1 expression in OC cells is regulated by JAK1, STAT1, and IRF1 signaling, and suggest that targeting the JAK1/ STAT1/IRF1 pathway may provide a leverage to regulate the PD-L1 levels in ovarian cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Body auscultation is a frequent clinical diagnostic procedure used to diagnose heart problems. The key advantage of this clinical method is that it provides a cheap and effective solution that enables medical professionals to interpret heart sounds for the diagnosis of cardiac diseases. Signal processing can quantify the distribution of amplitude and frequency content for diagnostic purposes. In this experiment, the use of signal processing and wavelet analysis in screening cardiac disorders provided enough evidence to distinguish between the heart sounds of a healthy and unhealthy heart. Real-time data was collected using an IoT device, and the noise was reduced using the REES52 sensor. It was found that mean frequency is sufficiently discriminatory to distinguish between a healthy and unhealthy heart, according to features derived from signal amplitude distribution in the time and frequency domain analysis. The results of the present study indicate the adequate discrimination between the characteristics of heart sounds for automatic detection of cardiac problems by signal processing from normal and abnormal heart sounds., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Amzad Hossain et al.)

Telemedicine ensures quality, cost-effective, and equally accessible healthcare services for everyone. Nonetheless, a poor usage rate could curb its progression in developing cultures like Bangladesh. Therefore, this research examines how external stimuli promote the continuous usage intentions of synchronous telemedicine services through engagement and satisfaction by deploying the stimulus-organism-response framework. A final sample of 312 telemedicine users was analyzed using the structural equation modeling in AMOS. The average age of the participants was 26.28 (std. deviation 5.53), and their average use of telemedicine was 2.39 times (std. deviation 1.31) over the last six months. This study empirically endorsed that the stimuli, including performance expectancy, information quality, and contamination avoidance, as well as organismic factors such as engagement and satisfaction, directly impacted the continuance desires for telemedicine use. In addition, the analyses validated the mediation roles of engagement and satisfaction. Furthermore, performance and effort expectancies influenced engagement, which affected satisfaction along with performance expectancy, functionality, and information quality. Accordingly, telemedicine facilitators should integrate these critical attributes into the system to sustain engagement, satisfaction, and usage intentions. This study has pioneered the effects of performance and effort expectancies on continuous usage intentions facilitated by engagement and satisfaction in the telemedicine landscape.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays' high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual., Results: We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women's Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy., Conclusions: Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale., (© 2022. The Author(s).)

This study aimed to study group differences in patients presenting with ST-elevation myocardial infarction (STEMI) based on the presence or absence of associated coronary artery aneurysms (CAA). The cause-and-effect relationship between CAAs and STEMI is largely unknown. The Nationwide Readmission database was used to identify and study group differences of patients with STEMI and with and without CAA from 2014 to 2018. The primary outcome in the 2 groups was mortality. Secondary outcomes in the 2 groups included differences in clinical outcomes, cardiovascular interventions performed, and prevalence of coronary artery dissection. The total number of patients with STEMI included was 1,038,299. In this sample, 1,543 (0.15%) had CAA. Compared with those without CAA, patients with CAAs and STEMI were younger (62.6 vs 65.4), more likely to be male (78 vs 66%), and had a higher prevalence of a history of Kawasaki disease (2.5 vs 0.01%). A difference exists in the prevalence of coronary dissection in patients with STEMI with and without CAA (73% vs 1%). Patients with CAA were more often treated with coronary artery bypass grafting (13.1 vs 5.6%), thrombectomy (16.5 vs 6%), and bare-metal stent implantation (8 vs 4.4). Patients in the CAA STEMI group had lower all-cause mortality (6.3 vs 11.7%). In conclusion, there are important differences in patients with STEMI with and without CAA, which include, but are not limited to, factors such as patient profile, the risk for coronary dissection, treatment, outcomes, and mortality., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Importance: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized nonatherosclerotic cause of acute myocardial infarction enriched among individuals with early-onset myocardial infarction but is of unclear etiology., Objective: To assess which genes contribute to the development of SCAD., Design, Setting, and Participants: To prioritize genes influencing risk for SCAD, whole-exome sequencing was performed among individuals with SCAD in the discovery and replication cohorts from a tertiary care hospital outpatient specialty clinic, and gene set enrichment analyses were also performed for disruptive coding variants. All patients were sequentially enrolled beginning July 2013. Aggregate prevalence of rare disruptive variants for prioritized gene sets was compared between individuals with SCAD with population-based controls comprising 46 468 UK Biobank participants with whole-exome sequencing. Complementary mice models were used for in vivo validation. Analysis took place between June 2020 and January 2021., Main Outcomes and Measures: The frequency and identity of rare genetic variants in individuals with SCAD., Results: Of 130 patients, 109 (83.8%) were female (26 of 32 [81.2%] in the discovery cohort and 83 of 98 [84.7%] in the replication cohort) with mean (SD) age at first SCAD event of 48.41 (8.76) years in the discovery cohort and 47.74 (10.09) years in the replication cohort. Across all patients with SCAD, rare disruptive variants were found within 10 collagen genes (COL3A1, COL5A1, COL4A1, COL6A1, COL5A2, COL12A1, COL4A5, COL1A1, COL1A2, and COL27A1) were 17-fold (P = 1.5 × 10-9) enriched among individuals with SCAD compared with a background of 2506 constrained genes expressed in coronary artery. Furthermore, compared with individuals from the UK Biobank, individuals with SCAD were 1.75-fold (P = .04) more likely to carry disruptive rare variants within fibrillar collagen genes. Complementary mice models haploinsufficient for Col3a1 or Col5a1, the 2 most common collagen gene variants identified in SCAD cases, demonstrated increased risk of arterial dissection and increased size of arterial diameters especially in female mice, with resulting changes in collagen fibril organization and diameter., Conclusions and Relevance: Unbiased gene discovery in patients with SCAD with independent human and murine validation highlights the role of the extracellular matrix dysfunction in SCAD.

Extraordinary self-healing efficiency is rarely observed in mechanically strong hydrogels, which often limits the applications of hydrogels in biomedical engineering. We have presented an approach to utilize a special type of graphene oxide-based crosslinker (GOBC) for the simultaneous improvement of toughness and self-healing properties of conventional hydrogels. The GOBC has been prepared from graphene oxide (GO) by surface oxidation and further introduction of vinyl groups. It has been designed in such a way that the crosslinker is able to form both covalent bonds and noncovalent interactions with the polymer chains of hydrogels. To demonstrate the efficacy of GOBC, it was incorporated in a conventional polyacrylamide (PAM) and polyacrylic acid (PAA) hydrogel matrix, and the mechanical and self-healing properties of the prepared hydrogels were investigated. In PAM-GOBC hydrogels, it has been observed that the mechanical properties such as tensile strength, Young's modulus, and toughness are significantly improved by the incorporation of GOBC without compromising the self-healing efficiency. The PAM-GOBC hydrogel with a modulus of about 0.446 MPa exhibited about 70% stress healing efficiency after 40 h. Whereas, under the same conditions a PAM hydrogel with commonly used crosslinker N , N '-methylene-bis(acrylamide) of approximately the same modulus demonstrated no self-healing at all. Similar improvement of self-healing properties and toughness in PAA-GOBC hydrogel has also been observed which demonstrated the universality of the crosslinker. This crosslinker-based approach to improve the self-healing properties is expected to offer the possibility of the application of commonly used hydrogels in many different sectors, particularly in developing artificial tissues., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke., Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes ( DNMT3A , TET2 , and ASXL1 ) with any stroke, ischemic stroke, and hemorrhagic stroke., Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke., Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH., (© 2022. The Author(s).)

Aquatic ecosystems are contaminated with heavy metals by natural and anthropogenic sources. Whilst some heavy metals are necessary for plants as micronutrients, others can be toxic to plants and humans even in trace concentrations. Among heavy metals, cadmium (Cd), arsenic (As), chromium (Cr), lead (Pb), and mercury (Hg) cause significant damage to aquatic ecosystems and can invariably affect human health. Rice, a staple diet of many nations, and other aquatic plants used as vegetables in many countries, can bioaccumulate heavy metals when they grow in contaminated aquatic environments. These metals can enter the human body through food chains, and the presence of heavy metals in food can lead to numerous human health consequences. Heavy metals in aquatic plants can affect plant physicochemical functions, growth, and crop yield. Various mitigation strategies are being continuously explored to avoid heavy metals entering aquatic ecosystems. Understanding the levels of heavy metals in rice and aquatic plants grown for food in contaminated aquatic environments is important. Further, it is imperative to adopt sustainable management approaches and mitigation mechanisms. Although narrowly focused reviews exist, this article provides novel information for improving our understanding about heavy metal accumulation in rice and aquatic plants, addressing the gaps in literature.

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation., Competing Interests: Disclosures: A. Niroula reported grants from the Knut and Alice Wallenberg Foundation outside the submitted work. A. Bick reported personal fees from Foresite Labs outside the submitted work. J. Pirruccello reported personal fees from Maze Therapeutics outside the submitted work. M. Agrawal reported personal fees from German Accelerator Life Sciences outside the submitted work, and is the co-founder of and holds equity in iuvando Health. None of these are related to the submitted work. D.P. Kiel reported grants from Amgen, Radius Health, and Solarea Bio; and "other" from Solarea Bio, Pfizer, and Wolters Kluwer outside the submitted work. J.B. Richards reported personal fees from GlaxoSmithKline and Deerfield Capital; grants from Biogen and Eli Lilly; and non-financial support from 5 Prime Sciences outside the submitted work. J.B. Richards has served as an advisor to GlaxoSmithKline and Deerfield Capital. His institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the founder of 5 Prime Sciences. M.N. Wein reported grants from Radius Health and Galapagos NV, and "other" from Relation Therapeutics outside the submitted work. S. Jaiswal reported personal fees from AVRO Bio, Novartis, Genentech, and Foresite Labs outside the submitted work. P. Natarajan reported grants from Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Apple, AstraZeneca, Genentech, Novartis, Blackstone Life Sciences, and Foresite Labs; and "other" from Vertex outside the submitted work. B.L. Ebert reported grants from Celgene, Novartis, Deerfield, and Calico; and personal fees from Exo Therapeutics, Skyhawk Therapeutics, Neomorph Therapeutics, and TenSixteen Bio outside the submitted work. No other disclosures were reported., (© 2021 Kim et al.)

Boron-rich chalcogenides have been predicted to have excellent properties for optical and mechanical applications in recent times. In this regard, we report the electronic, optical, and mechanical properties of recently synthesized boron-rich chalcogenide compounds B 12 X (X = S and Se) using density functional theory for the first time. The effects of exchange and correlation functionals on these properties are also investigated. The consistency of the obtained crystal structure with the reported experimental results has been checked in terms of lattice parameters. The considered materials are mechanically stable, brittle, and elastically anisotropic. Furthermore, the elastic moduli and hardness parameters are calculated, which show that B 12 S can be treated as a prominent member of the hard materials family compared to B 12 Se. The origin of differences in hardness is explained on the basis of density of states near the Fermi level. Reasonably good values of fracture toughness and the machinability index for B 12 X (X = S and Se) are reported. The melting point, T m , for the B 12 S and B 12 Se compounds suggests that both solids are stable, at least up to 4208 and 3577 K, respectively. Indirect band gaps of B 12 S (2.27 eV) and B 12 Se (1.30 eV) are obtained using the HSE06 functional. The energy gaps using local density approximation (LDA) and generalized gradient approximation (GGA) are found to be significantly lower. The electrons of the B 12 Se compound show a lighter average effective mass than that of the B 12 S compound, which signifies a higher mobility of charge carriers in B 12 Se. The optical properties such as the dielectric function, refractive index, absorption coefficient, reflectivity, and loss function are characterized using GGA-PBE and HSE06 methods and discussed in detail. These compounds possess bulk optical anisotropy, and excellent absorption coefficients in the visible-light region along with very low static values of reflectivity spectra (range of 7.42-14.0% using both functionals) are noted. Such useful features of the compounds under investigation show promise for applications in optoelectronic and mechanical sectors., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

We report the near-complete genome sequence and phylogenetic analysis of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant (B.1.617.2) strain. This variant is associated with increased transmission and immune evasion.

Interferon-γ (IFNγ) is a pleiotropic cytokine that has a crucial role in immune response and tumor immunity. Because of its anti-tumor effects, IFNγ has been used in cancer treatment. However, IFNγ also has tumor-promoting functions that are less well understood. Here, we show that IFNγ induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) in ovarian cancer (OC) cells. The IFNγ-induced IL-8 expression is dependent on JAK1, STAT1, and p65 NFκB, and is associated with an increased occupancy of K314/315 acetylated p65 NFκB and Ser-727 phosphorylated STAT1 at the IL-8 promoter. Neutralization of IL-8 using anti-IL-8 antibody reduces IFNγ-induced migration of OC cells, and their invasion ability in 3D spheroids. Together, these findings identify IL-8 as a novel target induced by IFNγ/JAK1/STAT1/p65 NFκB signaling, and indicate that the IFNγ-induced IL-8 contributes to IFNγ pro-tumorigenic effects in ovarian cancer cells., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Dogs, the most common companion animal of humans, perform not only the auxiliary of an individual, but also contribute to the nations' crime and defence departments. Knowing the determinant-based disease status of dogs is imperative to keep them healthy by subsequent prevention and control of those diseases; however, such baseline epidemiological information is limited. Therefore, a retrospective cross-sectional study was conducted to estimate the proportional incidence of dog diseases to explore their magnitudes, and we compared them to different levels of intrinsic (age, gender, breed) and extrinsic determinants (season). Purposively, data of a total of 1,557 cases of different diseases were collected from the record book of the Central Veterinary Hospital (CVH), Dhaka, Bangladesh. The proportional incidence was calculated as the proportion of cases of a specific disease among total number of cases of all types of diseases attended the hospital during the study period. Diseases of dog were categorized into infectious, non-infectious, and non-specific. Results showed that the highest proportional incidence was noted in infectious diseases (53.8%) followed by non-infectious diseases (23.4%) and the lowest in non-specific (22.7%) cases. Among them, disease-specific proportional incidence was remarkable in case of mange (9.5%), parvovirosis (8.7%), lacerated wound (8.5%), ectoparasitism (8.3%), helminthiasis (7.8%), and fracture (5.7%). The occurrence of mange varied significantly (p < 0.05) among all studied determinants (age, gender, breed, and season); while significant discrepancies (p < 0.05) in magnitudes of lacerated wound, dystocia, abortion, and gastroenteritis were observed among various groups of age, gender, and breed. Accordingly, dermatitis and orchitis had significant differences (p < 0.05) in proportional incidence amid various levels of age, gender, and season; whilst the burden of parvovirosis and alopecia differed significantly (p < 0.05) amongst different categories of age, breed, and season. The magnitude of otorrhoea showed a significant (p < 0.05) variation among different groups of gender, breed, and season. The proportional incidence of other diseases also varied significantly (p < 0.05) amongst either one or two studied determinants. This study provides a valuable insight about important diseases in dogs, which may serve as useful baseline information for disease prioritization and subsequent planning of effective control and prevention measures against those diseases., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

In response to the raging COVID-19 pandemic, Bangladesh started its vaccine administration in early 2021; however, due to the rapid development and launch of the vaccines in the market, many people had concerns regarding the safety of these vaccines. The purpose of this study was to evaluate the side effects that were experienced by the Bangladeshi residents after receiving the first dose of the Oxford-AstraZeneca's Covishield vaccine (ChAdOx1nCoV-19). The study was conducted using both online and printed questionnaires and the data were analysed using SPSS. The results included the responses of 474 vaccine recipients from March-April 2021. Pain at the site of injection, fever, myalgia, fatigue and headache were the most commonly reported symptoms, and the overall side effects were found to be significantly more prevalent in the younger population ( p ≤ 0.05). These findings were consistent with the results indicated by the clinical trial of ChAdOx1nCoV-19. Logistic regression analysis further revealed that compared to people aged 70 years or above, the incidence of reported side effects was significantly higher in people aged 18-30 years (odds ratio (OR) = 8.56), 31-40 years, (OR = 5.05), 41-50 years (OR = 4.08), 51-60 years (OR = 3.77) and 61-70 years (OR = 3.67). In addition, a significantly higher percentage of female participants suffered from post-vaccination side effects compared to males (OR = 1.51). It was concluded that the Covishield vaccine was well-tolerated among people of different age groups. Nevertheless, further long-term follow-up study with a larger sample size is warranted to establish the long-term safety of the COVID-19 vaccine.

Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Literature regarding trends of incidence, mortality, and complications of acute exacerbation of chronic obstructive pulmonary disease (COPD) in the emergency departments (ED) is limited. What are trends of COPD exacerbation in ED? Data were obtained from the Nationwide Emergency Department Sample (NEDS) that constitutes a 20% sample of hospital-owned EDs and inpatient sample in the US. All ED encounters were included in the analysis. Complications of AECOPD were obtained by using ICD codes. Out of 1.082 billion ED encounters, 5,295,408 (mean age 63.31 ± 12.63 years, females 55%) presented with COPD exacerbation. Among these patients, 353,563(6.7%) had AECOPD-plus (features of pulmonary embolism, acute heart failure and/or pneumonia) while 4,941,845 (93.3%) had exacerbation without associated features or precipitating factors which we grouped as AECOPD. The AECOPD-plus group was associated with statistically significantly higher proportion of cardiovascular complications including AF (5.6% vs 3.5%; p  < 0.001), VT/VF (0.14% vs 0.06%; p  < 0.001), STEMI (0.22% vs 0.11%; p  < 0.001) and NSTEMI (0.65% vs 0.2%; p  < 0.001). The in-hospital mortality rates were greater in the AECOPD-plus population (0.7% vs 0.1%; p  < 0.001). The incidence of both AECOPD and AECOPD-plus had worsened ( p -trend 0.004 and 0.0003) and the trend of mortality had improved ( p -trend 0.0055 and 0.003, respectively). The prevalence of smoking for among all COPD patients had increased ( p -value 0.004), however, the prevalence trend of smoking among AECOPD groups was static over the years 2010-2018. There was an increasing trend of COPD exacerbation in conjunction with smoking; however, mortality trends improved significantly. Moreover, the rising burden of AECOPD would suggest improvement in diagnostics and policy making regarding management.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been associated with atherosclerotic cardiovascular disease. Because the inherited risk of developing CHIP is low, lifestyle elements such as dietary factors may be associated with the development and outcomes of CHIP., Objective: To examine whether there is an association between diet quality and the prevalence of CHIP., Design, Setting, and Participants: This retrospective cohort study used data from participants in the UK Biobank, an ongoing population-based study in the United Kingdom that examines whole-exome sequencing data and survey-based information on health-associated behaviors. Individuals from the UK Biobank were recruited between 2006 and 2010 and followed up prospectively with linkage to health data records through May 2020. The present study included 44 111 participants in the UK Biobank who were age 40 to 70 years, had data available from whole-exome sequencing of blood DNA, and were free of coronary artery disease (CAD) or hematologic cancer at baseline., Exposures: Diet quality was categorized as unhealthy if the intake of healthy elements (fruits and vegetables) was lower than the median of all survey responses, and the intake of unhealthy elements (red meat, processed food, and added salt) was higher than the median. Diets were classified as healthy if the intake of healthy elements was higher than the median, and the intake of unhealthy elements was lower than the median. The presence of CHIP was detected by data from whole-exome sequencing of blood DNA., Main Outcomes and Measures: The primary outcome was CHIP prevalence. Multivariable logistic regression analysis was used to examine the association between diet quality and the presence of CHIP. Multivariable Cox proportional hazards models were used to assess the association of incident events (acute coronary syndromes, coronary revascularization, or death) in each diet quality category stratified by the presence of CHIP., Results: Among 44 111 participants (mean [SD] age at time of blood sample collection, 56.3 [8.0] years; 24 507 women [55.6%]), 2271 individuals (5.1%) had an unhealthy diet, 38 552 individuals (87.4%) had an intermediate diet, and 3288 individuals (7.5%) had a healthy diet. A total of 2507 individuals (5.7%) had CHIP, and the prevalence of CHIP decreased as diet quality improved from unhealthy (162 of 2271 participants [7.1%]) to intermediate (2177 of 38 552 participants [5.7%]) to healthy (168 of 3288 participants [5.1%]; P = .003 for trend). Compared with individuals without CHIP who had an intermediate diet, the rates of incident cardiovascular events progressively decreased among those with CHIP who had an unhealthy diet (hazard ratio [HR], 1.52; 95% CI, 1.04-2.22) and those with CHIP who had a healthy diet (HR, 0.99; 95% CI, 0.62-1.58) over a median of 10.0 years (interquartile range, 9.6-10.4 years) of follow-up., Conclusions and Relevance: This cohort study suggests that an unhealthy diet quality may be associated with a higher prevalence of CHIP and higher rates of adverse cardiovascular events and death independent of CHIP status.

Insects of the taxonomic order Coleoptera are recognised for considerable cellulolytic activity in their digestive fluid. The cellulolytic activity of the gut fluid in Hoplasoma unicolor , a member of Coleoptera, however, remains unexplored. In this study, we, for the first time, report the qualitative and quantitative analysis of cellulolytic activity in the digestive fluid of this insect. The cellulolytic endo-1,4-β-D-glucanase activity was confirmed in the supernatant of the insect's digestive fluid by agar plate assay using carboxymethyl cellulose as the substrate. To determine the optimum pH, enzyme activity was further assessed in an acidic pH range of 5 to 6, and the highest activity was observed at pH 5.3. For quantitative analysis, endoglucanase activity was measured using 3,5-dinitrosalicylic acid method which revealed that the specific activity of the gut sample was 0.69 (±0.01) units per mg of protein. For further characterisation of the cellulases in the sample, SDS-PAGE and zymogram analysis were carried out. Two active cellulolytic bands were detected on the zymogram suggesting the presence of two distinct endoglucanases which completely disappeared upon heating the sample at 55°C. Our study, therefore, highlights prospect of the gut fluid of H. unicolor as an important source of cellulase enzymes that merits further investigations into their extensive characterisation for potential industrial applications., (© Penerbit Universiti Sains Malaysia, 2021.)

Aortic mural thrombus (AMT) is an uncommon cause of arterial thromboembolism. It is very rare in patients without significant cardiovascular risk factors. Many aetiologies can cause AMT, but there are no clear guidelines for the evaluation and treatment. We present the case of a 43-year-old woman without arteriosclerotic disease who was admitted to the hospital with peripheral embolisation from the mural thrombus in the distal arch of the aorta. Therapy with systemic anticoagulation resulted in complete resolution without necessitating any surgical or endovascular interventions. There were no reported recurrence or complications of the intra-aortic thrombus within 1-year surveillance imaging study., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Retroperitoneal haemorrhage (RH) is not uncommon in patients with provoking events like trauma. However, spontaneous RH (SRH) is a rare and life-threatening complication described as the development of bleeding into the retroperitoneal cavity, appearing spontaneously and without a preceding history of trauma or other predisposing illness. We are reporting a case of an elderly patient with recurrent deep vein thrombosis who had developed SRH secondary to concurrent use of multiple anticoagulation agents, resulting from poor healthcare follow-up and lack of sufficient medication reconciliation. This article highlights the significance of recognising risk factors for SRH, as well as management strategies through literature review., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Takotsubo cardiomyopathy (TCM) secondary to an infusion reaction is extremely rare in the literature. Here, we present an unusual case of TCM in a patient with cervical squamous cell carcinoma who presented with acute hypoxic respiratory failure following the initiation of the first-cycle paclitaxel infusion therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Climate change-induced salinity intrusion into agricultural soils is known to negatively impact crop production and food security. However, the effects of salinity increase on plant-herbivore-natural enemy systems and repercussions for pest suppression services are largely unknown. Here, we examine the effects of increased salinity on communities of rice (Oryza sativa), brown planthopper (BPH), Nilaparvata lugens, and green mirid bug (GMB), Cyrtorhinus lividipennis, under greenhouse conditions. We found that elevated salinity significantly suppressed the growth of two rice cultivars. Meanwhile, BPH population size also generally decreased due to poor host plant quality induced by elevated salinity. The highest BPH density occurred at 2.0 dS/m salinity and declined thereafter with increasing salinity, irrespective of rice cultivar. The highest population density of GMB also occurred under control conditions and decreased significantly with increasing salinity. Higher salinity directly affected the rice crop by reducing plant quality measured with reference to biomass production and plant height, whereas inducing population developmental asynchrony between BPH and GMB observed at 2 dS/m salinity and potentially uncoupling prey-predator dynamics. Our results suggest that increased salinity has harmful effects on plants, herbivores, natural enemies, as well as plant-pest-predator interactions. The effects measured here suggest that the bottom-up effects of predatory insects on rice pests will likely decline in rice produced in coastal areas where salinity intrusion is common. Our findings indicate that elevated salinity influences tritrophic interactions in rice production landscapes, and further research should address resilient rice insect pest management combining multipests and predators in a changing environment., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF)., Objectives: This study sought to evaluate whether CHIP is associated with incident HF., Methods: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses., Results: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction., Conclusions: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF., Competing Interests: Funding Support and Author Disclosures Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: The Jackson Heart Study” (phs000964) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). WGS for “NHLBI TOPMed: Women's Health Initiative (WHI)” (phs001237) was performed at the Broad Institute (HHSN268201500014C). WGS for “NHLBI TOPMed: Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Study” (phs001368) was performed at Baylor (HHSN268201600033I, 3U54HG003273-12S2/HHSN268201500015C). Centralized read mapping and genotype calling along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). The Atherosclerosis Risk In Communities study has been funded in whole or in part with federal funds from the NHLBI, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the National Institutes of Health through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Whole exome sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273 and R01HL086694). The CHS (Cardiovascular Health Study) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006, and by grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. The WHI program is funded by the NHLBI, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Dr Yu is supported in part by R01HL141824 and R01HL148050. Dr Raffield was funded by T32 HL129982 and KL2TR00249. Dr Zekavat is supported by the National Institutes of Health’s NHLBI under award number 1F30HL149180-01 and the National Institutes of Health’s Medical Scientist Training Program at the Yale School of Medicine. Dr Shah is supported in part by grants from the NHLBI (R01HL135008, R01HL143224, R01HL150342, R01HL14818, and K24HL152008); has received research support from Novartis and Philips Ultrasound through Brigham and Women's Hospital; and has received consulting fees from Philips Ultrasound and Edwards Lifesciences. Dr Honigberg is supported by a grant from the NHLBI (T32HL094301-07). Dr Ebert has received research funding from Celgene, Deerfield, and Novartis; has received consulting fees from GRAIL; and has served on the scientific advisory boards and holds equity in Skyhawk Therapeutics, Exo Therapeutics, and Neomorph Therapeutics. Dr Reiner is supported by R01HL148565. Dr Natarajan is supported by grants from the NHLBI (R01HL142711, R01HL148050, R01HL148565) and Fondation Leducq (TNE-18CVD04); has received grants from Amgen, Apple, Boston Scientific, and Novartis; has received consulting income from Apple, Blackstone Life Sciences, Novartis, and Genentech; and has spousal employment at Vertex, all unrelated to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We made the first and successful attempt to detect SARS-CoV-2 genetic material in the vicinity wastewaters of an isolation centre i.e. Shaheed Bhulu Stadium, situated at Noakhali, Southeastern Bangladesh. Owing to the fact that isolation centre, in general, always contained a constant number of 200 COVID-19 patients, the prime objective of the study was to check if several drains carrying RNA of coronavirus are actually getting diluted or accumulated along with the sewage network. Our finding suggested that while the temporal variation of the genetic load decreased in small drains over the span of 50 days, the main sewer exhibited accumulation of SARS-CoV-2 RNA. Other interesting finding displays that probably distance of sampling location in meters is not likely to have a significant impact on the detected gene concentration, although the quantity of the RNA extracted in the downstream of the drain was higher. These findings are of immense value from the perspective of wastewater surveillance of COVID-19, as they largely imply that we do not need to monitor every wastewater system, and probably major drains monitoring may illustrate the city health. Perhaps, we are reporting the accumulation of SARS-CoV-2 genetic material along with the sewer network i.e. from primary to tertiary drains. The study sought further data collection in this line to simulate conditions prevailed in most of the developing countries and to shed further light on decay/accumulation processes of the genetic load of the SARS-COV-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10 -7 ), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10 -28 ), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10 -15 ), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10 -9 ) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10 -4 ). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

The ventromedial hypothalamic nucleus-ventrolateral part (VMNvl) is an estradiol-sensitive structure that controls sex-specific behavior. Electrical reactivity of VMNvl neurons to hypoglycemia infers that cellular energy stability is monitored there. Current research investigated the hypothesis that estradiol elicits sex-dimorphic patterns of VMNvl metabolic sensor activation and gluco-regulatory neurotransmission during hypoglycemia. Rostral-, middle-, and caudal-VMNvl tissue was separately micropunch-dissected from letrozole (Lz)- or vehicle-injected male and estradiol- or vehicle-implanted ovariectomized (OVX) female rats for Western blot analysis of total and phosphorylated 5'-AMP-activated protein kinase (AMPK) protein expression and gluco-stimulatory [neuronal nitric oxide synthase (nNOS); steroidogenic factor-1 (SF1) or -inhibitory (glutamate decarboxylase 65/67 (GAD)] transmitter marker proteins after sc insulin (INS) or vehicle injection. In both sexes, hypoglycemic up-regulation of phosphoAMPK was estradiol-dependent in rostral and middle, but not caudal VMNvl. AMPK activity remained elevated after recovery from hypoglycemia over the rostro-caudal VMNvl in female, but only in the rostral segment in male. In each sex, hypoglycemia correspondingly augmented or suppressed nNOS profiles in rostral and middle versus caudal VMNvl; these segmental responses persisted longer in female. Rostral and middle segment SF1 protein was inhibited by estradiol-independent mechanisms in hypoglycemic males, but increased by estradiol-reliant mechanisms in female. After INS injection, GAD expression was inhibited in the male rostral VMNvl without estradiol involvement, but this hormone was required for broader suppression of this profile in the female. Neuroanatomical variability of VMNvl metabolic transmitter reactivity to hypoglycemia underscores the existence of functionally different subgroups in that structure. The regional distribution and estradiol sensitivity of hypoglycemia-sensitive VMNvl neurons of each neurochemical phenotype evidently vary between sexes.

Definity is a contrast media used to enhance the endocardium during echocardiography. Cardiac arrest as an adverse reaction to Definity is still a debate. We are presenting a rare case of a 69-year-old male patient who developed cardiopulmonary arrest immediately after Definity injection during resting echocardiography., Competing Interests: Competing interests: None, (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (B reg ) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation., Competing Interests: Declaration of interests P. Santamaria is founder, scientific officer, and stockholder of Parvus Therapeutics. He is an inventor on patents on pMHC-based nanomedicines and receives funding from the company. D.A.A.V. is cofounder and stockholder in Novasenta, Tizona, and Potenza; a stockholder in Oncorus and Werewolf; has patents licensed and royalties received from Astellas and BMS; is a scientific advisory board member at Tizona, Werewolf, F-Star, and Bicara; is a consultant at Astellas, BMS, Almirall, and Incyte; and receives research funding from BMS, Astellas, and Novasenta., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Among patients with atrial fibrillation (AF) who have high risk of bleeding secondary to haematologic disorders, left atrial appendage (LAA) occlusion therapy has been shown to be an excellent alternative to long-term use of oral anticoagulation for thromboembolic stroke prevention. However, there remains a major concern of device-associated thrombosis post-procedure, that can lead to life-threatening embolic events. To this date, there is no systematic guideline for the selection and management of patients with haematological disorders with LAA occlusion therapy, especially in those with platelet disorders such as immune thrombocytopenia (ITP). Patients with platelet disorders are at a higher risk for bleeding; however, that does not prevent such patients from thromboembolic events secondary to AF. We present a case of ITP with permanent AF, where an LAA device was complicated by thrombus formation due to challenges faced with anticoagulation therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Lipoprotein(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease (ASCVD). It is unclear whether measured lipoprotein(a) or genetic factors associated with lipoprotein(a) can provide comparable or additional prognostic information for primary prevention., Objective: To determine whether a genetic risk score (GRS) comprising 43 variants at the LPA gene, which encodes apolipoprotein(a), has clinical utility in assessing ASCVD risk compared with and in addition to lipoprotein(a) measurement., Design, Setting, and Participants: The UK Biobank is a prospective observational study of approximately 500 000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. Using externally derived weights, an LPA GRS was calculated for 374 099 unrelated individuals with array-derived genotypes and lipoprotein(a) measures. Data were analyzed from April 2020 to March 2020., Exposures: Measured lipoprotein(a) and LPA GRS., Main Outcomes and Measures: We estimated the associations between measured lipoprotein(a) and LPA GRS with the incidence of ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) using Cox proportional hazards models. To determine the utility of using measured lipoprotein(a) and LPA GRS as risk enhancers for ASCVD, we assessed the potential improvement in ASCVD risk discrimination by QRISK3 and Pooled Cohort Equations among individuals with borderline to intermediate risk (n = 113 703 and 144 350, respectively)., Results: The mean age of the overall study population was 57.6 years, and 204 355 individuals were female (54.6%). During a median follow-up of 11.1 years (interquartile range, 1.4 years), 15 444 individuals developed an incident ASCVD event (5.1%). The LPA GRS explained approximately 60% of the variation in measured lipoprotein(a) for White/European individuals. Independently, both lipoprotein(a) and LPA GRS were associated with incident, composite ASCVD (hazard ratio per 120 nmol/L increase, 1.26; 95% CI, 1.23-1.28 vs hazard ratio, 1.29; 95% CI, 1.26-1.33; P < .001). The association between LPA GRS and ASCVD was substantially attenuated after adjusting for measured lipoprotein(a). Adding measured lipoprotein(a) or LPA GRS to QRISK3 provided modest improvements to the risk discrimination of incident ASCVD events (area under the receiver operating curve, 0.640; 95% CI, 0.633-0.647 vs 0.642; 95% CI, 0.635-0.649 for both; P = .005 and P = .01, respectively)., Conclusions and Relevance: When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or an LPA GRS.

Glycogen metabolism shapes ventromedial hypothalamic nucleus (VMN) control of glucose homeostasis. Brain glycogen mass undergoes compensatory expansion post‑recovery from insulin‑induced hypoglycemia (IIH). Current research utilized combinatory high‑resolution microdissection/high‑sensitivity Western blotting to investigate whether IIH causes residual adjustments in glycogen metabolism within the metabolic‑sensory ventrolateral VMN (VMNvl). Micropunch‑dissected tissue was collected from rostral, middle, and caudal levels of the VMNvl in each sex for analysis of glycogen synthase (GS) and glycogen phosphorylase (GP)‑muscle type (GPmm; norepinephrine‑sensitive) and GP‑brain type (GPbb; glucoprivic‑sensitive) isoform expression during and after IIH. Hypoglycemic suppression of VMNvl GS levels in males disappeared or continued after reestablishment of euglycemia, according to sampled segment. Yet, reductions in female VMNvl GS persisted after IIH. Males exhibited reductions in GPmm content in select rostro‑caudal VMNvl segments, but this protein declined in each segment post‑hypoglycemia. Females, rather, showed augmented or diminished GPmm levels during IIH, but no residual effects of IIH on this protein. In each sex, region‑specific up‑ or down‑regulation of VMNvl GPbb profiles during glucose decrements were undetected post‑recovery from IIH. Results provide novel proof of estradiol‑dependent sex‑dimorphic patterns of VMNvl GP variant expression at specific rostro‑caudal levels of this critical gluco‑regulatory structure. Sex differences in persistence of IIH‑associated GS and GPmm patterns of expression after restoration of euglycemia infer that VMNvl recovery from this metabolic stress may involve dissimilar glycogen accumulation in male versus female.

Brain glycogen is remodeled during metabolic homeostasis and provides oxidizable L-lactate equivalents. Brain glycogen phosphorylase (GP)-brain (GPbb; AMP-sensitive) and -muscle (GPmm; norepinephrine-sensitive) type isoforms facilitate stimulus-specific control of glycogen disassembly. Here, a whole animal model involving stereotactic-targeted delivery of GPmm or GPbb siRNA to the ventromedial hypothalamic nucleus (VMN) was used to investigate the premise that these variants impose differential control of gluco-regulatory transmission. Intra-VMN GPmm or GPbb siRNA administration inhibited glutamate decarboxylate 65/67 (GAD), a protein marker for the gluco-inhibitory transmitter γ--aminobutyric acid (GABA), in the caudal VMN. GPbb knockdown, respectively overturned or exacerbated hypoglycemia-associated GAD suppression in rostral and caudal VMN. GPmm siRNA caused a segment-specific reversal of hypoglycemic augmentation of the gluco-stimulatory transmitter indicator, neuronal nitric oxide synthase (nNOS). In both cell types, GP siRNA down-regulated 5'-AMP-activated protein kinase (AMPK) during euglycemia, but hypoglycemic suppression of AMPK was reversed by GPmm targeting. GP knockdown elevated baseline GABA neuron phosphoAMPK (pAMKP) content, and amplified hypoglycemic augmentation of pAMPK expression in each neuron type. GPbb knockdown increased corticosterone secretion in eu- and hypoglycemic rats. Outcomes validate efficacy of GP siRNA delivery for manipulation of glycogen breakdown in discrete brain structures in vivo, and document VMN GPbb control of local GPmm expression. Results document GPmm and/or -bb regulation of GABAergic and nitrergic transmission in discrete rostro-caudal VMN segments. Contrary effects of glycogenolysis on metabolic-sensory AMPK protein during eu- versus hypoglycemia may reflect energy state-specific astrocyte signaling. Amplifying effects of GPbb knockdown on hypoglycemic stimulation of pAMPK infer that glycogen mobilization by GPbb limits neuronal energy instability during hypoglycemia.