Assessing dengue risk globally using non-Markovian models.

Dengue is a vector-borne disease transmitted by Aedes mosquitoes. The worldwide spread of these mosquitoes and the increasing disease burden have emphasized the need for a spatio-temporal risk map capable of assessing dengue outbreak conditions and quantifying the outbreak risk. Given that the life cycle of Aedes mosquitoes is strongly influenced by habitat temperature, numerous studies have utilized temperature-dependent development rates of these mosquitoes to construct virus transmission and outbreak risk models. In this study, we contribute to existing research by developing a mechanistic model for the mosquito life cycle that accurately captures its non-Markovian nature. Beginning with integral equations to track the mosquito population across different life cycle stages, we demonstrate how to derive the corresponding differential equations using phase-type distributions. This approach can be further applied to similar non-Markovian processes that are currently described with less accurate Markovian models. By fitting the model to data on human dengue cases, we estimate several model parameters, allowing the development of a global spatiotemporal dengue risk map. This risk model employs temperature and precipitation data to assess the environmental suitability for dengue outbreaks in a given area.

Dose/Exposure Relationship of Exercise and Distant Recurrence in Primary Breast Cancer.

PURPOSE: Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC. METHODS: Multicenter prospective cohort analysis among 10,359 patients with primary BC from 26 centers in France between 2012 and 2018 enrolled in the CANcer TOxicities study, with follow-up through October 2021. Exercise exposure was assessed using the Global Physical Activity Questionnaire-16, quantified in standardized metabolic equivalent of task-hours per week (MET-h/wk). We examined the dose/exposure response of pretreatment exercise on distant recurrence-free interval (DRFI) for all patients and stratified by clinical subtype and menopausal status using inverse probability treatment weighted multivariable Cox models to estimate hazard ratios (HRs). RESULTS: For the overall cohort, the relationship between exercise and DRFI was nonlinear: increasing exercise ≥ 5 MET-h/wk was associated with an inverse linear reduction in DRFI events up to approximately 25 MET-h/wk; increasing exercise over this threshold did not provide any additional DRFI benefit. Compared with <5 MET-h/wk, the adjusted HR for DRFI was 0.82 (95% CI, 0.61 to 1.00) for ≥ 5 MET-h/wk. Stratification by subtype revealed the hormone receptor-/human epidermal growth factor receptor 2- (HR-/HER2-; HR, 0.59 [95% CI, 0.38 to 0.92]) and HR-/HER2+ (HR, 0.37 [95% CI, 0.14 to 0.96]) subtypes were preferentially responsive to exercise. The benefit of exercise was observed especially in the premenopausal population. CONCLUSION: Postdiagnosis/pretreatment exercise is associated with lower risk of DRFI events in a nonlinear fashion in primary BC; exercise has different impact on DRFI as a function of subtype and menopausal status.

Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi-centre factorial randomized trial.

BACKGROUND: Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations. METHODS: This hypothesis-generating analysis used biospecimens collected from a multi-centre 2 × 2 factorial randomized design of 116 patients with stage I-III breast and colorectal cancer who were randomized to 12 weeks of (1) aerobic exercise (moderate intensity titrated to 220 min/week); (2) metformin (850 mg daily for 2 weeks and then titrated to 850 mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were quantified using a multiplex panel. Myokine concentrations were log-transformed, and main effects analyses were conducted using linear mixed-effects regression models. The type I error rate was controlled with the Holm sequential testing procedure. RESULTS: Randomization to exercise increased leukaemia inhibitory factor (1.26 pg/mL, 95% confidence interval [CI]: 0.69, 1.84; adjusted P = 0.001) and interleukin-15 (2.23 pg/mL, 95% CI: 0.87, 3.60; adjusted P = 0.013) compared with randomization to no exercise. Randomization to metformin decreased apelin (-2.69 pg/mL, 95% CI: -4.31, -1.07; adjusted P = 0.014) and interleukin-15 (-1.74 pg/mL, 95% CI: -2.79, -0.69; adjusted P = 0.013) compared with randomization to no metformin. Metformin decreased myostatin, irisin, oncostatin M, fibroblast growth factor 21 and osteocrin; however, these changes were not statistically significant after correction for multiple comparisons. CONCLUSIONS: This pilot study demonstrates that randomization to exercise and metformin elicit unique effects on myokine concentrations in cancer patients. This hypothesis-generating observation warrants further basic, translational and clinical investigation and replication.

Long-Term Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Noninferiority Study Comparing Two Fractionation Schedules in Patients With Low-Risk Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI (P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773).

Normscan: open-source Python software to create average models from CT scans.

PURPOSE: Age-matched average 3D models facilitate both surgical planning and intraoperative guidance of cranial birth defects such as craniosynostosis. We aimed to develop an algorithm that accepts any number of CT scans as input and generates highly accurate, average models with minimal user input that are ready for 3D printing and clinical use. METHODS: Using a compiled database of 'normal' pediatric computed tomography (CT) scans, we report Normscan, an open-source platform built in Python that allows users to generate normative models of CT scans through user-defined landmarks. We use the basion, nasion, and left and right porions as anatomical landmarks for initial correspondence and then register the models using the iterative closest points algorithm before downstream averaging. RESULTS: Normscan is fast and easy to use via our user interface and also creates highly accurate average models of any number of input models. Additionally, it is highly repeatable, with coefficients of variance for the surface area and volume of the average model being less than 3% across ten independent trials. Average models can then be 3D printed and/or visualized in augmented reality. CONCLUSIONS: Normscan provides an end-to-end pipeline for the creation of average models of skulls. These models can be used for the generation of databases of specific demographic anatomical models as well as for intraoperative guidance and surgical planning. While Normscan was designed for craniosynostosis repair, due to the modular nature of the algorithm, Normscan has many applications in other areas of surgical planning and research.

Mosquitoes harvested from rice fields as alternative protein ingredient in broiler feed: insights from the first pilot study.

Global population continuous growth and increasing consumers' demands for protein-rich diets have posed sustainability challenges for traditional livestock feed sources. Consequently, exploring alternative and sustainable protein sources has become imperative to address the environmental burden and resource limitations associated with conventional ingredients. With respect to food security assurance, insects have emerged as a promising solution due to their exceptional nutritional profile, rapid reproduction rates, and low environmental impact. In the present pilot study, 10% of a soybean meal-based diet was replaced by adult mosquitoes harvested from rice fields. The objective was to assess the effect of this partial substitution on meat quality aspects and consumer acceptance. A total of 40 Cobb hybrid broiler chickens were randomly placed in a control and a mosquito-fed group. The study was conducted for 42 days and carcass physicochemical, nutritional, and microbiological characteristics, as well as sensory attributes were evaluated. Overall, results regarding quality attributes were comparable between the control and the treatment group. The organoleptic evaluation showed that the thighs from the mosquito-fed group had the highest overall consumer acceptance. These outcomes indicate that mosquitoes could be successfully used as a protein source for broiler feed without compromising the quality and acceptability of the meat.

Practice patterns of antiplatelet and anticoagulant therapy after fenestrated/branched endovascular aortic repair.

OBJECTIVE: Antiplatelet and/or anticoagulant therapy are commonly prescribed after fenestrated/branched endovascular aortic repair (F/BEVAR). However, the optimal regimen remains unknown. We sought to characterize practice patterns and outcomes of antiplatelet and anticoagulant use in patients who underwent F/BEVAR. METHODS: Consecutive patients enrolled (2012-2023) as part of the United States Aortic Research Consortium (US-ARC) from 10 independent physician-sponsored investigational device exemption studies were evaluated. The cohort was characterized by medication regimen on discharge from index F/BEVAR: (1) Aspirin alone OR P2Y12 alone (single-antiplatelet therapy [SAPT]); (2) Anticoagulant alone; (3) Aspirin + P2Y12 (dual-antiplatelet therapy [DAPT]); (4) Aspirin + anticoagulant OR P2Y12 + anticoagulant (SAPT + anticoagulant); (5) Aspirin + P2Y12 + anticoagulant (triple therapy [TT]); and (6) No therapy. Kaplan-Meier analysis and Cox proportional hazards modeling were used to compare 1-year outcomes including survival, target artery patency, freedom from bleeding complication, freedom from all reinterventions, and freedom from stent-specific reintervention. RESULTS: Of the 1525 patients with complete exposure and outcome data, 49.6% were discharged on DAPT, 28.8% on SAPT, 13.6% on SAPT + anticoagulant, 3.2% on TT, 2.6% on anticoagulant alone, and 2.2% on no therapy. Discharge medication regimen was not associated with differences in 1-year survival, bleeding complications, composite reintervention rate, or stent-specific reintervention rate. However, there was a significant difference in 1-year target artery patency. On multivariable analysis comparing with SAPT, DAPT conferred a lower hazard of loss of target artery patency (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27-0.84; P = .01). On sub-analyses of renal stents alone or visceral stents alone, DAPT no longer had a significantly lower hazard of loss of target artery patency (renal: HR, 0.66; 95% CI, 0.35-1.27; P = .22; visceral: HR, 0.31; 95% CI, 0.05-1.9; P = .21). Lastly, duration of DAPT therapy (1 month, 6 months, or 1 year) did not significantly affect target artery patency. CONCLUSIONS: Practice patterns for antiplatelet and anticoagulant regimens after F/BEVAR vary widely across the US-ARC. There were no differences in bleeding complications, survival or reintervention rates among different regimens, but higher branch vessel patency was noted in the DAPT cohort. These data suggest there is a benefit in DAPT therapy. However, the generalizability of this finding is limited by the retrospective nature of this data, and the clinical significance of this finding is unclear, as there is no difference in survival, bleeding, or reintervention rates amongst the different regimens. Hence, an "optimal" regimen, including the duration of such regimen, could not be clearly discerned. This suggests equipoise for a randomized trial, nested within this cohort, to identify the most effective antiplatelet/anticoagulant regimen for the growing number of patients being treated globally with F/BEVAR.

Low Temperature Dynamic Polaron Liquid in a Manganite Exhibiting Colossal Magnetoresistance.

Polarons-fermionic charge carriers bearing a strong companion lattice deformation-exhibit a natural tendency for self-localization due to the recursive interaction between electrons and the lattice. While polarons are ubiquitous in insulators, how they evolve in transitions to metallic and superconducting states in quantum materials remains an open question. Here, we use resonant inelastic x-ray scattering to track the electron-lattice coupling in the colossal magneto-resistive bi-layer manganite La_{1.2}Sr_{1.8}Mn_{2}O_{7} across its metal-to-insulator transition. The response in the insulating high-temperature state features harmonic emissions of a dispersionless oxygen phonon at small energy transfer. Upon cooling into the metallic state, we observe a drastic redistribution of spectral weight from the region of these harmonic emissions to a broad high energy continuum. In concert with theoretical calculations, we show that this evolution implies a shift in electron-lattice coupling from static to dynamic lattice distortions that leads to a distinct polaronic ground state in the low temperature metallic phase-a dynamic polaron liquid.

Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Impact of exercise on chemotherapy-induced peripheral neuropathy in survivors with post-treatment primary breast cancer.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of neurotoxic chemotherapy. Exercise activates neuromuscular function and may improve CIPN. We examined the association between exercise and CIPN symptoms in breast cancer survivors. METHODS: In a retrospective cross-sectional study, we included patients completing a survey assessing exercise exposure and neuropathy symptoms in a tertiary cancer center survivorship clinic. We evaluated exercise duration and intensity using a standardized questionnaire quantified in metabolic equivalent tasks (MET-h/wk). We defined exercisers as patients meeting the National Physical Activity Guidelines' criteria. We used multivariable logistic regressions to examine the relationship between exercise and CIPN and if this differed as a function of chemotherapy regimen adjusting for age, gender, and race. RESULTS: We identified 5444 breast cancer survivors post-chemotherapy (median age 62 years (interquartile range [IQR]: 55, 71); median 4.7 years post-chemotherapy (IQR: 3.3, 7.6)) from 2017 to 2022. CIPN overall prevalence was 34% (95% confidence interval [CI]: 33%, 36%), 33% for non-taxane, and 37% for taxane-based chemotherapy. CIPN prevalence was 28% (95% CI: 26%, 30%) among exercisers and 38% (95% CI: 37%, 40%) among non-exercisers (difference 11%; 95% CI: 8%, 13%; p < 0.001). Compared to patients with low (<6 MET-h/wk) levels of exercise (42%), 11% fewer patients with moderate (6-20.24 MET-h/wk) to high (>20.25 MET-h/wk) levels of exercise reported CIPN. Exercise was associated with reduced prevalence of all CIPN symptoms regardless of chemotherapy type. CONCLUSION: CIPN may persist several years following chemotherapy among patients with breast cancer but is significantly reduced by exercise in a dose-dependent manner.

Prospective randomized pilot trial comparing prophylactic and therapeutic cerebrospinal fluid drainage during complex endovascular thoracoabdominal aortic aneurysm repair.

BACKGROUND: Endovascular techniques have transformed the management of thoracoabdominal aortic aneurysms (TAAAs). However, spinal cord ischemia (SCI) remains a prevalent and devastating complication. Prophylactic drainage of cerebrospinal fluid (CSF) is among the proposed strategies for prevention of SCI. Although prophylactic CSF drainage is widely used and conceptually attractive, prophylactic CSF drains have not been demonstrated to definitively prevent the occurrence nor mitigate the severity of SCI in endovascular TAAA repair. Whether or not outcomes of prophylactic drains are superior to therapeutic drains remains unknown. This pilot study was performed to determine the feasibility of a randomized clinical trial designed to investigate the role of prophylactic vs therapeutic CSF drains in the prevention of SCI in patients undergoing endovascular TAAA repair using branched and fenestrated endovascular aortic repair (FBEVAR). METHODS: This was a prospective multicenter randomized pilot clinical trial conducted at The University of Alabama at Birmingham and The University of Massachusetts. Twenty patients were enrolled and randomized to either the prophylactic drainage or therapeutic drainage groups, prior to undergoing FBEVAR for extensive TAAAs and arch aortic aneurysms. This was a pilot feasibility study that was not powered to detect statistical differences in clinical outcomes. The primary outcome was feasibility of randomization and compliance with a shared lumbar drain protocol. Secondary outcomes included rate of drain complications and SCI. RESULTS: Twenty patients were enrolled and successfully randomized, without any crossovers, to either the control cohort (n = 10), without prophylactic drains, or the experimental cohort (n = 10), with prophylactic drains. There were no differences in age, comorbidities, or history of prior aortic surgery across the cohorts. All patients were treated with FBEVAR. Aneurysm classifications were as follows: Extent I (10%), Extent II (50%), Extent III (35%), and Extent IV (5%). The average length of aortic coverage was 207 ± 21.6 mm. The length of aortic coverage did not vary across cohorts, nor did procedural times or blood loss volume. Compliance with the SCI prevention protocol was 100% across both groups. Within the prophylactic drain cohort, one patient experienced an adverse event related to lumbar drain placement, manifested as an epidural hematoma requiring laminectomy, without neurologic deficit (n = 1/10; 10%). There was one SCI event (n = 1/20; 5%), which occurred in the prophylactic drain cohort on postoperative day 9 following an episode of hypotension related to a gastrointestinal bleed. CONCLUSIONS: The role of prophylactic CSF drains for the prevention of SCI following endovascular TAAA repair is a topic of ongoing research, with many current practices based on expert opinion and experience, rather than rigorous scientific data. This study demonstrates the feasibility of a multicenter randomized clinical trial to evaluate the role of prophylactic vs therapeutic CSF drains in the prevention of SCI in patients undergoing endovascular TAAA repair.

Alterations in Sphenoid Anatomy in Craniosynostosis: Implications for Fronto-Orbital Advancement.

OBJECTIVE: Fronto-orbital advancement involves removal of the fronto-orbital bandeau. Visualization of the saw blade is lost as it passes through the fronto-orbital-sphenoid junction (FOSJ), placing the temporal lobe at risk of injury. We aim to provide a 3D analysis of the space surrounding this osteotomy to differentiate various types of craniosynostoses. DESIGN: Retrospective cohort. SETTING: Institutional. PATIENTS: Thirty patients with isolated unicoronal synostosis, nonsyndromic bicoronal synostosis, metopic synostosis, Apert syndrome, Crouzon syndrome, and Muenke syndrome. INTERVENTIONS: CT scans conducted between 2 months to 2 years of age were 3D reconstructed to compare craniometrics against normal controls. MAIN OUTCOME MEASURE(S): Craniometrics. RESULTS: The mean bone thickness of the FOSJ at the level of the supraorbital rim was significantly small for the Apert, unicoronal and bicoronal groups. The mean vertical height of the middle cranial fossa from the lesser sphenoid wing was significantly greater in the unicoronal group. The mean vertical height of the tip of the temporal lobe from the lateral sphenoid ridge was greater in the unicoronal, isolated bicoronal, and Apert groups. The mean corneal protrusion beyond the lateral orbital rim was significantly greater in the Apert and unicoronal groups. The mean horizontal depth of the orbit was smallest in the Apert group. The mean vertical distance between the dacryon and the foramen cecum, and the mean volume of temporal lobe beneath the sphenoid shelf were the largest in the Apert group. CONCLUSIONS: Patients with Apert syndrome have the most unfavorable morphology of the anterior and middle cranial fossae.

Dose-Responsive Impacts of Social Frailty on Intrinsic Capacity and Healthy Aging among Community-Dwelling Middle-aged and Older Adults: Stronger Roles of Social Determinants over Biomarkers.

OBJECTIVE: The intricate relationship between social determinants, e.g., social frailty, biomarkers and healthy aging remains largely unexplored, despite the potential for social frailty to impact both intrinsic capacity (IC) and functional ability in the aging process. DESIGN: Retrospective longitudinal cohort study. SETTING AND PARTICIPANTS: Participants aged 50+ years from the Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan, stratified into three age groups: 50-64, 65-74 and 75+. MEASUREMENTS: Social frailty was defined based on a score derived from four domains: exclusion from general resources, social resources, social activity, and fulfillment of basic social needs. The scores were categorized as score=0 (no social frailty), 1 (social pre-frailty), and 2+ (social frailty). Multivariable logistic regression and Cox proportional hazard models were employed to examine the dose-responsive relationship between social frailty, low IC, functional and psychological health, and mortality. RESULTS: Of 1015 study participants, 24.9% and 7.9% were classified as social pre-frailty and social frailty, respectively. No significant differences were observed in most biomarkers between those with social frailty and those without. A dose-responsive relationship was found between social frailty and increased risk of low IC (social pre-frailty: aOR 2.20 [95% CI 1.59-3.04]; social frailty: 5.73 [3.39-9.69]). Similar results were found for functional and psychological health. However, no significant association between social frailty and all-cause mortality was found at the 4-year follow-up (social pre-frailty: aHR 1.52 [95% CI 0.94-2.43]; social frailty: 1.59 [0.81-3.09]). CONCLUSIONS: The significant association between social frailty and low IC, functional limitations, cognitive declines, and depressive symptoms underscores the pressing need for research on intervention strategies to enhance healthy aging in the lifespan course.

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

A new ground level neutron monitor for space weather assessment.

We report on a new ground-level neutron monitor design for studying cosmic rays and fluxes of solar energetic particles at the Earth's surface. The first-of-its-kind instrument, named the NM-2023 after the year it was standardised and following convention, will be installed at a United Kingdom Meteorological Office observatory (expected completion mid 2024) and will reintroduce such monitoring in the UK for the first time since ca. 1984. Monte Carlo radiation transport code is used for the development and application of parameterised models to investigate alternative neutron detectors, their location and bulk material geometry in a realistic cosmic ray neutron field. Benchmarked against a model of the current and most widespread design standardised in 1964 (the NM-64), two main parameterisation studies are conducted; a simplified standard model and a concept slab parameterisation. We show that the NM-64 standard is well optimised for the intended large-diameter boron trifluoride (BF 3 ) proportional counters but not for multiple smaller diameter counters. The new design (based on a novel slab arrangement) produces comparable counting efficiencies to an NM-64 with six BF 3 counters and has the added advantage of being more compact, lower cost and avoids the use of highly toxic BF 3 .

Evaluating Temperature Effects on Bluetongue Virus Serotype 10 and 17 Coinfection in Culicoides sonorensis.

Bluetongue virus (BTV) is a segmented, double-stranded RNA virus transmitted by Culicoides midges that infects ruminants. As global temperatures increase and geographical ranges of midges expand, there is increased potential for BTV outbreaks from incursions of novel serotypes into endemic regions. However, an understanding of the effect of temperature on reassortment is lacking. The objectives of this study were to compare how temperature affected Culicoides survival, virogenesis, and reassortment in Culicoides sonorensis coinfected with two BTV serotypes. Midges were fed blood meals containing BTV-10, BTV-17, or BTV serotype 10 and 17 and maintained at 20 °C, 25 °C, or 30 °C. Midge survival was assessed, and pools of midges were collected every other day to evaluate virogenesis of BTV via qRT-PCR. Additional pools of coinfected midges were collected for BTV plaque isolation. The genotypes of plaques were determined using next-generation sequencing. Warmer temperatures impacted traits related to vector competence in offsetting ways: BTV replicated faster in midges at warmer temperatures, but midges did not survive as long. Overall, plaques with BTV-17 genotype dominated, but BTV-10 was detected in some plaques, suggesting parental strain fitness may play a role in reassortment outcomes. Temperature adds an important dimension to host-pathogen interactions with implications for transmission and evolution.

Variable gut pH as a potential mechanism of tolerance to Bacillus thuringiensis subsp. israelensis toxins in the biting midge Culicoides sonorensis.

BACKGROUND: Toxins of Bacillus thuringiensis subsp. israelensis (Bti) are safer alternatives for controlling dipteran pests such as black flies and mosquitoes. The biting midge Culicoides sonorensis (Diptera: Ceratopogonidae) is an important pest of livestock in much of the United States and larval midges utilize semi-aquatic habitats which are permissive for Bti product application. Reports suggest that Bti products are ineffective at killing biting midges despite their taxonomic relation to black flies and mosquitoes. Here, we investigate the toxicity of a Bti-based commercial insecticide and its active ingredient in larval Culicoides sonorensis. A suspected mechanism of Bti tolerance is an acidic larval gut, and we used a pH indicator dye to examine larval Culicoides sonorensis gut pH after exposure to Bti. RESULTS: The lethal concentration to kill 90% (LC90) of larvae of the commercial product (386 mg/L) was determined to be almost 10 000 times more than that of some mosquito species, and no concentration of active ingredient tested achieved 50% larval mortality. The larval gut was found to be more acidic after exposure to Bti which inhibits Bti toxin activity. By comparison, 100% mortality was achieved in larval Aedes aegypti at the product's label rate for this species and mosquito larvae had alkaline guts regardless of treatment. Altering the larval rearing water to alkaline conditions enhanced Bti efficacy when using the active ingredient. CONCLUSION: We conclude that Bti is not practical for larval Culicoides sonorensis control at the same rates as mosquitos but show that alterations or additives to the environment could make the products more effective. © 2024 Society of Chemical Industry.

Elongated particulate burden in an individual who died of mesothelioma and had an occupational history as a talc "mucker".

INTRODUCTION: Tissue from a 77-year-old man diagnosed with mesothelioma was referred with a request for identification of the presence of fibrous structures in tissue samples. The individual's work history including working as a "mucker" at a specific "industrial" talc mine. METHODS: Ferruginous bodies in the tissue digests as well as asbestos fibers were found. A bulk sample of a talc containing product from that mine was also analyzed. DISCUSSIONS/CONCLUSIONS: The correlation between the unique asbestos mineral/fibrous content of the talc to which he was exposed and findings of the same type of asbestos found in his lung is discussed. The type of asbestos found (tremolite) is a "non-commercial" type of asbestos that has been identified in some talc deposits. Tremolite, like all forms of asbestos is a causative agent for mesothelioma-the disease from which this individual suffered.