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IntroductionEvaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities.MethodsWe analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), and assessed their interaction with apolipoprotein E (APOE).ResultsHigher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the apolipoprotein E*ε4 (APOE*ε4) risk effect and attenuated the APOE*ε2 protective effect.DiscussionOur findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health.HighlightsDementia risk scores demonstrate race/ethnic-specific effects on dementia risk. Unfavorable modifiable risk profiles moderate the effect of APOE on dementia risk. Dementia risk scores need to be validated in diverse populations.

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble models performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high β-sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting β-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19-residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau-ten times the length of the peptide-and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions.

Numerous biological systems contain vesicle-like biomolecular compartments without membranes, which contribute to diverse functions including gene regulation, stress response, signaling, and skin barrier formation. Coacervation, as a form of liquid-liquid phase separation (LLPS), is recognized as a representative precursor to the formation and assembly of membrane-less vesicle-like structures, although their formation mechanism remains unclear. In this study, a coacervation-driven membrane-less vesicle-like structure is constructed using two proteins, GG1234 (an anionic intrinsically disordered protein) and bhBMP-2 (a bioengineered human bone morphogenetic protein 2). GG1234 formed both simple coacervates by itself and complex coacervates with the relatively cationic bhBMP-2 under acidic conditions. Upon addition of dissolved bhBMP-2 to the simple coacervates of GG1234, a phase transition from spherical simple coacervates to vesicular condensates occurred via the interactions between GG1234 and bhBMP-2 on the surface of the highly viscoelastic GG1234 simple coacervates. Furthermore, the shell structure in the outer region of the GG1234/bhBMP-2 vesicular condensates exhibited gel-like properties, leading to the formation of multiphasic vesicle-like compartments. A potential mechanism is proposed for the formation of the membrane-less GG1234/bhBMP-2 vesicle-like compartments. This study provides a dynamic process underlying the formation of biomolecular multiphasic condensates, thereby enhancing the understanding of these biomolecular structures.

The study examined how childrens self-regulation skills measured by the strengths and weaknesses of ADHD symptoms and normal behavior rating are associated with story comprehension and how verbal engagement and e-book discussion prompts moderate this relation. Children aged 3-7 (N = 111, 50% female, Chinese as first language) read an interactive Chinese-English bilingual story e-book with or without discussion prompts twice with their parents (2020-2021). Results demonstrated that the lower childrens self-regulation skills, the more they struggled with story comprehension. Critically, our data suggest that embedding e-book discussion prompts and more verbalization in English can mitigate this negative association for children with inattention/hyperactivity. These findings have critical implications for future e-book design, interventions, and home reading practice for children with inattention/hyperactivity and those at risk for attention deficit/hyperactivity disorder.

The identification of catalytic RNAs is typically achieved through primarily experimental means. However, only a small fraction of sequence space can be analyzed even with high-throughput techniques. Methods to extrapolate from a limited data set to predict additional ribozyme sequences, particularly in a human-interpretable fashion, could be useful both for designing new functional RNAs and for generating greater understanding about a ribozyme fitness landscape. Using information theory, we express the effects of epistasis (i.e., deviations from additivity) on a ribozyme. This representation was incorporated into a simple model of the epistatic fitness landscape, which identified potentially exploitable combinations of mutations. We used this model to theoretically predict mutants of high activity for a self-aminoacylating ribozyme, identifying potentially active triple and quadruple mutants beyond the experimental data set of single and double mutants. The predictions were validated experimentally, with nine out of nine sequences being accurately predicted to have high activity. This set of sequences included mutants that form a previously unknown evolutionary bridge between two ribozyme families that share a common motif. Individual steps in the method could be examined, understood, and guided by a human, combining interpretability and performance in a simple model to predict ribozyme sequences by extrapolation.

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma.SignificanceAnalysis of a spectrum of subsolid pulmonary nodules by single-cell RNA sequencing provides insights into the immune regulation and cell-cell interactions in the tumor microenvironment during early lung tumor development.

BACKGROUND: Although Kawasaki disease is commonly regarded as a single disease entity, variability in clinical manifestations and disease outcome has been recognised. We aimed to use a data-driven approach to identify clinical subgroups. METHODS: We analysed clinical data from patients with Kawasaki disease diagnosed at Rady Childrens Hospital (San Diego, CA, USA) between Jan 1, 2002, and June 30, 2022. Patients were grouped by hierarchical clustering on principal components with k-means parcellation based on 14 variables, including age at onset, ten laboratory test results, day of illness at the first intravenous immunoglobulin infusion, and normalised echocardiographic measures of coronary artery diameters at diagnosis. We also analysed the seasonality and Kawasaki disease incidence from 2002 to 2019 by subgroup. To explore the biological underpinnings of identified subgroups, we did differential abundance analysis on proteomic data of 6481 proteins from 32 patients with Kawasaki disease and 24 healthy children, using linear regression models that controlled for age and sex. FINDINGS: Among 1016 patients with complete data in the final analysis, four subgroups were identified with distinct clinical features: (1) hepatobiliary involvement with elevated alanine transaminase, gamma-glutamyl transferase, and total bilirubin levels, lowest coronary artery aneurysm but highest intravenous immunoglobulin resistance rates (n=157); (2) highest band neutrophil count and Kawasaki disease shock rate (n=231); (3) cervical lymphadenopathy with high markers of inflammation (erythrocyte sedimentation rate, C-reactive protein, white blood cell, and platelet counts) and lowest age-adjusted haemoglobin Z scores (n=315); and (4) young age at onset with highest coronary artery aneurysm but lowest intravenous immunoglobulin resistance rates (n=313). The subgroups had distinct seasonal and incidence trajectories. In addition, the subgroups shared 211 differential abundance proteins while many proteins were unique to a subgroup. INTERPRETATION: Our data-driven analysis provides insight into the heterogeneity of Kawasaki disease, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation. FUNDING: US National Institutes of Health and the Irving and Francine Suknow Foundation.

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these supra-modal traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a general response pattern factor for each supra-modal construct and determine the added value of modality-specific response pattern scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many real-world sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

BackgroundBibliometric analysis of surgical research has become increasingly prevalent. Citation count (CC) is a commonly used marker of research quality, but may overlook impactful military research. The disruption score (DS) evaluates manuscripts on a spectrum from most innovative with more positive scores (disruptive [DR]) to most entrenched with more negative scores (developmental; DV). We sought to analyze the most DR and DV versus most cited research in military trauma.MethodsTop trauma articles by DS and by CC were identified via professional literature search. All publications in military journals were included. Military trauma-related keywords were used to query additional top surgical journals for military-focused publications. Publications were linked to the iCite NIH tool for CC and related metrics. The top 100 DR and DV publications by DS were analyzed and compared with the top 100 articles by CC.ResultsOverall, 32,040 articles published between 1954 and 2014 were identified. The average DS and CC were 0.01 and 22, respectively. Most articles were published in Mil Med ( 68%). The top 100 DR articles were frequently published in Mil Med (51%) with a mean DS of 0.148. Of these, the most cited article was only the 40th most disruptive. The top 100 CC articles averaged a DS of 0.009 and were commonly found in J Trauma (53%). Only five publications were on both the top 100 DR and top 100 CC lists; 19 were on both the top DV and CC lists. Citation count was not correlated with DR ( r = -0.134; p = 0.07) and only weakly correlated with DV ( r = 0.215; p = 0.003).ConclusionDS identifies publications that changed military paradigms and future research directions previously overlooked by citation count alone. The DR and DV articles are distinct with little overlap between highly cited military articles. Multiple bibliometric measures should be employed to avoid overlooking impactful military trauma research.Level of evidenceDiagnostic Test or Criteria; Level IV.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Hearing a task-irrelevant sound during object encoding can improve visual recognition memory when the sound is object-congruent (e.g., a dog and a bark). However, previous studies have only used binary old/new memory tests, which do not distinguish between recognition based on the recollection of details about the studied event or stimulus familiarity. In the present research, we hypothesized that hearing a task-irrelevant but semantically congruent natural sound at encoding would facilitate the formation of richer memory representations, resulting in increased recollection of details of the encoded event. Experiment 1 replicates previous studies showing that participants were more confident about their memory for items that were initially encoded with a congruent sound compared to an incongruent sound. Experiment 2 suggests that congruent object-sound pairings specifically facilitate recollection and not familiarity-based recognition memory, and Experiment 3 demonstrates that this effect was coupled with more accurate memory for audiovisual congruency of the item and sound from encoding rather than another aspect of the episode. These results suggest that even when congruent sounds are task-irrelevant, they promote formation of multisensory memories and subsequent recollection-based retention. Given the ubiquity of encounters with multisensory objects in our everyday lives, considering their impact on episodic memory is integral to building models of memory that apply to naturalistic settings.

BackgroundAlzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture. Until recently these efforts had identified 39 disease susceptibility loci in European ancestry populations.Recent developmentsTwo new AD/dementia GWAS have dramatically expanded the sample sizes and the number of disease susceptibility loci. The first increased total sample size to 1,126,563-with an effective sample size of 332,376-by predominantly including new biobank and population-based dementia datasets. The second, expands on an earlier GWAS from the International Genomics of Alzheimer's Project (IGAP) by increasing the number of clinically-defined AD cases/controls in addition to incorporating biobank dementia datasets, resulting in a total sample size to 788,989 and an effective sample size of 382,472. Collectively both GWAS identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. Pathway analyses indicate the susceptibility loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts for the novel loci identified 62 candidate causal genes. Many of the candidate genes from known and newly discovered loci play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD. WHERE NEXT?: While GWAS in European ancestry populations have substantially enhanced our understanding of AD genetic architecture, heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies. While this missing heritability is likely due to a combination of factors, it highlights that our understanding of AD genetic architecture and genetic risk mechanisms remains incomplete. These knowledge gaps result from several underexplored areas in AD research. First, rare variants remain understudied due to methodological issues in identifying them and the cost of generating sufficiently powered whole exome/genome sequencing datasets. Second, sample sizes of non-European ancestry populations in AD GWAS remain small. Third, GWAS of AD neuroimaging and cerebrospinal fluid endophenotypes remains limited due to low compliance and high costs associated with measuring amyloid-β and tau levels and other disease-relevant biomarkers. Studies generating sequencing data, including diverse populations, and incorporating blood-based AD biomarkers are set to substantially improve our knowledge of AD genetic architecture.

BACKGROUND: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction. PURPOSE: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patients outcome at 6-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction. RESULTS: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation (P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores (P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years. CONCLUSION: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.

Hexafluoropropylene oxide-dimer acid (HFPO-DA) is one of the emerging replacements for the "forever" carcinogenic and toxic long-chain PFAS. HFPO-DA is a polymerization aid used for manufacturing fluoropolymers, whose global distribution and undetermined toxic properties are a concern regarding human and ecological health. To assess embryotoxic potential, zebrafish embryos were exposed to HFPO-DA at concentrations of 0.5-20,000 mg/L at 24-, 48-, and 72-h post-fertilization (hpf). Heart rate increased significantly in embryos exposed to 2 mg/L and 10 mg/L HFPO-DA across all time points. Spinal deformities and edema phenotypes were evident among embryos exposed to 1000-16,000 mg/L HFPO-DA at 72 hpf. A median lethal concentration (LC50) was derived as 7651 mg/L at 72 hpf. Shallow RNA sequencing analysis of 9465 transcripts identified 38 consistently differentially expressed genes at 0.5 mg/L, 1 mg/L, 2 mg/L, and 10 mg/L HFPO-DA exposures. Notably, seven downregulated genes were associated with visual response, and seven upregulated genes were expressed in or regulated the cardiovascular system. This study identifies biological targets and molecular pathways affected during animal development by an emerging, potentially problematic, and ubiquitous industrial chemical.

Translating our knowledge of the biological aging from animal models to humans may give rise to novel approaches of targeting multiple aging-related diseases simultaneously and increasing health span. Here, for the first time, we use transcriptomic signatures of monocytes to identify biological aging pathways underlying multiple aging-related diseases in humans. The ordinal logistic regression was used to cross-sectionally investigate transcriptomics of the comorbidity index in 1264 community-based Multi-Ethnic Study of Atherosclerosis (MESA) adults, 47% Caucasian, 32% Hispanic, 21% African American, and 51% female, aged 55-94 years. The comorbidity index was defined as the number of prevalent aging-related diseases including cardiovascular disease, type-2 diabetes, hypertension, cancer, dementia, chronic kidney disease, chronic obstructive pulmonary disease, and hip fracture. We identified 708 gene transcripts associated with the comorbidity index (FDR

ImportanceA standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.ObjectiveTo revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).Evidence reviewPracticing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0.FindingsThe new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma.Conclusions and relevanceThe implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

The COVID-19 Vaccines Global Access (COVAX) is a World Health Organization (WHO) initiative that aims for an equitable access of COVID-19 vaccines. Despite potential heterogeneous infection levels across a country, countries receiving allotments of vaccines may follow WHO's allocation guidelines and distribute vaccines based on a jurisdictions' relative population size. Utilizing economic-epidemiological modeling, we benchmark the performance of this pro rata allocation rule by comparing it to an optimal one that minimizes the economic damages and expenditures over time, including a penalty representing the social costs of deviating from the pro rata strategy. The pro rata rule performs better when the duration of naturally- and vaccine-acquired immunity is short, when there is population mixing, when the supply of vaccine is high, and when there is minimal heterogeneity in demographics. Despite behavioral and epidemiological uncertainty diminishing the performance of the optimal allocation, it generally outperforms the pro rata vaccine distribution rule.

Calcific aortic valve disease, a condition of chronic inflammation, is associated with increased cardiovascular events and all-cause mortality. Omega-3 fatty acids (O3FAs) reduce both acute and chronic inflammation, but their associations with aortic valve calcium (AVC) have not been studied. The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6,814 adults without clinical cardiovascular disease. Plasma fatty acid levels and cardiac computed tomography (CT) scans were performed at baseline, and CT scans were performed at subsequent clinical visits over a median 9-year period. We assessed whether plasma levels of O3FAs and their species correlate with the presence, severity, and progression of AVC measured by CT in Multi-Ethnic Study of Atherosclerosis. The mean age of the 6,510 included participants with baseline fatty acid levels, AVC, and covariate data was 62.1 ± 10.2 years, and 47.1% of the participants were male. Race distribution was 38.6% White, 27.2% Black, 22.1% Hispanic/Latino, and 12.1% Chinese. Among the 6,510 participants, 5,884 had a subsequent CT scan, and 3,304 had a third CT scan with AVC measurements. At baseline, 862 participants (13.2%) had prevalent AVC (Agatston score >0), and were more likely to be of older age, male, of the White race, have a lower education level, and have co-morbidities that are associated with a higher risk for AVC. Plasma tertiles of eicosapentaenoic acid, docosahexaenoic acid, and total O3FA were not associated with prevalent AVC at baseline, incident AVC, or change in AVC. In conclusion, plasma levels of O3FAs in subjects not routinely supplemented with O3FAs are not useful for predicting the presence or development of AVC. Whether high plasma O3FA levels, achievable by high-dose O3FA over-the-counter supplementation or pharmacotherapy, is associated with AVC requires further investigation.

BackgroundCarbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms.MethodsTo overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years.ResultsOur CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment.ConclusionsCollectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.

AimsResistin is a circulating inflammatory biomarker that is associated with cardiovascular disease. We investigated the associations of resistin and incident heart failure (HF) and its subtypes, as well as specific measures of subclinical HF (myocardial fibrosis and relevant biomarkers).MethodsWe analysed data from 1968 participants in the Multi-Ethnic Study of Atherosclerosis with measurements of plasma resistin levels at clinic visits from 2002 to 2005. Participants were subsequently followed for a median of 10.5 years for HF events. The associations between resistin levels and incident HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF) were examined using multivariable Cox proportional hazards models. Linear regression models assessed the associations between resistin levels and myocardial fibrosis from cardiac magnetic resonance imaging, as well as hs-cTnT and NT-proBNP.ResultsThe mean age of the cohort was 64.7 years, and 50.0% were female. Seventy-four participants (4%) developed incident HF during follow-up. In a Cox proportional hazards model adjusted for age, gender, education level, race/ethnicity, and traditional risk factors, higher resistin levels were significantly associated with incident HF (HR 1.44, CI 1.18-1.75, P = 0.001) and HFrEF (HR 1.47, CI 1.07-2.02, P = 0.016), but not with HFpEF (HR 1.25, CI 0.89-1.75, P = 0.195). Resistin levels showed no significant associations with myocardial fibrosis, NT-proBNP, or hs-cTnT levels.ConclusionsIn a multi-ethnic cohort free of cardiovascular disease at baseline, elevated resistin levels were associated with incident HF, more prominently with incident HFrEF than HFpEF, but not with subclinical myocardial fibrosis or biomarkers of HF.

BackgroundDespite improvements in population health, marked racial and ethnic disparities in longevity and cardiovascular disease (CVD) mortality persist. This study aimed to describe risks for all-cause and CVD mortality by race and ethnicity, before and after accounting for socioeconomic status (SES) and other factors, in the MESA study (Multi-Ethnic Study of Atherosclerosis).MethodsMESA recruited 6814 US adults, 45 to 84 years of age, free of clinical CVD at baseline, including Black, White, Hispanic, and Chinese individuals (2000-2002). Using Cox proportional hazards modeling with time-updated covariates, we evaluated the association of self-reported race and ethnicity with all-cause and adjudicated CVD mortality, with progressive adjustments for age and sex, SES (neighborhood SES, income, education, and health insurance), lifestyle and psychosocial risk factors, clinical risk factors, and immigration history.ResultsDuring a median of 15.8 years of follow-up, 22.8% of participants (n=1552) died, of which 5.3% (n=364) died of CVD. After adjusting for age and sex, Black participants had a 34% higher mortality hazard (hazard ratio [HR], 1.34 [95% CI, 1.19-1.51]), Chinese participants had a 21% lower mortality hazard (HR, 0.79 [95% CI, 0.66-0.95]), and there was no mortality difference in Hispanic participants (HR, 0.99 [95% CI, 0.86-1.14]) compared with White participants. After adjusting for SES, the mortality HR for Black participants compared with White participants was reduced (HR, 1.16 [95% CI, 1.01-1.34]) but still statistically significant. With adjustment for SES, the mortality hazards for Chinese and Hispanic participants also decreased in comparison with White participants. After further adjustment for additional risk factors and immigration history, Hispanic participants (HR, 0.77 [95% CI, 0.63-0.94]) had a lower mortality risk than White participants, and hazard ratios for Black participants (HR, 1.08 [95% CI, 0.92-1.26]) and Chinese participants (HR, 0.81 [95% CI, 0.60-1.08]) were not significantly different from those of White participants. Similar trends were seen for CVD mortality, although the age- and sex-adjusted HR for CVD mortality for Black participants compared with White participants was greater than all-cause mortality (HR, 1.72 [95% CI, 1.34-2.21] compared with HR, 1.34 [95% CI, 1.19-1.51]).ConclusionsThese results highlight persistent racial and ethnic differences in overall and CVD mortality, largely attributable to social determinants of health, and support the need to identify and act on systemic factors that shape differences in health across racial and ethnic groups.

BackgroundLytic or malpositioned tunnels may require bone grafting during revision anterior cruciate ligament reconstruction (rACLR) surgery. Patient characteristics and effects of grafting on outcomes after rACLR are not well described.PurposeTo describe preoperative characteristics, intraoperative findings, and 2-year outcomes for patients with rACLR undergoing bone grafting procedures compared with patients with rACLR without grafting.Study designCohort study; Level of evidence, 3.MethodsA total of 1234 patients who underwent rACLR were prospectively enrolled between 2006 and 2011. Baseline revision and 2-year characteristics, surgical technique, pathology, treatment, and patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale [Marx]) were collected, as well as subsequent surgery information, if applicable. The chi-square and analysis of variance tests were used to compare group characteristics.ResultsA total of 159 patients (13%) underwent tunnel grafting-64 (5%) patients underwent 1-stage and 95 (8%) underwent 2-stage grafting. Grafting was isolated to the femur in 31 (2.5%) patients, the tibia in 40 (3%) patients, and combined in 88 patients (7%). Baseline KOOS Quality of Life (QoL) and Marx activity scores were significantly lower in the 2-stage group compared with the no bone grafting group (P≤ .001). Patients who required 2-stage grafting had more previous ACLRs (P < .001) and were less likely to have received a bone-patellar tendon-bone or a soft tissue autograft at primary ACLR procedure (P≤ .021) compared with the no bone grafting group. For current rACLR, patients undergoing either 1-stage or 2-stage bone grafting were more likely to receive a bone-patellar tendon-bone allograft (P≤ .008) and less likely to receive a soft tissue autograft (P≤ .003) compared with the no bone grafting group. At 2-year follow-up of 1052 (85%) patients, we found inferior outcomes in the 2-stage bone grafting group (IKDC score = 68; KOOS QoL score = 44; KOOS Sport/Recreation score = 65; and Marx activity score = 3) compared with the no bone grafting group (IKDC score = 77; KOOS QoL score = 63; KOOS Sport/Recreation score = 75; and Marx activity score = 7) (P≤ .01). The 1-stage bone graft group did not significantly differ compared with the no bone grafting group.ConclusionTunnel bone grafting was performed in 13% of our rACLR cohort, with 8% undergoing 2-stage surgery. Patients treated with 2-stage grafting had inferior baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting. Patients treated with 1-stage grafting had similar baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting.

Despite the likely benefits of palliative care (PC) for patients with cirrhosis, physician experiences and perspectives about best practices are variable. We aimed to assess PC experience and gaps in training among transplant hepatology fellows. We conducted a national survey of all transplant hepatology fellows enrolled in accredited fellowship programs during the 2020-2021 academic year. We assessed the frequency of PC provision and comfort with physical and psychological symptom management, psychosocial care, communication skills, advance care planning, and end-of-life care. A total of 45 of 56 (79%) of transplant hepatology fellows responded to the survey; 50% (n = 22) were female. Most trained at centers performing over 100 transplants per year (67%, n = 29) distributed evenly across geographic regions. Most fellows (69%, n = 31) had a PC or hospice care rotation during residency, and 42% (n = 19) of fellows received education in PC during transplant hepatology fellowship. Fellows reported feeling moderately to very comfortable with communication skills such as breaking bad news (93%, n = 41) and leading family meetings (75%, n = 33), but nearly one-third (30%, n = 13) reported feeling not very or not at all comfortable assessing and managing anxiety and depression (30%, n = 13) and spiritual distress (34%, n = 15). Nearly one-quarter (22%, n = 10) had never discussed or documented advance care plans during fellowship. Fellows wished to receive future instruction on the assessment and management of physical symptoms (68%, n = 30) and anxiety and depression (64%, n = 28). Conclusion: Our survey highlights gaps in PC experience and education during transplant hepatology fellowship, lack of comfort in managing psychological distress and advance care planning, and desire to improve skills, particularly in symptom management. Future studies should investigate how to enhance transplant hepatology competencies in these PC domains and whether this impacts clinical care, advance care planning, or patient experience.

BackgroundQuality measures provide a way to assess health care delivery and to identify areas for improvement that can inform patient care delivery. When operationalized by a hospital or a payer, quality measures can also be tied to physician or hospital reimbursement. Prior work on quality measures in orthopaedic surgery have identified substantial gaps in measurement portfolios and have highlighted areas for future measure development. This study aims to identify the portfolio of quality measures in pediatric orthopaedic surgery.MethodsWe used methodology of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and reviewed PubMed/ MEDLINE and EMBASE, the American Academy of Orthopaedic Surgery (AAOS), National Quality Forum (NQF), and the Agency for Healthcare Research and Quality (AHRQ), for quality measures and candidate quality measures. Quality measure and candidate quality measures were categorized as structure, process, or outcome. Measures were also classified into 1 of the 6 National Quality Strategy priorities (safety, effective, patient centered, timely, efficient, and equitable).ResultsA review of PubMed/EMBASE returned 1640 potential quality measures and articles. A review of AAOS, NQF, and AHRQ databases found 80 potential quality measures. After screening we found a total of 18 quality measures and candidate quality measures specifically for pediatric orthopaedic surgery. Quality measures addressed conditions such as supracondylar humerus fractures, developmental dysplasia of the hip, and osteochondritis dissecans. There were 10 process measures, 8 outcome measure, and 0 structure measures. When we categorized by National Quality Strategy priorities and found 50% (9/18) were effective clinical care, 44% (8/18) were person and care-giver centered experience and outcomes, 6% (1/18) were efficient use of resources.ConclusionsThere are few quality measures and candidate quality measures to assess pediatric orthopaedic surgery. Of the quality measure available, process measures are relatively over-represented. Pediatric orthopaedic surgeons can lead the development of outcome (eg, patient-reported outcomes after surgery) and structure measures (eg, subspecialty training certification) to assess quality of care in pediatric orthopaedic surgery.Level of evidenceLevel II-systematic review.

Unhoused people have higher COVID-19 mortality and lower vaccine uptake than housed community members. Understanding vaccine hesitancy among unhoused people is key for developing programs that address their unique needs. A three-round, rapid, field-based survey was conducted to describe attitudes toward COVID-19 vaccination. Round 1 assessed vaccine brand preference, round 2 assessed intention to accept a financial incentive for vaccination, and round 3 measured vaccine uptake and assessed reasons for vaccine readiness during implementation of a financial incentive program. A total of 5177 individuals were approached at COVID-19 vaccination events for unhoused people in Los Angeles County from May through November 2021. Analyses included 4949 individuals: 3636 (73.5%) unsheltered and 1313 (26.5%) sheltered. Per self-report, 2008 (40.6%) were already vaccinated, 1732 (35%) wanted to get vaccinated, 359 (7.3%) were not yet ready, and 850 (17.2%) did not want to get vaccinated. Brand preference was evenly split among participants (Moderna 31.0%, J&J 35.5%, either 33.5%, p = 0.74). Interest in a financial incentive differed between those who were not yet ready and those who did not want to get vaccinated (43.2% vs. 16.2%, p

In this survey study of institutions across the US, marked variability in evaluation, treatment, and follow-up of adolescents 12 through 18 years of age with mRNA coronavirus disease 2019 (COVID-19) vaccine-associated myopericarditis was noted. Only one adolescent with life-threatening complications was reported, with no deaths at any of the participating institutions.

In the United States, autistic individuals experience disproportionate physical and mental health challenges relative to non-autistic individuals, including higher rates of co-occurring and chronic conditions and lower physical, social, and psychological health-related quality of life. The Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multicenter research network for scientific collaboration and infrastructure that aims to increase the life expectancy and quality of life for autistic individuals, with a focus on underserved or vulnerable populations. The current paper describes the development of the AIR-P Research Agenda. Development of the research agenda involved an iterative and collaborative process between the AIR-P Advisory Board, Steering Committee, and Autistic Researcher Review Board. The methodology consisted of 3 phases: (1) ideation and design, (2) literature review and synthesis; and (3) network engagement. Six core research priorities related to the health of autistic individuals were identified: (1) primary care services and quality, (2) community-based lifestyle interventions, (3) health systems and services, (4) gender, sexuality, and reproductive health, (5) neurology, and (6) genetics. Specific topics within each of these priorities were identified. Four cross-cutting research priorities were also identified: (1) neurodiversity-oriented care, (2) facilitating developmental transitions, (3) methodologically rigorous intervention studies, and (4) addressing health disparities. The AIR-P Research Agenda represents an important step forward for enacting large-scale health-promotion efforts for autistic individuals across the lifespan. This agenda will catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health-promotion.

BackgroundDifferent 25-hydroxyvitamin D [25(OH)D] thresholds for treatment with vitamin D supplementation have been suggested and are derived almost exclusively from observational studies. Whether other characteristics, including race/ethnicity, BMI, and estimated glomerular filtration rate (eGFR), should also influence the threshold for treatment is unknown.ObjectivesThe aim was to identify clinical and biomarker characteristics that modify the response to vitamin D supplementation.MethodsA total of 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomly assigned to 16 wk of oral vitamin D3 (2000 IU/d; n = 499) or placebo (n = 167). Primary outcomes were changes in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations from baseline to 16 wk.ResultsAmong 666 participants randomly assigned (mean age: 72 y; 53% female; 66% racial/ethnic minority), 611 (92%) completed the study. The mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 compared with 2 (18) pg/mL with placebo (estimated mean difference: -5; 95% CI: -8, -2 pg/mL). Within the vitamin D3 group, lower baseline 25-hydroxyvitamin D [25(OH)D] was associated with a larger decline in PTH in a nonlinear fashion. With baseline 25(OH)D ≥30 ng/mL as the reference, 25(OH)D

BackgroundThe 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up.MethodsWe included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes.ResultsWe studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32-3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01-2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06-2.33).ConclusionsCurrent cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

BackgroundThe teleost fish Fundulus heteroclitus inhabit estuaries heavily polluted with persistent and bioaccumulative chemicals. While embryos of parents from polluted sites are remarkably resistant to toxic sediment and develop normally, embryos of parents from relatively clean estuaries, when treated with polluted sediment extracts, are developmentally delayed, displaying deformities characteristic of pollution-induced embryotoxicity. To gain insight into parental effects on sensitive and resistant phenotypes during late organogenesis, we established sensitive, resistant, and crossed embryo families using five female and five male parents from relatively clean and predominantly PAH-polluted estuaries each, measured heart rates, and quantified individual embryo expression of 179 metabolic genes.ResultsPollution-induced embryotoxicity manifested as morphological deformities, significant developmental delays, and altered cardiac physiology was evident among sensitive embryos resulting from crosses between females and males from relatively clean estuaries. Significantly different heart rates among several geographically unrelated populations of sensitive, resistant, and crossed embryo families during late organogenesis and pre-hatching suggest site-specific adaptive cardiac physiology phenotypes relative to pollution exposure. Metabolic gene expression patterns (32 genes, 17.9%, at p

BackgroundThe Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood.MethodsThis multicenter observational cohort study will enroll at least 600 patients

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18-49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

Sudden cardiac death (SCD), the unexpected death due to acquired or genetic cardiovascular disease, follows distinct 24-hour patterns in occurrence. These 24-hour patterns likely reflect daily changes in arrhythmogenic triggers and the myocardial substrate caused by day/night rhythms in behavior, the environment, and endogenous circadian mechanisms. To better address fundamental questions regarding the circadian mechanisms, the National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death. We present a 2-part report of findings from this workshop. Part 1 summarizes the workshop and serves to identify research gaps and opportunities in the areas of basic and translational research. Among the gaps was the lack of standardization in animal studies for reporting environmental conditions (eg, timing of experiments relative to the light dark cycle or animal housing temperatures) that can impair rigor and reproducibility. Workshop participants also pointed to uncertainty regarding the importance of maintaining normal circadian rhythmic synchrony and the potential pathological impact of desynchrony on SCD risk. One related question raised was whether circadian mechanisms can be targeted to reduce SCD risk. Finally, the experts underscored the need for studies aimed at determining the physiological importance of circadian clocks in the many different cell types important to normal heart function and SCD. Addressing these gaps could lead to new therapeutic approaches/molecular targets that can mitigate the risk of SCD not only at certain times but over the entire 24-hour period.

Sudden cardiac death (SCD) is the sudden, unexpected death due to abrupt loss of heart function secondary to cardiovascular disease. In certain populations living with cardiovascular disease, SCD follows a distinct 24-hour pattern in occurrence, suggesting day/night rhythms in behavior, the environment, and endogenous circadian rhythms result in daily spans of increased vulnerability. The National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death to identify fundamental questions regarding the role of the circadian rhythms in SCD. Part 2 summarizes research gaps and opportunities in the areas of population and clinical research identified in the workshop. Established research supports a complex interaction between circadian rhythms and physiological responses that increase the risk for SCD. Moreover, these physiological responses themselves are influenced by several biological variables, including the type of cardiovascular disease, sex, age, and genetics, as well as environmental factors. The emergence of new noninvasive biotechnological tools that continuously measure key cardiovascular variables, as well as the identification of biomarkers to assess circadian rhythms, hold promise for generating large-scale human data sets that will delineate which subsets of individuals are most vulnerable to SCD. Additionally, these data will improve our understanding of how people who suffer from circadian disruptions develop cardiovascular diseases that increase the risk for SCD. Emerging strategies to identify new biomarkers that can quantify circadian health (eg, environmental, behavioral, and internal misalignment) may lead to new interventions and therapeutic targets to prevent the progression of cardiovascular diseases that cause SCD.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.

Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.

Asthma often worsens at night. To determine if the endogenous circadian system contributes to the nocturnal worsening of asthma, independent of sleep and other behavioral and environmental day/night cycles, we studied patients with asthma (without steroid use) over 3 wk in an ambulatory setting (with combined circadian, environmental, and behavioral effects) and across the circadian cycle in two complementary laboratory protocols performed in dim light, which separated circadian from environmental and behavioral effects: 1) a 38-h "constant routine," with continuous wakefulness, constant posture, 2-hourly isocaloric snacks, and 2) a 196-h "forced desynchrony" incorporating seven identical recurring 28-h sleep/wake cycles with all behaviors evenly scheduled across the circadian cycle. Indices of pulmonary function varied across the day in the ambulatory setting, and both laboratory protocols revealed significant circadian rhythms, with lowest function during the biological night, around 4:00 AM, uncovering a nocturnal exacerbation of asthma usually unnoticed or hidden by the presence of sleep. We also discovered a circadian rhythm in symptom-based rescue bronchodilator use (β2-adrenergic agonist inhaler) whereby inhaler use was four times more likely during the circadian night than day. There were additive influences on asthma from the circadian system plus sleep and other behavioral or environmental effects. Individuals with the lowest average pulmonary function tended to have the largest daily circadian variations and the largest behavioral cycle effects on asthma. When sleep was modeled to occur at night, the summed circadian, behavioral/environmental cycle effects almost perfectly matched the ambulatory data. Thus, the circadian system contributes to the common nocturnal worsening of asthma, implying that internal biological time should be considered for optimal therapy.

[Figure: see text].

BackgroundAlthough graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome.HypothesisIn the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up.Study designCohort study; Level of evidence, 2.MethodsPatients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery.ResultsA total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores (P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized (P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts (P = .87) or between BTB autografts and soft tissue allografts (P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft (P = .010; OR, 0.56; 95% CI, 0.36-0.87).ConclusionBTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

The liquid-liquid phase separation (LLPS) of Tau has been postulated to play a role in modulating the aggregation property of Tau, a process known to be critically associated with the pathology of a broad range of neurodegenerative diseases including Alzheimers Disease. Tau can undergo LLPS by homotypic interaction through self-coacervation (SC) or by heterotypic association through complex-coacervation (CC) between Tau and binding partners such as RNA. What is unclear is in what way the formation mechanisms for self and complex coacervation of Tau are similar or different, and the addition of a binding partner to Tau alters the properties of LLPS and Tau. A combination of in vitro experimental and computational study reveals that the primary driving force for both Tau CC and SC is electrostatic interactions between Tau-RNA or Tau-Tau macromolecules. The liquid condensates formed by the complex coacervation of Tau and RNA have distinctly higher micro-viscosity and greater thermal stability than that formed by the SC of Tau. Our study shows that subtle changes in solution conditions, including molecular crowding and the presence of binding partners, can lead to the formation of different types of Tau condensates with distinct micro-viscosity that can coexist as persistent and immiscible entities in solution. We speculate that the formation, rheological properties and stability of Tau droplets can be readily tuned by cellular factors, and that liquid condensation of Tau can alter the conformational equilibrium of Tau.

Glucose is arguably the most important molecule in metabolism, and its dysregulation underlies diabetes. We describe a family of single-wavelength genetically encoded glucose sensors with a high signal-to-noise ratio, fast kinetics, and affinities varying over four orders of magnitude (1 μM to 10 mM). The sensors allow mechanistic characterization of glucose transporters expressed in cultured cells with high spatial and temporal resolution. Imaging of neuron/glia co-cultures revealed ∼3-fold faster glucose changes in astrocytes. In larval Drosophila central nervous system explants, intracellular neuronal glucose fluxes suggested a rostro-caudal transport pathway in the ventral nerve cord neuropil. In zebrafish, expected glucose-related physiological sequelae of insulin and epinephrine treatments were directly visualized. Additionally, spontaneous muscle twitches induced glucose uptake in muscle, and sensory and pharmacological perturbations produced large changes in the brain. These sensors will enable rapid, high-resolution imaging of glucose influx, efflux, and metabolism in behaving animals.

[Figure: see text].

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder that is associated with repetitive head impacts. Neuropathologically, it is defined by the presence of perivascular hyperphosphorylated tau aggregates in cortical tissue (McKee et al., 2016, Acta Neuropathologica, 131, 75-86). Although many pathological and assumed clinical correlates of CTE have been well characterized, its effects on cortical dendritic arbors are still unknown. Here, we quantified dendrites and dendritic spines of supragranular pyramidal neurons in tissue from human frontal and occipital lobes, in 11 cases with (Mage = 79 ± 7 years) and 5 cases without (Mage = 76 ± 11 years) CTE. Tissue was stained with a modified rapid Golgi technique. Dendritic systems of 20 neurons per region in each brain (N = 640 neurons) were quantified using computer-assisted morphometry. One key finding was that CTE neurons exhibited increased variability and distributional changes across six of the eight dendritic system measures, presumably due to ongoing degeneration and compensatory reorganization of dendritic systems. However, despite heightened variation among CTE neurons, CTE cases exhibited lower mean values than Control cases in seven of the eight dendritic system measures. These dendritic alterations may represent a new pathological marker of CTE, and further examination of dendritic changes could contribute to both mechanistic and functional understandings of the disease.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D3 supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.