SARS-CoV-2 infection and transmission via the skin to oro-nasal route with the production of bioaerosols in the ferret model.

Direct and indirect transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been attributed to virus survival in droplets, bioaerosols and on fomites including skin and surfaces. Survival of SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, and Delta) on the skin and virus transference following rounds of skin-to-skin contact were assessed on porcine skin as a surrogate for human skin. SARS-CoV-2 variants were detectable on skin by RT-qPCR after 72 h at biologically relevant temperatures (35.2 °C) with viral RNA (vRNA) detected after ten successive skin-to-skin contacts. Skin-to-skin virus transmission to establish infection in ferrets as a model for mild/asymptomatic SARS-CoV-2 infection in mustelids and humans was also investigated and compared to intranasal ferret inoculation. Naïve ferrets exposed to Delta variant SARS-CoV-2 in a 'wet' or 'dry' form on porcine skin resulted in robust infection with shedding detectable for up to 14 days post-exposure, at comparable viral loads to ferrets inoculated intranasally. Transmission of SARS-CoV-2 to naïve ferrets in direct contact with infected ferrets was achieved, with environmental contamination detected from ferret fur swabs and air samples. Genetic substitutions were identified in bioaerosol samples acquired following single contact passage in ferrets, including Spike, ORF1ab, and ORF3a protein sequences, suggesting a utility for monitoring host adaptation and virus evolution via air sampling. The longevity of SARS-CoV-2 variants survival directly on the skin and skin-to-skin transference, enabling subsequent infection via the skin to oro-nasal contact route, could represent a pathway for SARS-CoV-2 infection with implications to public and veterinary health.

Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension.

Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], -5.3 [5.2] versus -6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): -2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], -19.5 [26.9] versus -32.2 [38.5]; least squares mean difference, 11.5 [96% CI: -4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group. Funding: Funded by Sanifit, a CSL Vifor company.

A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis.

Introduction: Uremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis. Methods: We measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models. Results: The mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma. Conclusion: Quinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.

Role of vesicoureteral reflux on pediatric kidney allograft function.

BACKGROUND: Vesicoureteral reflux (VUR) is a common urologic complication of pediatric kidney transplant, though there is little data on the effect of VUR on histologic graft changes or graft survival. METHODS: All pediatric patients who received a kidney transplant from 2007 to 2020 were selected for retrospective chart review. All participants underwent a voiding cystourethrogram (VCUG) at a 6-month post-transplant. Patients were then categorized into two groups based on vesicoureteral reflux grade: no/low-grade VUR (grades 0-2) and high-grade VUR (grades 3-5). Outcomes collected included graft failure rates, graft function, urinary tract infections (UTIs), proteinuria, and Banff scores at 3- and 12-month post-transplant surveillance kidney biopsies. RESULTS: There were 74 pediatric patients who received a kidney transplant in the designated time-period, and of those 39 had no/low-grade VUR and 35 had high-grade VUR. There was no difference in graft failure among the two groups over time when stratified for age (p = 0.389, CI 0.53-5.08). Patients with high grade VUR had a higher risk of UTI development overall (RR 1.89, 95%CI 1-3.6, p = 0.041), mostly accounted for from increased development of febrile UTI (RR 1.66, 95%CI 1.1-2.6, p = 0.038). CONCLUSIONS: Unselected pediatric kidney transplant recipients with high-grade vesicoureteral reflux on VCUG at a 6-month post-kidney transplant are more likely to have febrile UTI compared to those in the low-grade VUR group. There is no difference in graft survival among the two groups.

Health Insurance Continuity and Mortality in Children and Adolescents/Young Adults with Blood Cancer.

BACKGROUND: Many uninsured patients do not receive Medicaid coverage until a cancer diagnosis, potentially delaying access to care for early cancer detection and treatment. We examine the association of Medicaid enrollment timing and patterns with survival among children and adolescents/young adults (AYAs) diagnosed with blood cancers, where disease onset can be acute and early detection is critical. METHODS: We identified 28,750 children and AYAs (0-39 years) newly diagnosed with blood cancers from the 2006-2013 SEER-Medicaid data. Enrollment patterns included continuous Medicaid (preceding through diagnosis), newly gained Medicaid (at/shortly after diagnosis), other noncontinuous Medicaid enrollment, and private/other insurance. We assessed cumulative incidence of death from diagnosis, censoring at last follow-up, five years post-diagnosis, or December 2018, whichever occurred first. Multivariable survival models estimated the association of insurance enrollment patterns with risk of death. RESULTS: One-fourth (26.1%) of the cohort were insured by Medicaid; of these, 41.1% had continuous Medicaid, 34.9% had newly gained Medicaid, and 24.0% had other noncontinuous enrollment. The cumulative incidence of all-cause death five-year post-diagnosis was highest in patients with newly gained Medicaid (30.2%, 95%CI = 28.4-31.9%), followed by other noncontinuous enrollment (23.2%, 95%CI = 21.3-25.2%), continuous Medicaid (20.5%, 95%CI = 19.1-21.9%), and private/other insurance (11.2%; 95%CI = 10.7-11.7%). In multivariable models, newly gained Medicaid was associated with a higher risk of all-cause (hazard ratio = 1.39, 95%CI = 1.27-1.53) and cancer-specific death (hazard ratio = 1.50, 95%CI = 1.35-1.68), compared to continuous Medicaid. CONCLUSIONS: Continuous Medicaid coverage is associated with survival benefits among pediatric and AYA patients diagnosed with blood cancers; however, less than half of Medicaid-insured patients have continuous coverage before diagnosis.

A response time model of the three-choice Mnemonic Similarity Task provides stable, mechanistically interpretable individual-difference measures.

Introduction: The Mnemonic Similarity Task (MST) is a widely used measure of individual tendency to discern small differences between remembered and presently presented stimuli. Significant work has established this measure as a reliable index of neurological and cognitive dysfunction and decline. However, questions remain about the neural and psychological mechanisms that support performance in the task. Methods: Here, we provide new insights into these questions by fitting seven previously-collected MST datasets (total N = 519), adapting a three-choice evidence accumulation model (the Linear Ballistic Accumulator). The model decomposes choices into automatic and deliberative components. Results: We show that these decomposed processes both contribute to the standard measure of behavior in this task, as well as capturing individual variation in this measure across the lifespan. We also exploit a delayed test/re-test manipulation in one of the experiments to show that model parameters exhibit improved stability, relative to the standard metric, across a 1 week delay. Finally, we apply the model to a resting-state fMRI dataset, finding that only the deliberative component corresponds to off-task co-activation in networks associated with long-term, episodic memory. Discussion: Taken together, these findings establish a novel mechanistic decomposition of MST behavior and help to constrain theories about the cognitive processes that support performance in the task.

The 123s and affective, behavioral, and cognitives of unaccompanied Latinx Minors: A trauma-informed composite case study.

OBJECTIVES: This article explores the stages where trauma is experienced (123s) and its physiopsychological impact (affect, behavior, and cognitions [ABCs]) in unaccompanied Latinx Minors through the analysis of a composite case study. Unaccompanied Latinx Minors represent a unique and growing population in the United States that warrants careful consideration from a trauma-informed and resilience-based framework. METHOD: A detailed case study was implemented, triangulating caregiver and client therapy records to illustrate the framework of stages of trauma exposure (123s) and physiopsychological impact (ABCs). RESULTS: Latinx children often encounter various potentially traumatic experiences and adverse childhood experiences at the following stages (123s): (1) Preimmigration; (2) During immigration; and (3) Postimmigration. The extended traumas experienced by immigrant youth may easily constitute toxic stress. Moreover, once in the destination country, youth may lack coping resources or encounter stressful circumstances that prolong or exacerbate the impact of previous traumas. This continuous physiological hyperarousal can also result in changes in brain neurobiology, which further compounds the experience of other symptoms (Krupnik, 2021). These potentially complex trauma responses may manifest for these children through ABCs. The cumulative impact of these incidents may have significant effects on minors' A. Affective, B. Behavioral, and C. Cognitive functioning. CONCLUSIONS: Relevant clinical implications and policy recommendations for addressing the multifaceted needs of unaccompanied Latinx minors. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Describing the characteristics and symptom profile of a group of urban patients experiencing socioeconomic inequity and receiving palliative care: a descriptive exploratory analysis.

Background: Individuals experiencing socioeconomic inequity have worse health outcomes and face barriers to palliative and end-of-life care. There is a need to develop palliative care programs tailored to this underserved population. Objectives: To understand the characteristics and symptom profiles of a group of urban patients experiencing socioeconomic inequity and receiving palliative care. Design: Descriptive exploratory analysis of a patient dataset. The patient dataset was generated through a pilot research study with patients experiencing socioeconomic inequity and life-limiting illness who received a community-based palliative care intervention. Methods: The intervention took place over 1 year in the Palliative Care Outreach and Advocacy Team, a community-based urban palliative care clinic in Edmonton, Alberta, Canada, serving persons experiencing socioeconomic inequity. Participants had to be at least 18 years of age, be able to communicate in English, require palliative care for a life-limiting illness, and be able to consent to inclusion in the study. Results: Twenty-five participants were enrolled. Participants predominantly identified as male and Indigenous, experienced poverty and housing instability, and had metastatic cancer. Our participants rated their pain, shortness of breath, and anxiety as more severe than the broader community-based palliative care population in the same city. Most patients died in inpatient hospices (73%). Conclusion: Our analysis provides an in-depth picture of an understudied, underserved population requiring palliative care. Given the higher symptom severity experienced by participants, our analysis highlights the importance of person-centered palliative care. We suggest that socioeconomic inequity should be considered in patients with life-limiting illnesses. Further research is needed to explore palliative care delivery to those facing socioeconomic inequity.

Longitudinal Health-Related Quality of Life Among Patients With High-Risk Pediatric Hodgkin Lymphoma Treated on the Children's Oncology Group AHOD 1331 Study.

PURPOSE: There have been no previous longitudinal assessments of health-related quality of life (HRQoL) during treatment for pediatric Hodgkin lymphoma (HL). The addition of brentuximab vedotin (BV) to a multidrug chemotherapy backbone demonstrated superior efficacy to standard chemotherapy for patients with pediatric high-risk HL in the AHOD 1331 trial. However, the impact on HRQoL is unknown. PATIENTS AND METHODS: After treatment random assignment, 268 participants older than 11 years were enrolled in a prespecified, longitudinal, patient-reported outcomes substudy. HRQoL was assessed using the seven-item Child Health Ratings Inventories (CHRIs)-Global scale before treatment (T1) and at cycle 2 (T2), cycle 5 (T3), and end of treatment (T4). A clinically meaningful increase in HRQoL was considered 7 points on the CHRIs-Global. Multivariable linear regression estimated associations between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated changes in HRQoL across the treatment arm. RESULTS: Participant characteristics were balanced by treatment arm. Ninety-three percent of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 77% at T4. At T1, female sex and fever (P < .05) were each associated with worse HRQoL. By T2, participants in the BV arm experienced a statistically and clinically significant improvement in HRQoL (ß = 7.3 [95% CI, 3.2 to 11.4]; P ≤ .001), which was greater than the change in the standard arm (difference in change ß = 5.1 [95% CI, -0.2 to 10.3]; P = .057). The standard arm did not experience a statistically or clinically significant increase in HRQoL until T4 (ß = 9.3 [95% CI, 4.7 to 11.5]; P < .001). CONCLUSION: These data demonstrate successful collection of serial HRQoL from youth with high-risk pediatric HL and improvement in HRQoL over the course of initial therapy, sooner and to a greater extent in the group receiving the novel agent BV.

Hodgkin lymphoma involving the extra-axial CNS: an AHOD1331, PHL-C1, and PHL-C2 report from the COG and EuroNet-PHL.

ABSTRACT: Hodgkin lymphoma (HL) involving the central nervous system (CNS) is exceedingly rare. Information regarding the presentation, management, treatment, and outcome of patients with CNS HL is limited to case reports or small series. We describe 45 pediatric patients with 55 extra-axial CNS lesions at diagnosis with HL from a cohort of 4995 patients enrolled on Children's Oncology Group AHOD1331 and the European Network for Pediatric Hodgkin lymphoma C1 and C2 trials, with an overall incidence of 0.9%. Up to 82.2% of patients had a single CNS lesion in the thoracic, lumbar, or sacral spine. In the evaluated cohort, HL did not occur within the CNS parenchyma. Lesions extended into the extra-axial CNS space from adjacent soft tissue or bone and never directly infiltrated through the dura into the brain or spinal cord. Patients with CNS involvement had a twofold greater incidence of extranodal lesions than previously reported cohorts without CNS involvement. After 2 cycles of chemotherapy, 89.1% of CNS lesions demonstrated a complete metabolic response and >75% decrease in volume. Thirteen CNS lesions (23.6%) received irradiation; none were sites of disease relapse. Relapse occurred at the site of 2 lesions involving the CNS, both of which had an adequate interim response to chemotherapy. In summary, we present, to our knowledge, the largest reported cohort of systemic HL involving the CNS at diagnosis, demonstrating that these lesions originate from surrounding tissues, extend into the extra-axial CNS space, and respond similarly to other nodal and extranodal disease. The trials were registered at www.clinicaltrials.gov as #NCT02166463, #NCT00433459, and #NCT02684708.

Toxicity profile of high-dose methotrexate in young children with central nervous system tumors.

High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m2) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring.

Helping athletes to select botanical supplements for the right reasons: A comparison of self-reported reasons for use versus evidence-based supplement claims.

Use of food supplements (FS) by athletes is well characterised but there is little information on 'herbal' or 'botanical' FS beyond 'natural'. This study determined, by questionnaire, whether athletes' main self-reported reason for using FS was reflective of what was written on product labels or, when these claims were unavailable, was in accordance with the scientific literature. In 217 elite (n = 55) and amateur (n = 162) athletes living on the island of Ireland, 71% (n = 153) consumed any kind of FS, with 16% (n = 34) of the entire cohort deemed botanical consumers. 'Protein' (21%, n = 46), 'vitamin D' (17%, n = 37) and 'vitamin C' (15% n = 32) were most consumed with the top reasons for use being 'to support health', 'to prevent illness/for immunity purposes' and 'recovery'. There was generally good agreement between approved nutrition and health claims for such products and athletes' main reported reasons for use. Only the amateur athletes in our pool described using botanical supplements, with reasons for use stated as 'sleep improvement' (21%), 'recovery' (14%), 'supporting health' (12%) and 'energy' (12%), resulting in poor agreement with either approved claims or scientific evidence. Only half of amateur athletes knew if their botanical FS were third-party tested. Athletes and practitioners require guidance to avoid consuming supplements for which there is little scientific evidence, and which may risk being contaminated/fraudulent.

Evaluating the epizootic and zoonotic threat of an H7N9 low-pathogenicity avian influenza virus (LPAIV) variant associated with enhanced pathogenicity in turkeys.

Between 2013 and 2017, the A/Anhui/1/13-lineage (H7N9) low-pathogenicity avian influenza virus (LPAIV) was epizootic in chickens in China, causing mild disease, with 616 fatal human cases. Despite poultry vaccination, H7N9 has not been eradicated. Previously, we demonstrated increased pathogenesis in turkeys infected with H7N9, correlating with the emergence of the L217Q (L226Q H3 numbering) polymorphism in the haemagglutinin (HA) protein. A Q217-containing virus also arose and is now dominant in China following vaccination. We compared infection and transmission of this Q217-containing 'turkey-adapted' (ty-ad) isolate alongside the H7N9 (L217) wild-type (wt) virus in different poultry species and investigated the zoonotic potential in the ferret model. Both wt and ty-ad viruses demonstrated similar shedding and transmission in turkeys and chickens. However, the ty-ad virus was significantly more pathogenic than the wt virus in turkeys but not in chickens, causing 100 and 33% mortality in turkeys respectively. Expanded tissue tropism was seen for the ty-ad virus in turkeys but not in chickens, yet the viral cell receptor distribution was broadly similar in the visceral organs of both species. The ty-ad virus required exogenous trypsin for in vitro replication yet had increased replication in primary avian cells. Replication was comparable in mammalian cells, and the ty-ad virus replicated successfully in ferrets. The L217Q polymorphism also affected antigenicity. Therefore, H7N9 infection in turkeys can generate novel variants with increased risk through altered pathogenicity and potential HA antigenic escape. These findings emphasize the requirement for enhanced surveillance and understanding of A/Anhui/1/13-lineage viruses and their risk to different species.

Genetic engineering of Salmonella spp. for novel vaccine strategies and therapeutics.

Salmonella enterica is a diverse species that infects both humans and animals. S. enterica subspecies enterica consists of more than 1,500 serovars. Unlike typhoidal Salmonella serovars which are human host-restricted, non-typhoidal Salmonella (NTS) serovars are associated with foodborne illnesses worldwide and are transmitted via the food chain. Additionally, NTS serovars can cause disease in livestock animals causing significant economic losses. Salmonella is a well-studied model organism that is easy to manipulate and evaluate in animal models of infection. Advances in genetic engineering approaches in recent years have led to the development of Salmonella vaccines for both humans and animals. In this review, we focus on current progress of recombinant live-attenuated Salmonella vaccines, their use as a source of antigens for parenteral vaccines, their use as live-vector vaccines to deliver foreign antigens, and their use as therapeutic cancer vaccines in humans. We also describe development of live-attenuated Salmonella vaccines and live-vector vaccines for use in animals.

Polygenic hazard score models for the prediction of Alzheimer's free survival using the lasso for Cox's proportional hazards model.

The prediction of the susceptibility of an individual to a certain disease is an important and timely research area. An established technique is to estimate the risk of an individual with the help of an integrated risk model, that is, a polygenic risk score with added epidemiological covariates. However, integrated risk models do not capture any time dependence, and may provide a point estimate of the relative risk with respect to a reference population. The aim of this work is twofold. First, we explore and advocate the idea of predicting the time-dependent hazard and survival (defined as disease-free time) of an individual for the onset of a disease. This provides a practitioner with a much more differentiated view of absolute survival as a function of time. Second, to compute the time-dependent risk of an individual, we use published methodology to fit a Cox's proportional hazard model to data from a genetic SNP study of time to Alzheimer's disease (AD) onset, using the lasso to incorporate further epidemiological variables such as sex, APOE (apolipoprotein E, a genetic risk factor for AD) status, 10 leading principal components, and selected genomic loci. We apply the lasso for Cox's proportional hazards to a data set of 6792 AD patients (composed of 4102 cases and 2690 controls) and 87 covariates. We demonstrate that fitting a lasso model for Cox's proportional hazards allows one to obtain more accurate survival curves than with state-of-the-art (likelihood-based) methods. Moreover, the methodology allows one to obtain personalized survival curves for a patient, thus giving a much more differentiated view of the expected progression of a disease than the view offered by integrated risk models. The runtime to compute personalized survival curves is under a minute for the entire data set of AD patients, thus enabling it to handle datasets with 60,000-100,000 subjects in less than 1 h.

Sex and gender in sports nutrition research: bridging the gap.

The Olympic Games have grown to be the largest, gender-equal sporting event in the world, and the International Olympic Committee is committed to gender equality in sports encouraging and supporting the promotion of women in sports at all levels and in all structures with a view to implementing the principle of equality of men and women (IOC, 2023). Women competed for the first time at the 1900 Olympic Games in Paris, and the number of women competing has grown exponentially over the last 100 years, so an estimated 5494 female athletes (48 %) competed in the Summer Olympic Games 2021 in Tokyo. Supporting women (alongside men) in achieving optimum performance is crucial, and understanding that there are sex and gender gaps in sports nutrition research is important. One reason for this gap is the historical bias in sports and exercise science research towards male participants. This has led to a poor understanding of the unique physiological and nutritional needs of female athletes. In summary, a balanced approach is crucial to address the nutritional needs of both male and female athletes. Researchers should continue exploring this important area to optimise performance and health for all athletes. The aim of this review is to summarise current sports nutrition literature and highlight research that seeks to understand and address where the gaps are with respect to several key areas in sports nutrition recommendations that can impact advice and practice with both males and females.

Association of PHACTR1 with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10-14) and among males (p = 1.0 × 10-9), but the signal was not genome-wide significant among females (p = 6.4 × 10-6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10-8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10-7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10-7) than former smokers (p = 7.5 × 10-3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10-8) and current smokers (p = 1.7 × 10-7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Roosting ecology drives the evolution of diverse bat landing maneuvers.

Bats and birds are the only living vertebrates capable of powered flight. However, bats differ from birds in that their flight required the evolution of ascending landing maneuvers that achieve their iconic head-under-heels roosting posture. We examined the evolution of landing flight in bats and tested its association with the physical properties of roosts. Bats performed four maneuvers, each correlated with patterns of peak impact force, impulse, and roosting ecology, a critical aspect of bat biology. Our findings indicate that the common ancestor of bats performed simple, four-limbed landings, similar to extant gliding mammals, and that rotationally complex landings enhancing control over impact forces coevolved multiple times with shifts to stiff, horizontal roosts. These results suggest landing biomechanics is central to bat biology: it was critical to flight adaptation in the past, mediates roost use in the present, and may affect bats' ability to respond to deforestation in the future.

Understanding futility in pancreaticoduodenectomy: Insights from a national cohort.

BACKGROUND AND OBJECTIVES: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort. METHODS: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy. RESULTS: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility. CONCLUSION: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations.