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Background: The residency program director (PD) position is a valued leadership appointment in academic medicine. PDs are responsible for the success of their program and its residents. The objective of this study is to provide a cross-sectional analysis of baseline demographics and academic backgrounds of current neurosurgery program directors., Methods: Data was compiled on neurosurgery PDs and their residency programs, as of the end of May 2021, using publicly available resources including Doximity, FREIDA, and Healthgrades. The Mann-Whitney and Fisher exact tests were used for statistical analysis., Results: Of 113 PDs identified, 91.15% are male (P < 0.01). The majority of PDs (88.5%) received their medical degrees from U.S. medical schools. The average age of current PDs is 54 years, and the average age at appointment was 48 years. Compared to their male counterparts, female PDs are more likely to be younger at appointment (41 vs. 48 years; P = 0.001) and while holding the same position (45 vs. 55 years; P = 0.001). As a result, female PDs experience less time to appointment after residency (8.6 years vs. 14.7 years, P = 0.013). There are no significant differences regarding the gender of the PD and university affiliation, current appointment, completion of a fellowship, and resident gender ratios., Conclusions: The position of neurosurgery residency PD is dominated by fellowship-trained men in their late 40s to 50s. The gender ratio of neurosurgery residents is consistent with the underrepresentation of women in this position. With increasing female representation in neurosurgery, more women may assume this leadership position and begin to hasten the gender balance., (Copyright © 2022. Published by Elsevier Inc.)

The research outlined in this article offers a systematic training methodology for students and licensed Traditional Chinese Medicine (TCM) practitioners to learn the clinical art and science of pulsology through dance. One of the greatest hurdles in learning pulse palpation is a TCM practitioner's inability to feel the pulse with a degree of certainty that adds value in a clinical setting. Through inter-operator reliability testing, our research indicates that if practitioners learn and repeat pre-choreographed movements that represent pulse imagery, there is increased agreement amongst the group as to what pulses are being expressed in the bodies of patients. The implications of our research are that TCM practitioners are able to increase their ability to feel pulses in their patients by dancing the pulses, thus making more informed diagnoses in a clinical setting.

Abstract Background Breast and prostate tumors are known to be less responsive to immune checkpoint inhibitors (ICIs). Tissue-based tumor mutation burden (tTMB) has emerged as a predictive biomarker of response to ICIs, including in these “cold tumors”. In clinical practice, when tTMB is not available, blood-based TMB score (bTMB) can be used to consider treatment with ICIs. Methods This retrospective, real-world study included a final cohort of metastatic breast and prostate cancer patients treated with an ICI following a liquid biopsy test. Multiple bTMB-High cut-offs were assessed. Clinical, genomic, and outcomes data were collected. We hypothesized that a cut-off of bTMB ≥10 mut/Mb is not a strong predictor of response to ICIs in this setting. The Guardant Health genomic database (GHGD) was then queried (N = 13,992) for associations of bTMB with genomic alterations. Results In the clinical cohort (N = 48), ICI treatment is offered after a median of 3 (1–9) lines of treatment. The median bTMB is 16.4 (10–186) mut/Mb. The median time on ICI and PFS is 2.1 (0–1.7) and 3.1 months (95%CI, 1.6–4.6) respectively; no difference by MSI/MMR status (p = 0.152). Response rate among eligible patients (n = 36) is 16.7%; only N = 1/6 in bTMB

Abstract Dysfunction of motile cilia can impair mucociliary clearance in the airway and result in primary ciliary dyskinesia (PCD). We previously showed that mutations in central pair apparatus (CPA) genes perturb ciliary motility and result in PCD in mouse models. However, little is known about how epithelial cell types in the ciliary microenvironment of the upper airway respond to defects in ciliary motility and mucociliary clearance. Here, we have used single-cell RNA sequencing to investigate responses in tracheal epithelial cells from mice with mutations in CPA genes Cfap221/ Pcdp1, Cfap54, and Spef2. Expected cell types were identified, along with an unidentified cell type not expressing markers of typical airway cells. Deuterosomal cells were found to exist in two states that differ largely in expression of genes involved in differentiation into ciliated cells. Functional enrichment analysis of differentially expressed genes (DEGs) revealed important cellular functions and molecular pathways for each cell type that are altered in mutant mice. Overlapping DEGs shed light on general responses to cilia dysfunction, while unique DEGs indicate that some responses may be specific to the individual mutation and ciliary defect.

Abstract Extreme short-duration rainfall is intensifying with climate warming, and growing evidence suggests that subhourly rainfall extremes are increasing faster than more widely studied durations at hourly and daily timescales. In this case study, we used 55 years (1968–2022) of 5-min precipitation data from Mahantango Creek, a long-term experimental agricultural watershed in east-central Pennsylvania, United States, to examine annual and seasonal changes in subhourly (15-min), hourly, and daily rainfall extremes. Specifically, we evaluated temporal trends in the magnitude and frequency of subhourly, hourly, and daily rainfall extremes. We then estimated apparent scaling rates between rainfall extremes and dew point temperature (Td) and compared these rates to the Clausius-Clapeyron (CC) rate (∼ 7% per °C). We also determined the coincidence of extreme rainfall trends with indicators of atmospheric instability and convective-type precipitation. Overall, we found the most significant changes in rainfall extremes at 15-min durations during the spring, with magnitudes of these subhourly extremes increasing by 0.6 to 0.9% per year, and frequencies rising by 3.4% per year. Apparent scaling rates in the spring showed that 15-min rainfall extremes transitioned from sub-CC scaling to greater than 2CC scaling when Td reached 11° C, implying a possible shift from stratiform rains to more intense convective rains above this Td threshold. Notably, trends in maximum hourly convective available potential energy (CAPE) increased during spring, as did the ratio of 15-min rainfall extremes to their corresponding daily rainfall totals. Findings indicate that convective-type precipitation may be playing an increasing role in the intensification of springtime 15-min rainfall extremes in Mahantango Creek.

Abstract Accurately identifying periodontal landmarks via acoustic imaging is increasingly important. Here, we evaluated the accuracy of cementoenamel junction (CEJ) identification using ultrasound by comparing it to clinical methods in 153 extracted human teeth. The distance between the CEJ to a reference point was measured using two clinical methods (visual examination and tactile sensation) as well as ultrasound imaging. Statistical analyses were performed across all teeth and sub-groups, including tooth types (incisors, cuspids, and molars/premolars), and two classifications: A- vs. B- (visually detectable or undetectable CEJ, respectively); and CL-S vs. CL-D (shallow or deep cervical lesions). In A- or CL-S teeth, ultrasound measurements highly agreed with clinical measurements, showing a 1.72-mm 95% CI for A- and 1.99-mm 95% CI for CL-S compared to visual examination, and a 1.77-mm 95% CI for A- and a 2.10-mm 95% CI for CL-S compared to tactile sensation, respectively. For 80% of A- and 76% of CL-S teeth, the difference between ultrasound and visual examination was within ± 20%. For 81% of A- and 80% of CL-S teeth, the difference between ultrasound and tactile sensation was within ± 20%. The variance of ultrasound versus clinical CEJ identifications showed a significant correlation (r = 0.6607) to the cervical lesion depth. The errors between ultrasound and clinical measurements show no significant bias across different tooth types.

Abstract Wolverine distribution contracted along the southern periphery of its range in North America during the 19th and 20th centuries due primarily to human influences. This history, along with low densities, sensitivity to climate change, and concerns about connectivity among fragmented habitats spurred the recent US federal listing of threatened status and special concern status in Canada. To help inform large scale landscape connectivity, we collected 882 genetic samples genotyped at 19 microsatellite loci. We employed multiple statistical models to assess the landscape factors (terrain complexity, human disturbance, forest configuration, and climate) associated with wolverine genetic connectivity across 2.2 million km2 of southwestern Canada and the northwestern contiguous United States. Genetic similarity (positive spatial autocorrelation) of wolverines was detected up to 555 km and a high-to-low gradient of genetic diversity occurred from north-to-south. Landscape genetics analyses confirmed that wolverine genetic connectivity has been negatively influenced by human disturbance at broad scales and positively influenced by forest cover and snow persistence at fine- and broad–scales, respectively. This information applied across large landscapes can be used to guide management actions with the goal of maintaining or restoring population connectivity.

Abstract Background Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma. Methods The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood from 319 participants from 94 families. They were part of the Netherlands Twin Register from families with at least one member suffering from severe asthma. Repeat blood samples were taken after 10 years from 182 individuals. Principal component analysis on the clinical asthma markers yielded ten principal components (PCs) that explained 92.8% of the total variance. We performed epigenome-wide association studies (EWAS) for each of the ten PCs correcting for familial structure and other covariates. Results 221 unique CpGs reached genome-wide significance at timepoint 1 after Bonferroni correction. PC7, which correlated with loadings of eosinophil counts and immunoglobulin levels, accounted for the majority of associations (204). Enrichment analysis via the EWAS Atlas identified 190 of these CpGs to be previously identified in EWASs of asthma and asthma-related traits. Proximity assessment to previously identified SNPs associated with asthma identified 17 unique SNPs within 1 MB of two of the 221 CpGs. EWAS in 182 individuals with epigenetic data at a second timepoint identified 49 significant CpGs. EWAS Atlas enrichment analysis indicated that 4 of the 49 were previously associated with asthma or asthma-related traits. Comparing the estimates of all the significant associations identified across the two time points yielded a correlation of 0.81. Conclusion We identified 270 unique CpGs that were associated with PC scores generated from 35 clinical markers of asthma, either cross-sectionally or 10 years later. A strong correlation was present between effect sizes at the 2 timepoints. Most associations were identified for PC7, which captured blood eosinophil counts and immunoglobulin levels and many of these CpGs have previous associations in earlier studies of asthma and asthma-related traits. The results point to a robust DNA methylation profile as a new, stable biomarker for asthma.

Abstract Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a few other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad spectrum of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

Abstract Background Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers. Methods Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion. Results Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120–184 h), with preserved viability throughout. Conclusions Livers can be reproducibly perfused in excess of 120 (range 121–184) hours with evidence of preserved hepatocyte and cholangiocyte function.

Abstract The blue bottle genus Physalia is one of the well-known siphonophore belonging to the Cnidaria, Hydrozoa. Physalia is also known as a ferocious predator, occasionally stinging and fatally wounding humans, but key details of its life cycle and reproductive biology are unclear. Physalia have separate sexes, and sexual reproduction occurs through the release of complex structures called gonodendra that contain many gonophores that will release either eggs or sperm. It is not known how mature the gonophores are when the gonodendra are released. In this study, we aim to characterize germ cell maturation by conducting histological, cytological, and gene expression analyses of the gonodendron of Physalia utriculus from Japan. We found a layered structure of the gonophore, consistent with other studies; however, gametes were not found even in gonophores that were within the released gonodendra. Moreover, haploid cells were not detected by flow cytometry. Analysis of the expression of putative germ cell marker and meiosis related genes showed high expression in the gonophore. These results strongly suggest that germ cells do not mature until after gonodendra are released. These findings provide valuable insights into the reproductive ecology and life cycle of Physalia.

Candida auris is considered a nosocomial pathogen of high concern and is currently spreading across the United States. Infection control measures for C. auris focus mainly on healthcare facilities, yet transmission levels may already be significant in the community before outbreaks are detected in healthcare settings. Wastewater-based epidemiology (culture, quantitative PCR, and whole-genome sequencing) can potentially gauge pathogen transmission in the general population and lead to early detection of C. auris before it is detected in clinical cases. To learn more about the sensitivity and limitations of wastewater-based surveillance, we used wastewater-based methods to detect C. auris in a southern Utah jurisdiction with no known clinical cases before and after the documented transfer of colonized patients from bordering Nevada. Our study illustrates the potential of wastewater-based surveillance for being sufficiently sensitive to detect C. auris transmission during the early stages of introduction into a community.

We evaluated the association between wastewater concentration and weekly percent positivity of patient testing for SARS-CoV-2, influenza, and respiratory syncytial virus in Oregon, USA. We found strong, positive correlations for SARS-CoV-2 (ρ = 0.84, p

Abstract Ge–Sb–Se–Te chalcogenides, namely Se-substituted Ge–Sb–Te, have been developed as an alternative optical phase change material (PCM) with a high figure-of-merit. A need for the integration of such new PCMs onto a variety of photonic platforms has necessitated the development of fabrication processes compatible with diverse material compositions as well as substrates of varying material types, shapes, and sizes. This study explores the application of chemical solution deposition as a method capable of creating conformally coated layers and delves into the resulting modifications in the structural and optical properties of Ge–Sb–Se–Te PCMs. Specifically, we detail the solution-based deposition of Ge–Sb–Se–Te layers and present a comparative analysis with those deposited via thermal evaporation. We also discuss our ongoing endeavor to improve available choice of processing-material combinations and how to realize solution-derived high figure-of-merit optical PCM layers, which will enable a new era for the development of reconfigurable photonic devices.

Abstract The microbiome is a key factor in the health, well-being, and success of vertebrates, contributing to the adaptive capacity of the host. However, the impact of geographic and biotic factors that may affect the microbiome of wild birds in polar environments is not well defined. To address this, we determined the bacterial 16S rRNA gene sequence profiles in faecal samples from pygoscelid penguin populations in the Scotia Arc, focusing on gentoo penguins. This mesopredatory group breeds in defined colonies across a wide geographic range. Since diet could influence microbiome structure, we extracted dietary profiles from a eukaryotic 18S rRNA gene sequence profile. The bacterial microbiome profiles were considered in the context of a diverse set of environmental and ecological measures. Integrating wide geographic sampling with bacterial 16S and eukaryotic 18S rRNA gene sequencing of over 350 faecal samples identified associations between the microbiome profile and a suite of geographic and ecological factors. Microbiome profiles differed according to host species, colony identity, distance between colonies, and diet. Interestingly there was also a relationship between the proportion of host DNA (in relation to total 18S rRNA gene signal) and the microbiome, which may reflect gut passage time. Colony identity provided the strongest association with differences in microbiome profiles indicating that local factors play a key role in the microbiome structure of these polar seabirds. This may reflect the influence of local transfer of microbes either via faecal-oral routes, during chick feeding or other close contact events. Other factors including diet and host species also associate with variation in microbiome profile, and in at least some locations, the microbiome composition varies considerably between individuals. Given the variation in penguin microbiomes associated with diverse factors there is potential for disruption of microbiome associations at a local scale that could influence host health, productivity, and immunological competence. The microbiome represents a sensitive indicator of changing conditions, and the implications of any changes need to be considered in the wider context of environmental change and other stressors.

Background: Hypertension remains one of the most important modifiable risk factors for stroke and heart disease. Anti-hypertensive medications are effective, but are often not used to maximum benefit. Sub-optimal dosing by prescribers and challenges with medication-taking for patients remain barriers to effective blood pressure control.Objectives: We aimed to systematically develop a theory-based complex intervention to support General Practitioners (GPs) and people with hypertension to maximise medication use to control blood pressure.Methods: We used the three-phase Behaviour Change Wheel (BCW) as the overarching intervention development framework. Collective Intelligence methodology was used to operationalise the stakeholder input to Phases 2 and 3 of the BCW. This took the form of a Collective Intelligence workshop with 19 stakeholders from diverse backgrounds including lived experience, general practice, nursing, pharmacy and health psychology. Techniques such as barrier identification, idea-writing and scenario-based design were used to generate possible intervention options. Intervention options were then selected and refined using the Acceptability, Practicability, Effectiveness, Affordability, Side-effects and Equity (APEASE) criteria and guidance from the MIAMI Public and Patient Involvement Panel.Results: The finalised MIAMI intervention consists of both GP and patient supports. GP supports include a 30-minute online training, information booklet and consultation guide (drop-down menu) embedded within the patient electronic health system. Patient supports include a pre-consultation plan, website, and a structured GP consultation with results from an Ambulatory Blood Pressure Monitor and urine chemical adherence test. The intervention components have been mapped to the intervention functions of the BCW and Behaviour Change Technique Ontology.Conclusion: Collective Intelligence offered a novel method to operationalise stakeholder input to Phases 2 and 3 of the BCW. The MIAMI intervention is now at pilot evaluation stage.

Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension (CE) during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar CE defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (gpc4), we identified dact1/2-specific roles during early development. Comparative whole transcriptome analysis between wildtype and gpc4 and wildtype and dact1/2 compound mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Overexpression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

BackgroundThe COVID-19 pandemic has generated a demand for timely data, resulting in a surge of mobile phone surveys for tracking the impacts of and responses to the pandemic. Mobile phone surveys have become a preferred mode of data collection across low- and middle-income countries. ObjectiveThis study piloted 2 population-based, cross-sectional mobile phone surveys among Sri Lankan residents in 2020 and 2021 during the COVID-19 pandemic. The surveys aimed to gather data on knowledge, attitudes, and practices, vaccine acceptability, availability, and barriers to COVID-19 testing, and use of a medicine distribution service. MethodsThe study used Surveda, an open-source survey tool developed by the NCD (noncommunicable disease) Mobile Phone Survey Data 4 Health Initiative, for data collection and management. The surveys were conducted through interactive voice response using automated, prerecorded messages in Sinhala, Tamil, and English. The sample design involved random sampling of mobile phone numbers, stratified by sex, proportional to the general population. Eligibility criteria varied between surveys, targeting adults aged 35 years and older with any noncommunicable disease for the first survey and all adults for the second survey. The data were adjusted to population estimates, and statistical analysis was conducted using SAS (SAS Institute) and R software (R Core Team). Descriptive statistics, Rao-Scott chi-square tests, and z tests were used to analyze the data. Response rates, cooperation rates, and productivity of the sampling approach were calculated. ResultsIn the first survey, n=5001, the overall response rate was 7.5%, with a completion rate of 85.6%. In the second survey, n=1250, the overall response rate was 10.9%, with a completion rate of 61.9%. Approximately 3 out of 4 adults reported that they avoided public places (888/1175, 75.6%), more than two-thirds avoided public transportation (808/1173, 68.9%), and 9 out of 10 practiced physical distancing (1046/1167, 89.7%). Approximately 1 out of 10 Sri Lankan persons reported being tested for COVID-19, and the majority of those received a polymerase chain reaction test (112/161, 70%). Significantly more males than females reported being tested for COVID-19 (98/554, 17.8% vs 61/578, 10.6%, respectively; P

Background It is unclear whether chronically training close to volitional failure influences motor unit recruitment strategies during fatigue. Purpose We compared resistance training to near volitional failure vs. non-failure on individual motor unit action potential amplitude (MUAP) and surface electromyographic excitation (sEMG) during fatiguing contractions. Methods Nineteen resistance-trained adults (11 males, 8 females) underwent 5 weeks (3×/week) of either low repetitions-in-reserve (RIR; 0–1 RIR) or high RIR training (4–6 RIR). Before and after the intervention, participants performed isometric contractions of the knee extensors at 30% of maximal peak torque until exhaustion while vastus lateralis sEMG signals were recorded and later decomposed. MUAP and sEMG excitation for the vastus lateralis were quantified at the beginning, middle, and end of the fatigue assessment. Results Both training groups improved time-to-task failure (mean change = 43.3 s, 24.0%), with no significant differences between low and high RIR training groups (low RIR = 28.7%, high RIR = 19.4%). Our fatigue assessment revealed reduced isometric torque steadiness and increased MUAP amplitude and sEMG excitation during the fatiguing task, but these changes were consistent between groups. Conclusion Both low and high RIR training improved time-to-task failure, but resulted in comparable motor unit recruitment during fatiguing contractions. Our findings indicate that both low and high RIR training can be used to enhance fatiguability among previously resistance-trained adults.

As a key sensor of double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) detects cytosolic dsDNA and initiates the synthesis of 2′3′ cyclic GMP-AMP (cGAMP) that activates the stimulator of interferon genes (STING). This finally promotes the production of type I interferons (IFN-I) that is crucial for bridging innate and adaptive immunity. Recent evidence show that several antitumor therapies, including radiotherapy (RT), chemotherapy, targeted therapies and immunotherapies, activate the cGAS-STING pathway to provoke the antitumor immunity. In the last decade, the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry. However, up to now, none of STING agonists have been approved for clinical use. Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node (dLN), research on the optimal way to activate STING in tumor microenvironment (TME) appears to be a promising direction. Moreover, besides enhancing IFN-I signaling, the cGAS-STING pathway also plays roles in senescence, autophagy, apoptosis, mitotic arrest, and DNA repair, contributing to tumor development and metastasis. In this review, we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.

Abstract Objective New characterized carbohydrate-active enzymes are needed for use as tools to discriminate complex carbohydrate structural features. Fungal glycoside hydrolase family 3 (GH3) β-xylosidases have been shown to be useful for the structural elucidation of glucuronic acid (GlcA) and arabinofuranose (Araf) substituted oligoxylosides. A homolog of these GH3 fungal enzymes from the bacterium Segatella baroniae (basonym Prevotella bryantii), Xyl3C, has been previously characterized, but those studies did not address important functional specificity features. In an interest to utilize this enzyme for laboratory methods intended to discriminate the structure of the non-reducing terminus of substituted xylooligosaccharides, we have further characterized this GH3 xylosidase. Results In addition to verification of basic functional characteristics of this xylosidase we have determined its mode of action as it relates to non-reducing end xylose release from GlcA and Araf substituted oligoxylosides. Xyl3C cleaves xylose from the non-reducing terminus of β-1,4-xylan until occurrence of a penultimate substituted xylose. If this substitution is O2 linked, then Xyl3C removes the non-reducing xylose to leave the substituted xylose as the new non-reducing terminus. However, if the substitution is O3 linked, Xyl3C does not hydrolyze, thus leaving the substitution one-xylose (penultimate) from the non-reducing terminus. Hence, Xyl3C enables discrimination between O2 and O3 linked substitutions on the xylose penultimate to the non-reducing end. These findings are contrasted using a homologous enzyme also from S. baroniae, Xyl3B, which is found to yield a penultimate substituted nonreducing terminus regardless of which GlcA or Araf substitution exists.

Abstract NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta (IL-1β). Permanent ligation of the left anterior descending artery was used to induce MI in WT and NLRP3−/− mice as well as in NLRP3−/− recipient mice transfused with either WT or NLRP3−/− neutrophils. NLRP3 deficiency reduced infarct size to roughly a third of WT heart injury and preserved left ventricular (LV) function at 12 h after MI as assessed by echocardiography and triphenyltetrazolium chloride staining of live tissue. Transfusion of WT but not NLRP3−/− neutrophils after MI increased infarct size in NLRP3−/− mice and significantly reduced LV function. The key features of myocardial tissue in WT neutrophil transfused recipients were increased H3Cit-positive deposits with NET-like morphology and increased tissue levels of IL-1β and plasma levels of von Willebrand Factor (VWF). Flow cytometry analysis also revealed that neutrophil NLRP3 increased the number of labeled and transfused neutrophils in the bone marrow of recipient mice following MI. Our data suggest a key role for neutrophil NLRP3 in the production of IL-1β and deposition of NETs in cardiac tissue exacerbating injury following MI. We provide evidence for a link between neutrophil NLRP3 and VWF release likely enhancing thromboinflammation in the heart. Neutrophil NLRP3 deficiency conferred similar cardioprotective effects to general NLRP3 deletion in MI rendering anti-neutrophil NLRP3 therapy a promising target for early cardioprotective treatment.

Abstract Despite hundreds of studies examining belief in conspiracy theories, it is still unclear who—demographically—is most likely to believe such theories. To remedy this knowledge gap, we examine survey data containing various operationalizations of conspiracism across diverse sociopolitical contexts. Study 1 employs a 2021 U.S. survey (n = 2021) to examine associations between sociodemographic characteristics and beliefs in 39 conspiracy theories. Study 2 similarly employs a survey of 20 countries (n = 26,416) and 11 conspiracy theory beliefs. Study 3 reports results from a 2020 U.S. survey (n = 2015) measuring perceptions about which groups are engaging in conspiracies. Study 4 interrogates data from nine U.S. surveys (2012–2022; n = 14,334) to examine the relationships between sociodemographic characteristics and generalized conspiracy thinking. Study 5 synchronizes studies 1–4 to provide an intersectional analysis of conspiracy theory belief. Across studies, we observe remarkably consistent patterns: education, income, age (older), and White identification are negatively related to conspiracism, while Black identification is positively related. We conclude by discussing why conspiracy theories may appeal most to historically marginalized groups and how our findings can inform efforts to mitigate the negative effects of conspiracy theories.

Abstract As natural landscapes are modified and converted into simplified agricultural landscapes, the community composition and interactions of organisms persisting in these modified landscapes are altered. While many studies examine the consequences of these changing interactions for crops, few have evaluated the effects on wild plants. Here, we examine how pollinator and herbivore interactions affect reproductive success for wild resident and phytometer plants at sites along a landscape gradient ranging from natural to highly simplified. We tested the direct and indirect effects of landscape composition on plant traits and reproduction mediated by insect interactions. For phytometer plants exposed to herbivores, we found that greater landscape complexity corresponded with elevated herbivore damage, which reduced total flower production but increased individual flower size. Though larger flowers increased pollination, the reduction in flowers ultimately reduced plant reproductive success. Herbivory was also higher in complex landscapes for resident plants, but overall damage was low and therefore did not have a cascading effect on floral display and reproduction. This work highlights that landscape composition directly affects patterns of herbivory with cascading effects on pollination and wild plant reproduction. Further, the absence of an effect on reproduction for resident plants suggests that they may be adapted to their local insect community.

Abstract Continued spread of chronic wasting disease (CWD) through wild cervid herds negatively impacts populations, erodes wildlife conservation, drains resource dollars, and challenges wildlife management agencies. Risk factors for CWD have been investigated at state scales, but a regional model to predict locations of new infections can guide increasingly efficient surveillance efforts. We predicted CWD incidence by county using CWD surveillance data depicting white-tailed deer (Odocoileus virginianus) in 16 eastern and midwestern US states. We predicted the binary outcome of CWD-status using four machine learning models, utilized five-fold cross-validation and grid search to pinpoint the best model, then compared model predictions against the subsequent year of surveillance data. Cross validation revealed that the Light Boosting Gradient model was the most reliable predictor given the regional data. The predictive model could be helpful for surveillance planning. Predictions of false positives emphasize areas that warrant targeted CWD surveillance because of similar conditions with counties known to harbor CWD. However, disagreements in positives and negatives between the CWD Prediction Web App predictions and the on-the-ground surveillance data one year later underscore the need for state wildlife agency professionals to use a layered modeling approach to ensure robust surveillance planning. The CWD Prediction Web App is at https://cwd-predict.streamlit.app/ .

Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

Few precise estimates of hospitalization and fatality rates from COVID-19 exist for naive populations, especially within demographic subgroups. We estimated rates among persons with SARS-CoV-2 infection in the United States during May 1–December 1, 2020, before vaccines became available. Both rates generally increased with age; fatality rates were highest for persons >85 years of age (24%) and lowest for children 1–14 years of age (0.01%). Age-adjusted case hospitalization rates were highest for African American or Black, not Hispanic persons (14%), and case-fatality rates were highest for Asian or Pacific Islander, not Hispanic persons (4.4%). Eighteen percent of hospitalized patients and 44.2% of those admitted to an intensive care unit died. Male patients had higher hospitalization (6.2% vs. 5.2%) and fatality rates (1.9% vs. 1.5%) than female patients. These findings highlight the importance of collecting surveillance data to devise appropriate control measures for persons in underserved racial/ethnic groups and older adults.

Abstract Background Definitive local therapy with stereotactic ablative radiation therapy (SABR) for ultracentral lung lesions is associated with a high risk of toxicity, including treatment related death. Stereotactic MR-guided adaptive radiation therapy (SMART) can overcome many of the challenges associated with SABR treatment of ultracentral lesions. Methods We retrospectively identified 14 consecutive patients who received SMART to ultracentral lung lesions from 10/2019 to 01/2021. Patients had a median distance from the proximal bronchial tree (PBT) of 0.38 cm. Tumors were most often lung primary (64.3%) and HILUS group A (85.7%). A structure-specific rigid registration approach was used for cumulative dose analysis. Kaplan-Meier log-rank analysis was used for clinical outcome data and the Wilcoxon Signed Rank test was used for dosimetric data. Results Here we show that SMART dosimetric improvements in favor of delivered plans over predicted non-adapted plans for PBT, with improvements in proximal bronchial tree DMax of 5.7 Gy (p = 0.002) and gross tumor 100% prescription coverage of 7.3% (p = 0.002). The mean estimated follow-up is 17.2 months and 2-year local control and local failure free survival rates are 92.9% and 85.7%, respectively. There are no grade ≥ 3 toxicities. Conclusions SMART has dosimetric advantages and excellent clinical outcomes for ultracentral lung tumors. Daily plan adaptation reliably improves target coverage while simultaneously reducing doses to the proximal airways. These results further characterize the therapeutic window improvements for SMART. Structure-specific rigid dose accumulation dosimetric analysis provides insights that elucidate the dosimetric advantages of SMART more so than per fractional analysis alone.

Abstract We estimated the effect of community-level natural hazard exposure during prior developmental stages on later anxiety and depression symptoms among young adults and potential differences stratified by gender. We analyzed longitudinal data (2002–2020) on 5585 young adults between 19 and 26 years in Ethiopia, India, Peru, and Vietnam. A binary question identified community-level exposure, and psychometrically validated scales measured recent anxiety and depression symptoms. Young adults with three exposure histories (“time point 1,” “time point 2,” and “both time points”) were contrasted with their unexposed peers. We applied a longitudinal targeted minimum loss-based estimator with an ensemble of machine learning algorithms for estimation. Young adults living in exposed communities did not exhibit substantially different anxiety or depression symptoms from their unexposed peers, except for young women in Ethiopia who exhibited less anxiety symptoms (average causal effect [ACE] estimate = − 8.86 [95% CI: − 17.04, − 0.68] anxiety score). In this study, singular and repeated natural hazard exposures generally were not associated with later anxiety and depression symptoms. Further examination is needed to understand how distal natural hazard exposures affect lifelong mental health, which aspects of natural hazards are most salient, how disaster relief may modify symptoms, and gendered, age-specific, and contextual differences.

Abstract Interest continues to grow in Arctic megafaunal ecological engineering, but, since the mass extinction of megafauna ~ 12–15 ka, key physiographic variables and available forage continue to change. Here we sought to assess the extent to which contemporary Arctic ecosystems are conducive to the rewilding of megaherbivores, using a woolly mammoth (M. primigenius) proxy as a model species. We first perform a literature review on woolly mammoth dietary habits. We then leverage Oak Ridge National Laboratories Distributive Active Archive Center Global Aboveground and Belowground Biomass Carbon Density Maps to generate aboveground biomass carbon density estimates in plant functional types consumed by the woolly mammoth at 300 m resolution on Alaska’s North Slope. We supplement these analyses with a NASA Arctic Boreal Vulnerability Experiment dataset to downgrade overall biomass estimates to digestible levels. We further downgrade available forage by using a conversion factor representing the relationship between total biomass and net primary productivity (NPP) for arctic vegetation types. Integrating these estimates with the forage needs of woolly mammoths, we conservatively estimate Alaska’s North Slope could support densities of 0.0–0.38 woolly mammoth km−2 (mean 0.13) across a variety of habitats. These results may inform innovative rewilding strategies.

Abstract Personalized, ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) is designed to administer tumoricidal doses in a pulsed mode with extended intervals, spanning weeks or months. This approach leverages longer intervals to adapt the treatment plan based on tumor changes and enhance immune-modulated effects. In this investigation, we seek to elucidate the potential synergy between combined PULSAR and PD-L1 blockade immunotherapy using experimental data from a Lewis Lung Carcinoma (LLC) syngeneic murine cancer model. Employing a long short-term memory (LSTM) recurrent neural network (RNN) model, we simulated the treatment response by treating irradiation and anti-PD-L1 as external stimuli occurring in a temporal sequence. Our findings demonstrate that: (1) The model can simulate tumor growth by integrating various parameters such as timing and dose, and (2) The model provides mechanistic interpretations of a “causal relationship” in combined treatment, offering a completely novel perspective. The model can be utilized for in-silico modeling, facilitating exploration of innovative treatment combinations to optimize therapeutic outcomes. Advanced modeling techniques, coupled with additional efforts in biomarker identification, may deepen our understanding of the biological mechanisms underlying the combined treatment.

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Lesion studies have historically been instrumental for establishing causal connections between brain and behavior. They stand to provide additional insight if integrated with multielectrode techniques common in systems neuroscience. Here, we present and test a platform for creating electrolytic lesions through chronically implanted, intracortical multielectrode probes without compromising the ability to acquire neuroelectrophysiology. A custom-built current source provides stable current and allows for controlled, repeatable lesions in awake-behaving animals. Performance of this novel lesioning technique was validated using histology from ex vivo and in vivo testing, current and voltage traces from the device, and measurements of spiking activity before and after lesioning. This electrolytic lesioning method avoids disruptive procedures, provides millimeter precision over the extent and submillimeter precision over the location of the injury, and permits electrophysiological recording of single-unit activity from the remaining neuronal population after lesioning. This technique can be used in many areas of cortex, in several species, and theoretically with any multielectrode probe. The low-cost, external lesioning device can also easily be adopted into an existing electrophysiology recording setup. This technique is expected to enable future causal investigations of the recorded neuronal population’s role in neuronal circuit function, while simultaneously providing new insight into local reorganization after neuron loss.

Introduction Diabetes is one of the leading causes of chronic kidney disease. Social deprivation is recognised as a risk factor for complications of diabetes, including diabetic kidney disease. The effect of deprivation on rate of decline in renal function has not been explored in the Irish Health System to date. The objective of this study is to explore the association between social deprivation and the development/progression of diabetic kidney disease in a cohort of adults living with diabetes in Ireland. Methods This is a retrospective cohort study using an existing dataset of people living with diabetes who attended the diabetes centre at University Hospital Galway from 2012 to 2016. The variables included in this dataset include demographic variables, type and duration of diabetes, clinical variables such as medication use, blood pressure and BMI and laboratory data including creatinine, urine albumin to creatinine to ratio, haemoglobin A1c and lipids. This dataset will be updated with laboratory data until January 2023. Individual’s addresses will be used to calculate deprivation indices using the Pobal Haase Pratschke (HP) deprivation index. Rate of renal function decline will be calculated using linear mixed-effect models. The relationship between deprivation and renal function will be assessed using linear regression (absolute and relative rate of renal function decline based on eGFR) and logistic regression models (rapid vs. non-rapid decline).

Abstract Background and Aims East African countries have high rates of maternal and child mortality and morbidity. Studies have shown that the involvement of male partners in reproductive health can benefit maternal and child health (MCH). This scoping review aims to provide an overview of the evidence across East Africa that describes male partner involvement and its effect on maternal, reproductive, and child well‐being. Methods Ten databases were searched to identify quantitative data on male's involvement in East Africa. Studies reporting qualitative data, “intention to use” data or only reporting on male partner's education or economic status were excluded. Studies were organized into five a priori categories: antenatal care (ANC), human immunodeficiency virus, breastfeeding, family planning, and intimate partner violence with further categories developed based on studies included. Results A total of 2787 records were identified; 644 full texts were reviewed, and 96 studies were included in this review. Data were reported on 118,967 mothers/pregnant women and 15,361 male partners. Most of the studies (n = 83) were reported from four countries Ethiopia (n = 49), Kenya (n = 14), Tanzania (n = 12) and Uganda (n = 10). The evidence indicates that male partner involvement and support is associated with improved reproductive, MCH across a wide range of outcomes. However, the studies were heterogeneous, using diverse exposure and outcome measures. Also, male partners' lack of practical and emotional support, and engagement in violent behaviors towards partners, were associated with profound negative impacts on MCH and well‐being. Conclusions The body of evidence, although heterogeneous, provides compelling support for male involvement in reproductive health programs designed to support MCH. To advance research in this field, an agreement is needed on a measure of male partner “involvement.” To optimize benefits of male partners' involvement, developing core outcome sets and regional coordination are recommended.

Background Managed populations of the alfalfa leafcutting bee (ALCB), Megachile rotundata (F.), are often not sustainable. In addition to numerous mortality factors that contribute to this, the dense bee populations used to maximize alfalfa pollination quickly deplete floral resources available to bees later in the summer. Providing alternative floral resources as alfalfa declines may help to improve ALCB reproduction. Methods We examined the relationship between floral resource availability and ALCB reproduction and offspring condition via (1) a field study using alfalfa plots with and without late-blooming wildflower strips to supply food beyond alfalfa bloom, and (2) a field-cage study in which we provided bees with alfalfa, wildflowers, or both as food resources. Results In the field study, bee cell production closely followed alfalfa floral density with an initial peak followed by large declines prior to wildflower bloom. Few bees visited wildflower strips, whose presence or absence was not associated with any measure of bee reproduction. However, we found that female offspring from cells provisioned earlier in the season, when alfalfa predominated as a source of provisions, eclosed with greater body sizes and proportion body lipids relative to total body mass. For bees restricted to cages, the proportion of offspring that survived to adults was highest on pure alfalfa diets. Adding wildflowers to cages with alfalfa did not affect adult offspring production or female offspring body size and lipid content. Furthermore, although similar numbers of adults were produced on wildflowers alone as with alfalfa alone, females eclosed with smaller body sizes and lower proportion body lipids on wildflowers despite the higher protein content we estimated for wildflower pollen. We found no evidence that adding the late-season wildflower species that we chose to plant enhanced ALCB offspring numbers. Our results highlight the importance of considering multiple measures of reproductive success, including offspring body size and lipid stores, when designing and evaluating floral resource management strategies for agroecosystems.

Objective To analyse progress in global vaccination against human papillomavirus (HPV) during the covid-19 pandemic, with a particular focus on equity.Design Descriptive study of World Health Organization-Unicef vaccination coverage estimates.Setting WHO-Unicef estimates of global, regional, and national HPV vaccination coverage, before (2010-19) and during (2020-21) the covid-19 pandemic.Participants Girls aged 9-14 years who received a HPV vaccine globally before (12.3 million in 2019) and during (2020-21) the covid-19 pandemic (10.6 million in 2021).Main outcome measures Mean programme and population adjusted coverage for first dose HPV vaccine (HPV1) by country, country income (World Bank income categories), sex, and WHO region, before (2010-19) and during (2020-21) the covid-19 pandemic, based on WHO-Unicef estimates of HPV vaccination coverage. Annual number of national HPV vaccine programme introduced since the first HPV vaccine licence was granted in 2006, based on data reported to WHO-Unicef. Number of girls vaccinated before (2019) versus during (2020-21) the covid-19 pandemic period.Results Mean coverage of HPV vaccination programmes among girls decreased from 65% in 2010-19 to 50% in 2020-21 in low and middle income countries compared with an increase in high income countries from 61% to 69% for the same periods. Population adjusted HPV1 coverage was higher among girls in high income countries before and during the covid-19 pandemic than in girls in low and middle income countries. During the covid-19 pandemic, population adjusted HPV1 coverage among boys in high income countries was higher and remained higher than coverage among girls in low and middle income countries. Globally, 23 countries recorded a severe reduction in their HPV programme (≥50% reduction in coverage), and another 3.8 million girls globally did not receive a HPV vaccine in countries with existing HPV vaccination programmes in 2020-21 compared with 2019. A reduction was seen in the annual rate of new introductions of national HPV vaccine programmes during 2020-21, affecting countries in all income categories, followed by an increase in introductions during 2022. During the second half of 2023, several low and middle income countries with large birth cohorts and a high relative burden of cervical cancer have yet to introduce HPV vaccination.Conclusions Although HPV vaccines have been available for more than 15 years, global HPV vaccination coverage is low. During the covid-19 pandemic period (2020-21 globally), worsening coverage, delayed introductions of national vaccine programmes, and an increase in missed girls globally (ie, girls who did not receive a HPV vaccine compared with the previous year in countries with an existing HPV vaccination programme) that disproportionately affected girls in low and middle income countries were found. Urgent and innovative recovery efforts are needed to accelerate national introduction of HPV vaccination programmes and achieve high coverage of HPV vaccination worldwide.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Introduction Hypertension, the clinical condition of persistent high blood pressure (BP), is preventable yet remains a significant contributor to poor cardiovascular outcomes. Digital self-management support tools can increase patient self-care behaviours to improve BP. We created a patient-facing and provider-facing clinical decision support (CDS) application, called the Collaboration Oriented Approach to Controlling High BP (COACH), to integrate home BP data, guideline recommendations and patient-centred goals with primary care workflows. We leverage social cognitive theory principles to support enhanced engagement, shared decision-making and self-management support. This study aims to measure the effectiveness of the COACH intervention and evaluate its adoption as part of BP management.Methods and analysis The study design is a multisite, two-arm hybrid type III implementation randomised controlled trial set within primary care practices across three health systems. Randomised participants are adults with high BP for whom home BP monitoring is indicated. The intervention arm will receive COACH, a digital web-based intervention with effectively enhanced alerts and displays intended to drive engagement with BP lowering; the control arm will receive COACH without the alerts and a simple display. Outcome measures include BP lowering (primary) and self-efficacy (secondary). Implementation preplanning and postevaluation use the Consolidated Framework for Implementation Research and Reach-Effectiveness-Adoption-Implementation-Maintenance metrics with iterative cycles for qualitative integration into the trial and its quantitative evaluation. The trial analysis includes logistic regression and constrained longitudinal data analysis.Ethics and dissemination The trial is approved under a single IRB through the University of Missouri-Columbia, #2091483. Dissemination of the intervention specifications and results will be through open-source mechanisms.Trial registration number NCT06124716.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Abstract The allometric trophic network (ATN) framework for modeling population dynamics has provided numerous insights into ecosystem functioning in recent years. Herein we extend ATN modeling of the intertidal ecosystem off central Chile to include empirical data on pelagic chlorophyll-a concentration. This intertidal community requires subsidy of primary productivity to support its rich ecosystem. Previous work models this subsidy using a constant rate of phytoplankton input to the system. However, data shows pelagic subsidies exhibit highly variable, pulse-like behavior. The primary contribution of our work is incorporating this variable input into ATN modeling to simulate how this ecosystem may respond to pulses of pelagic phytoplankton. Our model results show that: (1) closely related sea snails respond differently to phytoplankton variability, which is explained by the underlying network structure of the food web; (2) increasing the rate of pelagic-intertidal mixing increases fluctuations in species’ biomasses that may increase the risk of local extirpation; (3) predators are the most sensitive species to phytoplankton biomass fluctuations, putting these species at greater risk of extirpation than others. Finally, our work provides a straightforward way to incorporate empirical, time-series data into the ATN framework that will expand this powerful methodology to new applications.

Background: The proportion of the population aged 65 years or older is increasing. Typically, physical activity and health decline with age, which is why action to promote active ageing is a major public health priority, particularly due to health inequalities in older adults. The aim of this study is to assess the effectiveness and cost-effectiveness of the Walk with Me peer-led walking intervention for older adults. Methods: This study is a two-arm, assessor-blind, randomised controlled trial. The intervention is a 12-week peer-led walking intervention based on social cognitive theory. Participants in the control group will receive information on active ageing and healthy nutrition. The study will target 348 community-dwelling older adults, aged 60 years or over living in areas of socio-economic disadvantage communities. Trained peer mentors will deliver the intervention. The primary outcome will be a mean between-group change in moderate-to-vigorous physical activity at 12 months from baseline, measured using an Actigraph accelerometer. Secondary outcomes will include quality of life, mental wellbeing, blood pressure, BMI and waist circumference. An embedded process evaluation will involve focus groups and participant diaries. Discussion: Evidence-based, cost-effective interventions to promote physical activity in older adults living in socio-economically disadvantaged communities are needed to address health inequalities.

Abstract Here we present a sample of 12 massive quiescent galaxy candidates at $$z\sim 3-4$$ z ∼ 3 - 4 observed with the James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec). These galaxies were pre-selected from the Hubble Space Telescope imaging and 10 of our sources were unable to be spectroscopically confirmed by ground based spectroscopy. By combining spectroscopic data from NIRSpec with multi-wavelength imaging data from the JWST Near Infrared Camera (NIRCam), we analyse their stellar populations and their formation histories. We find that all of our galaxies classify as quiescent based on the reconstruction of their star formation histories but show a variety of quenching timescales and ages. All our galaxies are massive ( $$\sim 0.1-1.2\times 10^{11}$$ ∼ 0.1 - 1.2 × 10 11 M $$_\odot$$ ⊙ ), with masses comparable to massive galaxies in the local Universe. We find that the oldest galaxy in our sample formed $$\sim 1.0\times 10^{11}$$ ∼ 1.0 × 10 11 M $$_\odot$$ ⊙ of mass within the first few hundred million years of the Universe and has been quenched for more than a billion years by the time of observation at $$z\sim 3.2$$ z ∼ 3.2 ( $$\sim 2$$ ∼ 2 billion years after the Big Bang). Our results point to very early formation of massive galaxies requiring a high conversion rate of baryons to stars in the early Universe.

Abstract The companion dog is one of the most phenotypically diverse species. Variability between breeds extends not only to morphology and aspects of behaviour, but also to longevity. Despite this fact, little research has been devoted to assessing variation in life expectancy between breeds or evaluating the potential for phylogenetic characterisation of longevity. Using a dataset of 584,734 unique dogs located within the UK, including 284,734 deceased, we present variation in longevity estimates within the following: parental lineage (purebred = 1 breed, crossbred ≥ 2 breeds), breed (n = 155), body size (large, medium, small), sex (male, female) and cephalic index (brachycephalic, mesocephalic, dolichocephalic). Survival estimates were then partitioned amongst phylogenetic clades: providing evidence that canine evolutionary history (via domestication and associated artificial selection) is associated with breed lifespan. This information provides evidence to inform discussions regarding pedigree health, whilst helping current/prospective owners, breeders, policy makers, funding bodies and welfare organisations improve decision making regarding canine welfare.

Abstract High-quality epitaxial p-type V2O3 thin films have been synthesized by spray pyrolysis. The films exhibited excellent electrical performance, with measurable mobility and high carrier concentration. The conductivity of the films varied between 115 and 1079 Scm−1 while the optical transparency of the films ranged from 32 to 65% in the visible region. The observed limitations in thinner films’ mobility were attributed to the nanosized granular structure and the presence of two preferred growth orientations. The 60 nm thick V2O3 film demonstrated a highly competitive transparency-conductivity figure of merit compared to the state-of-the-art.

Abstract Background Co-production of research aims to include people with lived experience of a phenomena throughout the research process. People experiencing homelessness often experience advance ill-health at a young age, yet access palliative care services at a disparately low rate to the level of palliative care need. The voices of people experiencing homelessness are infrequently heard throughout palliative care research, despite the complexities and intricacies of the area. Aim To explore the experiences of experts in the field to identify key context considerations for involving people with lived experience of homelessness in palliative and end of life care research. Methods Qualitative study comprising two data collection streams: interviews with professionals with experience of involving people experiencing homelessness in their work, and focus groups with people with lived experience (PWLE) of homelessness. Data were analysed using iterative, reflexive thematic analysis. Patient and Public Involvement contributors gave feedback on themes. Results A total of 27 participants took part in semi-structured interviews (N = 16; professionals) or focus groups (N = 11; PWLE homelessness). Key considerations of involving people experiencing homelessness in palliative and end of life care research were developed into four key themes: complexity of lived experience of homelessness; representation of homelessness within experts by experience; professionalising lived experience; and methods for involvement. Conclusions Involvement of people with lived experience of homelessness is important in developing palliative care research. This paper begins to outline some contextual considerations for promoting involvement in a complex and intricate field of research.

BackgroundHigher availability of alcohol is associated with higher levels of alcohol consumption and harm. Alcohol is increasingly accessible online, with rapid delivery often offered by a third-party driver. Remote delivery and online availability are important from a public health perspective, but to date, relatively little research has explored the availability of alcohol offered by online platforms. ObjectiveThis cross-sectional exploratory study describes the availability of alcohol on the third-party platform Deliveroo within London, England. MethodsWe extracted the number of outlets offering alcohol on Deliveroo for each London borough and converted these into crude rates per 1000 population (18-64 years). Outlets were grouped as outlets exclusively selling alcohol, off-licenses, and premium. We calculated Pearson correlation coefficients to explore the association between borough’s crude rate of outlets per 1000 population and average Indices of Multiple Deprivation (IMD) 2019 scores. We extracted the number of outlets also selling tobacco or e-cigarettes and used non-Deliveroo drivers. We searched addresses of the top 20 outlets delivering to the most boroughs by outlet type (60 total) to determine their associated premise. ResultsWe identified 4277 total Deliveroo-based outlets offering alcohol across London, including outlets delivering in multiple boroughs. The crude rate of outlets per 1000 population aged 18-64 years was 0.73 and ranged from 0.22 to 2.29 per borough. Most outlets exclusively sold alcohol (3086/4277, 72.2%), followed by off-licenses (770/4277, 18.0%) and premium (421/4277, 9.8%). The majority of outlets exclusively selling alcohol sold tobacco or e-cigarettes (2951/3086, 95.6%) as did off-licenses to a lesser extent (588/770, 76.4%). Most outlets exclusively offering alcohol used drivers not employed by Deliveroo (2887/3086, 93.6%), and the inverse was true for premium outlets (50/421, 11.9%) and off-licenses (73/770, 9.5%). There were 1049 unique outlets, of which 396 (37.8%) were exclusively offering alcohol—these outlets tended to deliver across multiple boroughs unlike off-licenses and premium outlets. Of outlets with confirmed addresses, self-storage units were listed as the associated premise for 85% (17/20) of outlets exclusively offering alcohol, 11% (2/19) of off-licenses, and 12% (2/17) of premium outlets. We found no significant relationship between borough IMD scores and crude rate of outlets per 1000 population overall (P=.87) or by any outlet type: exclusively alcohol (P=.41), off-license (P=.58), and premium (P=.18). ConclusionsLondon-based Deliveroo outlets offering alcohol are common and are sometimes operating from self-storage units that have policies prohibiting alcohol storage. This and the potential for increased alcohol accessibility online have implications for public health given the relationship between alcohol’s availability and consumption or harm. There is a need to ensure that regulations for delivery are adequate for protecting children and vulnerable adults. The Licensing Act 2003 may require modernization in the digital age. Future research must explore a relationship between online alcohol availability and deprivation.