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OBJECTIVES:. We planned to synthesize evidence examining the potential efficacy and safety of performing physical rehabilitation and/or mobilization (PR&M) in adult patients receiving extracorporeal life support (ECLS). DATA SOURCES:. We included any study that compared PR&M to no PR&M or among different PR&M strategies in adult patients receiving any ECLS for any indication and any cannulation. We searched seven electronic databases with no language limitations. STUDY SELECTION AND DATA EXTRACTION:. Two reviewers, independently and in duplicate, screened all citations for eligibility. We used the Cochrane Risk of Bias 2 and Cochrane Risk Of Bias In Non-randomized Studies of Interventions tools to assess individual study risk of bias. Although we had planned for meta-analysis, this was not possible due to insufficient data, so we used narrative and tabular data summaries for presenting results. We assessed the overall certainty of the evidence for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation framework. DATA SYNTHESIS:. We included 17 studies that enrolled 996 patients. Most studies examined venovenous extracorporeal membrane oxygenation (ECMO) and/or venoarterial ECMO as a bridge to recovery in the ICU. We found an uncertain effect of high-intensity/active PR&M on mortality, duration of mechanical ventilation, ICU length of stay, hospital length of stay, or quality of life compared with low-intensity/passive PR&M in patients receiving ECLS (very low certainty due to very serious imprecision). There was similarly an uncertain effect on safety events including clinically important bleeding, spontaneous intracerebral hemorrhage, limb ischemia, accidental decannulation, or ECLS circuit dysfunction (very low certainty due to very serious risk of bias and imprecision). CONCLUSIONS:. Based on the currently available summary of evidence, there is an uncertain effect of high-intensity/active PR&M on patient important outcomes or safety in patients receiving ECLS. Despite indirect data from other populations suggesting potential benefit of high-intensity PR&M in the ICU; further high-quality randomized trials evaluating the benefits and risks of physical therapy and/or mobilization in this population are needed.

Organ-on-chip (OOC) models can be useful tools for cancer drug discovery. Advances in OOC technology have led to the development of more complex assays, yet analysis of these systems does not always account for these advancements, resulting in technical challenges. A challenging task in the analysis of these two-channel microfluidic models is to define the boundary between the channels so objects moving within and between channels can be quantified. We propose a novel imaging-based application of a thin plate spline method – a generalized cubic spline that can be used to model coordinate transformations – to model a tissue boundary and define compartments for quantification of invaded objects, representing the early steps in cancer metastasis. To evaluate its performance, we applied our analytical approach to an adapted OOC developed by Emulate, Inc., utilizing a two-channel system with endothelial cells in the bottom channel and colorectal cancer (CRC) patient-derived organoids (PDOs) in the top channel. Initial application and visualization of this method revealed boundary variations due to microscope stage tilt and ridge and valley-like contours in the endothelial tissue surface. The method was functionalized into a reproducible analytical process and web tool – the Chip Invasion and Contour Analysis (ChICA) – to model the endothelial surface and quantify invading tumor cells across multiple chips. To illustrate applicability of the analytical method, we applied the tool to CRC organoid-chips seeded with two different endothelial cell types and measured distinct variations in endothelial surfaces and tumor cell invasion dynamics. Since ChICA utilizes only positional data output from imaging software, the method is applicable to and agnostic of the imaging tool and image analysis system used. The novel thin plate spline method developed in ChICA can account for variation introduced in OOC manufacturing or during the experimental workflow, can quickly and accurately measure tumor cell invasion, and can be used to explore biological mechanisms in drug discovery.

Background: Airway management is a core component of the treatment of cardiac arrest. Where a rescuer cannot establish a patent airway to provide oxygenation and ventilation using standard basic and advanced airway techniques, there may be a need to consider emergency front-of-neck airway access (eFONA, e.g., cricothyroidotomy), but there is limited evidence to inform this approach. Objectives: This scoping review aims to identify the evidence for the use of eFONA techniques in patients with cardiac arrest. Methods: In November 2023, we searched Medline, Embase, and Cochrane Central to identify studies on eFONA in adults. We included randomised controlled trials, non-randomised studies, and case series with at least five cases that described any use of eFONA. We extracted data, including study setting, population characteristics, intervention characteristics, and outcomes. Our analysis focused on four key areas: incidence of eFONA, eFONA success rates, clinical outcomes, and complications. Results: The search identified 21,565 papers, of which 18,934 remained after de-duplication. After screening, we included 69 studies (53 reported incidence, 40 reported success rate, 38 reported clinical outcomes; 36 studies reported complications). We identified only one randomised controlled trial. Across studies, there was a total of 4,457 eFONA attempts, with a median of 31 attempts (interquartile range 16–56.5) per study. There was marked heterogeneity across studies that precluded any pooling of data. There were no studies that included only patients in cardiac arrest. Conclusion: The available evidence for eFONA is extremely heterogeneous, with no studies specifically focusing on its use in adults with cardiac arrest.

Introduction: Treatment for recurrent ovarian clear cell carcinoma (OCCC) is clinically challenging as response rates to traditional chemotherapy are low, and recurrence rates are high. Immunotherapy has shown promise for this ovarian cancer (OC) subtype, and tumor molecular testing allows for the identification of a patient population that might benefit most from this treatment. We describe the clinical course and somatic genomic testing of 4 patients who received pembrolizumab for recurrent OCCC concurrent with a combination of bevacizumab and/or cyclophosphamide. Methods: All patients with OCCC treated with immune checkpoint inhibitors (ICI) within a single health system between 2018 and 2023 (excluding those on clinical trials) were identified via retrospective chart review. Results: Four patients were included. The average age at diagnosis was 56.5 years, and the number of prior treatments ranged from 1 to 6. All patients received pembrolizumab combined with either bevacizumab and/or cyclophosphamide. All patients (n = 3) who received pembrolizumab and bevacizumab experienced a partial response. Responses were durable, ranging from 6 to 15 months. Somatic genomic testing results demonstrated microsatellite stability and low tumor mutational burden in all patient tumors, and 3 had AT-Rich Interaction Domain 1A gene (ARID1A) mutations. Notably, two patients had treatment-limiting toxicities, one with presumed immune-mediated grade 2 myocarditis, and another with grade 5 hepatitis. Conclusions: Pembrolizumab, combined with bevacizumab and cyclophosphamide, is a promising treatment option for patients with recurrent OCCC, though careful risk assessment and counseling regarding toxicities is necessary to maximize the safety and efficacy of this treatment regimen. Prospective studies are needed for validation.

In patients with mood disorders, negative affective biases – systematically prioritising and interpreting information negatively – are common. A translational cognitive task testing this bias has shown that depressed patients have a reduced preference for a high reward under ambiguous decision-making conditions. The precise mechanisms underscoring this bias are, however, not yet understood. We therefore developed a set of measures to probe the underlying source of the behavioural bias by testing its relationship to a participant’s reward sensitivity, value sensitivity and reward learning rate. One-hundred-forty-eight participants completed three online behavioural tasks: the original ambiguous-cue decision-making task probing negative affective bias, a probabilistic reward learning task probing reward sensitivity and reward learning rate, and a gambling task probing value sensitivity. We modelled the learning task through a dynamic signal detection theory model and the gambling task through an expectation-maximisation prospect theory model. Reward sensitivity from the probabilistic reward task (β = 0.131, p = 0.024) and setting noise from the probabilistic reward task (β = –0.187, p = 0.028) both predicted the affective bias score in a logistic regression. Increased negative affective bias, at least on this specific task, may therefore be driven in part by a combination of reduced sensitivity to rewards and more variable responses.

BackgroundPrevious research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers.ObjectiveIt is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans.MethodsSerotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts.ResultsPharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics.ConclusionsSerotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.

IntroductionCancer therapies predispose childhood cancer survivors to various treatment-related late effects, which contribute to a higher symptom burden, chronic health conditions (CHCs), and premature mortality. Regular monitoring of symptoms between clinic visits is useful for timely medical consultation and interventions that can improve quality of life (QOL). The Health Share Study aims to utilize mHealth to collect patient-generated health data (PGHD; daily symptoms, momentary physical health status) and develop survivor-specific risk prediction scores for mitigating adverse health outcomes including poor QOL and emergency room admissions. These personalized risk scores will be integrated into the hospital-based electronic health record (EHR) system to facilitate clinician communications with survivors for timely management of late effects.MethodsThis prospective study will recruit 600 adult survivors of childhood cancer from the St. Jude Lifetime Cohort study. Data collection include 20 daily symptoms via a smartphone, objective physical health data (physical activity intensity, sleep performance, and biometric data including resting heart rate, heart rate variability, oxygen saturation, and physical stress) via a wearable activity monitor, patient-reported outcomes (poor QOL, unplanned healthcare utilization) via a smartphone, and clinically ascertained outcomes (physical performance deficits, onset of/worsening CHCs) assessed in the survivorship clinic. Participants will complete health surveys and physical/functional assessments in the clinic at baseline, 2) report daily symptoms, wear an activity monitor, measure blood pressure at home over 4 months, and 3) complete health surveys and physical/functional assessments in the clinic 1 and 2 years from the baseline. Socio-demographic and clinical data abstracted from the EHR will be included in the analysis. We will invite 20 cancer survivors to investigate suitable formats to display predicted risk information on a dashboard and 10 clinicians to suggest evidence-based risk management strategies for adverse health outcomes.AnalysisMachine and statistical learning will be used in prediction modeling. Both approaches can handle a large number of predictors, including longitudinal patterns of daily symptoms/other PGHD, along with cancer treatments and socio-demographics.ConclusionThe individualized risk prediction scores and added communications between providers and survivors have the potential to improve survivorship care and outcomes by identifying early clinical presentations of adverse events.

Social infrastructure (SI) may buffer against suicide risk by improving social cohesion, social support, and information and resource sharing. The authors use an ecological approach to examine the relationship between county-level SI availability and suicide rates among working-age adults (25–64 years) in the United States, a population among which suicide rates are high, rising, and geographically unequal. Mortality data are from the National Vital Statistics System for 2016 to 2019. SI data are from the National Neighborhood Data Archive for 2013 to 2015 and capture the availability of typically free SI (e.g., libraries, community centers) and commercial SI (e.g., coffee shops, diners, entertainment venues). Results from negative binomial models show that suicide rates are significantly lower in counties with more SI availability, net of county demographic, socioeconomic, and health care factors. This relationship held for both typically free and commercial SI. Policy makers should consider strengthening existing and developing new SI as part of a broader strategy to reduce suicide rates in the United States.

Abstract Background Frailty indicators can operate in dynamic amalgamations of disease conditions, clinical symptoms, biomarkers, medical signals, cognitive characteristics, and even health beliefs and practices. This study is the first to evaluate which, among these multiple frailty-related indicators, are important and differential predictors of clinical cohorts that represent progression along an Alzheimer’s disease (AD) spectrum. We applied machine-learning technology to such indicators in order to identify the leading predictors of three AD spectrum cohorts; viz., subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD. The common benchmark was a cohort of cognitively unimpaired (CU) older adults. Methods The four cohorts were from the cross-sectional Comprehensive Assessment of Neurodegeneration and Dementia dataset. We used random forest analysis (Python 3.7) to simultaneously test the relative importance of 83 multi-modal frailty indicators in discriminating the cohorts. We performed an explainable artificial intelligence method (Tree Shapley Additive exPlanation values) for deep interpretation of prediction effects. Results We observed strong concurrent prediction results, with clusters varying across cohorts. The SCI model demonstrated excellent prediction accuracy (AUC = 0.89). Three leading predictors were poorer quality of life ([QoL]; memory), abnormal lymphocyte count, and abnormal neutrophil count. The MCI model demonstrated a similarly high AUC (0.88). Five leading predictors were poorer QoL (memory, leisure), male sex, abnormal lymphocyte count, and poorer self-rated eyesight. The AD model demonstrated outstanding prediction accuracy (AUC = 0.98). Ten leading predictors were poorer QoL (memory), reduced olfaction, male sex, increased dependence in activities of daily living (n = 6), and poorer visual contrast. Conclusions Both convergent and cohort-specific frailty factors discriminated the AD spectrum cohorts. Convergence was observed as all cohorts were marked by lower quality of life (memory), supporting recent research and clinical attention to subjective experiences of memory aging and their potentially broad ramifications. Diversity was displayed in that, of the 14 leading predictors extracted across models, 11 were selectively sensitive to one cohort. A morbidity intensity trend was indicated by an increasing number and diversity of predictors corresponding to clinical severity, especially in AD. Knowledge of differential deficit predictors across AD clinical cohorts may promote precision interventions.

Abstract Species occurrence data are foundational for research, conservation, and science communication, but the limited availability and accessibility of reliable data represents a major obstacle, particularly for insects, which face mounting pressures. We present BeeBDC, a new R package, and a global bee occurrence dataset to address this issue. We combined >18.3 million bee occurrence records from multiple public repositories (GBIF, SCAN, iDigBio, USGS, ALA) and smaller datasets, then standardised, flagged, deduplicated, and cleaned the data using the reproducible BeeBDC R-workflow. Specifically, we harmonised species names (following established global taxonomy), country names, and collection dates and, we added record-level flags for a series of potential quality issues. These data are provided in two formats, “cleaned” and “flagged-but-uncleaned”. The BeeBDC package with online documentation provides end users the ability to modify filtering parameters to address their research questions. By publishing reproducible R workflows and globally cleaned datasets, we can increase the accessibility and reliability of downstream analyses. This workflow can be implemented for other taxa to support research and conservation.

Abstract Background Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and death. The use of low-molecular-weight heparin (LMWH), despite being the standard of care to prevent VTE, comes with some challenges. Shared decision-making (SDM) interventions are recommended to support patients and clinicians in making preference-sensitive decisions. The quality of the SDM process has been widely assessed with the decisional conflict scale (DCS). Our aim is to report participants’ perspectives of each of the components of an SDM intervention (DASH-TOP) in relation to the different subscales of the DCS. Methods Design: A convergent, parallel, mixed-methods design. Participants: The sample consisted of 22 health care professionals, students of an Applied Clinical Research in Health Sciences (ICACS) master program. Intervention: We randomly divided the participants in three groups: Group 1 received one component (evidence -based information), Group 2 received two components (first component and value elicitation exercises), and Group 3 received all three components (the first two and a decision analysis recommendation) of the SDM intervention. Analysis: For the quantitative strand, we used a non-parametric test to analyze the differences in the DCS subscales between the three groups. For the qualitative strand, we conducted a content analysis using the decisional conflict domains to deductively categorize the responses. Results Groups that received more intervention components experienced less conflict and better decision-making quality, although the differences between groups were not statistically significant. The decision analysis recommendation improved the efficacy with the decision-making process, however there are some challenges when implementing it in clinical practice. The uncertainty subscale showed a high decisional conflict for all three groups; contributing factors included low certainty of the evidence-based information provided and a perceived small effect of the drug to reduce the risk of a VTE event. Conclusions The DASH-TOP intervention reduced decisional conflict in the decision -making process, with decision analysis being the most effective component to improve the quality of the decision. There is a need for more implementation research to improve the delivery of SDM interventions in the clinical encounter.

The offshore Northern shrimp (Pandalus borealis) bottom trawl fishery in eastern Canada currently uses 22 and 28 mm bar spacing Nordmøre grids to limit bycatch from using small mesh codends. However, a recent rebound of juvenile redfish (Sebastes spp.), that can pass through the grids, has greatly increased bycatch. To address this concern, this study investigated the effectiveness of 17 and 15 mm bar spacing Nordmøre grids in a twin-trawl (paired) configuration against the traditional 22 mm bar spacing grid. Size selectivity analyses showed that the 17 and 15 mm grids resulted in no significant reduction in shrimp catch across all length classes. The 17 mm grid significantly reduced redfish bycatch for all length classes and the 15 mm grid significantly reduced redfish bycatch for individuals larger than 95 mm total length. Less redfish entered the codend with the experimental grids, however, the overlap in width between redfish and Northern shrimp limits the overall sorting efficiency of the grids, leaving some redfish still vulnerable to capture.

Abstract The nasal and bronchial epithelium are unified parts of the respiratory tract that are affected in the monogenic disorder cystic fibrosis (CF). Recent studies have uncovered that nasal and bronchial tissues exhibit intrinsic variability, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins which relate to germ layer origin. In the present study, we explored whether intrinsic differences between nasal and bronchial epithelial cells persist in cell cultures and affect epithelial cell functioning in CF. Comparison of air–liquid interface (ALI) differentiated epithelial cells from subjects with CF revealed distinct mucociliary differentiation states of nasal and bronchial cultures. Moreover, using RNA sequencing we identified cell type-specific signature transcription factors in differentiated nasal and bronchial epithelial cells, some of which were already poised for expression in basal progenitor cells as evidenced by ATAC sequencing. Analysis of differentiated nasal and bronchial epithelial 3D organoids revealed distinct capacities for fluid secretion, which was linked to differences in ciliated cell differentiation. In conclusion, we show that unique phenotypical and functional features of nasal and bronchial epithelial cells persist in cell culture models, which can be further used to investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF.

Abstract Background While laboratory testing for infectious diseases such as COVID-19 is the surveillance gold standard, it is not always feasible, particularly in settings where resources are scarce. In the small country of Lesotho, located in sub-Saharan Africa, COVID-19 testing has been limited, thus surveillance data available to local authorities are limited. The goal of this study was to compare a participatory influenza-like illness (ILI) surveillance system in Lesotho with COVID-19 case count data, and ultimately to determine whether the participatory surveillance system adequately estimates the case count data. Methods A nationally-representative sample was called on their mobile phones weekly to create an estimate of incidence of ILI between July 2020 and July 2021. Case counts from the website Our World in Data (OWID) were used as the gold standard to which our participatory surveillance data were compared. We calculated Spearman’s and Pearson’s correlation coefficients to compare the weekly incidence of ILI reports to COVID-19 case count data. Results Over course of the study period, an ILI symptom was reported 1,085 times via participatory surveillance for an average annual cumulative incidence of 45.7 per 100 people (95% Confidence Interval [CI]: 40.7 – 51.4). The cumulative incidence of reports of ILI symptoms was similar among males (46.5, 95% CI: 39.6 – 54.4) and females (45.1, 95% CI: 39.8 – 51.1). There was a slightly higher annual cumulative incidence of ILI among persons living in peri-urban (49.5, 95% CI: 31.7 – 77.3) and urban settings compared to rural areas. The January peak of the participatory surveillance system ILI estimates correlated significantly with the January peak of the COVID-19 case count data (Spearman’s correlation coefficient = 0.49; P

Abstract Background Untreated perinatal mood and anxiety disorders (PMAD) have short- and long-term health and social consequences; online cognitive behavioral therapy (CBT) interventions can reduce symptoms. Despite partner support being protective online interventions rarely target couples. This study builds on research on an existing CBT-based intervention, the Mothers and Babies Online Course (eMB), by testing its feasibility with prenatal couples. Methods We conducted a pilot, randomized, controlled feasibility trial using a 1:1 parallel design. To be eligible, participant dyads were pregnant people (between 13–30 weeks gestation and with a score of 10 or greater on either the GAD-7 or PHQ-9 scale indicating elevated symptoms of anxiety or depression) and their cohabitating partners, living in Missouri, with access to the internet; both in the dyad consented to participate. Recruitment occurred via Facebook ads, flyers, and a snowball approach. The intervention group received eMB, and the control group received a list of community resources. We examined retention and adherence data extracted from eMB analytics and study databases. All participants were given depression and anxiety scales at baseline, 4 and 8 weeks to test preliminary efficacy; satisfaction and acceptability were measured at trial end (i.e., eight weeks) and via interview. Results There were 441 people who responded to recruitment materials, 74 pregnant people were screened; 19 partners did not complete enrolment, and 25 dyads were ineligible. There were 15 dyads per group (N = 30) who enrolled; all completed the study. The survey response rate was 90% but partners required nearly twice the number of reminders. No participant completed all lessons. Mean depression and anxiety scores dropped over time for dyads in control (M = -1.99, -1.53) and intervention (M = -4.80, -1.99). Intervention pregnant people’s anxiety significantly decreased (M = -4.05; 95% CI [0.82, 7.27]) at time two compared to control. Twelve pregnant people and four partners participated in post-intervention interviews and suggested improvements for eMB. Conclusion Online dyadic interventions can potentially reduce PMAD symptoms. However, to feasibly study eMB with couples, strategies to increase program adherence are necessary. Tailoring interventions to overtly include partners may be advantageous. Trial registration ClinicalTrials.gov NCT05867680, 19/05/2023.

Abstract M3 muscarinic receptors (M3R) modulate β-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, βPix, binds to β-catenin in colon cancer cells, augmenting β-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of βPix and β-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of βPix with β-catenin. βPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing βPix dose-dependently augmented β-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of βPix. Expression levels of β-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from βPix-deficient conditional knockout mice. Targeting the M3R/βPix/β-catenin axis may have therapeutic potential.

During population-based HIV impact assessments (PHIAs), some participants who self-reported testing HIV-positive (PSRP) tested negative in one or more subsequent survey HIV tests. These unexpected discrepancies between their self-reported results and the survey results draw into question the validity of either the self-reported status or the test results. We analyzed PSRP with negative test results aged 15–59 years old using data collected from 2015 to 2021 in 13 countries, assessing prevalence, self-report status, survey HIV status, viral load, rapid tests and confirmatory tests, and answers to follow-up questions (such as years on treatment). Across these surveys, 19,026 participants were PSRP, and 256 (1.3%) of these were concluded to be HIV-negative after additional survey-based testing and review. PSRP determined to be HIV-negative trended higher in countries with a higher HIV prevalence, but their number was small enough that accepting self-reported HIV-positive status without testing would not have significantly affected the prevalence estimates for HIV or viral load suppression. Additionally, using more detailed information for Uganda, we examined 107 PSRP with any negative test results and found no significant correlation with years on treatment or age. Using these details, we examined support for the possible reasons for these discrepancies beyond misdiagnosis and false reporting. These findings suggest that those conducting surveys would benefit from a nuanced understanding of HIV testing among PSRP to conduct surveys ethically and produce high-quality results.

A characteristic feature of Alzheimer’s disease (AD) is the formation of neuronal extracellular senile plaques composed of aggregates of fibrillar amyloid β (Aβ) peptides, with the Aβ1-42 peptide being the most abundant species. These Aβ peptides have been proposed to contribute to the pathophysiology of the disease; however, there are few tools available to test this hypothesis directly. In particular, there are no data that establish a dose–response relationship between Aβ peptide expression level and disease. We have generated a panel of transgenic Caenorhabditis elegans strains expressing the human Aβ1-42 peptide under the control of promoter regions of two pan-neuronal expressed genes, snb-1 and rgef-1. Phenotypic data show strong age-related defects in motility, subtle changes in chemotaxis, reduced median and maximum lifespan, changes in health span indicators, and impaired learning. The Aβ1-42 expression level of these strains differed as a function of promoter identity and transgene copy number, and the timing and severity of phenotypes mediated by Aβ1-42 were strongly positively correlated with expression level. The pan-neuronal expression of varying levels of human Aβ1-42 in a nematode model provides a new tool to investigate the in vivo toxicity of neuronal Aβ expression and the molecular and cellular mechanisms underlying AD progression in the absence of endogenous Aβ peptides. More importantly, it allows direct quantitative testing of the dose–response relationship between neuronal Aβ peptide expression and disease for the first time. These strains may also be used to develop screens for novel therapeutics to treat Alzheimer’s disease.

Legionella pneumophila is the waterborne pathogen primarily responsible for causing both Pontiac Fever and Legionnaire’s Disease in humans. L. pneumophila is transmitted via aerosolized water droplets. The purpose of this study was to design and test primers to allow for rapid polymerase chain reaction (PCR) melt detection and identification of this infectious agent in cases of clinical or emergency response detection. New PCR primers were designed for this species of bacteria; the primer set was purchased from IDT and the target bacterial DNA was purchased from ATCC. The L. pneumophila primers targeted the macrophage infectivity potentiator gene (mip), which inhibits macrophage phagocytosis. The primers were tested for specificity, repeatability, and sensitivity using PCR–high-resolution melt (HRM) assays. The primer set was found to be specific to the designated bacteria and did not amplify the other twenty-one species from the panel. The L. pneumophila assay was able to be multiplexed. The duplex assay consists of primers for L. pneumophila and Vibrio parahaemolyticus, which are both waterborne pathogens. The triplex assay consists of primers for L. pneumophila, V. parahaemolyticus, and Campylobacter jejuni. The unique melting temperature for the L. pneumophila primer assay is 82.84 ± 0.19 °C, the C. jejuni assay is 78.10 ± 0.58 °C, and the V. parahaemolyticus assay is 86.74 ± 0.65 °C.

Abstract Objective We aimed to determine the longitudinal distribution of hand function skills in individuals with classic Rett syndrome (RTT), an X‐linked dominant neurodevelopmental disorder, and correlate with MECP2 variants. Method We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus of this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups. Results Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C‐terminal truncations) compared with groups composed of individuals with more severe variants. Conclusions These temporal variations in hand use represent specific considerations that could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

The title compound, C8H18NO2+·Br−·C8H17NO2, crystallizes as the bromide salt of a 50:50 mixture of (triethylazaniumyl)carboxylic acid and the zwitterionic (triethylazaniumyl)carboxylate. The two organic entities are linked by a half-occupied bridging carboxylic acid hydrogen atom that is hydrogen-bonded to the carboxylate group of the second molecule. The tetralkylammonium group adopts a nearly perfect tetrahedral shape around the nitrogen atom with bond lengths that agree with known values. The carboxylic acid/carboxylate group is oriented anti to one of the ethyl groups on the ammonium group, and the carbonyl oxygen atom is engaged in intramolecular C—H...O hydrogen bonds.

Abstract Background Insurance claims data have been used to inform an understanding of Lyme disease epidemiology and cost of care, however few such studies have incorporated post-treatment symptoms following diagnosis. Using longitudinal data from a private, employer-based health plan in an endemic US state, we compared outpatient care utilization pre- and post-Lyme disease diagnosis. We hypothesized that utilization would be higher in the post-diagnosis period, and that temporal trends would differ by age and gender. Methods Members with Lyme disease were required to have both a corresponding ICD-9 code and a fill of an antibiotic indicated for treatment of the infection within 30 days of diagnosis. A 2-year ‘pre- diagnosis’ period and a 2-year ‘post-diagnosis period’ were centered around the diagnosis month. Lyme disease-relevant outpatient care visits were defined as specific primary care, specialty care, or urgent care visits. Descriptive statistics examined visits during these pre- and post-diagnosis periods, and the association between these periods and the number of visits was explored using generalized linear mixed effects models adjusting for age, season of the year, and gender. Results The rate of outpatient visits increased 26% from the pre to the post-Lyme disease diagnosis periods among our 317-member sample (rate ratio = 1.26 [1.18, 1.36], p

Abstract Background Spatial analysis can identify communities where men are at risk for aggressive prostate cancer (PCan) and need intervention. However, there are several definitions for aggressive PCan. In this study, we evaluate geospatial patterns of 3 different aggressive PCan definitions in relation to PCan-specific mortality and provide methodologic and practical insights into how each definition may affect intervention targets. Methods Using the Pennsylvania State Cancer Registry data (2005–2015), we used 3 definitions to assign “aggressive” status to patients diagnosed with PCan. Definition one (D1, recently recommended as the primary definition, given high correlation with PCan death) was based on staging criteria T4/N1/M1 or Gleason score ≥ 8. Definition two (D2, most frequently-used definition in geospatial studies) included distant SEER summary stage. Definition three (D3) included Gleason score ≥ 7 only. Using Bayesian spatial models, we identified geographic clusters of elevated odds ratios for aggressive PCan (binomial model) for each definition and compared overlap between those clusters to clusters of elevated hazard ratios for PCan-specific mortality (Cox regression). Results The number of “aggressive” PCan cases varied by definition, and influenced quantity, location, and extent/size of geographic clusters in binomial models. While spatial patterns overlapped across all three definitions, using D2 in binomial models provided results most akin to PCan-specific mortality clusters as identified through Cox regression. This approach resulted in fewer clusters for targeted intervention and less sensitive to missing data compared to definitions that rely on clinical TNM staging. Conclusions Using D2, based on distant SEER summary stage, in future research may facilitate consistency and allow for standardized comparison across geospatial studies.

Abstract Opioid use disorders (OUD) and overdose are public health threats worldwide. Widespread access to highly potent illicit synthetic opioids such as fentanyl is driving the recent rise in fatal overdoses. Vaccines containing fentanyl-based haptens conjugated to immunogenic carrier proteins offer a long-lasting, safe, and cost-effective strategy to protect individuals from overdose upon accidental or deliberate exposure to fentanyl and its analogs. Prophylactic or therapeutic active immunization with an anti-fentanyl vaccine induces the production of fentanyl-specific antibodies that bind the drug in the blood and prevent its distribution to the brain, which reduces its reinforcing effects and attenuates respiratory depression and bradycardia. To increase the efficacy of a lead anti-fentanyl vaccine, this study tested whether the incorporation of synthetic toll-like receptor (TLR) 4 and TLR7/8 agonists as vaccine adjuvants would increase vaccine efficacy against fentanyl challenge, overdose, and self-administration in either rats or Hanford miniature pigs. Formulation of the vaccine with a nucleolipid TLR7/8 agonist enhanced its immunogenicity and efficacy in preventing fentanyl-induced respiratory depression, analgesia, bradycardia, and self-administration in either rats or mini-pigs. These studies support the use of TLR7/8 adjuvants in vaccine formulations to improve their clinical efficacy against OUD and potentially other substance use disorders (SUD).

Abstract Opioid use disorders (OUD) and opioid-related fatal overdoses are a public health concern in the United States. Approximately 100,000 fatal opioid-related overdoses occurred annually from mid-2020 to the present, the majority of which involved fentanyl or fentanyl analogs. Vaccines have been proposed as a therapeutic and prophylactic strategy to offer selective and long-lasting protection against accidental or deliberate exposure to fentanyl and closely related analogs. To support the development of a clinically viable anti-opioid vaccine suitable for human use, the incorporation of adjuvants will be required to elicit high titers of high-affinity circulating antibodies specific to the target opioid. Here we demonstrate that the addition of a synthetic TLR7/8 agonist, INI-4001, but not a synthetic TLR4 agonist, INI-2002, to a candidate conjugate vaccine consisting of a fentanyl-based hapten, F1, conjugated to the diphtheria cross-reactive material (CRM), significantly increased generation of high-affinity F1-specific antibody concentrations, and reduced drug distribution to the brain after fentanyl administration in mice.

Abstract Background Legal cannabis is available in more than half of the United States. Health care professionals (HCPs) rarely give recommendations on dosing or safety of cannabis due to limits imposed by policy and lack of knowledge. Customer-facing cannabis dispensary staff, including clinicians (pharmacists, nurses, physician’s assistants), communicate these recommendations in the absence of HCP recommendations. Little is known about how dispensary staff approach individuals with complex medical and psychiatric comorbidities. Using responses from a national survey, we describe how cannabis dispensary staff counsel customers with medical and psychiatric comorbidities on cannabis use and examine whether state-specific cannabis policy is associated with advice given to customers. Methods National, cross-sectional online survey study from February 13, 2020 to October 2, 2020 of dispensary staff at dispensaries that sell delta-9-tetrahydrocannabinol containing products. Measures include responses to survey questions about how they approach customers with medical and psychiatric comorbidities; state medicalization score (scale 0-100; higher score indicates more similarity to regulation of traditional pharmacies); legalized adult-use cannabis (yes/no). We conducted multiple mixed effects multivariable logistic regression analyses to understand relationships between state medicalization and dispensary employees’ perspectives. Results Of 434 eligible respondents, most were budtenders (40%) or managers (32%), and a minority were clinicians (18%). State medicalization score was not associated with responses to most survey questions. It was associated with increased odds of encouraging customers with medical comorbidities to inform their traditional HCP of cannabis use (Odds ratio [OR]=1.2, 95% confidence interval [CI] 1.0-1.4, p=0.03) and reduced odds of recommending cannabis for individuals with cannabis use disorder (CUD) (OR=0.8, 95% CI 0.7-1.0, p=0.04). Working in a state with legalized adult-use cannabis was associated with recommending traditional health care instead of cannabis in those with serious mental illness (OR 2.2, 95% CI 1.1-4.7, p=0.04). Less than half of respondents believed they had encountered CUD (49%), and over a quarter did not believe cannabis is addictive (26%). Conclusions When managing cannabis dosing and safety in customers with medical and psychiatric comorbidity, dispensary staff preferred involving individuals’ traditional HCPs. Dispensary staff were skeptical of cannabis being addictive. While state regulations of dispensaries may impact the products individuals have access to, they were not associated with recommendations that dispensary staff gave to customers. Alternative explanations for dispensary recommendations may include regional or store-level variation not captured in this analysis.

Objective To identify and describe evidence on brief emergency department (ED)-delivered behavioural and care process interventions among patients presenting with suicide attempt or acute ideation, substance overdose or psychosis.Design We employed a scoping review design and searched multiple data sources, clinical trial registries and references lists through March 2023. We included English-language trials and rigorously designed observational studies. In alignment with scoping review guidelines, we did not assess the quality of included studies or rate the strength of evidence of intervention effectiveness.Population Our population of interest was adults presenting to the ED with suicidality (eg, attempt or acute ideation), any substance overdose or acute psychosis from a primary mental health condition.Intervention We included studies of brief behavioural or care process interventions delivered in the ED.Outcome measures Health outcomes (eg, symptom reduction), healthcare utilisation and harms.Results Our search identified 2034 potentially relevant articles. We included 40 studies: 3 systematic reviews and 39 primary studies. Most studies (n=34) examined ED interventions in patients with suicide attempt or suicidal ideation, while eight studies examined interventions in patients with opioid overdose. No studies examined ED interventions in patients with acute psychosis. Most suicide prevention studies reported that brief psychological, psychosocial or screening and triage interventions reduce suicide and suicide attempt following an ED visit. Most clinical trial interventions were multicomponent and included at least one follow-up. All substance overdose studies focused on opioids. These studies often contained medication and referral or consultation components. Multiple studies reported increases in substance use disorder treatment utilisation; evidence on repeat overdose events was limited.Conclusions A wide range of multicomponent ED-delivered behavioural health interventions for suicidality and opioid use disorder show short-term improvement on primary outcomes such as suicide reattempt. Few studies on non-opioid substances and psychosis are available.

Background: Canadian data suggests that Black candidates may be less successful than other groups when applying to medical school. We sought to comprehensively describe the racial and/or ethnic identity, gender identity, sexual orientation, and ability of applicants to a single Canadian medical school. We also examined for an association between success at each application stage and applicant gender and racial identity. Methods: Class of 2024 applicants to a single Canadian medical school were invited to complete a demographics survey. The odds of achieving each application stage (offered an interview, offered a position, and matriculating) were determined for each demographic group. Results: There were 595 participants (32.4% response rate). The demographics of the applicant pool and matriculating class were similar. There was no difference in interview offers or matriculation between BIPOC and white candidates. Cisgender men were overrepresented in interviews compared to cisgender women (OR 0.64; 95%CI 0.43-0.95; p = 0.03) but not in matriculation. BIPOC cisgender women received more interview invitations compared to other groups (OR 2.74, 95%CI 1.20-6.25; p = 0.02). Conclusions: Differences in applicant success for differing demographic groups were most pronounced being offered an interview.

PurposeSomatic molecular profiling of pediatric brain tumors aids with the diagnosis and treatment of patients with a variety of high- and low-grade central nervous system neoplasms. Here, we report follow-up targeted germline evaluation for patients with possible germline variants following tumor only testing in the initial year in which somatic molecular testing was implemented at a single institution.Patients and MethodsSomatic testing was completed for all tumors of the central nervous system (CNS) undergoing diagnostic workup at Seattle Children’s Hospital during the study period of November 2015 to November 2016. Sequencing was performed in a College of American Pathologists-accredited, Clinical Laboratory Improvements Amendments-certified laboratory using UW-OncoPlex™ assay (version 5), a DNA-based targeted next generation sequencing panel validated to detect genetic alterations in 262 cancer-related genes. We tracked subsequent clinical evaluation and testing on a subgroup of this cohort found to have potential germline variants of interest.ResultsMolecular sequencing of 88 patients’ tumors identified 31 patients with variants that warranted consideration of germline testing. To date, 19 (61%) patients have been tested. Testing confirmed germline variants for ten patients (31% of those identified for testing), one with two germline variants (NF1 and mosaic TP53). Eight (26%) patients died before germline testing was sent. One patient (13%) has not yet had testing.ConclusionClinically validated molecular profiling of pediatric brain tumors identifies patients who warrant further germline evaluation. Despite this, only a subset of these patients underwent the indicated confirmatory sequencing. Further work is needed to identify barriers and facilitators to this testing, including the role of genetic counseling and consideration of upfront paired somatic-germline testing.

Background: Transcatheter aortic valve replacement (TAVR) are not offered equitably to vulnerable population groups. Adequate levels of insurance may narrow gaps among patients with higher social vulnerability index (SVI). Among a national population of individuals with commercial or Medicare insurance, we sought to determine whether SVI was associated with urgency of receipt of TAVR for aortic stenosis. Methods and results: Using Optum's de-identified Clinformatics Data Mart Database (CDM), we identified admissions for TAVR with aortic stenosis between January 2018 and March 2022. Admission urgency was identified by CDM claims codes. SVI was cross-referenced to patient zip codes and grouped into quintiles. Generalized linear mixed effects models were used to predict the probability of a TAVR admission being urgent based on SVI quintiles, adjusting for patient and hospital-level covariates. Results: Among 6680 admissions for TAVR [median age 80 years (interquartile range 75–85), 43.9 % female], 8.5 % (n = 567) were classified as urgent. After adjusting for patient and hospital-level variables, there were no significant differences in the odds of urgent admission for TAVR according to SVI quintiles [OR 5th (greatest social vulnerability) vs 1st quintile (least social vulnerability): 1.29 (95 % CI: 0.90–1.85)]. Conclusions: Among commercial or Medicare beneficiaries with aortic stenosis, SVI was not associated with admission urgency for TAVR. To clarify whether cardiovascular care delivery is improved across SVI with higher paying beneficiaries, future investigation should identify whether relationships between SVI and TAVR urgency vary for Medicaid beneficiaries compared to commercial beneficiaries.

Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also generated through a non-enzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in mediating histone lactoylation and inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH and histone lactoylation with a corresponding potentiation of the inflammatory response when exposed to lipopolysaccharides. An analysis of chromatin accessibility shows that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state; upon stimulation, however, regions of the genome associated with lactoylation become markedly more accessible. Lastly, we demonstrate a spontaneous S-to-S acyltransfer of lactate from LGSH to CoA, yielding lactoyl-CoA. This represents the first known mechanism for the generation of this metabolite. Collectively, these data suggest that LGSH, and not intracellular lactate, is the primary driving factor facilitating histone lactoylation and a major contributor to inflammatory signaling.

Providers’ recommendation is among the strongest predictors to patients engaging in preventive care. Therefore, the aim of this study was to compare providers’ Hepatitis C Virus (HCV) screening recommendation quality between high-risk and average-risk patients to determine if providers are universally recommending HCV screening, regardless of risk behaviors. This cross-sectional survey of 284 Indiana providers in 2020 assessed provider characteristics, HCV screening recommendation practices (strength, presentation, frequency, timeliness), self-efficacy, and barriers to recommending HCV screening. T-test and Chi-square compared recommendation practices for high-risk and average-risk patients. Prevalence ratios were calculated for variables associated with HCV recommendation strength comparing high-risk and average-risk patients. Logistic regression analyses examined factors associated with HCV recommendation strength for high- and average-risk patients, with odds ratios. Compared to average-risk patients, high-risk patients received higher proportion of HCV recommendations that were strong (70.4 % v. 42.4 %), routine (61.9 % v. 55.6 %), frequent (37.7 % v. 28 %), and timely (74.2 % v. 54.9 %) (P-values

Abstract This review describes the barriers and challenges faced by older adults of color with cancer and highlights methods to improve their overall care. In the next decade, cancer incidence rates are expected to increase in the United States for people aged ≥65 years. A large proportion will be older adults of color who often have worse outcomes than older White patients. Many issues contribute to racial disparities in older adults, including biological factors and social determinants of health (SDOH) related to healthcare access, socioeconomic concerns, systemic racism, mistrust, and the neighborhood where a person lives. These disparities are exacerbated by age‐related challenges often experienced by older adults, such as decreased functional status, impaired cognition, high rates of comorbidities and polypharmacy, poor nutrition, and limited social support. Additionally, underrepresentation of both patients of color and older adults in cancer clinical research results in a lack of adequate data to guide the management of these patients. Use of geriatric assessments (GA) can aid providers in uncovering age‐related concerns and personalizing interventions for older patients. Research demonstrates the ability of GA‐directed care to result in fewer treatment‐related toxicities and improved quality of life, thus supporting the routine incorporation of validated GA into these patients' care. GA can be enhanced by including evaluation of SDOH, which can help healthcare providers understand and address the needs of older adults of color with cancer who face disparities related to their age and race.

Abstract Light detection and ranging (lidar) has emerged as a valuable tool for examining the fine‐scale characteristics of vegetation. However, lidar is rarely used to examine coastal wetland vegetation or the habitat selection of small mammals. Extensive anthropogenic modification has threatened the endemic species in the estuarine wetlands of the California coast, such as the endangered salt marsh harvest mouse (Reithrodontomys raviventris; SMHM). A better understanding of SMHM habitat selection could help managers better protect this species. We assessed the ability of airborne topographic lidar imagery in measuring the vegetation structure of SMHM habitats in a coastal wetland with a narrow range of vegetation heights. We also aimed to better understand the role of vegetation structure in habitat selection at different spatial scales. Habitat selection was modeled from data compiled from 15 small mammal trapping grids collected in the highly urbanized San Francisco Estuary in California, USA. Analyses were conducted at three spatial scales: microhabitat (25 m2), mesohabitat (2025 m2), and macrohabitat (~10,000 m2). A suite of structural covariates was derived from raw lidar data to examine vegetation complexity. We found that adding structural covariates to conventional habitat selection variables significantly improved our models. At the microhabitat scale in managed wetlands, SMHM preferred areas with denser and shorter vegetation and selected for proximity to levees and taller vegetation in tidal wetlands. At the mesohabitat scale, SMHM were associated with a lower percentage of bare ground and with pickleweed (Salicornia pacifica) presence. All covariates were insignificant at the macrohabitat scale. Our results suggest that SMHM preferentially selected microhabitats with access to tidal refugia and mesohabitats with consistent food sources. Our findings showed that lidar can contribute to improving our understanding of habitat selection of wildlife in coastal wetlands and help to guide future conservation of an endangered species.

IntroductionCerebrovascular pathologies contribute to cognitive decline during aging, leading to vascular cognitive impairment and dementia (VCID). Levels of circulating insulin-like growth factor 1 (IGF-1), a vasoprotective hormone, decrease during aging. Decreased circulating IGF-1 in animal models leads to the development of VCID-like symptoms, but the cellular mechanisms underlying IGF-1-deficiency associated pathologies in the aged cerebrovasculature remain poorly understood. Here, we test the hypothesis that vascular smooth muscle cells (VSMCs) play an integral part in mediating the vasoprotective effects of IGF-1.MethodsWe used a hypertension-based model of cerebrovascular dysfunction in mice with VSMC-specific IGF-1 receptor (Igf1r) deficiency and evaluated the development of cerebrovascular pathologies and cognitive dysfunction.ResultsVSMC-specific Igf1r deficiency led to impaired cerebral myogenic autoregulation, independent of blood pressure changes, which was also associated with impaired spatial learning and memory function as measured by radial arm water maze and impaired motor learning measured by rotarod. In contrast, VSMC-specific IGF-1 receptor knockdown did not lead to cerebral microvascular rarefaction.DiscussionThese studies suggest that VSMCs are key targets for IGF-1 in the context of cerebrovascular health, playing a role in vessel stability alongside other cells in the neurovascular unit, and that VSMC dysfunction in aging likely contributes to VCID.

No consensus exists for heart transplant listing for patients who use cannabis. We conducted a web-based survey to assess knowledge, and practice patterns towards patients with heart failure who use cannabis referred for transplant. A total of 140 clinicians (cardiologists (41.4%, n = 58), surgeons (7.1%, n = 10), pharmacists (9.3%, n = 13), advanced practice providers and coordinators) responded and responses were grouped by whether they responded that cannabis is "illegal in my state" (illegal), or "legal for medical and recreational use in my state," (legal). There was a statistically significant difference in responses between the groups in the frequency of cannabis use that should preclude a patient from HT listing p = 0.0330) with respondents where cannabis is legal tending to answer that higher frequencies were acceptable. The groups in the "legal group" responded that a validated cannabis screening questionnaire could evaluate HT eligibility (p = 0.0111). A majority in the illegal group responding "No" as to whether their program allows pre- or post-transplant patients to use prescribed cannabis products (p < 0.0001). A majority in the illegal group responding "No" while the majority in the legal group responded "Yes" to "Does your HT center's current selection criteria policy address medical cannabis use in potential transplant candidates?" (p = 0.0001). Health care providers generally agreed that a validated cannabis use disorder screening questionnaire would be useful and that 6 months of abstinence from cannabis is sufficient prior to HT listing. Significant heterogeneity exists regarding cannabis use as it relates to heart transplantation.

BackgroundForty percent of new cancer cases in the United States are attributed to modifiable risks, which can be influenced by the built environment. Recent cancer prevention guidelines include recommendations for making communities conducive to healthy living. Focused on the city of Philadelphia, the present study aims to 1) evaluate neighborhood-level adherence to cancer prevention guidelines by developing two novel indices and 2) identify factors driving low compliance in neighborhoods with high cancer mortality.MethodsPhiladelphia neighborhoods were compared to the city overall on ten cancer prevention recommendations. Comparison scores informed two indices: one focused on the American Cancer Society's guidelines for Physical Activity, Nutrition, and Smoking, and the other focused on Healthy People 2030's guidelines for Prevention Services. Indices were mapped by neighborhood and compared to cancer mortality. Where low adherence overlapped with high cancer mortality, the recommendations driving low compliance were identified.ResultsDistinct geospatial patterns were observed in adherence to guidelines, and while drivers of low adherence varied by neighborhood, general trends emerged in different areas of the city. Concerning Physical Activity, Nutrition, and Smoking Guideline adherence, some areas appeared to be more influenced by the built environment, while others were impacted by specific behavioral risk factors such as excessive alcohol consumption. Preventive Service recommendation adherence was driven in some parts by self-reported poor health and, in others, low cancer screening rates and a high physician-to-resident ratio. In neighborhoods where poor guideline adherence overlapped with high cancer mortality, the built environment emerged as a potentially important factor.DiscussionThis study considers the importance of the built environment in influencing adherence to cancer prevention guidelines. Policymakers and public health officials can use this information to prioritize interventions for neighborhoods with low guideline adherence and high cancer burden and tailor interventions to focus on indicators of low guideline adherence.

OBJECTIVES:. To perform a systematic review and meta-analysis to evaluate the association of various measures of glycemic variability, including time-domain and complexity-domain, with short-term mortality in patients with critical illness. DATA SOURCES:. We searched Embase Classic +, MEDLINE, and the Cochrane Database of Systematic Reviews from inception to November 3, 2023. STUDY SELECTION:. We included English language studies that assessed metrics of glycemic variation or complexity and short-term mortality in patients admitted to the ICU. DATA EXTRACTION:. Two authors performed independent data abstraction and risk-of-bias assessments. We used a random-effects model to pool binary and continuous data and summarized estimates of effect using odds ratios and mean difference. We used the Quality in Prognosis Studies tool to assess risk of bias and the Grading of Recommendations, Assessment, Development and Evaluations to assess certainty of pooled estimates. DATA SYNTHESIS:. We included 41 studies (n = 162,259). We demonstrate that increased sd, coefficient of variance, glycemic lability index, and decreased time in range are probably associated with increased mortality in critically ill patients (moderate certainty) and that increased mean absolute glucose, mean amplitude of glycemic excursion, and detrended fluctuation analysis may be associated with increased mortality (low certainty). CONCLUSIONS:. We found a consistent association between increased measures of glycemic variability and higher short-term mortality in patient with critical illness. Further research should focus on standardized measurements of glycemic variation and complexity, along with their utility as therapeutic targets and prognostic markers.

BackgroundWhile much progress has been made in the control and elimination of onchocerciasis across Africa, the extent to which vector migration might confound progress towards elimination or result in re-establishment of endemism in areas where transmission has been eliminated remains unclear. In Northern Ethiopia, Metema and Metekel-two foci located near the Sudan border-exhibit continuing transmission. While progress towards elimination has been faster in Metema, there remains a problematic hotspot of transmission. Whether migration from Metekel contributes to this is currently unknown.Methodology/principle findingsTo assess the role of vector migration from Metekel into Metema, we present a population genomics study of 151 adult female vectors using 47,638 RADseq markers and mtDNA CoI sequencing. From additional cytotaxonomy data we identified a new cytoform in Metema, closely related to S. damnosum s.str, here called the Gondar form. RADseq data strongly indicate the existence of two distinctly differentiated clusters within S. damnosum s.l.: one genotypic cluster found only in Metema, and the second found predominantly in Metekel. Because blackflies from both clusters were found in sympatry (in all four collection sites in Metema), but hybrid genotypes were not detected, there may be reproductive barriers preventing interbreeding. The dominant genotype in Metema was not found in Metekel while the dominant genotype in Metekel was found in Metema, indicating that (at the time of sampling) migration is primarily unidirectional, with flies moving from Metekel to Metema. There was strong differentiation between clusters but little genetic differentiation within clusters, suggesting migration and gene flow of flies within the same genetic cluster are sufficient to prevent genetic divergence between sites.Conclusions/significanceOur results confirm that Metekel and Metema represent different transmission foci, but also indicate a northward movement of vectors between foci that may have epidemiological importance, although its significance requires further study.

Background The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes.Methods 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial.Results CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone.Conclusions Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

Background & Aims: The hospital frailty risk score (HFRS) identifies older patients at risk of poor outcomes and may have value in cirrhosis. We compared the Charlson (CCI), Elixhauser (ECI), and cirrhosis (CirCom) comorbidity indices with the HFRS in predicting outcomes for cirrhosis hospitalisations. Methods: Using the National Inpatient Sample (quarter 4 of 2015–2019), we analysed cirrhosis hospitalisations. For each index, we described the prevalence of comorbid conditions and inpatient mortality. We compared the ability of CCI, ECI, CirCom, and HFRS to predict inpatient mortality. Raw and adjusted models predicting inpatient mortality were compared using the area under the receiver operating characteristic curve and the Akaike information criterion. Results: The cohort’s (N = 626,553) median age was 61 years (IQR 52–68 years), 60% were male, cirrhosis was caused by alcohol in 43%, and 38% had ascites. The median comorbidity scores are as follows: ECI 4 (IQR 3–6), CCI 5 (IQR 4–8), and HFRS 5.6 (IQR 3.0–8.6). The most common CirCom score was 0 + 0 (44%). Across the range of values of each index, we observed different mortality ranges: CCI 1.9–13.1%, ECI 3.2–8.7%, CirCom 4.9–13.8%, and HFRS 1.0–15.2%. An adjusted model with HFRS had the highest area under the receiver operating characteristic curve in predicting mortality (HFRS 0.782 vs. ECI 0.689, CCI 0.695, and CirCom 0.692). We observed substantial variation in mortality with HFRS within each level of CCI, ECI, and CirCom. For example, for ECI 4, mortality increased from 0.6 to 16.4%, as HFRS increased from 0 to 15. Conclusions: Comorbidity indices predict inpatient cirrhosis mortality, but HFRS performs better than CCI, ECI, and CirCom. HFRS is an ideal tool for measuring comorbidity burden and disease severity risk adjustment in cirrhosis-related administrative database studies. Impact and Implications: We compared commonly used comorbidity indices to a more recently described risk score (hospital frailty risk score [HFRS]) in patients with cirrhosis using a national sample of hospital records. Comorbid conditions are common in hospitalised patients with cirrhosis. There is significant variability in mortality across the range of each index. HFRS outperforms the Charlson comorbidity index, Elixhauser comorbidity index, and CirCom (cirrhosis-specific comorbidity scoring system) in predicting inpatient mortality. HFRS is a valuable index for risk adjustment in inpatient administrative database studies.

Abstract Background Despite similar incidence rates among Black and White women, breast cancer mortality rates are 40% higher among Black women. More than half of the racial difference in breast cancer mortality can be attributed to triple negative breast cancer (TNBC), an aggressive subtype of invasive breast cancer that disproportionately affects Black women. Recent research has implicated neighborhood conditions in the etiology of TNBC. This study investigated the relationship between cumulative neighborhood‐level exposures and TNBC risk. Methods This single‐institution retrospective study was conducted on a cohort of 3316 breast cancer cases from New Castle County, Delaware (from 2012 to 2020), an area of the country with elevated TNBC rates. Cases were stratified into TNBC and “Non‐TNBC” diagnosis and geocoded by residential address. Neighborhood exposures included census tract‐level measures of unhealthy alcohol use, metabolic dysfunction, breastfeeding, and environmental hazards. An overall cumulative risk score was calculated based on tract‐level exposures. Results Univariate analyses showed each tract‐level exposure was associated with greater TNBC odds. In multivariate analyses that controlled for patient‐level race and age, tract‐level exposures were not associated with TNBC odds. However, in a second multivariate model that included patient‐level variables and considered tract‐level risk factors as a cumulative exposure risk score, each one unit increase in cumulative exposure was significantly associated with a 10% increase in TNBC odds. Higher cumulative exposure risk scores were found in census tracts with relatively high proportions of Black residents. Conclusions Cumulative exposure to neighborhood‐level risk factors that disproportionately affect Black communities was associated with greater TNBC risk.

Abstract Although APOE ɛ4 has been identified as the strongest genetic risk factor for Alzheimer’s Disease, there are some APOE ɛ4 carriers who do not go on to develop Alzheimer’s disease or cognitive impairment. This study aims to investigate factors contributing to this “resilience” separately by gender. Data were drawn from APOE ɛ4 positive participants who were aged 60 + at baseline in the Personality and Total Health Through Life (PATH) Study (N = 341, Women = 46.3%). Participants were categorised into “resilient” and “non-resilient” groups using Latent Class Analysis based on their cognitive impairment status and cognitive trajectory across 12 years. Logistic regression was used to identify the risk and protective factors that contributed to resilience stratified by gender. For APOE ɛ4 carriers who have not had a stroke, predictors of resilience were increased frequency of mild physical activity and being employed at baseline for men, and increased number of mental activities engaged in at baseline for women. The results provide insights into a novel way of classifying resilience among APOE ɛ4 carriers and risk and protective factors contributing to resilience separately for men and women.

Abstract Snow algae are ubiquitous in the Pacific Northwest cryosphere in the summer where snowmelt is an important contribution to regional watersheds. However, less attention has been given to biological impurities as drivers of snowmelt compared to inorganic light-absorbing particles. Here we map snow algae near Mt. Baker with a multispectral camera on an uncrewed aerial vehicle using (1) principal components and (2) spectral indexing. The two approaches are tested under differing bloom states and verified with coincident algal pigment and cell count data. During high bloom intensity we found an average instantaneous radiative forcing of 237 W m−2 with a maximum of 360 W m−2. This translated to 1,508 ± 536 m3 of melted snow water equivalent in the 0.1 km2 basin. These results demonstrate snow algae contribute to snowmelt at mid-latitudes and the potential for uncrewed autonomous vehicles to map snow algae over expansive areas of the cryosphere.

Abstract Our recent work has shown that DCAF1 (also known as VprBP) is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether DCAF1 also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that DCAF1 phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, DCAF1-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a mechanism underlying DCAF1-driven colonic tumorigenesis by linking DCAF1-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.

This paper compares variations on a structure model derived from an X-ray diffraction data set from a solid solution of chalcogenide derivatives of cis-1,2-bis(diphenylphosphanyl)ethylene, namely, 1,2-(ethene-1,2-diyl)bis(diphenylphoshpine sulfide/selenide), C26H22P2S1.13Se0.87. A sequence of processes are presented to ascertain the composition of the crystal, along with strategies for which aspects of the model to inspect to ensure a chemically and crystallographically realistic structure. Criteria include mis-matches between Fobs2 and Fcalc2, plots of |Fobs| vs |Fcalc|, residual electron density, checkCIF alerts, pitfalls of the OMIT command used to suppress ill-fitting data, comparative size of displacement ellipsoids, and critical inspection of interatomic distances. Since the structure is quite small, solves easily, and presents a number of readily expressible refinement concepts, we feel that it would make a straightforward and concise instructional piece for students learning how to determine if their model provides the best fit for the data and show students how to critically assess their structures.

The molecular structure of tert-butyl 3,6-diiodocarbazole-9-carboxylate, C17H15I2NO2, features a nearly planar 13-membered carbazole ring with C—I bond lengths of 2.092 (4) and 2.104 (4) Å. The carbamate group has key bond lengths of 1.404 (6) Å (N—C), 1.330 (5) Å (O—C), and 1.201 (6) Å (C=O). The crystal contains intermolecular π–π interactions, as well as both type I and type II intermolecular I...I interactions.

IntroductionDespite a growing emphasis on discourse processing in clinical neuroscience, relatively little is known about the neurobiology of discourse production impairments. Individuals with a history of left or right hemisphere stroke can exhibit difficulty with communicating meaningful discourse content, which implies both cerebral hemispheres play a role in this skill. However, the extent to which successful production of discourse content relies on network connections within domain-specific vs. domain-general networks in either hemisphere is unknown.MethodsIn this study, 45 individuals with a history of either left or right hemisphere stroke completed resting state fMRI and the Cookie Theft picture description task.ResultsParticipants did not differ in the total number of content units or the percentage of interpretative content units they produced. Stroke survivors with left hemisphere damage produced significantly fewer content units per second than individuals with right hemisphere stroke. Intrinsic connectivity of the left language network was significantly weaker in the left compared to the right hemisphere stroke group for specific connections. Greater efficiency of communication of picture scene content was associated with stronger left but weaker right frontotemporal connectivity of the language network in patients with a history of left hemisphere (but not right hemisphere) stroke. No significant relationships were found between picture description measures and connectivity of the dorsal attention, default mode, or salience networks or with connections between language and other network regions.DiscussionThese findings add to prior behavioral studies of picture description skills in stroke survivors and provide insight into the role of the language network vs. other intrinsic networks during discourse production.