Distal Ventricular Pacing for Drug-Refractory Mid-Cavity Obstructive Hypertrophic Cardiomyopathy: A Randomized, Placebo-Controlled Trial of Personalized Pacing.

BACKGROUND: Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms. METHODS: Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP. RESULTS: A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mm Hg fell to 31±21 mm Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP. CONCLUSIONS: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO. REGISTRATION: URL: https://clinicaltrials.gov/study; Unique Identifier: NCT03450252.

The impact of COVID-19 national lockdowns on drug-resistant tuberculosis in KwaZulu-Natal, South Africa: A spatial analysis.

PURPOSE: We sought to understand the impact of the initial COVID-19 mitigation strategies in 2020 on drug-resistant (DR) TB diagnoses in KwaZulu-Natal province (KZN), South Africa. METHODS: We compared the number, spatial distribution, and characteristics of DR TB diagnoses before and after the initial COVID-19 lockdown on March 26th, 2020. Information on DR TB diagnoses was collected from the CONTEXT prospective cohort study and municipality characteristics were collected from Statistics South Africa. We used Bayesian conditional autoregressive models and relative-risk surface maps to examine spatial correlates and patterns of DR TB notifications. RESULTS: Between October 2018 and February 2022, there were 693 individuals diagnosed with DR TB in KZN, South Africa. The rate of diagnoses per year was 274 and 155 prior and after to the initial lockdowns, respectively, corresponding to a 43 % decrease in the notification rate of cases. Compared to cases diagnosed before the lockdown, cases diagnosed after were less likely to have a fuel source for heating, piped water, a flush toilet, or own a phone (p-values≤0.02). Changes in notifications were not homogenously distributed, with predominantly rural northeastern and southwestern municipalities having significantly greater relative-risks after the lockdown. CONCLUSIONS: We found a reduction in the rate of DR TB diagnoses after the COVID-19 pandemic lockdowns and observed that individuals diagnosed after the lockdowns had worse living conditions, fewer household resources, and more adults living in their household compared to before the pandemic.

Willingness and capacity of publicly-funded vector control programs in the USA to engage in tick management.

BACKGROUND: The vast majority of vector-borne diseases in the USA are associated with mosquitoes or ticks. Mosquito control is often conducted as part of community programs run by publicly-funded entities. By contrast, tick control focuses primarily on individual residential properties and is implemented predominantly by homeowners and the private pest control firms they contract. We surveyed publicly-funded vector control programs (VCPs), presumed to focus mainly on mosquitoes, to determine what tick-related services they currently offer, and their interest in and capacity to expand existing services or provide new ones. METHODS: We distributed a survey to VCPs in the Northeast, Upper Midwest and Pacific Coast states of the USA, where humans are at risk for bites by tick vectors (Ixodes scapularis or Ixodes pacificus) of agents causing Lyme disease and other tick-borne diseases. The data we report are based on responses from 118 VCPs engaged in vector control and with at least some activities focused on ticks. RESULTS: Despite our survey targeting geographic regions where ticks and tick-borne diseases are persistent and increasing public health concerns, only 11% (12/114) of VCPs reported they took direct action to suppress ticks questing in the environment. The most common tick-related activities conducted by the VCPs were tick bite prevention education for the public (70%; 75/107 VCPs) and tick surveillance (48%; 56/116). When asked which services they would most likely include as part of a comprehensive tick management program, tick bite prevention education (90%; 96/107), tick surveillance (89%; 95/107) and tick suppression guidance for the public (74%; 79/107) were the most common services selected. Most VCPs were also willing to consider engaging in activities to suppress ticks on public lands (68%; 73/107), but few were willing to consider suppressing ticks on privately owned land such as residential properties (15%; 16/107). Across all potential tick-related services, funding was reported as the biggest obstacle to program expansion or development, followed by personnel. CONCLUSIONS: Considering the hesitancy of VCPs to provide tick suppression services on private properties and the high risk for tick bites in peridomestic settings, suppression of ticks on residential properties by private pest control operators will likely play an important role in the tick suppression landscape in the USA for the foreseeable future. Nevertheless, VCPs can assist in this effort by providing locally relevant guidelines to homeowners and private pest control firms regarding best practices for residential tick suppression efforts and associated efficacy evaluations. Publicly-funded VCPs are also well positioned to educate the public on personal tick bite prevention measures and to collect tick surveillance data that provide information on the risk of human encounters with ticks within their jurisdictions.

CNNs trained with adult data are useful in pediatrics. A pneumonia classification example.

BACKGROUND AND OBJECTIVES: The scarcity of data for training deep learning models in pediatrics has prompted questions about the feasibility of employing CNNs trained with adult images for pediatric populations. In this work, a pneumonia classification CNN was used as an exploratory example to showcase the adaptability and efficacy of such models in pediatric healthcare settings despite the inherent data constraints. METHODS: To develop a curated training dataset with reduced biases, 46,947 chest X-ray images from various adult datasets were meticulously selected. Two preprocessing approaches were tried to assess the impact of thoracic segmentation on model attention outside the thoracic area. Evaluation of our approach was carried out on a dataset containing 5,856 chest X-rays of children from 1 to 5 years old. RESULTS: An analysis of attention maps indicated that networks trained with thorax segmentation placed less attention on regions outside the thorax, thus eliminating potential bias. The ensuing network exhibited impressive performance when evaluated on an adult dataset, achieving a pneumonia discrimination AUC of 0.95. When tested on a pediatric dataset, the pneumonia discrimination AUC reached 0.82. CONCLUSIONS: The results of this study show that adult-trained CNNs can be effectively applied to pediatric populations. This could potentially shift focus towards validating adult models over pediatric population instead of training new CNNs with limited pediatric data. To ensure the generalizability of deep learning models, it is important to implement techniques aimed at minimizing biases, such as image segmentation or low-quality image exclusion.

A human autoimmune organoid model reveals IL-7 function in coeliac disease.

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury1-4. Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.

The MET Family of Receptor Tyrosine Kinases Promotes a Shift to Pro-Tumor Metabolism.

The development and growth of cancer is fundamentally dependent on pro-tumor changes in metabolism. Cancer cells generally shift away from oxidative phosphorylation as the primary source of energy and rely more heavily on glycolysis. Receptor tyrosine kinases (RTKs) are a type of receptor that is implicated in this shift to pro-tumor metabolism. RTKs are important drivers of cancer growth and metastasis. One such family of RTKs is the MET family, which consists of MET and RON (MST1R). The overexpression of either MET or RON has been associated with worse cancer patient prognosis in a variety of tumor types. Both MET and RON signaling promote increased glycolysis by upregulating the expression of key glycolytic enzymes via increased MYC transcription factor activity. Additionally, both MET and RON signaling promote increased cholesterol biosynthesis downstream of glycolysis by upregulating the expression of SREBP2-induced cholesterol biosynthesis enzymes via CTTNB1. These changes in metabolism, driven by RTK activity, provide potential targets in limiting tumor growth and metastasis via pharmacological inhibition or modifications in diet. This review summarizes pro-tumor changes in metabolism driven by the MET family of RTKs. In doing so, we will offer our unique perspective on metabolic pathways that drive worse patient prognosis and provide suggestions for future study.

Wastewater and clinical surveillance of respiratory viral pathogens on a university campus.

Areas of dense population congregation are prone to experience respiratory virus outbreaks. We monitored wastewater and clinic patients for the presence of respiratory viruses on a large, public university campus. Campus sewer systems were monitored in 16 locations for the presence of viruses using next generation sequencing over 22 weeks in 2023. During this period, we detected a surge in human adenovirus (HAdV) levels in wastewater. Hence, we initiated clinical surveillance at an on-campus clinic from patients presenting with acute respiratory infection. From whole genome sequencing of 123 throat and/or nasal swabs collected, we identified an outbreak of HAdV, specifically of HAdV-E4 and HAdV-B7 genotypes overlapping in time. The temporal dynamics and proportions of HAdV genotypes found in wastewater were corroborated in clinical infections. We tracked specific single nucleotide polymorphisms (SNPs) found in clinical virus sequences and showed that they arose in wastewater signals concordant with the time of clinical presentation, linking community transmission of HAdV to the outbreak. This study demonstrates how wastewater-based epidemiology can be integrated with surveillance at ambulatory healthcare settings to monitor areas prone to respiratory virus outbreaks and provide public health guidance.

Minimal Detectable Change of Cough and Lingual Strength Outcomes in Neurodegenerative Disease.

OBJECTIVE: Minimal detectable change (MDC) represents the smallest amount of change required for an outcome to be considered real and not merely due to measurement error or task variability. This study aimed to examine MDC for cough and lingual strength outcomes among individuals with neurodegenerative disease. METHODS: In a single session, individuals diagnosed with Parkinson's disease (PD), progressive supranuclear palsy (PSP), and cerebellar ataxia completed repeated measurements of voluntary sequential cough via spirometry (n = 143) and lingual isometric and swallowing pressure with the Iowa Oral Performance Instrument (n = 231). The MDC at the 95% confidence level was calculated with the following formula: MDC = 1.96 × âˆš2 × SEM. RESULTS: MDC for cough strength was 0.52 L/s (PD), 0.57 L/s (PSP), and 0.20 L/s (ataxia). On trials with the same number of coughs, MDC for cough strength was 0.18 L/s in PD and 0.24 L/s in ataxia. MDC for lingual isometric pressure was 5.44 kPa (PD), 2.35 kPa (PSP), and 3.41 kPa (ataxia), whereas swallowing pressure was 5.60 kPa (PD), 2.97 kPa (PSP), and 7.34 kPa (ataxia). CONCLUSIONS: These findings elucidate MDC for cough and lingual strength outcomes and expand our understanding of change that can be considered "real" and not merely due to task variability. MDC facilitates valid interpretations of changes following treatment, as well as power analyses to determine the smallest effect size of interest before data collection. To illustrate the application of MDC, we situate these findings in the context of hypothetical case studies and research studies. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

T1 colorectal cancer patients' perspective on information provision and therapeutic decision-making after local resection.

BACKGROUND: Decision-making after local resection of T1 colorectal cancer (T1CRC) is often complex and calls for optimal information provision as well as active patient involvement. OBJECTIVE: The aim was to evaluate the perceptions of patients with T1CRC on information provision and therapeutic decision-making. METHODS: This multicenter cross-sectional study included patients who underwent endoscopic or local surgical resection as initial treatment. Information provision was assessed using the EORTC QLQ-INFO25 questionnaire. In patients with high-risk T1CRC, we evaluated decisional involvement and satisfaction regarding the choice as to whether to undergo additional treatment after local resection, and the level of decisional conflict using the Decisional Conflict Scale. RESULTS: Ninety-eight patients with T1CRC were included (72% response rate; 79/98 endoscopic and 19/98 local surgical resection; 45/98 high-risk T1CRC). Median time since local resection was 28 months (IQR 18); none had developed recurrence. Unmet information needs were reported by 29 patients (30%; 18 low-risk, 11 high-risk), mostly on post-treatment related topics (follow-up visits, recovery time, recurrence prevention). After local resection, 24 of the 45 high-risk patients (53%) underwent additional treatment, while others were subjected to surveillance. Higher-educated patients were more often actively involved in decision-making (93% vs. 43%, p = 0.002) and more frequently underwent additional treatment (79% vs. 40%, p = 0.02). Decisional conflict (p = 0.19) and satisfaction (p = 0.78) were comparable between higher- and lower-educated high-risk patients. CONCLUSION: Greater attention should be given to the post-treatment course during consultations following local T1CRC resection. The differences in decisional involvement and selected management strategies between higher- and lower-educated high-risk patients warrant further investigation.

Ligand Equilibrium Influences Photoluminescence Blinking in CsPbBr3: A Change Point Analysis of Widefield Imaging Data.

Photoluminescence intermittency remains one of the biggest challenges in realizing perovskite quantum dots (QDs) as scalable single photon emitters. We compare CsPbBr3 QDs capped with different ligands, lecithin, and a combination of oleic acid and oleylamine, to elucidate the role of surface chemistry on photoluminescence intermittency. We employ widefield photoluminescence microscopy to sample the blinking behavior of hundreds of QDs. Using change point analysis, we achieve the robust classification of blinking trajectories, and we analyze representative distributions from large numbers of QDs (Nlecithin = 1308, Noleic acid/oleylamine = 1317). We find that lecithin suppresses blinking in CsPbBr3 QDs compared with oleic acid/oleylamine. Under common experimental conditions, lecithin-capped QDs are 7.5 times more likely to be nonblinking and spend 2.5 times longer in their most emissive state, despite both QDs having nearly identical solution photoluminescence quantum yields. We measure photoluminescence as a function of dilution and show that the differences between lecithin and oleic acid/oleylamine capping emerge at low concentrations during preparation for single particle experiments. From experiment and first-principles calculations, we attribute the differences in lecithin and oleic acid/oleylamine performance to differences in their ligand binding equilibria. Consistent with our experimental data, density functional theory calculations suggest a stronger binding affinity of lecithin to the QD surface compared to oleic acid/oleylamine, implying a reduced likelihood of ligand desorption during dilution. These results suggest that using more tightly binding ligands is a necessity for surface passivation and, consequently, blinking reduction in perovskite QDs used for single particle and quantum light experiments.

Mitral Annulus Disjunction: A Comprehensive Cardiovascular Magnetic Resonance Phenotype and Clinical Outcomes Study.

BACKGROUND: Clinical importance of mitral annulus disjunction (MAD) is not well established. PURPOSE: Characterize a population of MAD all-comers diagnosed by cardiac magnetic resonance imaging (MRI). STUDY TYPE: Retrospective. POPULATION: MAD confirmed in 222 patients, age of 49.2 ± 19.3 years, 126 (56.8%) males. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/steady-state free precession and inversion recovery. ASSESSMENT: Clinical history, outcomes, imaging, and arrhythmia data. MAD defined as a separation ≥2 mm between left ventricular myocardium and mitral annulus. Presence and pattern of late gadolinium enhancement (LGE) were analyzed. LGE in the papillary muscles and adjacent to MAD were identified as MAD related. Ventricular arrhythmias (VA) were grouped into non-sustained ventricular arrhythmias (NSVA) or sustained. Cardiovascular death assessed. STATISTICAL TESTS: Differences between baseline characteristics were compared. Univariate regression was used to investigate possible associations between ventricular arrhythmia and cardiovascular death with characteristics associated with the severity of MAD. A multivariable logistic regression included significant variables from the univariate analysis and was performed for MAD-related and global LGE. RESULTS: MAD extent 5.0 ± 2.6 mm. MV annulus expanded during systole for MAD ≥6 mm. Systolic expansion associated with prolapse, billowing, and curling. LGE present in 82 patients (36.9%). Twenty-three patients (10.4%) showed MAD-related LGE by three different observers. No association of LGE with MAD extent (P = 0.545) noted. Follow-up 4.1 ± 2.4 years. No sustained VA observed. In univariable analysis, NSVA was more prevalent in patients with MAD ≥6 mm (33.3% vs. 9.9%), but this was attenuated on multivariate analysis (P = 0.054). The presence of NSVA was associated with global LGE but not MAD-related LGE in isolation (P = 0.750). Three patients died of cardiovascular causes (1.4%) and none had MAD-related LGE. None died of sudden cardiac arrest. CONCLUSION: In patients referred for cardiac MRI, mitral valve dysfunction was associated with MAD severity. Scar was not related to the extent of MAD, but associated with NSVA. The risk of sustained arrhythmias and cardiovascular death was low in this population. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

A common genetic variant in the Neurexin family member CNTNAP2 is related to language but not communication skills in youth with Autism Spectrum Disorder.

One of the candidate genes related to language variability in individuals with Autism Spectrum Disorder (ASD) is the contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin family. However, due to the different assessment tools used, it is unknown whether the polymorphisms of the CNTNAP2 gene are linked to structural language skills or more general communication abilities. A total of 302 youth aged 7 to 18 years participated in the present study: 131 verbal youth with ASD (62 female), 130 typically developing (TD) youth (64 female), and 41 unaffected siblings (US) of youth with ASD (25 female). Blood samples were collected to obtain genomic DNA and processed by the Rutgers University Cell and Data Repository or using standard protocols (Gentra Puregene Blood DNA extraction kit; Qiagen). Language and verbal communication skills were screened with the Clinical Evaluation of Language Fundamental-4 (CELF-4) and Vineland-II Communication domain, subsequently. The results showed that the polymorphism of CNTNAP2 (SNP rs2710102) was related to structural language abilities, such that participants carrying the A-allele had lower language skills in comparison to the G-allele homozygotes. No relationship was found between the polymorphism of CNTNAP2 and more general communication abilities. Although the study revealed genetic mechanisms that are associated with CELF-4 measures but not Vineland-II in youth with ASD, follow-up studies are needed that will include measures of language and communication that are less correlated to each other as well as will include a group of minimally and/or non-verbal individuals with ASD.

TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions.

Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNFα-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro-inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair.

Reducing Cardiovascular Disease-An Alternative Approach.

PURPOSE: Statin drugs are effective at reducing cardiovascular events, but adherence to statin therapy remains a problem for patients and their physicians. We review a paper estimating the economic costs of poor adherence to statin drugs. METHODS: The authors examined two large databases (Medicare and Market Scan databases) including 230,000 patients with hospitalization for myocardial infarction between 2018 and 2019 to determine how many patients were not adhering to guideline-recommended anti-hyperlipidemic medications. They have also calculated the potential consequences of patients who are not adhering to the recommended therapy. RESULTS: The authors estimate that if all patients were receiving guideline-directed medical therapy, then a 22% relative risk reduction would occur in the 3-year period following discharge from the initial cardiovascular event. These findings are consistent with prior reports. This editorial discusses rationale and strategies clinicians can use to improve patients' compliance with recommendations for lipid-lowering therapy. CONCLUSION: The authors conclude that better compliance with guideline-directed lipid therapy after a cardiovascular event would lead to a large reduction in second events. Increased efforts by clinicians to improve adherence to statin therapy are warranted.

Associations between COVID-19 therapies and outcomes in rural and urban America: A multisite, temporal analysis from the Alpha to Omicron SARS-CoV-2 variants.

PURPOSE: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes. METHODS: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression. FINDINGS: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization. CONCLUSIONS: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies.

Genome-wide association study reveals marker-trait associations for major agronomic traits in proso millet (Panicum miliaceum L.).

MAIN CONCLUSION: The pilot-scale genome-wide association study in the US proso millet identified twenty marker-trait associations for five morpho-agronomic traits identifying genomic regions for future studies (e.g. molecular breeding and map-based cloning). Proso millet (Panicum miliaceum L.) is an ancient grain recognized for its excellent water-use efficiency and short growing season. It is an indispensable part of the winter wheat-based dryland cropping system in the High Plains of the USA. Its grains are endowed with high nutritional and health-promoting properties, making it increasingly popular in the global market for healthy grains. There is a dearth of genomic resources in proso millet for developing molecular tools to complement conventional breeding for developing high-yielding varieties. Genome-wide association study (GWAS) is a widely used method to dissect the genetics of complex traits. In this pilot study of the first-ever GWAS in the US proso millet, 71 globally diverse genotypes of 109 the US proso millet core collection were evaluated for five major morpho-agronomic traits at two locations in western Nebraska, and GWAS was conducted to identify single nucleotide polymorphisms (SNPs) associated with these traits. Analysis of variance showed that there was a significant difference among the genotypes, and all five traits were also found to be highly correlated with each other. Sequence reads from genotyping-by-sequencing (GBS) were used to identify 11,147 high-quality bi-allelic SNPs. Population structure analysis with those SNPs showed stratification within the core collection. The GWAS identified twenty marker-trait associations (MTAs) for the five traits. Twenty-nine putative candidate genes associated with the five traits were also identified. These genomic regions can be used to develop genetic markers for marker-assisted selection in proso millet breeding.