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BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) is influenced by seasonality, but there is limited understanding of how specific climatic variables contribute to disease spread. This information aids in understanding disease transmission dynamics and could potentially inform public health modeling. METHODS: This retrospective cohort study analyzed public health data from Ontario, Canada, between 2012 and 2021, along with historical climate data from Environment Canada. We employed Seasonal Autoregressive Integrated Moving Average (S-ARIMA) models to assess how temperature and precipitation impact the incidence of STEC infections, measured per 10,000,000 population. RESULTS: The study included 1658 confirmed STEC cases. A significant correlation was found between STEC incidence and climatic variables. Each degree Celsius increase in maximum temperature was associated with a rise of 3 STEC cases per 10,000,000 population (Centers for Disease Control and Prevention (2024)). Additionally, each millimeter of increased precipitation correlated with an increase of 1.1 cases per 10,000,000 population. CONCLUSIONS: The findings demonstrate a significant impact of temperature and precipitation on STEC transmission, highlighting the importance of integrating meteorological data into public health surveillance. This integration may help inform public health responses and support healthcare systems in planning for future outbreaks. Further studies are needed to refine predictive models and develop effective early warning systems for clinical settings.

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The burden of long-term functional impairment following curative treatment for tuberculosis (TB) constitutes a significant global health problem. By some estimates, chronic respiratory impairment, or post-tuberculosis lung disease (PTLD), is present in just over half of all patients who have completed TB therapy. Despite this high prevalence and substantial associated morbidity, discussion of PTLD is essentially absent from international and national TB policies and guidelines. Clear and ambitious clinical standards should be established for the diagnosis and management of PTLD, including the stipulation that all patients completing TB therapy should be screened for PTLD. Patients diagnosed with PTLD should receive linkage to chronic care, with access to inhalers and home oxygen, as indicated based on individual symptoms and pathophysiology. Leveraging their considerable influence, major funders, such as The Global Fund, could help close the gap in PTLD care by including PTLD in their strategic vision and funding streams. Immediate action is needed to address the substantial burden of disease associated with PTLD. This will require expanding the global approach to TB to include a commitment to diagnosing and treating long-term complications following initial curative therapy.

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Potato (Solanum tuberosum L.) is the most widely grown vegetable in the world. Consumers and processors evaluate potatoes based on quality traits such as shape and skin color, making these traits important targets for breeders. Achieving and evaluating genetic gain is facilitated by precise and accurate trait measures. Historically, quality traits have been measured using visual rating scales, which are subject to human error and necessarily lump individuals with distinct characteristics into categories. Image analysis offers a method of generating quantitative measures of quality traits. In this study, we use TubAR, an image-analysis R package, to generate quantitative measures of shape and skin color traits for use in genomic prediction. We developed and compared different genomic models based on additive and additive plus non-additive relationship matrices for two aspects of skin color, redness, and lightness, and two aspects of shape, roundness, and length-to-width ratio for fresh market red and yellow potatoes grown in Minnesota between 2020 and 2022. Similarly, we used the much larger chipping potato population grown during the same time to develop a multi-trait selection index including roundness, specific gravity, and yield. Traits ranged in heritability with shape traits falling between 0.23 and 0.85, and color traits falling between 0.34 and 0.91. Genetic effects were primarily additive with color traits showing the strongest effect (0.47), while shape traits varied based on market class. Modeling non-additive effects did not significantly improve prediction models for quality traits. The combination of image analysis and genomic prediction presents a promising avenue for improving potato quality traits.

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Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific. In beta cells, donor age associated with hypoxia, apoptosis, unfolded protein response, and external signal-dependent transcriptional regulators, while HbA1c associated with inflammatory responses and gender with chromatin organization. We identified 10.8K loci where genetic variants were QTLs for cis regulatory element (cRE) accessibility, including 20% with lineage- or cell type-specific effects which disrupted distinct transcription factor motifs. Type 2 diabetes and glycemic trait associated variants were enriched in both phenotype- and QTL-associated beta cell cREs, whereas type 1 diabetes showed limited enrichment. Variants at 226 diabetes and glycemic trait loci were QTLs in beta and other cell types, including 40 that were statistically colocalized, and annotating target genes of colocalized QTLs revealed genes with putatively novel roles in disease. Our findings reveal diverse responses of pancreatic cell types to phenotype and genotype in physiology, and identify pathways, networks, and genes through which physiology impacts diabetes risk.

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Establishing a nonproductive, quiescent infection within monocytes is essential for the spread of human cytomegalovirus (HCMV). We investigated the mechanisms through which HCMV establishes a quiescent infection in monocytes. US28 is a virally encoded G protein-coupled receptor (GPCR) that is essential for silent infections within cells of the myeloid lineage. We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic infection able to produce progeny virus. Infection with US28Δ HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser473 and Thr308, in contrast with the phosphorylation of Akt only at Ser473 after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser473. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.

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INTRODUCTION: People with HIV (PWH) have an increased risk of atherosclerotic cardiovascular disease (ASCVD) compared to non-PWH, but the reasons for this increased risk remain elusive. We investigated the change in ASCVD risk scores over 4 years to identify clinical factors associated with change in risk scores or high-risk scores. METHODS: We conducted a preliminary study using retrospective analysis of PWH, between 40 and 75 years old, seen at the Evelyn Jordan Center with at least two routine HIV visits. We collected clinical and demographic data and calculated the ASCVD risk scores using the Pooled Cohort Equation. Exploratory analyses examined change in risk score categories over time. Final adjusted analysis examined factors associated with change in continuous risk scores over time. RESULTS: Our sample included 187 PWH; 166 were black/African American and 79 were female. We found no significant change in ASCVD risk score over time. The risk score was significantly higher in PWH with hepatitis C (7.34%; 95% CI: 2.59, 12.09; p = 0.003) and trended higher in those with dual hepatitis B/C and hepatitis B compared to those without hepatitis (p = 0.07). CONCLUSION: We found that ASCVD risk did not change over a 4-year period among predominantly black young PWH, but infection with hepatitis C and dual hepatitis B/C were associated with higher ASCVD risk scores. Our findings illustrate the need for further longitudinal studies evaluating change in cardiovascular disease (CVD) risk and investigating viral hepatitis as an added potential contributor to increased CVD risk in high-risk, vulnerable populations.

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Older adults with impairment in contrast sensitivity (CS), the ability to visually perceive differences in light and dark, are more likely to demonstrate limitations in mobility function, but the mechanisms underlying this relationship are poorly understood. We sought to determine if functional brain networks important to visual processing and mobility may help elucidate possible neural correlates of this relationship. This cross-sectional analysis utilized functional MRI both at rest and during a motor imagery (MI) task in 192 community-dwelling, cognitively-unimpaired older adults ≥ 70 years of age from the Brain Networks and Mobility study (B-NET). Brain networks were partitioned into network communities, groups of regions that are more interconnected with each other than the rest of the brain, the spatial consistency of the communities for multiple brain subnetworks was assessed. Lower baseline binocular CS was significantly associated with degraded sensorimotor network (SMN) community structure at rest. During the MI task, lower binocular CS was significantly associated with degraded community structure in both the visual (VN) and default mode network (DMN). These findings may suggest shared neural pathways for visual and mobility dysfunction that could be targeted in future studies.

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Maintaining dynamic balance during transitional movements like sit-to-walk (STW) can be challenging for older adults. Age-related neuromuscular decline can alter movement in STW, such as rising with greater trunk flexion, narrowing the feet, or using arms to push off. Initial foot and arm position can affect subsequent movement biomechanics, with different ground reaction forces (GRFs) that stabilize and advance the body center of mass (COM). The purpose of this study was to quantify whole-body biomechanics and trunk control of STW transitions. Fifteen younger adults (18-35 years) and fifteen older adults (50-79 years) performed STW from four initial foot positions and two arm positions. Three-dimensional (3D) GRFs, 3D body COM displacement, and integrated electromyography values from the lumbar paraspinals and gluteus medius were evaluated. Younger adults generated greater mediolateral GRF ranges while rising, whereas older adults generated greater mediolateral GRF ranges when stepping forward suggesting different strategies to laterally control the body COM. Initial foot position affected the STW movement, with narrow foot positions having smaller body COM displacement than wide foot positions, associated with smaller medial GRFs to move the body COM toward the stance limb. Rising with arm support required less lumbar paraspinal excitation, which was further reduced when with a posteriorly offset foot. Gluteus medius activity was greater for older adults compared to younger adults in STW. Completing STW with arm support can reduce the muscle activity required to stabilize the torso when rising, which likely has implications for balance control and low back loading.

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Importance: Anti-ß-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD. Objective: To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies. Design, Setting, Participants: The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024. Exposure: The binding properties of lecanemab were assessed in brain tissue. Main Outcome: The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels. Results: Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years. Conclusions and Relevance: These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.

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Declining physical function with aging is associated with structural and functional brain network organization. Gaining a greater understanding of network associations may be useful for targeting interventions that are designed to slow or prevent such decline. Our previous work demonstrated that the Short Physical Performance Battery (eSPPB) score and body mass index (BMI) exhibited a statistical interaction in their associations with connectivity in the sensorimotor cortex (SMN) and the dorsal attention network (DAN). The current study examined if components of the eSPPB have unique associations with these brain networks. Functional magnetic resonance imaging was performed on 192 participants in the BNET study, a longitudinal and observational trial of community-dwelling adults aged 70 or older. Functional brain networks were generated for resting state and during a motor imagery task. Regression analyses were performed between eSPPB component scores (gait speed, complex gait speed, static balance, and lower extremity strength) and BMI with SMN and DAN connectivity. Gait speed, complex gait speed, and lower extremity strength significantly interacted with BMI in their association with SMN at rest. Gait speed and complex gait speed were interacted with BMI in the DAN at rest while complex gait speed, static balance, and lower extremity strength interacted with BMI in the DAN during motor imagery. Results demonstrate that different components of physical function, such as balance or gait speed and BMI, are associated with unique aspects of brain network organization. Gaining a greater mechanistic understanding of the associations between low physical function, body mass, and brain physiology may lead to the development of treatments that not only target specific physical function limitations but also specific brain networks.

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Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) H5N1 virus was detected in the South American sea lions found dead in Santa Catarina, Brazil, in October 2023. Whole genome sequencing and comparative phylogenetic analysis were conducted to investigate the origin, genetic diversity, and zoonotic potentials of the H5N1 viruses. The H5N1 viruses belonged to the genotype B3.2 of clade 2.3.4.4b H5N1 virus, which was identified in North America and disseminated to South America. They have acquired new amino acid substitutions related to mammalian host affinity. Our study provides insights into the genetic landscape of HPAI H5N1 viruses in Brazil, highlighting the continuous evolutionary processes contributing to their possible adaptation to mammalian hosts.

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Lactic Acid Bacteria (LAB) have a long history of safe use in milk fermentation and are generally recognized as health-promoting microorganisms when present in fermented foods. LAB are also important components of the human intestinal microbiota and are widely used as probiotics. Considering their safe and health-beneficial properties, LAB are considered appropriate vehicles that can be genetically modified for food, industrial and pharmaceutical applications. Here, this review describes (1) the potential opportunities for application of genetically modified LAB strains in dairy fermentation and (2) the various genomic modification tools for LAB strains, such as random mutagenesis, adaptive laboratory evolution, conjugation, homologous recombination, recombineering, and CRISPR (clustered regularly interspaced short palindromic repeat)- Cas (CRISPR-associated protein) based genome engineering. Lastly, this review also discusses the potential future developments of these genomic modification technologies and their applications in dairy fermentations.

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Introduction: Transcranial direct current stimulation (tDCS) administers low-intensity direct current electrical stimulation to brain regions via electrodes arranged on the surface of the scalp. The core promise of tDCS is its ability to modulate brain activity and affect performance on diverse cognitive functions (affording causal inferences regarding regional brain activity and behavior), but the optimal methodological parameters for maximizing behavioral effects remain to be elucidated. Here we sought to examine the effects of 10 stimulation and experimental design factors across a series of five cognitive domains: motor performance, visual search, working memory, vigilance, and response inhibition. The objective was to identify a set of optimal parameter settings that consistently and reliably maximized the behavioral effects of tDCS within each cognitive domain. Methods: We surveyed tDCS effects on these various cognitive functions in healthy young adults, ultimately resulting in 721 effects across 106 published reports. Hierarchical Bayesian meta-regression models were fit to characterize how (and to what extent) these design parameters differentially predict the likelihood of positive/negative behavioral outcomes. Results: Consistent with many previous meta-analyses of tDCS effects, extensive variability was observed across tasks and measured outcomes. Consequently, most design parameters did not confer consistent advantages or disadvantages to behavioral effects-a domain-general model suggested an advantage to using within-subjects designs (versus between-subjects) and the tendency for cathodal stimulation (relative to anodal stimulation) to produce reduced behavioral effects, but these associations were scarcely-evident in domain-specific models. Discussion: These findings highlight the urgent need for tDCS studies to more systematically probe the effects of these parameters on behavior to fulfill the promise of identifying causal links between brain function and cognition.

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Numerous studies have demonstrated that dementia is associated with increased utilization of health care services, which in turn results in increased costs of care. Dementia with Lewy bodies (DLB) is associated with greater costs of care relative to other forms of dementia due to higher rates of hospitalization and nursing home placement directly related to neuropsychiatric symptoms, parkinsonism, increased susceptibility to delirium, and elevated rates of caregiver burden. There is a critical need for researchers to identify potentially modifiable factors contributing to increased costs of care and poor clinical outcomes for patients with DLB, which may include comorbidities, polypharmacy/contraindicated medications, and access to specialty care. Previous research has utilized Medicare claims data, limiting the ability to study patients with early-onset (ie, prior to age 65) DLB. Integrated health systems offer the ability to combine electronic medical record data with Medicare, Medicaid, and commercial claims data and may therefore be ideal for utilization research in this population. The goals of this narrative review are to 1) synthesize and describe the current literature on health care utilization studies for patients with DLB, 2) highlight the current gaps in the literature, and 3) provide recommendations for stakeholders, including researchers, health systems, and policymakers. It is important to improve current understanding of potentially modifiable factors associated with increased costs of care among patients with DLB to inform public health policies and clinical decision-making, as this will ultimately improve the quality of patient care.

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A refugial population of the endangered delta smelt (Hypomesus transpacificus) has been maintained at the Fish Conservation and Culture Laboratory (FCCL) at UC Davis since 2008. Despite intense genetic management, fitness differences between wild and cultured fish have been observed at the FCCL. To investigate the molecular underpinnings of hatchery domestication, we used whole-genome bisulfite sequencing to quantify epigenetic differences between wild and hatchery-origin delta smelt. Differentially methylated regions (DMRs) were identified from 104 individuals by comparing the methylation patterns in different generations of hatchery fish (G1, G2, G3) with their wild parents (G0). We discovered a total of 132 significant DMRs (p < .05) between G0 and G1, 132 significant DMRs between G0 and G2, and 201 significant DMRs between G0 and G3. Our results demonstrate substantial differences in methylation patterns emerged between the wild and hatchery-reared fish in the early generations in the hatchery, with a higher proportion of hypermethylated DMRs in hatchery-reared fish. The rearing environment was found to be a stronger predictor of individual clustering based on methylation patterns than family, sex or generation. Our study indicates a reinforcement of the epigenetic status with successive generations in the hatchery environment, as evidenced by an increase in methylation in hypermethylated DMRs and a decrease in methylation in hypomethylated DMRs over time. Lastly, our results demonstrated heterogeneity in inherited methylation pattern in families across generations. These insights highlight the long-term consequences of hatchery practices on the epigenetic landscape, potentially impacting wild fish populations.

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Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, ~1% were transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate focal initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of >5,000X across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a focal presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

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Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, < 1% were transmitted by misfolded PrP, ~ 15% are inherited, and ~ 85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate localized initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of > 5000× across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a localized presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

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Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations. Results show that elevated triglyceride and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.

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Objectives: In an era of increasing paediatric obesity and inflammatory bowel disease (IBD), this study evaluates the disease phenotype and clinical course of Crohn's disease (CD) in paediatric patients who are obese or overweight. Methods: This is a retrospective, single-center, descriptive observational study from January 2010 to May 2020. Participants were included if they were: aged 2 to 18 years at the time of diagnosis, had a confirmed diagnosis of CD, and met WHO criteria for overweight or obesity at the time of diagnosis or within one year before diagnosis. Results: A total of 345 patient charts with CD were screened during the study period, with 16 patients meeting inclusion criteria. Median age of patients was 15.5 years (IQR = 13.6, 16.1). Of the 15 patients over 10 years of age, median anthropometrics at diagnosis included body mass index (BMI) of 27.2 (IQR = 24.9, 29.4) and BMI for age z-score of 1.82 (IQR = 1.58, 2.19). Presenting symptoms included abdominal pain (80.0%), diarrhea (66.7%), hematochezia (66.7%), and weight loss (26.7%). Five patients (33.3%) had obesity-related complications. Median time from symptom onset to diagnosis was 146 days (IQR = 31, 367), and median time from diagnosis to remission was 229 days (IQR = 101.8, 496.3). Conclusions: Patients with elevated BMI and CD present with typical symptoms of IBD, although weight loss was a less common presenting symptom. Time to disease remission is delayed, and obesity-related complications are common. Primary care providers must have a high degree of clinical suspicion in patients to prevent delays to gastroenterology referral and to improve time to disease remission.