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Abstract Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5’ untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Abstract We examined the effect of annual exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), on the rate of first hospitalization with a PD-related diagnosis (hospitalization with PD) among Medicare Fee-for-Service beneficiaries (2001-2016). Machine learning-derived annual air pollution concentrations were linked to residential ZIP codes. For each exposure, we fitted four models: 1) traditional outcome stratification, 2) marginal structural, 3) doubly robust, and 4) generalized propensity score matching Poisson regression models, adjusted for sociodemographic and meteorological confounders and long-term trends. Among 49,121,026 beneficiaries, incidence rate ratios of 1.08 (95% CI: 1.07, 1.10), 1.07 (95% CI: 1.05, 1.08), and 1.03 (95% CI: 1.02, 1.05) for an interquartile range increase in PM2.5 (3.72 µg/m3), NO2 (13.84 ppb), and O3 (10.09 ppb), respectively, were estimated from doubly robust models. Results were similar across modeling approaches. In this nationwide study, higher air pollution exposure increased the rate of hospitalizations with PD.

Abstract The canonical G406R mutation that increases Ca2+ influx through the CACNA1C-encoded CaV1.2 Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by life-threatening arrhythmias. Severe episodic hypoglycemia is among the poorly characterized non-cardiac TS pathologies. While hypothesized from increased Ca2+ influx in pancreatic beta cells and consequent hyperinsulinism, this hypoglycemia mechanism is undemonstrated because of limited clinical data and lack of animal models. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features, including hypoglycemia. Unexpectedly, these mice do not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. Patient data confirm the absence of hyperinsulinism. We discover multiple alternative contributors, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic control of glucose homeostasis. These data provide new insights into contributions of CaV1.2 channels and reveal integrated consequences of the mutant channels driving life-threatening events in TS.

Abstract Anthropogenic climate change has significantly altered terrestrial and marine ecosystems globally, often in the form of climate-related events such as thermal anomalies and disease outbreaks. Although the isolated effects of these stressors have been well documented, a growing body of literature suggests that stressors often interact, resulting in complex effects on ecosystems. This includes coral reefs where sequential associations between heat stress and disease have had profound impacts. Here we used the model cnidarian Exaiptasia diaphana to investigate mechanisms linking prior heat stress to increased disease susceptibility. We examined anemone pathogen susceptibility and physiology (symbiosis, immunity, and energetics) following recovery from heat stress. We observed significantly increased pathogen susceptibility in anemones previously exposed to heat stress. Notably, prior heat stress reduced anemone energetic reserves (carbohydrate concentration), and activity of multiple immune components. Minimal effects of prior heat stress on symbiont density were observed. Together, results suggest changes in energetic availability might have the strongest effect on pathogen susceptibility and immunity following heat stress. The results presented here provide critical insight regarding the interplay between heat stress recovery and pathogen susceptibility in cnidarians and are an important first step towards understanding temporal associations between these stressors.

Abstract Rationale Tobacco use is a risk factor for COVID-19 adverse outcomes. Despite health implications, data conflict regarding COVID-19 and tobacco consumption. We present results from a survey of health behaviors during the pandemic to identify how COVID-19 influenced tobacco behaviors. Methods A nationally administered, internet-based survey was deployed between May–September 2020. Of respondents, we analyzed participants who reported current smoking and/or vaping. Our primary outcome of interest was change in tobacco or vape use using measures from the Behavioral Risk Factor Surveillance System, as well as whether participants reported that these changes were related to COVID-19. Our principal exposures were previously psychometrically evaluated measures of anxiety, depression, and novel perceived COVID-19 threat scale with additional adjustment for age. We employed multinomial logistic regression to determine associations between these factors and tobacco consumption. Results We identified 500 respondents who reported ever smoking in their lifetime, 150 of which reported currently smoking at the time of the survey. Of 220 participants who reported any use of vapes, 110 reported currently vaping. Increased perceived threat of COVID-19 was associated with both increased (aRRincrease 1.75, 95% CI [1.07–2.86], P = 0.03) and decreased (aRRdecrease 1.72 [1.04–2.85], P = 0.03) tobacco consumption relative to no change. There were no significant relationships found between perceived threat of COVID-19 and vaping behavior. Conclusions As perceived COVID-19 threat increased, people were more likely to increase or decrease their smoking as opposed to continue at the same amount of use, even after controlling for anxiety and depression, both of which are known to affect smoking in either direction. Further study into motivators of changing tobacco consumption behaviors, and how barriers to care from safer-at-home policies and changes in care delivery moderate change in tobacco use will aid planning tobacco reduction interventions during the ongoing and future respiratory viral pandemics. Trial registration This manuscript is derived from baseline survey data obtained in the “Understanding Community Considerations, Opinions, Values, Impacts, and Decisions in COVID-19” study. ClinicalTrials.gov registration NCT04373135, registered 04/30/2020.

Abstract Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined posterior-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses for resting EEG best discriminated non-mosaic FXS males via frontal theta resting relative power (AUC = 0.8759), even with data reduced to a 20-channel clinical montage (AUC = 0.9062). In the chirp task, FXS females and non-mosaic males were nearly perfectly discriminated by combined theta, alpha, and gamma power (AUC = 0.9444) and a combination of all variables (AUC = 0.9610), respectively. Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

Abstract Background Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficiency and potentially cost-saving benefits. Despite a large number of statistical methods in the literature on different adaptations to trials, the characteristics, advantages and limitations of such designs remain unfamiliar to large parts of the clinical and research community. This systematic review provides an overview of the use of ADs in published clinical trials (Part I). A follow-up (Part II) will compare the application of AD in trials in adult and pediatric studies, to provide real-world examples and recommendations for the child health community. Methods Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Clinical trial protocols, reports, and a secondary analyses using AD were included. We excluded trial registrations and interventions other than drugs or vaccines to align with regulatory guidance. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein. Results Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. The most frequent disease was oncology (168/317, 53%). Most trials included only adult participants (265, 83.9%),16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults, 8 trials did not report the ages of the included populations. Some studies reported using more than one adaptation (there were 390 reported adaptations in 317 clinical trial reports). Most trials were early in drug development (phase I, II (276/317, 87%). Dose-finding designs were used in the highest proportion of the included trials (121/317, 38.2 %). Adaptive randomization (53/317, 16.7%), with drop-the-losers (or pick-the-winner) designs specifically reported in 29 trials (9.1%) and seamless phase 2-3 design was reported in 27 trials (8.5%). Continual reassessment methods (60/317, 18.9%) and group sequential design (47/317, 14.8%) were also reported. Approximately two-thirds of trials used frequentist statistical methods (203/309, 64%), while Bayesian methods were reported in 24% (75/309) of included trials. Conclusion This review provides a comprehensive report of methodological features in adaptive clinical trials reported between 2010 and 2020. Adaptation details were not uniformly reported, creating limitations in interpretation and generalizability. Nevertheless, implementation of existing reporting guidelines on ADs and the development of novel educational strategies that address the scientific, operational challenges and ethical considerations can help in the clinical trial community to decide on when and how to implement ADs in clinical trials. Study protocol registration https://doi.org/10.1186/s13063-018-2934-7 .

Patients with limited English proficiency (LEP) experience reduced pain assessment and treatment, less comprehensive physical exams, and fewer explanations of the next steps in care. These disparities persist in hospitals with staffed professional interpreters, raising questions about interpreter access and the impact on outcomes. A retrospective review of 1133 trauma activations at a single center Level 1 Trauma Center in 2021–2022 was conducted. Demographic, injury, and outcome data were drawn from the institutional trauma registry, and patient-preferred language was pulled from EMR data. Early interpreter use was defined as documentation of professional interpreter use within 24 h of arrival. LOS and ICU LOS were compared between language groups using Cox regression, and mortality was compared using Fischer's exact test. 1114 patients had data available on initial injury severity and preferred language. Of the 70 LEP patients, 62 (88.6 %) required an interpreter, and 41 of those (66.1 %) had evidence of professional interpreter use within 24 h of arrival. LEP patients who lacked early interpreter use had longer hospital stays than both English proficient (EP) patients (HR 0.59, p

Abstract Background Kidney replacement therapy (KRT) needs preparation and its timing is difficult to predict. Nephrologists’ predictions of kidney failure risk tend to be more pessimistic than the Kidney Failure Risk Equation (KFRE) predictions. We aimed to explore how physicians’ risk estimate related to referral to KRT education, vs. the objective calculated KFRE. Methods Prospective observational study of data collected in chronic kidney disease (CKD) clinics of the Veterans Affairs Medical Center San Diego and the University of California, San Diego. The study included 257 participants who were aged 18 years or older, English speaking, prevalent CKD clinic patients, with estimated glomerular filtration rate (eGFR)

Abstract Background Duchenne muscular dystrophy (DMD) is a genetic disease resulting in progressive muscle weakness, loss of ambulation, and cardiorespiratory complications. Direct estimation of health-related quality of life for patients with DMD is challenging, highlighting the need for proxy measures. This study aims to catalog and compare existing published health state utility estimates for DMD and related conditions. Methods Using two search strategies, relevant utilities were extracted from the Tufts Cost-Effectiveness Analysis Registry, including health states, utility estimates, and study and patient characteristics. Analysis One identified health states with comparable utility estimates to a set of published US patient population utility estimates for DMD. A minimal clinically important difference of ± 0.03 was applied to each DMD utility estimate to establish a range, and the registry was searched to identify other health states with associated utilities that fell within each range. Analysis Two used pre-defined search terms to identify health states clinically similar to DMD. Mapping was based on the degree of clinical similarity. Results Analysis One identified 4,308 unique utilities across 2,322 cost-effectiveness publications. The health states captured a wide range of acute and chronic conditions; 34% of utility records were extrapolated for US populations (n = 1,451); 1% were related to pediatric populations (n = 61). Analysis Two identified 153 utilities with health states clinically similar to DMD. The median utility estimates varied among identified health states. Health states similar to the early non-ambulatory DMD phase exhibited the greatest difference between the median estimate of the sample (0.39) and the existing estimate from published literature (0.21). Conclusions When available estimates are limited, using novel search strategies to identify utilities of clinically similar conditions could be an approach for overcoming the information gap. However, it requires careful evaluation of the utility instruments, tariffs, and raters (proxy or self).

Abstract This study was performed to determine whether prolonged endurance running results in acute endothelial dysfunction and wave‐reflection, as endothelial dysfunction and arterial stiffness are cardiovascular risk factors. Vascular function (conduit artery/macrovascular and resistance artery/microvascular) was assessed in 11 experienced runners (8 males, 3 females) before, during and after a 50 km ultramarathon. Blood pressure (BP), heart rate (HR), wave reflection, augmentation index (AIx) and AIx corrected for HR (AIx75) were taken at all time points—Baseline (BL), following 10, 20, 30 and 40 km, 1 h post‐completion (1HP) and 24 h post‐completion (24HP). Flow‐mediated dilatation (FMD) and inflammatory biomarkers were examined at BL, 1HP and 24HP. Reactive hyperaemia area under the curve (AUC) and shear rate AUC to peak dilatation were lower (∼75%) at 1HP compared with BL (P

Abstract Background Outcomes for individuals with cystic fibrosis (CF) have improved due to highly effective modulator therapy (HEMT). However, lung transplant (LTx) remains an important treatment for people with advanced lung disease. This study assessed attitudes and knowledge about LTx in the HEMT era. Methods All patients from the University of Washington CF clinic were surveyed March 25-May 30, 2020. Questions addressed self-rated LTx preparedness and knowledge, as well as barriers and facilitators to discussing LTx. Demographic and clinical data were extracted from the electronic health record. Results There were 159/224 (71%) responses. Respondents had a median forced expiratory volume in one second (FEV1) of 70%, and 142 (89%) were on modulatory therapy. One hundred thirteen (71%) respondents felt that it was moderately or very important to be prepared to make decisions about LTx, though only 56 (35%) felt moderately or very prepared. Only 83 (30%) and 47 (52%) participants correctly answered questions about life expectancy and improved quality of life after LTx, respectively. Respondents with Medicaid insurance less frequently answered questions correctly. The most common barriers to discussing LTx were fear of being a burden on loved ones for 58 respondents (36%) and cost of LTx for 46 (29%). Most participants (94%) trusted their CF doctor, and 75% of participants selected trust as a facilitator for LTx discussions. Conclusions Many individuals with CF, especially those with lower socioeconomic status, lacked knowledge and did not feel very prepared for decisions about LTx. Earlier education and discussions about LTx represent an area for improvement in CF care.

Abstract Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.

Abstract Antibodies to Ebola virus glycoprotein (EBOV GP) represent an important correlate of the vaccine efficiency and infection survival. Both neutralization and some of the Fc-mediated effects are known to contribute the protection conferred by antibodies of various epitope specificities. At the same time, the role of the complement system remains unclear. Here, we compare complement activation by two groups of representative monoclonal antibodies (mAbs) interacting with the glycan cap (GC) or the membrane-proximal external region (MPER) of GP. Binding of GC-specific mAbs to GP induces complement-dependent cytotoxicity (CDC) in the GP-expressing cell line via C3 deposition on GP in contrast to MPER-specific mAbs. In the mouse model of EBOV infection, depletion of the complement system leads to an impairment of protection exerted by one of the GC-specific, but not MPER-specific mAbs. Our data suggest that activation of the complement system represents an important mechanism of antiviral protection by GC antibodies.

Abstract DNA methylation is a key component of the mammalian epigenome, playing a regulatory role in development, disease, and other processes. Robust, high-throughput single-cell DNA methylation assays are now possible (sciMET); however, the genome-wide nature of DNA methylation results in a high sequencing burden per cell. Here, we leverage target enrichment with sciMET to capture sufficient information per cell for cell type assignment using substantially fewer sequence reads (sciMET-cap). Accumulated off-target coverage enables genome-wide differentially methylated region (DMR) calling for clusters with as few as 115 cells. We characterize sciMET-cap on human PBMCs and brain (middle frontal gyrus).

Abstract Background Experiences during the birth hospitalization affect a family’s ability to establish and maintain breastfeeding. The Ten Steps to Successful Breastfeeding (Ten Steps) describe evidence-based hospital policies and practices shown to improve breastfeeding outcomes. We aim to describe hospitals’ implementation of the Ten Steps, changes over time, and hospitals’ implementation of a majority (≥ 6) of the Ten Steps by hospital characteristics and state. Methods The biennial Maternity Practices in Infant Nutrition and Care (mPINC) survey assesses all hospitals in the United States (including the District of Columbia and territories) that routinely provide maternity care services. We analyzed data from 2018, 2020, and 2022 survey cycles to describe trends in the prevalence of hospitals implementing maternity care policies and practices that are consistent with the Ten Steps. Differences were calculated using the absolute difference in percentage-points between 2018 and 2022. Results Between 2018 and 2022, the percentage of hospitals that implemented Step 2: Staff Competency and Step 5: Support Mothers with Breastfeeding increased 12 and 8 percentage points, respectively. The percentage of hospitals that implemented Step 6: Exclusive Breastfeeding Among Breastfed Infants was 7 percentage points lower in 2022 than 2018. Implementation of the remaining seven steps did not change by more than 5 percentage points in either direction between 2018 and 2022. Nationally, the percentage of hospitals that implemented ≥ 6 of the Ten Steps increased from 44.0% in 2018 to 51.1% in 2022. Differences were seen when comparing implementation of ≥ 6 of the Ten Steps by hospital characteristics including state, hospital size, and highest level of neonatal care offered. Conclusions Nationally, maternity care policies and practices supportive of breastfeeding continued to improve; however, certain practices lost progress. Differences in implementation of the Ten Steps were observed across states and by certain hospital characteristics, suggesting more work is needed to ensure all people receive optimal breastfeeding support during their delivery hospitalization.

Abstract Background In the mammalian retina, intrinsically-photosensitive retinal ganglion cells (ipRGC) detect light and integrate signals from rods and cones to drive multiple non-visual functions including circadian entrainment and the pupillary light response (PLR). Non-visual photoreception and consequently non-visual sensitivity to light may change across child development. The PLR represents a quick and reliable method for examining non-visual responses to light in children. The purpose of this study was to assess differences in the PLRs to blue and red stimuli, measured one hour prior to bedtime, between children and adolescents. Methods Forty healthy participants (8–9 years, n = 21; 15–16 years, n = 19) completed a PLR assessment 1 h before their habitual bedtime. After a 1 h dim-light adaptation period (

Abstract Purpose: To validate a convolutional neural network (CNN)-based smartphone application for the identification of glaucoma eye drop medications in patients with normal and impaired vision. Methods: Sixty-eight patients with visual acuity (VA) of 20/70 or worse in at least one eye who presented to an academic glaucoma clinic from January 2021 through August 2022 were included. Non-English-speaking patients were excluded. Enrolled subjects participated in an activity in which they identified a predetermined and preordered set of six topical glaucoma medications, first without the CNN and then with the CNN for a total of six sequential measurements per subject. Responses to a standardized survey were collected during and after the activity. Primary quantitative outcomes were medication identification accuracy and time. Primary qualitative outcomes were subjective ratings of ease of smartphone application use. Results: Topical glaucoma medication identification accuracy (OR = 12.005, P < 0.001) and time (OR = 0.007, P < 0.001) both independently improved with CNN use. CNN use significantly improved medication accuracy in patients with glaucoma (OR = 4.771, P = 0.036) or VA ≤ 20/70 in at least one eye (OR = 4.463, P = 0.013) and medication identification time in patients with glaucoma (OR = 0.065, P = 0.017). CNN use had a significant positive association with subject-reported ease of medication identification (X2(1) = 66.117, P < 0.001). Conclusion: Our CNN-based smartphone application is efficacious at improving glaucoma eye drop identification accuracy and time. This tool can be used in the outpatient setting to avert preventable vision loss by improving medication adherence in patients with glaucoma.

The amphipod family Chevaliidae Myers & Lowry, 2003 (Amphipoda: Senticaudata) contains two genera: Chevalia Walker, 1904 (13 species), and Bryoconversor Lörz, Myers & Gordon, 2014 (1 species). Chevalia is a marine genus with a cosmopolitan distribution in circumtropical and temperate waters. Prior to this study, records of Chevalia from Australian waters were limited. Here, we describe five new species of Chevalia from Australian waters, C. bardi sp. nov., C. burrewarra sp. nov., C. csiro sp. nov., C. freycinet sp. nov. and C. sprightly sp. nov. The original description of Chevalia aviculae no longer adequately defined the species and is redescribed based on syntypic material from East Cheval Paar, Sri Lanka. Additionally, new distribution records are provided for the New Zealand species Bryoconversor tutus Lörz, Myers & Gordon, 2014. Material reported is from both shallow and deep-water samples from 1–660 m depth. The prevalence of various gender and intersex states within specimens of chevaliids is discussed. An updated key to the 19 world species of Chevaliidae and a field guide to the seven known Australian and New Zealand species is provided.

Abstract Free Fecal Liquid (FFL), also termed Fecal Water Syndrome (FWS), is an ailment in horses characterized by variable solid and liquid (water) phases at defecation. The liquid phase can be excreted before, during, or after the solid defecation phase. While the underlying causes of FFL are unknown, hindgut dysbiosis is suggested to be associated with FFL. Three European studies investigated dysbiosis in horses with FFL using 16S rRNA sequencing and reported results that conflicted between each other. In the present study, we also used 16S rRNA sequencing to study the fecal microbial composition in 14 Canadian horses with FFL, and 11 healthy stable mate controls. We found no significant difference in fecal microbial composition between FFL and healthy horses, which further supports that dysbiosis is not associated with FFL.

Abstract Background Patient participation in treatment decision making is a pillar of recovery-oriented care and is associated with improvements in empowerment and well-being. Although demand for increased involvement in treatment decision-making is high among veterans with serious mental illness, rates of involvement are low. Collaborative decision skills training (CDST) is a recovery-oriented, skills-based intervention designed to support meaningful patient participation in treatment decision making. An open trial among veterans with psychosis supported CDST’s feasibility and demonstrated preliminary indications of effectiveness. A randomized control trial (RCT) is needed to test CDST’s effectiveness in comparison with an active control and further evaluate implementation feasibility. Methods The planned RCT is a hybrid type 1 trial, which will use mixed methods to systematically evaluate the effectiveness and implementation feasibility of CDST among veterans participating in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) in Southern California. The first aim is to assess the effectiveness of CDST in comparison with the active control via the primary outcome, collaborative decision-making behavior during usual care appointments between veterans and their VA mental health clinicians, and secondary outcomes (i.e., treatment engagement, satisfaction, and outcome). The second aim is to characterize the implementation feasibility of CDST within the VA PRRC using the Practical Robust Implementation and Sustainability Model framework, including barriers and facilitators within the PRRC context to support future implementation. Discussion If CDST is found to be effective and feasible, implementation determinants gathered throughout the study can be used to ensure sustained and successful implementation at this PRRC and other PRRCs and similar settings nationally. Trial registration ClinicalTrials.gov NCT04324944. Registered on March 27, 2020. Trial registration data can be found in Appendix 1.

Abstract Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19. A retrospective electronic health record (EHR) cohort study of 2,391,006 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 76 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28–120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression. There were significant associations between a diagnosis of any psychiatric disease and five categories of PASC-AMs with odds ratios highest for neurological, cardiovascular, and constitutional PASC-AMs with odds ratios of 1.31, 1.29, and 1.23 respectively. Secondary analysis revealed that the proportions of 50 individual clinical features significantly differed between patients diagnosed with different psychiatric diseases. Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.

ABSTRACT Grapes have been cultivated for wine production for millennia. Wine production involves a complex biochemical process where sugars in grape must are converted into alcohol and other compounds by microbial fermentation, primarily by the yeast Saccharomyces cerevisiae. Commercially available S. cerevisiae strains are often used in winemaking, but indigenous (native) strains are gaining attention for their potential to contribute unique flavors. Recent advancements in high-throughput DNA sequencing have revolutionized our understanding of microbial communities during wine fermentation. Indeed, transcriptomic analysis of S. cerevisiae during wine fermentation has revealed a core gene expression program and provided insights into how this yeast adapts to fermentation conditions. Here, we assessed how the age of vines impacts the grape fungal microbiome and used transcriptomics to characterize microbial functions in grape must fermented with commercial and native S. cerevisiae. We discovered that ~130-year-old Zinfandel vines harbor higher fungal loads on their grapes compared to 20-year-old Zinfandel vines, but fungal diversity is similar. Additionally, a comparison of inoculated and uninoculated fermentations showed distinct fungal dynamics, with uninoculated fermentations harboring the yeasts Metschnikowia and Pichia. Transcriptomic analysis revealed significant differences in gene expression between fermentations inoculated and not inoculated with a commercial S. cerevisiae strain. Genes related to metabolism, stress response, and cell adhesion were differentially expressed, indicating varied functionality of S. cerevisiae in these fermentations. These findings provide insights into S. cerevisiae function during fermentation and highlight the potential for indigenous yeast to contribute to wine diversity.IMPORTANCEUnderstanding microbial functions during wine fermentation, particularly the role of Saccharomyces cerevisiae, is crucial for enhancing wine quality. While commercially available S. cerevisiae strains are commonly used, indigenous strains can offer unique flavors, potentially reflecting vineyard terroir. By leveraging high-throughput DNA sequencing and transcriptomic analysis, we explored the impact of vine age on the grape mycobiome and characterized microbial functions during grape fermentation. Our findings revealed that older vines harbor higher fungal loads, but fungal diversity remains similar across vine ages. Additionally, uninoculated fermentations exhibited diverse fungal dynamics, including the beneficial wine yeasts Metschnikowia and Pichia. Transcriptomic analysis uncovered significant differences in S. cerevisiae gene expression between inoculated and uninoculated fermentations, highlighting the potential of indigenous yeast to enhance wine diversity and inform winemaking practices.

Conservation programs worldwide pursue social equity alongside environmental benefits and economic efficiency. When the spatial patterning of human diversity differs from the patterning of biological diversity, conservation planners face complex tradeoffs between social and biological objectives. Here, we quantify how these tradeoffs depend on the correlation between the spatial distributions of social and biological diversity. We used empirical patterns in the commonness and rarity of species to generate simulated landscapes with pre-defined correlations between biological diversity and human social diversity. Our analysis shows how tradeoffs between social equity and environmental benefits are unavoidable when human and biological diversity are negatively correlated. However, when human and biological diversity are strongly positively correlated, then biological and social priorities are congruent. In these settings, well-designed conservation programs may engender positive feedbacks between social equity and ecosystem services, enhancing both. Our analysis focused on distributional equity, but similar dynamics are likely to occur with procedural, recognitional and contextual equity. Given growing evidence that socially equitable conservation programs are more likely to be successful, our findings underscore the importance of carefully assessing the potential for conflicts and synergies between the social and biological goals of conservation programs.

Summary: Human neural organoid models have become an important tool for studying neurobiology. However, improving the representativeness of neural cell populations in such organoids remains a major effort. In this work, we compared Matrigel, a commercially available matrix, to a neural cadherin (N-cadherin) peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids. We determined that peptide presentation can tune cell fate and diversity in gelatin-based matrices during differentiation. Of particular note, cortical organoids cultured in GelMA-Cad hydrogels mapped more closely to human fetal populations and produced neurons with more spontaneous excitatory postsynaptic currents relative to Matrigel. These results provide compelling evidence that matrix-tethered signaling peptides can influence neural organoid differentiation, opening an avenue to control stem cell fate. Moreover, outcomes from this work showcase the technical utility of GelMA-Cad as a simple and defined hydrogel alternative to Matrigel for neural organoid culture.

Alcohol use disorder (AUD) is the most prevalent substance use disorder but there is incomplete knowledge of the underlying molecular etiology. Here, we examined the cytosolic proteome from the nucleus accumbens core (NAcC) of ethanol drinking rhesus macaques to identify ethanol-sensitive signaling proteins. The targets were subsequently investigated using bioinformatics, genetic, and pharmacological manipulations in mouse models of ethanol drinking. Of the 1000+ cytosolic proteins identified in our screen, 50 proteins differed significantly between control and ethanol drinking macaques. Gene Ontology analysis of the differentially expressed proteins identified enrichment in pathways regulating metabolic processes and proteasome activity. Because the family of Glutathione S-transferases (GSTs) was enriched in these pathways, validation studies targeted GSTs using bioinformatics and genetically diverse mouse models. Gstp1 and Gstm2 were identified in Quantitative Trait Loci and published gene sets for ethanol-related phenotypes (e.g., ethanol preference, conditioned taste aversion, differential expression), and recombinant inbred strains that inherited the C57BL/6J allele at the Gstp2 interval consumed higher amounts of ethanol than those that inherited the DBA/2J allele. Genetic deletion of Gstp1/2 led to increased ethanol consumption without altering ethanol metabolism or sucrose preference. Administration of the pharmacologic activator of Gstp1/2, carnosic acid, decreased voluntary ethanol drinking. Proteomic analysis of the NAcC cytosolic of heavy drinking macaques that were validated in mouse models indicate a role for glutathione-mediated redox regulation in ethanol-related neurobiology and the potential of pharmacological interventions targeting this system to modify excessive ethanol drinking.

Prompt evaluation and genetic testing of patients who present with recurrent and recalcitrant warts, before onset of severe infection or myelodysplastic syndrome, leads to improved outcomes in patients with GATA2 deficiency.

Epilepsy is a common neurological condition in dogs. Analysis of primary care populations across countries can provide a more complete understanding of the epidemiology of this condition and provide context for spectrum of care discussions. This narrative literature review was aimed at understanding canine epilepsy/seizure prevalence in primary care populations, and changes in occurrence across geography, culture, and socioeconomic status. There are few studies to give insight into the true general population of epileptic canines and there is inconsistency in the literature regarding the standards applied for epilepsy diagnosis across primary care and referral practices. Therefore, the future focus should be on more epidemiological research in primary care and mixed populations, more veterinary education to standardize use of medical guidelines in primary care settings, and increased awareness of the benefits of having pet insurance to mitigate the potentially substantial cost of care for dogs with epilepsy.

Extracorporeal blood purification (ECBP) has become a popular treatment option for non-steroidal anti-inflammatory drug (NSAID) toxicity in small animals. However, challenges arise when using ECBP for small dogs and cats because the priming volume required by most machine-based ECBP platforms might be excessive, leading to cardiovascular instability if a blood prime is not used. This report describes the successful use of manual carbon hemoperfusion (MCHP) to reduce plasma meloxicam levels in a cat following an inadvertent overdose and its use in a dog following suspected ibuprofen ingestion. In both animals, MCHP reduced the circuit volume needed for ECBP from 125 mL with a machine-based therapeutic plasma exchange or 104 mL with an in-series carbon hemoperfusion on an intermittent hemodialysis platform to just 40–50 mL. In the cat, MCHP reduced plasma meloxicam levels by 44%, and in both animals, the use of MCHP in these pets was well-tolerated and safe. Due to pre-existing anemia, the cat required a blood transfusion but the dog did not. MCHP is technically simple and can be performed at any hospital with access to carbon filters and blood bank resources. This technique may represent a reasonable alternative to treat NSAID toxicities in animals that are too small for conventional extracorporeal decontamination methods using either machine-based platforms without using a blood prime or in locations where these machines are unavailable.

Introduction Diabetes disparities exist based on socioeconomic status, race, and ethnicity. The aim of this study is to compare two cohorts with diabetes from California and Florida to better elucidate how health outcomes are stratified within underserved communities according to state location, race, and ethnicity.Research design and methods Two cohorts were recruited for comparison from 20 Federally Qualified Health Centers as part of a larger ECHO Diabetes program. Participant-level data included surveys and HbA1c collection. Center-level data included Healthcare Effectiveness Data and Information Set metrics. Demographic characteristics were summarized overall and stratified by state (frequencies, percentages, means (95% CIs)). Generalized linear mixed models were used to compute and compare model-estimated rates and means.Results Participant-level cohort: 582 adults with diabetes were recruited (33.0% type 1 diabetes (T1D), 67.0% type 2 diabetes (T2D)). Mean age was 51.1 years (95% CI 49.5, 52.6); 80.7% publicly insured or uninsured; 43.7% non-Hispanic white (NHW), 31.6% Hispanic, 7.9% non-Hispanic black (NHB) and 16.8% other. Center-level cohort: 32 796 adults with diabetes were represented (3.4% with T1D, 96.6% with T2D; 72.7% publicly insured or uninsured). Florida had higher rates of uninsured (p9% HbA1c (p

Adenoviruses (Ads) have demonstrated significant success as replication-deficient (RD) viral vectored vaccines, as well as broad potential across gene therapy and cancer therapy. Ad vectors transduce human cells via direct interactions between the viral fiber knob and cell surface receptors, with secondary cellular integrin interactions. Ad receptor usage is diverse across the extensive phylogeny. Commonly studied human Ad serotype 5 (Ad5), and chimpanzee Ad-derived vector “ChAdOx1” in licensed ChAdOx1 nCoV-19 vaccine, both form primary interactions with the coxsackie and adenovirus receptor (CAR), which is expressed on human epithelial cells and erythrocytes. CAR usage is suboptimal for targeted gene delivery to cells with low/negative CAR expression, including human dendritic cells (DCs) and vascular smooth muscle cells (VSMCs). We evaluated the performance of an RD Ad5 vector pseudotyped with the fiber knob of human Ad serotype 49, termed Ad5/49K vector. Ad5/49K demonstrated superior transduction of murine and human DCs over Ad5, which translated into significantly increased T cell immunogenicity when evaluated in a mouse cancer vaccine model using 5T4 tumor-associated antigen. Additionally, Ad5/49K exhibited enhanced transduction of primary human VSMCs. These data highlight the potential of Ad5/49K vector for both vascular gene therapy applications and as a potent vaccine vector.

Abstract Partial heart transplantation (PHT) is a novel surgical approach that involves transplantation of only the part of the heart containing a valve. The rationale for this approach is to deliver growing heart valve implants that reduce the need for future re-operations in children. However, prior to clinical application of this approach, it was important to assess it in a preclinical model. To investigate PHT short-term outcomes and safety, we performed PHT in a piglet model. Yorkshire piglets (n = 14) were used for PHT of the pulmonary valve. Donor and recipient pairs were matched based on blood types. The piglets underwent PHT at an average age of 44 days (range 34–53). Post-operatively, the piglets were monitored for a period of two months. Of the 7 recipient piglets, one mortality occurred secondary to anesthesia complications while undergoing a routine echocardiogram on post-operative day 19. All piglets had appropriate weight gain and laboratory findings throughout the post-operative period indicating a general state of good health and rehabilitation after undergoing PHT. We conclude that PHT has good short-term survival in the swine model. PHT appears to be safe for clinical application.

IntroductionCommunication is vital for effective and precise public health practice. The limited formal educational opportunities in health communication render professional development opportunities especially important. Competencies for public health communication describe the integrated knowledge, values, skills and behaviours required for practitioner and organizational performance. Many countries consider communication a core public health competency and use communication competencies in workforce planning and development. MethodsWe conducted an environmental scan and content analysis to determine the availability of public health communication professional development opportunities in Canada and the extent to which they support communication-related core competencies. Three relevant competency frameworks were used to assess the degree to which professional development offerings supported communication competency development. ResultsOverall, 45 professional development offerings were included: 16 “formalized offerings” (training opportunities such as courses, webinars, certificate programs) and 29 “materials and tools” (resources such as toolkits, guidebooks). The formalized offerings addressed 25% to 100% of the communication competencies, and the materials and tools addressed 67% to 100%. Addressing misinformation and disinformation, using current technology and communicating with diverse populations are areas in need of improved professional development. ConclusionThere is a significant gap in public health communication formalized offerings in Canada and many of the materials and tools are outdated. Public health communication professional development offerings lack coordination and do not provide comprehensive coverage across the communication competencies, limiting their utility to strengthen the public health workforce. More, and more comprehensive, professional development offerings are needed.

IntroductionLa communication est essentielle à une pratique efficace et précise en santé publique. Les offres limitées de formation formelle en communication dans le domaine de la santé rendent les programmes de perfectionnement professionnel particulièrement importants. Les compétences en communication dans le domaine de la santé publique portent sur les connaissances, les valeurs, les compétences et les comportements intégrés requis pour un bon fonctionnement des professionnels et des organisations. De nombreux pays considèrent la communication comme une compétence de base en santé publique et utilisent les compétences en communication dans la planification et le perfectionnement de la main d’oeuvre. MéthodologieNous avons effectué une analyse contextuelle et une analyse de contenu pour cerner les offres de perfectionnement professionnel en communication en santé publique disponibles au Canada et vérifier dans quelle mesure elles permettent l’acquisition des compétences essentielles liées à la communication. Trois cadres de compétences pertinents ont été utilisés pour évaluer à quel point les programmes de perfectionnement professionnel contribuent à l’amélioration des compétences en communication. RésultatsAu total, 45 offres de perfectionnement professionnel ont été incluses : 16 « programmes formels » (offres de formation telles que cours, webinaires, programmes de certification) et 29 « documents et outils » (ressources telles que trousses d’outils, guides). Les programmes formels traitaient d’entre 25 % et 100 % des compétences en communication et les documents et outils en abordaient entre 67 % et 100 %. La lutte contre la mésinformation et la désinformation, l’utilisation des technologies actuelles et la communication avec des populations variées sont des domaines dans lesquels il faudrait améliorer le perfectionnement professionnel. ConclusionOn constate une lacune importante dans les programmes formels de communication en santé publique au Canada, et bon nombre des documents et des outils disponibles sont désuets. Les offres de perfectionnement professionnel en communication en santé publique ne sont pas coordonnées et ne couvrent pas l’ensemble des compétences en communication, ce qui limite leur utilité pour le personnel en santé publique. Des offres de perfectionnement professionnel plus nombreuses et plus complètes sont nécessaires.

Autologous fat grafting, or lipotransfer, is an important surgical approach to relocate adipose tissue within an individual to create volume. While used extensively in plastic and reconstructive surgery, significant drawbacks exist, including unpredictable volume retention. Thus, considerable research has been undertaken to identify surgical or therapeutic approaches that improve outcomes, primarily utilizing a xenograft immunocompromised mouse model. Large animal models are an important step in translating preclinical laboratory studies to the clinic, and previous studies utilizing pigs have been applied successfully for fat grafting research, but protocol variability exists across studies, and no previous publication has adequately described the impact of the swine breed on the experimental outcomes. In this report, we provide information on the critical attributes of the swine fat grafting model, including the following: (1) model selection; (2) donor site and surgical harvest approach; (3) tissue processing; (4) recipient site location and preparation; (5) post-operative care; and (6) longitudinal fat grafting assessments. Our experience comparing the use of Yorkshire and Yucatan breeds in our model showed that Yorkshire adipose tissue was fibrotic, extremely difficult to obtain through liposuction, and labor intensive to process into injectable formats. Alternatively, Yucatan adipose was more similar to human tissue, could be readily obtained through the surgical excision of inguinal fat pads, was amenable to mincing with surgical scissors, and yielded injectable tissue with a 95% efficiency. We determined that generation of a surgical pocket reduced the graft migration and spread, consequently facilitating the graft retrieval without significantly impacting retention. Using 5 cc grafts, the ultimate 3-month volume retention in 16 grafts was 19% ± 17% (or 1.14 cc ± 1.08 cc). While the use of ultrasound did not readily enable graft volume approximation during the study, it was a useful method to visualize the graft placement and ensure injection into the subcutaneous adipose layers.

Abstract We present a novel data set for drought in the continental US (CONUS) built to enable computationally efficient spatio-temporal statistical and probabilistic models of drought. We converted drought data obtained from the widely-used US Drought Monitor (USDM) from its native geo-referenced polygon format to a 0.5 degree regular grid. We merged known environmental drivers of drought, including those obtained from the North American Land Data Assimilation System (NLDAS-2), US Geological Survey (USGS) streamflow data, and National Oceanic and Atmospheric Administration (NOAA) teleconnections data. The resulting data set permits statistical and probabilistic modeling of drought with explicit spatial and/or temporal dependence. Such models could be used to forecast drought at short-range, seasonal to sub-seasonal, and inter-annual timescales with uncertainty, extending the reach and value of the current US Drought Outlook from the National Weather Service Climate Prediction Center. This novel data product provides the first common gridded dataset that includes critical variables used to inform hydrological and meteorological drought.

Abstract Background A lack of safety data on postpartum medication use presents a potential barrier to breastfeeding and may result in infant exposure to medications in breastmilk. The type and extent of medication use by lactating women requires investigation. Methods Data were collected from the CHILD Cohort Study which enrolled pregnant women across Canada between 2008 and 2012. Participants completed questionnaires regarding medications and non-prescription medications used and breastfeeding status at 3, 6 and 12 months postpartum. Medications, along with self-reported reasons for medication use, were categorized by ontologies [hierarchical controlled vocabulary] as part of a large-scale curation effort to enable more robust investigations of reasons for medication use. Results A total of 3542 mother-infant dyads were recruited to the CHILD study. Breastfeeding rates were 87.4%, 75.3%, 45.5% at 3, 6 and 12 months respectively. About 40% of women who were breastfeeding at 3 months used at least one prescription medication during the first three months postpartum; this proportion decreased over time to 29.5% % at 6 months and 32.8% at 12 months. The most commonly used prescription medication by breastfeeding women was domperidone at 3 months (9.0%, n = 229/2540) and 6 months (5.6%, n = 109/1948), and norethisterone at 12 months (4.1%, n = 48/1180). The vast majority of domperidone use by breastfeeding women (97.3%) was for lactation purposes which is off-label (signifying unapproved use of an approved medication). Non-prescription medications were more often used among breastfeeding than non-breastfeeding women (67.6% versus 48.9% at 3 months, p

Abstract The formation of extracellular DNA traps (ETosis) is a first response mechanism by specific immune cells following exposure to microbes. Initially characterized in vertebrate neutrophils, cells capable of ETosis have been discovered recently in diverse non-vertebrate taxa. To assess the conservation of ETosis between evolutionarily distant non-vertebrate phyla, we observed and quantified ETosis using the model ctenophore Mnemiopsis leidyi and the oyster Crassostrea gigas. Here we report that ctenophores – thought to have diverged very early from the metazoan stem lineage – possess immune-like cells capable of phagocytosis and ETosis. We demonstrate that both Mnemiopsis and Crassostrea immune cells undergo ETosis after exposure to diverse microbes and chemical agents that stimulate ion flux. We thus propose that ETosis is an evolutionarily conserved metazoan defense against pathogens.

Abstract African Americans (AA) have a higher risk for cardiovascular disease (CVD) as compared to their White (W) counterparts. CVD is characterized by increased blood pressure (BP), arterial stiffness and systemic inflammation. An acute inflammatory stimulus may explain physiological manifestations responsible for amplified CVD in AA that are not apparent at rest. The purpose of this study was to evaluate central and peripheral BP, central and local arterial stiffness, and indices of pulse wave morphology in young healthy AA and W participants in response to acute inflammation. Concentrations of the inflammatory cytokine interleukin‐6 (IL‐6) and measures of central and peripheral BP, central arterial stiffness (carotid–femoral pulse wave velocity (cfPWV)), local carotid arterial stiffness (β‐stiffness, elastic modulus (Ep)), and indices of pulse wave morphology were assessed in 28 participants (21 ± 2 years, AA: n = 11) at baseline (BL), 24 h and 48 h post‐inflammation. Changes in IL‐6 concentrations (ΔIL‐6) were significantly greater at 24 h as compared to 48 h post‐inflammation (0.652 ± 0.644 vs. −0.146 ± 0.532 pg/μl, P ≤ 0.0001). Among AA participants, central and peripheral diastolic BP were significantly decreased at 24 h post‐inflammation as compared to BL (aortic diastolic BP: −4 ± 4 mmHg, P = 0.016; brachial diastolic BP: −4 ± 4 mmHg, P = 0.014). AA participants also experienced a significant decrease in central and peripheral mean arterial BP at 48 h post‐inflammation as compared to BL (aortic mean arterial pressure: −4 ± 4 mmHg, P = 0.009; brachial mean arterial pressure: −4 ± 4 mmHg, P = 0.012). Despite haemodynamic changes, there were no differences in central or local carotid arterial stiffness or indices of pulse wave morphology.

Abstract Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assessed circadian timing’s impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. The aim of the study was to evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes and to identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities. An IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017–2021), receiving over 80% of treatments in the morning or afternoon, was performed. Survival analyses utilized Kaplan–Meier curves. This was a single-institution study involving patients receiving whole-brain radiotherapy. Demographic, disease, and socioeconomic parameters from electronic medical records were collected. Morning treatment (n = 158) showed a trend toward improved overall survival vs. afternoon (n = 79); the median survival was 158 vs. 79 days (p = 0.20, HR = 0.84, CI95% 0.84–0.91). Subgroup benefits for morning treatment in females (p = 0.04) and trends in controlled primary disease (p = 0.11) and breast cancer metastases (p = 0.08) were observed. Black patients exhibited diminished circadian influence. The present study emphasized chronobiological factors’ relevance in brain metastases radiation therapy. Morning treatment correlated with improved survival, particularly in specific subgroups. Potential circadian influence disparities were identified, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

Background: A recent international consensus conference called for the development of risk prediction models to identify ICU survivors at increased risk of each of the post-ICU syndrome domains. We previously developed and validated a risk prediction tool for functional impairment after ICU admission among older adults. Research Question: In this pilot study, we assessed the feasibility of administering the risk prediction tool in the hospital to older adults who had just survived critical illness. An exploratory objective was to evaluate whether augmentation of the model with additional hospital-related factors improved discrimination. Study Design and Methods: Between January and October 2020, 50 adults aged 65 years and older underwent in-hospital administration of the risk prediction tool. Survivors were called monthly for 6 months after discharge. Feasibility was defined as completion of all tool components by ≥ 70% of enrolled participants. Persistent functional impairment was defined as failure to return to the functional baseline from before the ICU stay at the 6-month interview based on seven daily activities. The model was sequentially refit after adding three in-hospital factors as predictors, one at a time and then all together. Model discrimination was assessed with receiver operating characteristic curves. Results: The tool met the a priori feasibility threshold, with 92.0% of enrolled participants completing all eight components. In the exploratory analysis, the addition of Acute Physiology and Chronic Health Evaluation II score, presence of delirium, and maximum in-hospital mobility resulted in a 5% gain in discrimination that did not achieve statistical significance (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.68-0.82; P = .09). Interpretation: Our results indicate that the risk prediction tool is feasible for use in the hospital setting, enabling the identification of ICU survivors at high risk of persistent functional impairment at 6 months after discharge. Augmentation with hospital-related factors improved model discrimination, but did not achieve statistical significance in this pilot study. Future studies should evaluate the augmented model in larger cohorts.

Summary: Herein, we present a protocol for culturing patient-derived organoids (PDOs) of cervical cancer that includes workflows for tumor biopsy/resection tissue and cytobrush-sampled cells. We describe steps for PDO culture initiation, including rinsing, gentle dissociation, Lymphoprep separation, and cell assessment, as well as seeding cells from surgical and cytobrush tissue digestion. We then provide guidance on PDO maintenance and passage and techniques for producing conditioned medium. Overall, this protocol serves as a valuable guide for establishing and maintaining cervical cancer PDOs.For complete details on the use and execution of this protocol, please refer to Colbert et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Polybrominated diphenyl ethers (PBDEs) used in consumer goods and flame retardants have been replaced by alternatives such as tetrabromobisphenol A (TBBPA). TBBPA does not readily undergo global distal transport, but local sources still threaten aquatic ecosystems. We studied the photofate of TBBPA with a specific focus on how Arctic-derived dissolved organic matter (DOM) affects its reaction kinetics, degradation pathways and formation of photoproducts in artificial and natural sunlight. Our results corroborate earlier studies that reveal a pH-dependent trend in TBBPA’s direct photolysis with longer degradation times for its acidic form. DOM either plays no role or it slightly reduces TBBPA’s rate of photodegradation via inner-filter effects. Photolysis experiments conducted at our Arctic field site, Toolik Lake Field Station, revealed slower than anticipated degradation, which magnified the half-life significantly during in-lake experiments. Importantly, the composition of DOM was found to influence the type and distribution of TBBPA photoproducts formed, which suggests that different degradation pathways occur in the presence of DOM. These findings provide valuable insights into the intricate interplay of environmental variables that govern the fate of TBBPA in sunlit aquatic ecosystems globally.

ABSTRACTMultiple weight loss attempts, and weight regain are common. Various lifestyle changes are often required for success, but just diet and exercise are often promoted. The amount of lifestyle changes needed for successful weight management is still unclear. Lifestyle metrics, such as the Lifestyle Score (LS) of The Lifestyle Questionnaire for Weight Management (LQ-WM), may provide clarification and predict success rates. The range of possible scores on this measure is from −49 to 77, where higher scores suggest healthier lifestyles. Hypotheses are that higher lifestyle scores will be found with successful weight management outcomes. Method: 1,007 online participants completed the LQ-WM and other items related to weight management. Results: 90.7% (39/43) of participants with an LS of 50 + reported successful weight loss, while just 5% (2/40) reported weight regain. 35.7% (20/56) of those with LS below zero reported weight loss success, and 39.4% (13/33) reported weight regain. Significant (p

Objective: Adolescents are at greater risk for poor sleep compared to childhood; however, there is limited data regarding psychosocial determinants of adverse sleep health among semi-rural adolescents. We investigated associations of mood, stress, and social support with self-reported sleep duration and daytime sleepiness among adolescents. Methods: Adolescents (n = 254) in semi-rural Georgia self-reported depressive and anxiety symptoms, stress, social support, sleep duration and daytime sleepiness in November 2020. Multinomial linear and logistic models were fit to examine associations of psychosocial factors with sleep duration and sleepiness; and effect modification by social support was tested after adjustment for covariates. Results: Most participants were non-Hispanic White (55 %), female (53 %), and approximately 35 % were eligible for free-reduced lunch. Mean sleep duration (± SD) and daytime sleepiness was 8.04 ± 1.36 and 5.17 ± 2.37, respectively; and 42 % of participants reported insufficient sleep (

Background COVID-19 remains a challenge to individual health and healthcare resources worldwide. Telemedical surveillance might minimise hospitalisation and direct patient–physician contacts. Yet, randomised clinical trials evaluating telemedical management of COVID-19 patients are lacking. Methods COVID-SMART is a randomised, open-label, controlled clinical trial investigating whether telemedicine reduces the primary end-point of hospitalisation or any unscheduled utilisation of an emergency medical service within 30 days of follow-up. Key secondary end-points included mortality and primary end-point components. We enrolled acutely infected SARS-CoV-2 patients suitable for outpatient care. All presented with ≥1 risk factor for an adverse COVID-19 course. Patients were randomised 1:1 into a control group receiving standard of care and an intervention group receiving smartphone-based assessment of oxygen saturation, heart rate and electrocardiogram, and telemedical counselling via a 24/7 emergency hotline. Results Of 607 enrolled patients (mean±sd age 46.7±13.5 years), 304 were randomised into the intervention and 303 into the control group. The primary end-point occurred in 6.9% (n=21) of the intervention and in 9.6% (n=29) of the control group (hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.41–1.26; p=0.24). No deaths occurred during follow-up. Fewer intervention group participants utilised outpatient-based emergency medical services (HR 0.43, 95% CI 0.20–0.90; p=0.03). Conclusions COVID-SMART is the first randomised clinical trial assessing the benefit of telemedicine in an acute respiratory infectious disease. Whereas telemedical management did not reduce the primary end-point of hospitalisation, fewer intervention group patients used outpatient-based emergency services, suggesting a potential benefit for less-acutely infected individuals.

Background Foodborne and waterborne illnesses affect over four million Canadians annually and pose a preventable burden on the nation’s healthcare system. Climate change can increase the risk of such illnesses by increasing the likelihood of exposure to contaminants. As climate change progresses, it is imperative to better understand its impact on the dissemination of foodborne and waterborne contaminants throughout the food system. Currently, there is limited, synthesised evidence for how future changes in Canada’s climate may affect the risk of contamination of preharvest foods. The aim of this research is to collate and describe available information on effects of climate variables on biological and chemical contamination of preharvest foods in Canada. This information will contribute to improved understanding of climate change impacts and potential adaptation and mitigation strategies to increase climate resiliency in Canada’s food system.Methods A preliminary search of MEDLINE, Web of Science and Google was conducted to verify the absence of existing reviews and to inform the development of this review protocol. Information will be identified by searching four academic databases: MEDLINE via Ovid, AGRICultural OnLine Access (AGRICOLA), CAB International and Web of Science. This search will be supplemented by a targeted grey literature search. The search strategy includes index terms and keywords for Canada-relevant foodborne and waterborne pathogens and chemical contaminants, preharvest foods and climate change. Search results will be managed using Covidence during all phases of the review, conducted by two independent reviewers. Data will be extracted, synthesised and presented using graphical and tabular formats.This scoping review protocol describes the process for retrieving a comprehensive set of evidence for how climate change variables may increase risk of biological or chemical contamination of preharvest foods in Canada. This review will provide decision-makers with a detailed understanding of climate variable-preharvest food-contaminant combinations using the best available evidence.Ethics and dissemination Ethical considerations are not applicable to this protocol as scoping reviews conduct secondary data analysis that synthesises data from publicly available sources. The results from this review will be disseminated through a peer-reviewed publication and conference presentation.