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Abstract Aims New tools are needed to identify heart failure (HF) risk earlier in its course. We evaluated the association of multidimensional cardiopulmonary exercise testing (CPET) phenotypes with subclinical risk markers and predicted long‐term HF risk in a large community‐based cohort. Methods and results We studied 2532 Framingham Heart Study participants [age 53 ± 9 years, 52% women, body mass index (BMI) 28.0 ± 5.3 kg/m2, peak oxygen uptake (VO2) 21.1 ± 5.9 kg/m2 in women, 26.4 ± 6.7 kg/m2 in men] who underwent maximum effort CPET and were not taking atrioventricular nodal blocking agents. Higher peak VO2 was associated with a lower estimated HF risk score (Spearman correlation r: −0.60 in men and −0.55 in women, P

Context: PhD is one of the programs pursued by faculty working in health sciences institutions. It is valuable to know about the perceived challenges and support available for the faculty to pursue PhD. Aims: The aim was to study the factors affecting the pursuit of PhD by faculty employed in institutions offering medicine and dentistry in the state of Karnataka. Settings and Design: This was a cross-sectional questionnaire-based survey conducted among 366 faculty across 22 medical and 12 dental institutions. Subjects and Methods: The questionnaire was administered online after content and face validation. Statistical Analysis: The Mann–Whitney U-test and Spearman’s correlation coefficient were used. Results: Knowledge creation (86.1%), personal career advancement in the form of promotions (75.5%), and contribution to the health of society or community (73.8%) were generally perceived as the motives to pursue PhD. Work commitments in the department (80.6%) and lack of appropriate academic position after completing PhD (79.5%) were identified as the major factors obstructing the enrollment for PhD. Respondents reported that the scientific rigor of research might be undermined by career-related motives (70.7%). Routine professional activities like clinical work (72.7%) and academic work (71.9%) were reported to be adversely affected while pursuing PhD. 68.8% of faculty believed that a PhD holder would be a better researcher. Conclusions: Both personal and altruistic motives influence the pursuit of PhD. Many factors hinder the pursuit of PhD and the conduct of quality research. Institutional support may enhance the enrollment.

Abstract Sunflower (Helianthus annuus L.) plays an essential role in meeting the demand for edible oil worldwide. The yield of sunflower seeds encompasses several component traits, including the disc diameter. Over three consecutive years, 2019, 2020, and 2022, we assessed phenotypic variation in disc diameter across a diverse set of sunflower accessions (N = 342) in replicated field trials. Upon aggregating the phenotypic data from multiple years, we estimated the broad sense heritability (H2) of the disc diameter trait to be 0.88. A subset of N = 274 accessions was genotyped by using the tunable genotyping‐by‐sequencing (tGBS) method, resulting in 226,779 high‐quality SNPs. Using these SNPs and the disc diameter phenotype, we conducted a genome‐wide association study (GWAS) employing two statistical approaches: the mixed linear model (MLM) and the fixed and random model circulating probability unification (farmCPU). The MLM and farmCPU GWAS approaches identified 106 and 8 significant SNPs located close to 53 and 21 genes, respectively. The MLM analysis identified two significant peaks: a prominent signal on chromosome 10 and a relatively weaker signal on chromosome 16, both of which were also detected by farmCPU. The genetic loci associated with disc diameter, as well as the related candidate genes, present promising avenues for further functional validation and serve as a basis for sunflower oil yield improvement.

Summary: Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human “ome” and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation.

Abstract In the forthcoming decades, significant advancements will shape the construction and operations of distribution systems. Particularly, the increasing prominence of photovoltaic (PV) systems in the power industry will impact the security of these systems. This study employs Monte Carlo Simulation (MCS) in conjunction with genetic algorithm (GA) and differential evolution (DE) to address uncertainties. The probability density functions (pdf) for total voltage harmonic distortion (UTHD), individual voltage harmonic distortion (UIHDh), and RMS voltage (URMS) have been determined for utilization in chance constrained framework. In addition, the uncertainty effects of PV systems on grid losses for various solar radiation conditions are also investigated. Specifically, the paper aims to evaluate these impacts within the context of stochastic limits. The PV system sizing problem has been addressed inside the distribution system using a chance-constrained framework. A key contribution is the integration of GA, DE, and MCS into a cohesive approach, and the study evaluates the benefits of this approach through an analysis of outcomes derived from the stochastic method. The simulation results illustrate the advantages of the proposed stochastic GA methodology.

BackgroundResting heart rate (HR) and routine physical activity are associated with cardiorespiratory fitness levels. Commercial smartwatches permit remote HR monitoring and step count recording in real-world settings over long periods of time, but the relationship between smartwatch-measured HR and daily steps to cardiorespiratory fitness remains incompletely characterized in the community. ObjectiveThis study aimed to examine the association of nonactive HR and daily steps measured by a smartwatch with a multidimensional fitness assessment via cardiopulmonary exercise testing (CPET) among participants in the electronic Framingham Heart Study. MethodsElectronic Framingham Heart Study participants were enrolled in a research examination (2016-2019) and provided with a study smartwatch that collected longitudinal HR and physical activity data for up to 3 years. At the same examination, the participants underwent CPET on a cycle ergometer. Multivariable linear models were used to test the association of CPET indices with nonactive HR and daily steps from the smartwatch. ResultsWe included 662 participants (mean age 53, SD 9 years; n=391, 59% women, n=599, 91% White; mean nonactive HR 73, SD 6 beats per minute) with a median of 1836 (IQR 889-3559) HR records and a median of 128 (IQR 65-227) watch-wearing days for each individual. In multivariable-adjusted models, lower nonactive HR and higher daily steps were associated with higher peak oxygen uptake (VO2), % predicted peak VO2, and VO2 at the ventilatory anaerobic threshold, with false discovery rate (FDR)–adjusted P values

Background The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community‐dwelling adults. Methods and Results Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O2). A 100‐point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O2 (log‐transformed) and complementary CRF measures. In age‐ and sex‐adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O2, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all P

Abstract Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value

Background: Cholecystectomy is a commonly performed laparoscopic surgery but because of variability in anatomy, surrounding inflammation and fibrosis because of recurrent attacks of cholecystitis, can be a potentially difficult surgery. Laparoscopic total cholecystectomy in difficult gall bladder cases sometimes can cause severe complications. Laparoscopic subtotal cholecystectomy can be a bridge and a safe and feasible option between open subtotal cholecystectomy and laparoscopic cholecystectomy. Aim: To study indications, morbidity and clinical outcomes in patients undergoing subtotal cholecystectomy with laparoscopy or with open surgery. Settings and Design: It was a prospective observational study. Patients presenting with signs and symptoms of cholecystitis in either OPD or IPD and in emergency were included in this study. Materials and Methods: Total 38 patients who presented to our institute with clinical and ultrasonographic evidence of acute cholecystitis were included in the study. All patients underwent detailed and thorough clinical examination, laboratory investigations, ultrasonographic, and contrast enhanced computed tomography scan in selected patients. Based on intraoperative findings, decision of subtotal cholecystectomy either by laparoscopy or via open method was made. Various outcomes like intraoperative complications, postoperative complications and need of postoperative interventions, hospital stay, and returning to daily activity were observed and charted. Statistical Analysis: The data obtained were tabulated in Microsoft Excel and analyzed using SPSS version 17.0. Continuous variables were expressed as mean ± standard deviation value. Probability value (P value) was used to determine the level of significance. P value

Abstract Background Transcription bridges genetic information and phenotypes. Here, we evaluated how changes in transcriptional regulation enable maize (Zea mays), a crop originally domesticated in the tropics, to adapt to temperate environments. Result We generated 572 unique RNA-seq datasets from the roots of 340 maize genotypes. Genes involved in core processes such as cell division, chromosome organization and cytoskeleton organization showed lower heritability of gene expression, while genes involved in anti-oxidation activity exhibited higher expression heritability. An expression genome-wide association study (eGWAS) identified 19,602 expression quantitative trait loci (eQTLs) associated with the expression of 11,444 genes. A GWAS for alternative splicing identified 49,897 splicing QTLs (sQTLs) for 7614 genes. Genes harboring both cis-eQTLs and cis-sQTLs in linkage disequilibrium were disproportionately likely to encode transcription factors or were annotated as responding to one or more stresses. Independent component analysis of gene expression data identified loci regulating co-expression modules involved in oxidation reduction, response to water deprivation, plastid biogenesis, protein biogenesis, and plant-pathogen interaction. Several genes involved in cell proliferation, flower development, DNA replication, and gene silencing showed lower gene expression variation explained by genetic factors between temperate and tropical maize lines. A GWAS of 27 previously published phenotypes identified several candidate genes overlapping with genomic intervals showing signatures of selection during adaptation to temperate environments. Conclusion Our results illustrate how maize transcriptional regulatory networks enable changes in transcriptional regulation to adapt to temperate regions.

Background During exercise, a healthy arterial system facilitates increased blood flow and distributes it effectively to essential organs. Accordingly, we sought to understand how arterial stiffening might impair cardiorespiratory fitness in community‐dwelling individuals. Methods and Results Arterial tonometry and maximum effort cardiopulmonary exercise testing were performed on Framingham Heart Study participants (N=2898, age 54±9 years, 53% women, body mass index 28.1±5.3 kg/m2). We related 5 arterial stiffness measures (carotid‐femoral pulse wave velocity [CFPWV]: a measure of aortic wall stiffness; central pulse pressure, forward wave amplitude, characteristic impedance: measures of pressure pulsatility; and augmentation index: a measure of relative wave reflection) to multidimensional exercise responses using linear models adjusted for age, sex, resting heart rate, habitual physical activity, and clinical risk factors. Greater CFPWV, augmentation index, and characteristic impedance were associated with lower peak oxygen uptake (VO2; all P0.05). However, the CFPWV‐peak oxygen uptake relation was attenuated in individuals with obesity (P=0.002 for obesity*CFPWV interaction). Higher CPFWV, augmentation index, and characteristic impedance were also related to cardiopulmonary exercise testing measures reflecting adverse O2 kinetics and lower stroke volume and peripheral O2 extraction but not to ventilatory efficiency, a prognostic measure of right ventricular‐pulmonary vascular performance. Conclusions Our findings delineate relations of arterial stiffness and cardiorespiratory fitness in community‐dwelling individuals. Future studies are warranted to evaluate whether the physiological measures implicated here may represent potential targets for improving cardiorespiratory fitness in the general population.

Background While exercise impairments are central to symptoms and diagnosis of heart failure with preserved ejection fraction (HFpEF), prior studies of HFpEF biomarkers have mostly focused on resting phenotypes. We combined precise exercise phenotypes with cardiovascular proteomics to identify protein signatures of HFpEF exercise responses and new potential therapeutic targets. Methods and Results We analyzed 277 proteins (Olink) in 151 individuals (N=103 HFpEF, 48 controls; 62±11 years; 56% women) with cardiopulmonary exercise testing with invasive monitoring. Using ridge regression adjusted for age/sex, we defined proteomic signatures of 5 physiological variables involved in HFpEF: peak oxygen uptake, peak cardiac output, pulmonary capillary wedge pressure/cardiac output slope, peak pulmonary vascular resistance, and peak peripheral O2 extraction. Multiprotein signatures of each of the exercise phenotypes captured a significant proportion of variance in respective exercise phenotypes. Interrogating the importance (ridge coefficient magnitude) of specific proteins in each signature highlighted proteins with putative links to HFpEF pathophysiology (eg, inflammatory, profibrotic proteins), and novel proteins linked to distinct physiologies (eg, proteins involved in multiorgan [kidney, liver, muscle, adipose] health) were implicated in impaired O2 extraction. In a separate sample (N=522, 261 HF events), proteomic signatures of peak oxygen uptake and pulmonary capillary wedge pressure/cardiac output slope were associated with incident HFpEF (odds ratios, 0.67 [95% CI, 0.50–0.90] and 1.43 [95% CI, 1.11–1.85], respectively) with adjustment for clinical factors and B‐type natriuretic peptides. Conclusions The cardiovascular proteome is associated with precision exercise phenotypes in HFpEF, suggesting novel mechanistic targets and potential methods for risk stratification to prevent HFpEF early in its pathogenesis.

Abstract Background New biomarkers to identify cardiovascular disease (CVD) risk earlier in its course are needed to enable targeted approaches for primordial prevention. We evaluated whether intraindividual changes in blood metabolites in response to an oral glucose tolerance test (OGTT) may provide incremental information regarding the risk of future CVD and mortality in the community. Methods An OGTT (75 g glucose) was administered to a subsample of Framingham Heart Study participants free from diabetes (n = 361). Profiling of 211 plasma metabolites was performed from blood samples drawn before and 2 h after OGTT. The log2(post/pre) metabolite levels (Δmetabolites) were related to incident CVD and mortality in Cox regression models adjusted for age, sex, baseline metabolite level, systolic blood pressure, hypertension treatment, body mass index, smoking, and total/high-density lipoprotein cholesterol. Select metabolites were related to subclinical cardiometabolic phenotypes using Spearman correlations adjusted for age, sex, and fasting metabolite level. Results Our sample included 42% women, with a mean age of 56 ± 9 years and a body mass index of 30.2 ± 5.3 kg/m2. The pre- to post-OGTT changes (Δmetabolite) were non-zero for 168 metabolites (at FDR ≤ 5%). A total of 132 CVD events and 144 deaths occurred during median follow-up of 24.9 years. In Cox models adjusted for clinical risk factors, four Δmetabolites were associated with incident CVD (higher glutamate and deoxycholate, lower inosine and lysophosphatidylcholine 18:2) and six Δmetabolites (higher hydroxyphenylacetate, triacylglycerol 56:5, alpha-ketogluturate, and lower phosphatidylcholine 32:0, glucuronate, N-monomethyl-arginine) were associated with death (P

Introduction : Preserved congenital heart specimens are an important component of training professionals working with children and adults with congenital heart disease. They are curated in few institutions worldwide and not freely accessible. This was a proof-of-concept project to explore the use of advanced cardiac imaging modalities (computed tomography [CT] and magnetic resonance imaging [MRI]) and virtual reality (VR) simulation to assess the feasibility and identify the best method of imaging curated cardiac pathology specimens. Methods : Seven specimens in glass jars with formalin, with varied anatomic lesions, from a curated collection were imaged using MRI and high-dose CT to compare the fidelity of models created via each modality. Three-dimensional (3D) models were created and loaded into a VR headset and viewed in virtual space. Two independent physicians performed a “virtual dissection” and scored the resultant models. Results : The highest fidelity and tissue characterization of more delicate structures was achieved with T2 spoiled gradient-echo sequences on MRI (median score of 4 out of 5). CT (median score of 3), while excellent for external anatomy, lost some fidelity with delicate internal anatomy, even at high-radiation doses. No specimens were damaged. Conclusions : We believe that in vitro heart specimens can be easily scanned with high fidelity at a relatively low cost, without causing damage, using high-dose CT and MRI. The ability to “walk through” different chambers of the heart makes the understanding of anatomy easy and intuitive. VR and 3D printing are technologies that could be easily adapted to digitize preserved heart specimens, making it globally accessible for teaching and training purposes.

Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.

Abstract Domesticated ~10,000 years ago in northern China, Proso millet (Panicum miliaceum L.) is a climate‐resilient and human health‐promoting cereal crop. The genome size of this self‐pollinated allotetraploid is 923 Mb. Proso millet seeds are an important part of the human diet in many countries. In the USA, its use is restricted to the birdseed and pet food market. Proso millet is witnessing gradual demand in the global human health and wellness food market owing to its health‐promoting properties such as low glycemic index and gluten‐free. The breeding efforts for developing improved proso millet cultivars are hindered by the dearth of genomic resources available to researchers. The publication of the reference genome and availability of cost‐effective NGS methodologies could lead to the identification of high‐quality genetic variants, which can be incorporated into breeding pipelines. Here, we report the identification of single‐nucleotide polymorphisms (SNPs) by low‐pass (1×) genome sequencing of 85 diverse proso millet accessions from 23 different countries. The 2 × 150 bp Illumina paired‐end reads generated after sequencing were aligned to the proso millet reference genome. The resulting sequence alignment information was used to call SNPs. We obtained 972,863 bi‐allelic SNPs after quality filtering of the raw SNPs. These SNPs were used to assess the population structure and phylogenetic relationships among the accessions. Most of the accessions were found to be highly inbred with heterozygosity ranging between .05 and .20. Principal component analysis (PCA) showed that PC1 (principal component) and PC2 explained 19% of the variability in the population. PCA also clustered all the genotypes into three groups. A neighbor‐joining tree clustered the genotypes into four distinct groups exhibiting diverse representation within the population. The SNPs identified in our study could be used for molecular breeding and genetics research (e.g., genetic and association mapping, and population genetics) in proso millet after proper validation.

Background Cardiorespiratory fitness is a powerful predictor of health outcomes that is currently underused in primary prevention, especially in young adults. We sought to develop a blood‐based biomarker of cardiorespiratory fitness that is easily translatable across populations. Methods and Results Maximal effort cardiopulmonary exercise testing for quantification of cardiorespiratory fitness (by peak oxygen uptake) and profiling of >200 metabolites at rest were performed in the FHS (Framingham Heart Study; 2016–2019). A metabolomic fitness score was derived/validated in the FHS and was associated with long‐term outcomes in the younger CARDIA (Coronary Artery Risk Development in Young Adults) study. In the FHS (derivation, N=451; validation, N=914; age 54±8 years, 53% women, body mass index 27.7±5.3 kg/m2), we used LASSO (least absolute shrinkage and selection operator) regression to develop a multimetabolite score to predict peak oxygen uptake (correlation with peak oxygen uptake r=0.77 in derivation, 0.61 in validation; both P

Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high‐impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital‐University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.

Summary: Patients with SARS-CoV-2 infection (COVID-19) risk developing long-term neurologic symptoms after infection. Here, we identify biomarkers associated with neurologic sequelae one year after hospitalization for SARS-CoV-2 infection. SARS-CoV-2-positive patients were followed using post-SARS-CoV-2 online questionnaires and virtual visits. Hospitalized adults from the pre-SARS-CoV-2 era served as historical controls. 40% of hospitalized patients develop neurological sequelae in the year after recovery from acute COVID-19 infection. Age, disease severity, and COVID-19 infection itself was associated with additional risk for neurological sequelae in our cohorts. Glial fibrillary astrocytic protein (GFAP) and neurofilament light chain (NF-L) were significantly elevated in SARS-CoV-2 infection. After adjusting for age, sex, and disease severity, GFAP and NF-L remained significantly associated with longer term neurological symptoms in patients with SARS-CoV-2 infection. GFAP and NF-L warrant exploration as biomarkers for long-term neurologic complications after SARS-CoV-2 infection.

Cheilostomatid bryozoans are present in large quantities in Miocene sediments of western Kachchh. A detailed investigation, as presented here, has yielded 11 species. Among them, two species – Canda ukirensis sp. nov. and Antropora ramaniaensis sp. nov. – are new to science. Five species had already been reported from the same region, while a genus and the remaining three species are left in open nomenclature pending an exhaustive study using better preserved material.

Introduction: Data are limited on antibody response to the ChAdOx1 nCoV-19 vaccine (AZD1222; Covishield®) in cirrhosis. We studied the antibody response following two doses of the ChAdOx1 vaccine, given 4–12 weeks apart, in cirrhosis. Methods: Prospectively enrolled, 131 participants (71% males; age 50 (43–58); alcohol-related etiology 14, hepatitis B 33, hepatitis C 46, cryptogenic 21, autoimmune 9, others 8; Child–Turcott–Pugh class A/B/C 52/63/16). According to dose intervals, the participants were grouped as ≤6 weeks (group I), 7–12 weeks (group II), and 13–36 weeks (group III). Blood specimens collected at ≥4 weeks after the second dose were tested for anti-spike antibody titre (ASAb; positive ≥ 0.80 U/mL) and neutralizing antibody (NAb; positive ≥20% neutralization) using Elecsys Anti-SARS-CoV-2 S (Roche) and SARS-CoV-2 NAb ELISA Kit (Invitrogen), respectively. Data are expressed as number (proportion) and median (interquartile range) and compared using non-parametric tests. Results: Overall, 99.2% and 84% patients developed ASAb (titre 5440 (1719–9980 U/mL)) and NAb (92 (49.1–97.6%)), respectively. When comparing between the study groups, the ASAb titres were significantly higher in group II than in group I (2613 (310–7518) versus 6365 (2968–9463), p = 0.027) but were comparable between group II and III (6365 (2968–9463) versus 5267 (1739–11,653), p = 0.999). Similarly, NAb was higher in group II than in group I (95.5 (57.6–98.0) versus 45.9 (15.4–92.0); p < 0.001), but not between the groups II and III (95.5 (57.6–98.0) versus 92.4 (73.8–97.5); p = 0.386). Conclusion: Covishield® induces high titres of ASAb and NAb in cirrhosis. A higher titre is achieved if two doses are given at an interval of more than six weeks.

Kidney transplant recipients (KTRs) are at a much higher risk of complications and death following COVID-19 and are poor vaccine responders. The data are limited on the immune response to Covishield® in KTRs. We prospectively recruited a cohort of 67 KTRs aged >18 between April 2021 and December 2021. Each participant was given two intramuscular doses of Covishield®, each of 0.5 mL, at an interval of 12 weeks. A blood specimen of 5.0 mL was collected from each participant at two points within a few days before administering the first dose of the vaccine and at any time between 4–12 weeks after administering the second dose. The sera were tested for anti-RBD antibody (ARAb) titre and neutralising antibody (NAb). An ACE2 competition assay was used as a proxy for virus neutralization. According to the prior COVID-19 infection, participants were grouped as (i) group A: prior symptomatic COVID-19 infection, (ii) group B: prior asymptomatic COVID-19 infection as evidenced by detectable ARAb in the prevaccination specimen, (iii) Group C: no prior infection with COVID-19, (iv) group D: Unclassified, i.e., participants had no symptoms suggestive of COVID-19, but their prevaccination specimen was not available for ARAb testing before vaccination. Fifty of sixty-seven participants (74.6%) provided paired specimens (group A 14, group B 27, and group C 9) and 17 participants (25.4%) provided only postvaccination specimens (group D). In the overall cohort (n = 67), 91% and 77.6% of participants developed ARAb and NAb, respectively. Their ARAb titre and NAb proportion were 2927 (520–7124) U/mL and 87.9 (24.4–93.2) %, respectively. Their median ARAb titre increased 65.6 folds, from 38.2 U/mL to 3137 U/mL. Similarly, the proportion of participants with NAb increased from 56% to 86%, and the NAb proportion raised 2.7 folds, from 23% to 91%. A comparison of vaccine response between the study groups showed that all those with or without prior COVID-19 infection showed a significant rise in ARAb titre (p < 0.05) and NAb proportion (p < 0.05) after the two doses of vaccine administration. The median value of folds rise in anti-RBD and NAb between groups A and B were comparable. Hence, ARAb is present in more than 3/4th of KTRs before the ChAdOx1 vaccine in India. The titer of ARAb and the proportion of NAb significantly increased after the two doses of the ChAdOx1 vaccine in KTRs.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

BackgroundHeart Failure (HF) is the most common cause of death in Friedreich's ataxia (FRDA), an inherited mitochondrial disease. Myocardial fibrosis and myocardial hypertrophy are well-documented autopsy features among FRDA patients with HF.ObjectivesTo leverage the unique tissue characterization features of cardiac magnetic resonance (CMR) for characterizing myocardial remodeling in patients with genetically confirmed FRDA without HF and preserved left ventricular ejection fraction (LVEF > 55%).MethodsTwenty-seven FRDA's patients (age 27.6 ± 9.7 years, 15 women) and 10 healthy controls (32.6±7.3 years, 5 women) underwent a CMR for assessment of LV function, myocardial T1, late gadolinium enhancement (LGE), extracellular volume fraction (ECV), and intracellular water-lifetime (τic), a marker of cardiomyocyte size.ResultsAs compared to controls, FRDA patients had a preserved LVEF (LVEF: 70.5±7.4% vs. 63.9±9.0%, PConclusionsLV hypertrophy and concentric LV remodeling in FRDA are associated at the tissue level with an expansion of the ECV and an increase in cardiomyocyte size. The adverse tissue remodeling assessed by ECV and τic is associated with more severe cardiomyopathy classification, suggesting a role for these markers in tracking disease progression.

The automotive industry is marching towards cleaner energy in the impending future. The need for cleaner energy is promoted by the government to a large degree in the global market in order to reduce pollution. Automobiles contribute to an upper scale in regard to the level of pollution in the environment. For cleaner energy in automobiles, the industry needs to be revolutionized in all needed ways to a massive extent. The industry has to move from the traditional internal combustion engine, for which the main sources of energy are nonrenewable sources, to alternative methods and sources of energy. The automotive industry is now focusing on electric vehicles, and more research is being highlighted from vehicle manufacturers to find solutions for the problems faced in the field of electrification. Therefore, to accomplish full electrification, there is a long way to go, and this also requires a change in the existing infrastructure in addition to many innovations in the fields of infrastructure and grid connectively as well as the economic impacts of electric vehicles in society. In this work, an analysis of the electric vehicle market with the economic impacts of electric vehicles is studied. This therefore requires the transformation of the automotive industry.

Abstract Background Arthropod-borne diseases remain a leading cause of human morbidity and mortality and exact an enormous toll on global agriculture. The practice of insecticide-based control is fraught with issues of excessive cost, human and environmental toxicity, unwanted impact on beneficial insects and selection of resistant insects. Efforts to modulate insects to eliminate pathogen transmission have gained some traction and remain future options for disease control. Results Here, we report a paratransgenic strategy that targets transmission of Xylella fastidiosa, a leading bacterial pathogen of agriculture, by the Glassy-Winged Sharpshooter (GWSS), Homalodisca vitripennis. Earlier, we identified Pantoea agglomerans, a bacterial symbiont of the GWSS as the paratransgenic control agent. We genetically engineered P. agglomerans to express two antimicrobial peptides (AMP)-melittin and scorpine-like molecule (SLM). Melittin and SLM were chosen as the effector molecules based on in vitro studies, which showed that both molecules have anti-Xylella activity at concentrations that did not kill P. agglomerans. Using these AMP-expressing strains of P. agglomerans, we demonstrated disruption of pathogen transmission from insects to grape plants below detectable levels. Conclusion This is the first report of halting pathogen transmission from paratransgenically modified insects. It is also the first demonstration of paratransgenic control in an agriculturally important insect vector.

Abstract Background Evolving interest in comprehensively profiling the full range of small RNAs present in small tissue biopsies and in circulating biofluids, and how the profile differs with disease, has launched small RNA sequencing (RNASeq) into more frequent use. However, known biases associated with small RNASeq, compounded by low RNA inputs, have been both a significant concern and a hurdle to widespread adoption. As RNASeq is becoming a viable choice for the discovery of small RNAs in low input samples and more labs are employing it, there should be benchmark datasets to test and evaluate the performance of new sequencing protocols and operators. In a recent publication from the National Institute of Standards and Technology, Pine et al., 2018, the investigators used a commercially available set of three tissues and tested performance across labs and platforms. Results In this paper, we further tested the performance of low RNA input in three commonly used and commercially available RNASeq library preparation kits; NEB Next, NEXTFlex, and TruSeq small RNA library preparation. We evaluated the performance of the kits at two different sites, using three different tissues (brain, liver, and placenta) with high (1 μg) and low RNA (10 ng) input from tissue samples, or 5.0, 3.0, 2.0, 1.0, 0.5, and 0.2 ml starting volumes of plasma. As there has been a lack of robust validation platforms for differentially expressed miRNAs, we also compared low input RNASeq data with their expression profiles on three different platforms (Abcam Fireplex, HTG EdgeSeq, and Qiagen miRNome). Conclusions The concordance of RNASeq results on these three platforms was dependent on the RNA expression level; the higher the expression, the better the reproducibility. The results provide an extensive analysis of small RNASeq kit performance using low RNA input, and replication of these data on three downstream technologies.

Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain.

Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.

ObjectiveThe goal for this research was to identify molecular mechanisms that explain animal-to-animal variability in chronic intracortical recordings.ApproachMicrowire electrodes were implanted into Sprague Dawley rats at an acute (1 week) and a chronic (14 weeks) time point. Weekly recordings were conducted, and action potentials were evoked in the barrel cortex by deflecting the rat’s whiskers. At 1 and 14 weeks, tissue was collected, and mRNA was extracted. mRNA expression was compared between 1 and 14 weeks using a high throughput multiplexed qRT-PCR. Pearson correlation coefficients were calculated between mRNA expression and signal-to-noise ratios at 14 weeks.Main resultsAt 14 weeks, a positive correlation between signal-to-noise ratio (SNR) and NeuN and GFAP mRNA expression was observed, indicating a relationship between recording strength and neuronal population, as well as reactive astrocyte activity. The inflammatory state around the electrode interface was evaluated using M1-like and M2-like markers. Expression for both M1-like and M2-like mRNA markers remained steady from 1 to 14 weeks. Anti-inflammatory markers, CD206 and CD163, however, demonstrated a significant positive correlation with SNR quality at 14 weeks. VE-cadherin, a marker for adherens junctions, and PDGFR-β, a marker for pericytes, both partial representatives of blood–brain barrier health, had a positive correlation with SNR at 14 weeks. Endothelial adhesion markers revealed a significant increase in expression at 14 weeks, while CD45, a pan-leukocyte marker, significantly decreased at 14 weeks. No significant correlation was found for either the endothelial adhesion or pan-leukocyte markers.SignificanceA positive correlation between anti-inflammatory and blood–brain barrier health mRNA markers with electrophysiological efficacy of implanted intracortical electrodes has been demonstrated. These data reveal potential mechanisms for further evaluation to determine potential target mechanisms to improve consistency of intracortical electrodes recordings and reduce animal-to-animal/implant-to-implant variability.

Introduction: Emergency departments (ED) and hospitals face increasing challenges related to capacity, throughput, and stewardship of limited resources while maintaining high quality. Appropriate utilization of extremity magnetic resonance imaging (MRI) examinations within the emergency setting is not well known. Therefore, this study aimed to determine indications for and appropriateness of MRI of the extremities for musculoskeletal conditions in the ED observation unit (EDOU). Methods: We conducted this institutional review board-approved, retrospective study in a large, quaternary care academic center and Level I trauma center. An institutional database was queried retrospectively to identify all adult patients undergoing an extremity MRI while in the EDOU during the two-year study period from October 2013 through September 2015. We compared clinical history with the American College of Radiology (ACR) Appropriateness Criteria® for musculoskeletal indications. The primary outcome was appropriateness of musculoskeletal MRI exams of the extremities; examinations with an ACR Criteria score of seven or higher were deemed appropriate. Secondary measures included MRI utilization and imaging findings. Results: During the study period, 22,713 patients were evaluated in the EDOU. Of those patients, 4,409 had at least one MRI performed, and 88 MRIs met inclusion criteria as musculoskeletal extremity examinations (2% of all patients undergoing an MRI exam in the EDOU during the study period). The most common exams were foot (27, 31%); knee (26, 30%); leg/femur (10, 11%); and shoulder (10, 11%). The most common indications were suspected infection (42, 48%) and acute trauma (23, 26%). Fifty-six percent of exams were performed with intravenous contrast; and 83% (73) of all MRIs were deemed appropriate based on ACR Criteria. The most common reason for inappropriate imaging was lack of performance of radiographs prior to MRI. Conclusion: The majority of musculoskeletal extremity MRI examinations performed in the EDOU were appropriate based on ACR Appropriateness Criteria. However, the optimal timing and most-appropriate site for performance of many clinically appropriate musculoskeletal extremity MRIs performed in the EDOU remains unclear. Potential deferral to the outpatient setting may be a preferred population health management strategy.

Context: There is a need to evaluate the quality of postgraduate dissertations of dentistry submitted to university in the light of the international standards of reporting. Aims: We conducted the review with an objective to document the use of sampling methods, measurement standardization, blinding, methods to eliminate bias, appropriate use of statistical tests, appropriate use of data presentation in postgraduate dental research and suggest and recommend modifications. Settings and Design: The public access database of the dissertations from Rajiv Gandhi University of Health Sciences was reviewed. Subjects and Methods: Three hundred and thirty-three eligible dissertations underwent preliminary evaluation followed by detailed evaluation of 10% of randomly selected dissertations. The dissertations were assessed based on international reporting guidelines such as strengthening the reporting of observational studies in epidemiology (STROBE), consolidated standards of reporting trials (CONSORT), and other scholarly resources. Statistical Analysis Used: The data were compiled using MS Excel and SPSS 10.0. Numbers and percentages were used for describing the data. Results: The “in vitro” studies were the most common type of research (39%), followed by observational (32%) and experimental studies (29%). The disciplines conservative dentistry (92%) and prosthodontics (75%) reported high numbers of in vitro research. Disciplines oral surgery (80%) and periodontics (67%) had conducted experimental studies as a major share of their research. Lacunae in the studies included observational studies not following random sampling (70%), experimental studies not following random allocation (75%), not mentioning about blinding, confounding variables and calibrations in measurements, misrepresenting the data by inappropriate data presentation, errors in reporting probability values and not reporting confidence intervals. Few studies showed grossly inappropriate choice of statistical tests and many studies needed additional tests. Conclusions: Overall observations indicated the need to comply with standard guidelines of reporting research.

George Ejiofor Aninwene II,1 Zifan Yang,2 Vishnu Ravi,3 Gregory D Jay,2,4 Thomas J Webster1,51Department of Chemical Engineering and Program in Bioengineering, Northeastern University, Boston, MA, USA; 2School of Engineering, Brown University, Providence, RI, USA; 3Albany Medical College, Albany, NY, USA; 4Department of Emergency Medicine, Brown University, School of Medicine, Providence, RI, USA; 5Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi ArabiaAbstract: Excessive fibroblast adhesion and proliferation on the surface of medical implants (such as catheters, endotracheal tubes, intraocular lenses, etc) can lead to major postsurgical complications. This study showed that when coated on tissue culture polystyrene, lubricin, a nanostructured mucinous glycoprotein found in the synovial fluid of joints, decreased fibroblast density for up to 2 days of culture compared to controls treated with phosphate buffered saline (PBS). When examining why, similar antifibroblast density results were found when coating tissue culture polystyrene with bovine submaxillary mucin (BSM), an even smaller protein closely related to the central subregion of lubricin. Additionally, results from this study demonstrated that in contrast to BSM or controls (PBS-coated and non-coated samples), lubricin was better at preserving the health of nonadherent or loosely adherent fibroblasts; fibroblasts that did not adhere or loosely adhered on the lubricin-coated tissue culture polystyrene adhered and proliferated well for up to an additional day when they were reseeded on uncoated tissue culture polystyrene. In summary, this study provides evidence for the promise of nanostructured lubricin (and to a lesser extent BSM) to inhibit fibroblast adhesion and growth when coated on medical devices; lubricin should be further explored for numerous medical device applications.Keywords: lubricin, antiadhesive, fibroblasts, mucin

Black versus white older Americans are more likely to experience frailty, a condition associated with adverse health outcomes. To reduce racial disparities in health, a complete understanding of the pathophysiology of frailty is needed. Metabolomics may further our understanding by characterizing differences in the body during a vigorous versus frail state. We sought to identify metabolites and biological pathways associated with vigor to frailty among 287 black men ages 70−81 from the Health, Aging, and Body Composition study. Using liquid chromatography-mass spectrometry, 350 metabolites were measured in overnight-fasting plasma. The Scale of Aging Vigor in Epidemiology (SAVE) measured vigor to frailty based on weight change, strength, energy, gait speed, and physical activity. Thirty-seven metabolites correlated with SAVE scores (p < 0.05), while adjusting for age and site. Fourteen metabolites remained significant after multiple comparisons adjustment (false discovery rate < 0.30). Lower values of tryptophan, methionine, tyrosine, asparagine, C14:0 sphingomyelin, and 1-methylnicotinamide, and higher values of glucoronate, N-carbamoyl-beta-alanine, isocitrate, creatinine, C4-OH carnitine, cystathionine, hydroxyphenylacetate, and putrescine were associated with frailer SAVE scores. Pathway analyses identified nitrogen metabolism, aminoacyl-tRNA biosynthesis, and the citric acid cycle. Future studies need to confirm these SAVE-associated metabolites and pathways that may indicate novel mechanisms involved in the frailty syndrome.

BackgroundThe effects of the renin-angiotensin-aldosterone system in cardiovascular system have been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity (PRA) and cardiovascular structure and function.MethodsWe studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and PRA blood assays at 2003-2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded.ResultsThe aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m2 higher left ventricle (LV) mass index (P = 0.04) and 0.11 ml/m2 higher left atrium (LA) minimal volume index (P < 0.01). Additionally, higher log-transformed aldosterone was associated with lower LA maximum strain and LA emptying fraction (P < 0.01). Aldosterone levels were not significantly associated with aortic measures. Log-transformed PRA was associated with lower LV end diastolic volume index (β standardized = 0.08, P = 0.05). PRA levels were not significantly associated with LA and aortic structural or functional differences.ConclusionsHigher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes.

Objectives: To assess the Knowledge and Practice regarding Oral Health among the Rural Government Primary school teachers of Mangalore, Karnataka, India. Materials & Method: A self administered close ended questionnaire consisting of 15 items was distributed among the rural primary school teachers of Mangalore (n= 165). Comparison of knowledge and practice amongst the three age groups was done with Kruskal Wallis test. Comparison of mean scores between the genders was done using Mann-Whitney-U test. Comparison of mean scores across four educational qualification groups was done using Kruskal Wallis test. Results: Significant difference (p< 0.01) was found across the three age groups for the mean practice scores. There was significant difference between the genders with females scoring better for the mean knowledge, practice and the total scores. Conclusions: Oral health knowledge was lacking among the primary school teachers of rural Mangalore, although practices were satisfactory. Oral health education program targeting only the teachers is of utmost importance in the light of the present study results.