Outcomes utilizing inverted iliac limb bifurcate components in fenestrated/branched endografting.

INTRODUCTION: Utilization of standard bifurcate pieces in fenestrated/branched endovascular aortic repair (F/BEVAR) requires adequate length from the lowest branch or fenestration to the aortic bifurcation. In patients with prior aortic surgery, the aortic bifurcation is often artificially established in a more proximal position, compromising the infrarenal length, which hinders the placement of a standard bifurcate component below the fenestrated/branched component. Short bifurcate bodies utilizing an inverted contralateral limb have been purpose-built to address this challenge. However, reported outcomes for this device remain limited, with specific concerns about the durability of the inverted iliac limb sealing region. We sought to evaluate outcomes of F/BEVAR utilizing an investigational inverted iliac limb bifurcate, manufactured by Cook Medical. METHODS: This study was a retrospective review of prospectively maintained data from the US-Aortic Research Consortium (US-ARC) from 2005-2022. Patients were included if they underwent F/BEVAR for thoracoabdominal or complex abdominal aortic aneurysms. Patients were excluded if they did not have a bifurcate device placed. Patients were then compared based on the utilization of an inverted iliac limb or standard bifurcate component. The primary outcome for this study was technical success. Secondary outcomes included 30-day mortality, freedom from ischemic leg complications, freedom from type 1 endoleaks (T1ELs), freedom from type 2 endoleaks (T2ELs), freedom from type 3 endoleaks (T3ELs), and graft component separations. RESULTS: A total of 1,944 patients met study criteria with 442 (22.8%) inverted iliac limb bifurcates and 1,502 (77.2%) standard bifurcates. Patients who received inverted iliac limbs were more likely to have had prior aortic surgery (63.8% versus 28.5%, P<.001). Patients receiving inverted iliac limbs had longer procedure times (265 minutes [IQR 201-342 minutes] versus 241 minutes [IQR 186-313 minutes], P<.001), more contrast usage (89 mL [IQR 55-135] versus 109 mL [IQR 75-156 mL], P<.001), and higher estimated blood loss (250 mL [IQR 150-500 mL] versus 250 mL [IQR 110-400 mL], P=.042). There were no differences in rates of technical success (97.3% versus 96.1%, P=.310), rates of endoleaks upon completion of the case (18.0% versus 21.4%, P=.123) or 30-day mortality (1.8% versus 2.5%, P=.466) between patients receiving inverted bifurcates and standard bifurcated components. There were no differences in cumulative survival, freedom from limb ischemia, freedom from aneurysm rupture, and freedom from T3ELs over the course of 5 years between patients receiving inverted bifurcates and standard bifurcated components. Patients with inverted iliac limb bifurcate components had decreased freedom from reinterventions, T1ELs, and T2ELs. After adjustment of potential confounders, the use of an inverted iliac limb was not associated with reinterventions (HR 1.044, 95 % CI 0.849-1.285, P=.682). There was a total of 2 (0.1%) component separations of the bifurcate component from the fenestrated/branched component over the study period, both of which occurred in the standard bifurcate components. CONCLUSION: The use of investigational inverted iliac limb bifurcate components is a safe option with favorable mid-term outcomes in patients who are not anatomic candidates for standard bifurcate components. Patients undergoing investigational inverted iliac limb bifurcate component implantation had decreased freedom from reinterventions which likely corresponds to the complexity of repair associated with them.

High-throughput screen to identify and optimize NOT gate receptors for cell therapy.

Logic-gated engineered cells are an emerging therapeutic modality that can take advantage of molecular profiles to focus medical interventions on specific tissues in the body. However, the increased complexity of these engineered systems may pose a challenge for prediction and optimization of their behavior. Here we describe the design and testing of a flow cytometry-based screening system to rapidly select functional inhibitory receptors from a pooled library of candidate constructs. In proof-of-concept experiments, this approach identifies inhibitory receptors that can operate as NOT gates when paired with activating receptors. The method may be used to generate large datasets to train machine learning models to better predict and optimize the function of logic-gated cell therapeutics.

Exercise and nutrition to improve cancer Treatment-Related outcomes (ENICTO).

Chemotherapy treatment-related side-effects are common and increase the risk of suboptimal outcomes. Exercise interventions during cancer treatment improve self-reported physical functioning, fatigue, anxiety, and depression, but it is unclear whether these interventions improve important clinical outcomes, such as chemotherapy relative dose intensity (RDI). The National Cancer Institute funded the Exercise and Nutrition to Improve Cancer Treatment-Related Outcomes (ENICTO) Consortium, to address this knowledge gap. This paper describes the mechanisms hypothesized to underpin intervention effects on clinically-relevant treatment outcomes, briefly outlines each project's distinct research aims, summarizes the scope and organizational structure of ENICTO, and provides an overview of the integrated common data elements used to pursue research questions collectively. In addition, the paper includes a description of consortium-wide activities and broader research community opportunities for collaborative research. Findings from the ENICTO Consortium have the potential to accelerate a paradigm shift in oncology care such that cancer patients could receive exercise and nutrition programming as the standard of care in tandem with chemotherapy to improve RDI for a curative outcome.

Association between dietary patterns and obesity: a longitudinal prospective cohort study.

OBJECTIVES: The obesity prevalence in South Korea in 2021 stood at 38.4%. South Korea faces unique challenges in providing essential and emergency guidelines for weight management because of stepping into an aging society. We aimed to determine the daily diet patterns among the general Korean population and to investigate the association between such patterns and different obesity. STUDY DESIGN: Longitudinal prospective cohort study. METHODS: A total of 6539 adult participants (mean age 50.8 years, 52.9% male) with normal-weight adults were included from the Ansan-Ansung cohort of 10,030 Korean adults aged 40 or older and followed for an average of 11 years. Obesity was defined according to the criteria from the Korean Society for The Study of Obesity. Baseline dietary intake was assessed using a validated 103-item food frequency questionnaire. Dietary patterns were derived from k-means cluster analysis. RESULTS: In the multivariate analysis, referring to white rice + baechu kimchi, participants from multigrain rice + baechu kimchi showed lower HR for obesity development (waist circumference defined-obesity; HR: 0.87, 95% CI: 0.79, 0.95; body fat percentage defined-obesity; HR: 0.89, 95% CI: 0.80, 0.98). Further analysis documented that except for body fat percentage defined-obesity, consuming milk or dairy products was linked to a reduced incidence of the other three obesity (body mass index defined-obesity; HR: 0.84, 95% CI: 0.72, 0.99; waist circumference defined-obesity; HR: 0.82, 95% CI: 0.71, 0.94; waist-to-hip ratio defined-obesity; HR: 0.75, 95% CI: 0.61, 0.91). CONCLUSIONS: Following a diet that includes multigrain rice, fermented baechu kimchi, and dairy products is linked to a decreased risk of obesity in Korean adults. Public health programs and policies could incorporate these dietary recommendations, targeting specific population groups such as schoolchildren, adults, and the elderly. Additionally, further research is needed to explore the synergistic effects of various foods and their interactions within dietary patterns on obesity outcomes.

Acousto-optic-based time domain electric field sensor for magnetic resonance imaging applications.

An acousto-optic (AO)-based electric field sensor is presented for time domain measurement under magnetic resonance imaging (MRI). A fully MR-compatible sensor is designed and fabricated using a phase-shifted fiber Bragg grating mechanically coupled to a piezoelectric transducer. Mechanical resonance of the piezoelectric transducer is matched to the operating frequencies of commonly used MRI systems to increase the sensitivity of the sensor. Sensitivity of the sensor is measured as 1.27 mV/V/m, with a minimum detectable electric field of 4.4 mV/m/√/Hz. Directivity of the sensor is measured with a 18 dB orthogonal component rejection. The dynamic range of the sensor is calculated as 117 dB/Hz, which allows the measurement of electric fields up to 3.2 kV/m. In MRI studies, the AO sensor was able detect local hot spots around a reference implant accurately with high signal-to-noise ratio. AO sensor exhibited similar or better performance when compared with commercially available MRI compatible electric field sensors. Furthermore, the small size of the sensor with the flexible fiber optic link could allow in situ measurements of electric fields during critical interventional procedures such as pacemaker lead or deep brain stimulator placement as an MRI dosimeter during diagnostic scans.

Upper respiratory Streptococcus pneumoniae colonization among working-age adults with prevalent exposure to overcrowding.

Most pneumococcal disease occurs among infants and older adults and is thought to be driven by the transmission of Streptococcus pneumoniae from young children to these vulnerable age groups. However, pneumococcal disease outbreaks also affect non-elderly adults living or working in congregate, close-contact settings. Little is known about pneumococcal carriage in such populations. From July to November 2020, we collected saliva from low-income adult farmworkers in Monterey County, California, and tested for pneumococcal carriage following culture enrichment via quantitative PCR assays targeting the pneumococcal lytA and piaB genes. Participants were considered to carry pneumococci if lytA and piaB cycle threshold values were both below 40. Among 1,283 participants enrolled in our study, 117 (9.1%) carried pneumococci. Carriers tended more often than non-carriers to be exposed to children aged <5 years [odds ratio (OR) = 1.45 (0.95-2.20)] and overcrowding [OR = 1.48 (0.96-2.30) and 2.84 (1.20-6.73), respectively, for participants in households with >2-4 and >4 persons per bedroom vs ≤2 persons per bedroom]. Household overcrowding remained associated with increased risk of carriage among participants not exposed to children aged <5 years [OR = 2.05 (1.18-3.59) for participants living in households with >2 vs ≤2 persons per bedroom]. Exposure to children aged <5 years and overcrowding were each associated with increased pneumococcal density among carriers [piaB cT difference of 2.04 (0.36-3.73) and 2.44 (0.80-4.11), respectively]. While exposure to young children was a predictor of pneumococcal carriage, associations of overcrowding with increased prevalence and density of carriage in households without young children suggest that transmission also occurs among adults in close-contact settings.IMPORTANCEAlthough infants and older adults are the groups most commonly affected by pneumococcal disease, outbreaks are known to occur among healthy, working-age populations exposed to overcrowding, including miners, shipyard workers, military recruits, and prisoners. Carriage of Streptococcus pneumoniae is the precursor to pneumococcal disease, and its relation to overcrowding in adult populations is poorly understood. We used molecular methods to characterize pneumococcal carriage in culture-enriched saliva samples from low-income adult farmworkers in Monterey County, CA. While exposure to children in the household was an important risk factor for pneumococcal carriage, living in an overcrowded household without young children was an independent predictor of carriage as well. Moreover, participants exposed to children or overcrowding carried pneumococci at higher density than those without such exposures, suggesting recent transmission. Our findings suggest that, in addition to transmission from young children, pneumococcal transmission may occur independently among adults in overcrowded settings.

Early and Late Aortic-Related Mortality and Rupture After Fenestrated-Branched Endovascular Aortic Repair of Thoracoabdominal Aortic Aneurysms: A Prospective Multicenter Cohort Study.

BACKGROUND: Fenestrated-branched endovascular aortic repair (FB-EVAR) has been used as a minimally invasive alternative to open surgical repair to treat patients with thoracoabdominal aortic aneurysms (TAAAs). The aim of this study was to evaluate aortic-related mortality (ARM) and aortic aneurysm rupture after FB-EVAR of TAAAs. METHODS: Patients enrolled in 8 prospective, nonrandomized, physician-sponsored investigational device exemption studies between 2005 and 2020 who underwent elective FB-EVAR of asymptomatic intact TAAAs were analyzed. Primary end points were ARM, defined as any early mortality (30 days or in hospital) or late mortality from aortic rupture, dissection, organ or limb malperfusion attributable to aortic disease, complications of reinterventions, or aortic rupture. Secondary end points were early major adverse events, TAAA life-altering events (defined as death, permanent spinal cord injury, permanent dialysis, or stroke), all-cause mortality, and secondary interventions. RESULTS: A total of 1109 patients were analyzed; 589 (53.1%) had extent I-III and 520 (46.9%) had extent IV TAAAs. Median age was 73.4 years (interquartile range, 68.1-78.3 years); 368 (33.2%) were women. Early mortality was 2.7% (n=30); congestive heart failure was associated with early mortality (odds ratio, 3.30 [95% CI, 1.22-8.02]; P=0.01). Incidence of early aortic rupture was 0.4% (n=4). Incidence of early major adverse events and TAAA life-altering events was 20.4% (n=226) and 7.7% (n=85), respectively. There were 30 late ARMs; 5-year cumulative incidence was 3.8% (95% CI, 2.6%-5.4%); older age and extent I-III TAAAs were independently associated with late ARM (each P<0.05). Fourteen late aortic ruptures occurred; 5-year cumulative incidence was 2.7% (95% CI, 1.2%-4.3%); extent I-III TAAAs were associated with late aortic rupture (hazard ratio, 5.85 [95% CI, 1.31-26.2]; P=0.02). Five-year all-cause mortality was 45.7% (95% CI, 41.7%-49.4%). Five-year cumulative incidence of secondary intervention was 40.3% (95% CI, 35.8%-44.5%). CONCLUSIONS: ARM and aortic rupture are uncommon after elective FB-EVAR of asymptomatic intact TAAAs. Half of the ARMs occurred early, and most of the late deaths were not aortic related. Late all-cause mortality rate and the need for secondary interventions were 46% and 40%, respectively, 5 years after FB-EVAR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02089607, NCT02050113, NCT02266719, NCT02323581, NCT00583817, NCT01654133, NCT00483249, NCT02043691, and NCT01874197.

Neoadjuvant Exercise Therapy in Prostate Cancer: A Phase 1, Decentralized Nonrandomized ControlledTrial.

Importance: Observational data have shown that postdiagnosis exercise is associated with reduced risk of prostate cancer death. The feasibility and tumor biological activity of exercise therapy is not known. Objective: To identify recommended phase 2 dose of exercise therapy for patients with prostate cancer. Design, Setting, and Participants: This single-center, phase 1a dose-finding trial was conducted at a tertiary cancer center using a patientcentric, decentralized platform and included 53 inactive men with treatment-naive localized prostate cancer scheduled to undergo surgical resection between June 2019 and January 2023. Data were analyzed in June 2024. Intervention: Six escalated exercise therapy dose levels ranging from 90 to 450 minutes per week of individualized, moderate-intensity treadmill walking, allocated using adaptive continual reassessment. All exercise therapy sessions were conducted remotely with real-time monitoring. Main Outcomes and Measures: Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater. Activity end points were changes in tumor cell proliferation (Ki67) and plasma prostate-specific antigen levels between pretreatment and postintervention. Safety and changes in patient physiology were also assessed. Results: A total of 53 men were enrolled (median [IQR] age, 61 [56-66] years). All dose levels were feasible (≥75% REDI). The mean (95% CI) changes in Ki67 were 5.0% (-4.3% to 14.0%) for 90 minutes per week, 2.4% (-1.3% to 6.2%) for 150 minutes per week, -1.3% (-5.8% to 3.3%) for 225 minutes per week, -0.2% (-4.0% to 3.7%) for 300 minutes per week, -2.6% (-9.2% to 4.1%) for 375 minutes per week, and 2.2% (-0.8% to 5.1%) for 450 minutes per week. Changes in prostate-specific antigen levels were 1.0 ng/mL (-1.8 to 3.8) for 90 minutes per week, 0.2 ng/mL (-1.1 to 1.5) for 150 minutes per week, -0.5 ng/mL (-1.2 to 0.3) for 225 minutes per week, -0.2 (-1.7 to 1.3) for 300 minutes per week, -0.7 ng/mL (-1.7 to 0.4) for 375 minutes per week, and -0.9 ng/mL (-2.4 to 0.7) for 450 minutes per week. No serious adverse events were observed. Overall, 225 minutes per week (approximately 5 minutes per treatment at 5 times weekly) was selected as the recommended phase 2 dose. Conclusions and Relevance: The results of this nonrandomized clinical trial suggest that neoadjuvant exercise therapy is feasible and safe with promising activity in localized prostate cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03813615.

Contemporary Experience of the Neo-Aortoiliac System (NAIS) Procedure: A Case Series with Review of the Literature.

OBJECTIVES: Aortic graft infection (AGI) is a life-threatening complication that can result in death, amputation, sepsis, aorto-enteric fistula, and pseudoaneurysm formation. After explantation of the infected graft, options for reconstruction include extra-anatomic bypass or in-line reconstruction using antibiotic-coated prosthetic graft, cryopreserved allograft, or a neo-aortoiliac system (NAIS) using autogenous femoral veins. While the NAIS procedure has shown promising results, there is relatively limited clinical experience due the magnitude and morbidity of the surgery. In this study, we reviewed our single-center experience using the NAIS procedure and performed a systematic review of the contemporary literature more than the past decade. METHODS: A retrospective review was performed on all patients undergoing NAIS reconstruction with autogenous femoral vein conduits at a single institution from 2010 to 2022. Pubmed, Embase, and Cochrane Library databases were queried for studies published from 2012 to 2022 to identify those reporting on outcomes of patients undergoing the NAIS procedure. Outcome variables included early and late mortality, major complications including amputation, graft or conduit related complications, re-infection, and re-intervention. Additional variables collected include patient demographics, operative technique, and follow up. RESULTS: There were 14 patients included in our case series with 30-day mortality of 21%. At a mean follow up of 22 months, complication rate was 64.3%, re-intervention rate was 14.3%, re-infection rate was 7.1%, and amputation rate was 7.1%. On review of the literature, 12 studies ultimately met criteria to be included in analysis with a combined total of 368 patients. Pooled averages included 30-day mortality of 9.0%, re-intervention rate of 20.5%, re-infection rate of 5.6%, and amputation rate of 6.5%. CONCLUSIONS: The NAIS procedure for management of AGI is a formidable procedure with significant early mortality and morbidity. This treatment should be considered in the context of other revascularization options for management of an AGI.

MINIstock: Model for INsect Inclusion in sustainable agriculture: USDA-ARS's research approach to advancing insect meal development and inclusion in animal diets.

Animal agriculture is under pressure to increase efficiency, sustainability, and innovation to meet the demands of a rising global population while decreasing adverse environmental effects. Feed cost and availability are 2 of the biggest hurdles to sustainable production. Current diets depend on sources of grain and animal byproduct protein for essential amino acids which have limited sustainability. Insects have arisen as an attractive, sustainable alternative protein source for animal diets due to their favorable nutrient composition, low space and water requirements, and natural role in animal diets. Additionally, insects are capable of bioremediating waste streams including agricultural and food waste, manure, and plastics helping to increase their sustainability. The insect rearing industry has grown rapidly in recent years and shows great economic potential. However, state-of-the-art research is urgently needed to overcome barriers to adoption in commercial animal diets such as regulatory restrictions, production scale issues, and food safety concerns. To address this need, the USDA Agricultural Research Service "MINIstoc: Model for INsect Inclusion" project was created to bring together diverse scientists from across the world to synergistically advance insect meal production and inclusion in animal diets. Here, we provide a short review of insects as feed while describing the MINIstock project which serves as the inspiration for the Journal of Economic Entomology Special Collection "Insects as feed: sustainable solutions for food waste and animal production practices."

Conceptualization, design, and construction of a novel insect mass trapping device: the USDA Biomass Harvest Trap (USDA-BHT).

The use of insects as animal feed has the potential to be a green revolution for animal agriculture as insects are a rich source of high-quality protein. Insect farming must overcome challenges such as product affordability and scalability before it can be widely incorporated as animal feed. An alternative is to harvest insect pests from the environment using mass trapping devices and use them as animal feed. For example, intensive agricultural environments generate large quantities of pestiferous insects and with the right harvest technologies, these insects can be used as a protein supplement in traditional animal daily rations. Most insect trapping devices are limited by the biomass they can collect. In that context, and with the goal of using wild collected insects as animal feed, the United States Department of Agriculture-Biomass Harvest Trap (USDA-BHT) was designed and built. The USDA-BHT is a valuable mass trapping device developed to efficiently attract, harvest, and store flying insects from naturally abundant agricultural settings. The trap offers a modular design with adjustable capabilities, and it is an inexpensive device that can easily be built with commonly available parts and tools. The USDA-BHT is also user-friendly and has customizable attractants to target various pest species.

Harvesting insect pests for animal feed: potential to capture an unexploited resource.

The demand for animal protein grows as the human population increases. Technological and genetic advances in traditional animal agriculture will not produce enough protein to meet future needs without significant innovations such as the use of insects as protein sources. Insect farming is growing insects, whereas insect harvesting is collecting insects from their natural habitats to produce high-quality protein for animal feed or human food. Intensive agricultural environments produce tremendous quantities of pestiferous insects and with the right harvest technologies these insects can be used as a protein supplement in traditional animal daily rations. An avenue to exploit these insects is to use traps such as the United States Department of Agriculture-Biomass Harvest Trap (USDA-BHT) to efficiently attract, harvest, and store insects from naturally abundant agricultural settings. The modular design allows for a low cost, easy to build and fix device that is user friendly and has customizable attractants to target various pest species. Although insect harvesting faces substantial challenges, including insect biomass quantity, seasonal abundance and preservation, food safety, and economic and nutritional evaluation, the potential for utilizing these pests for protein shows tremendous promise. In this forum, insect harvesting is discussed, including its potential, limitations, challenges, and research needs. In addition, the use of a mass trapping device is discussed as a tool to increase the biomass of insects collected from the environment.

Assessment of the USDA Biomass Harvest Trap (USDA-BHT) device as an insect harvest and mosquito surveillance tool.

Insects are a promising source of high-quality protein, and the insect farming industry will lead to higher sustainability when it overcomes scaling up, cost effectiveness, and automation. In contrast to insect farming (raising and breeding insects as livestock), wild insect harvesting (collecting agricultural insect pests), may constitute a simple sustainable animal protein supplementation strategy. For wild harvest to be successful sufficient insect biomass needs to be collected while simultaneously avoiding the collection of nontarget insects. We assessed the performance of the USDA Biomass Harvest Trap (USDA-BHT) device to collect flying insect biomass and as a mosquito surveillance tool. The USDA-BHT device was compared to other suction traps commonly used for mosquito surveillance (Centers for Disease Control and Prevention (CDC) light traps, Encephalitis virus surveillance traps, and Biogents Sentinel traps). The insect biomass harvested in the USDA-BHT was statistically higher than the one harvested in the other traps, however the mosquito collections between traps were not statistically significantly different. The USDA-BHT collected some beneficial insects, although it was observed that their collection was minimized at night. These findings coupled with the fact that sorting time to separate the mosquitoes from the other collected insects was significantly longer for the USDA-BHT, indicate that the use of this device for insect biomass collection conflicts with its use as an efficient mosquito surveillance tool. Nevertheless, the device efficiently collected insect biomass, and thus can be used to generate an alternative protein source for animal feed.

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.

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.

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.

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.