Dynamic Drop Penetration of Horizontally Oriented Fiber Arrays.

In this experimental study, we combine drop impact into porous media and onto a single fiber to study drop impact into fiber arrays inspired by mammalian fur coats. In our 3D-printed arrays, we vary the packing density, fiber alignment, strand cross-section, and wettability. Drops impact fibers fixed at both ends, penetrating over short periods of time by momentum and laterally spreading throughout the array. Using image analysis, we measure penetration depth and wetted width into the array. Impact Weber number and intrinsic porosity define penetration, retraction, and rebound regimes. On average, at an impact Weber number of ≈80, staggered fibers reduce penetration by 24% in hydrophilic fibers and 34% in hydrophobic fibers, and the penetration reduction percentage is expected to increase with increasing Weber number. Our results indicate that as density grows toward the density of mammalian pelts, penetration will reach a maximum value independent of drop impact velocity, thereby providing an effective rain barrier. Hydrophilicity at the densities we test, 50-150 strands/cm2, aids fiber array resistance to dynamic penetration by impacting drops through the promotion of lateral drop spreading and inhibition of drop fragmentation. Conversely, hydrophobic fibers best resist low-speed wicking. The fraction of a drop that infiltrates hydrophilic and hydrophobic fibers is nearly identical for a fixed Weber number because lateral spreading restricts the penetration depth into hydrophilic fibers but does not restrict mass infiltration. Above a critical Weber number, the entire drop mass penetrates fiber arrays regardless of strand wettability.

Multi-Center Two-Year Patency Outcomes of Endovascular Arteriovenous Fistulas (endoAVF) Created with a 4 French System.

PURPOSE: To assess multicenter two-year patency outcomes of endovascular arteriovenous fistulas (endoAVF) created with the WavelinQ device. MATERIALS AND METHODS: Patients who had fistulas created at three centers from January 2018 to December 2020 were included in this retrospective study. In total, 112 patients underwent endoAVF creation [40 females, 72 males; mean age 60 years (range 18-88)]. Data collected included patient demographics, location of fistula creation, interventions performed, and brachial artery flows pre- and post-creation. Two-year cumulative patency, functional patency, and primary patency were assessed with Kaplan-Meier methodology. Factors affecting patency and maturation were examined using the Cox proportional hazards model. RESULTS: Technical success defined as angiographically successful endoAVF creation was 97.3% (109/112). In 11 patients the fistula did not mature for dialysis use. For 98 patients (87%) with endoAVF maturation, 12- and 24-month cumulative patency was 94.3% and 91.7%. Functional patency (two-needle cannulation) at 12 and 24 months was 95.7% and 92.7%, respectively. Median maturation time is 95 days (IQR 51-231 days). Male gender and brachial vein coiling at the time of endoAVF creation were predictive of maturation. There were 34 censored events (four patients undergoing renal transplantation; 30 patients deceased). Number of reinterventions per patient year was 0.73 where 43 were maturation procedures and 101 were maintenance procedures. One Grade 3 complication occurred of arterial access puncture site pseudoaneurysm. CONCLUSION: A high two-year functional and cumulative patency following endoAVF creation with the WavelinQ device was observed in this multicenter real-world experience Level of Evidence: 3 Level of Evidence III.

Toxicities of Novel Agents for the Treatment of Advanced Bladder Cancer.

Enfortumab vedotin and erdafitinib have specific toxicities that need careful management in order to optimise drug exposure while maintaining patients' quality of life. Patient education, meticulous monitoring, and a multidisciplinary approach are key to optimising outcomes so that patients can reap the benefits of these new treatments.

Dormancy of a specialist herbivore, Anthonomus rufipennis (Coleoptera: Curculionidae), in a dry tropical forest.

The life history aspects of dormancy of the weevil Anthonomus rufipennis LeConte (Coleoptera: Curculionidae) were studied a 57-month period in a seasonally dry tropical forest of central Mexico. Weevil populations and their physiological status were monitored on both the reproductive host tree, Senna polyantha (Collad.) H.S: Irwin & Barneby (Fabales: Fabaceae) and the highly favored refuge host, Tillandsia recurvata L. (Poales: Bromeliaceae) or "ball moss." During the dry season, weevils were only found on the refuge host with a mean total density of 1.014 ± 2.532 individuals/ball moss (N = 1,681). Weevil densities on T. recurvata between early and late dry seasons were not significantly different, suggesting that dry season survival was relatively high. Weevils collected during these seasons revealed little reproductive development and relatively high-fat accumulation in both sexes. During 5 of 6 yr, densities of the weevils in T. recurvata dropped significantly during the early rainy seasons, when the reproductive host trees leafed out and began producing oviposition sites (flower buds). At this time, more males than females initially moved to vegetative trees and showed significant signs of reproductive development. Recolonization of ball moss by weevils began during the late rainy season when oviposition sites (flower buds) were still available. A proportion of the weevils remained on the reproductive host, suggesting that A. rufipennis is facultatively multivoltine. The methodologies and results of the study can serve as a model system for future studies of the dormancy of other insects in dry tropical forests and provide insight into the dormancy of other anthonomine weevils of economic importance.

Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.

Work-life balance is essential to reducing burnout, improving well-being.

OBJECTIVE: To assess levels of burnout, well-being, and mental health of veterinarians and compare them to those of nonveterinarians by use of validated instruments, and to identify the predictive values of techniques individuals can use to help reduce burnout and/or improve well-being and mental health. SAMPLE: An online survey of 4,636 veterinarians from a random sample of 40,000 US veterinarians provided by the AVMA. METHODS: The study was fielded from September 11 to October 9, 2023. RESULTS: Burnout and well-being of veterinarians were generally consistent with that of employed US adults. Serious psychological distress was more common among veterinarians than in the general population. Veterinarians on average were more likely to score higher in neuroticism than nonveterinarians, and neuroticism was a predictor of low well-being, poor mental health, and burnout. Work-life balance, an effective coping mechanism for stress, and working in a positive clinic culture were among the significant factors that predicted good well-being and mental health and reduced burnout. CLINICAL RELEVANCE: The higher percentage than the norm of veterinarians with serious psychological distress was a concern. Focusing on maintaining a good work-life balance and adopting a reliable coping mechanism can potentially help reduce distress. Veterinary medicine is an inherently stressful profession. The purpose of this study was to identify key factors that contribute to burnout, well-being, and mental health and to determine what behaviors and management techniques help reduce stress and burnout and contribute to well-being and mental health, thus improving job satisfaction and personal fulfillment.

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

A review of Musca sorbens (Diptera: Muscidae) and Musca domestica behavior and responses to chemical and visual cues.

Musca flies (Diptera: Muscidae) have been found culpable in the mechanical transmission of several infectious agents, including viruses, bacteria, protozoans, and helminths, particularly in low-income settings in tropical regions. In large numbers, these flies can negatively impact the health of communities and their livestock through the transmission of pathogens. In some parts of the world, Musca sorbens is of particular importance because it has been linked with the transmission of trachoma, a leading cause of preventable and irreversible blindness or visual impairment caused by Chlamydia trachomatis, but the contribution these flies make to trachoma transmission has not been quantified and even less is known for other pathogens. Current tools for control and monitoring of house flies remain fairly rudimentary and have focused on the use of environmental management, insecticides, traps, and sticky papers. Given that the behaviors of flies are triggered by chemical cues from their environment, monitoring approaches may be improved by focusing on those activities that are associated with nuisance behaviors or with potential pathogen transmission, and there are opportunities to improve fly control by exploiting behaviors toward semiochemicals that act as attractants or repellents. We review current knowledge on the odor and visual cues that affect the behavior of M. sorbens and Musca domestica, with the aim of better understanding how these can be exploited to support disease monitoring and guide the development of more effective control strategies.

Cardiovascular Eligibility Criteria and Adverse Event Reporting in Combined Immune Checkpoint and VEGF Inhibitor Trials.

Background: Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors (VEGFIs) has improved cancer outcomes and is increasingly used. These drug classes are associated with cardiovascular toxicities when used alone, but heterogeneity in trial design and reporting may limit knowledge of toxicities in patients receiving these in combination. Objectives: The aim of this study was to assess consistency and clarity in definitions and reporting of cardiovascular eligibility criteria, baseline characteristics, and cardiovascular adverse events in ICI and VEGFI combination trials. Methods: A scoping review was conducted of phase 2 to 4 randomized controlled trials of ICI and VEGFI combination therapy for solid tumors. Trial cardiovascular eligibility criteria and baseline cardiovascular characteristic reporting in trial publications was assessed, and cardiovascular adverse event definitions and reporting criteria were also examined. Results: Seventeen trials (N = 10,313; published 2018-2022) were included. There were multiple cardiovascular exclusion criteria in 15 trials. No primary trial publication reported baseline cardiovascular characteristics. Thirteen trials excluded patients with prior heart failure, myocardial infarction, hypertension, or stroke. There was heterogeneity in defining cardiovascular conditions. "Grade 1 to 4" cardiovascular adverse events were reported when incidence was ≥5% to 25% in 15 trials. Incident hypertension was recorded in all trials, but other cardiovascular events were not consistently reported. No trial specifically noted the absence of cardiovascular events. Conclusions: In ICI and VEGFI combination trials, there is heterogeneity in cardiovascular exclusion criteria, reporting of baseline characteristics, and reporting of cardiovascular adverse events. This limits an optimal understanding of the incidence and severity of events relating to these combinations. Better standardization of these elements should be pursued. (Exclusions and Representation of Patients With Kidney Disease and Cardiovascular Disease in Drug Trials of the Novel Systemic Anti-Cancer Therapies VEGF-Signalling Pathway Inhibitors Alone or in Combination With Immune Checkpoint Inhibitors; CRD42022337942).

Ontogeny of Human Liver Aldehyde Oxidase: Developmental Changes and Implications for Drug Metabolism.

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC (n = 121 donors) and HH (n = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate. AO activity showed high technical variability and poor correlation with the content in HLC samples, whereas hepatocyte samples showed a strong correlation between the content and activity. Similarly, AO content and activity showed no significant age-dependent differences in HLC samples, whereas the average AO content and activity in hepatocytes increased significantly (∼20-40-fold) from the neonatal levels (0-28 days). Based on the hepatocyte data, the age at which 50% of the adult AO content is reached (age50) was 3.15 years (0.32-13.97 years, 95% CI). Metabolite profiling of carbazeran revealed age-dependent metabolic switching and the role of non-AO mechanisms (glucuronidation and desmethylation) in carbazeran elimination. The content-activity correlation in hepatocytes improved significantly (R2 = 0.95; p < 0.0001) in samples showing <10% contribution of glucuronidation toward the overall metabolism, confirming that AO-mediated oxidation and glucuronidation are the key routes of carbazeran metabolism. Considering the confounding effect of glucuronidation on AO activity, AO content-based ontogeny data are a more direct reflection of developmental changes in protein expression. The comprehensive ontogeny data of AO in HH samples are more reliable than HLC data, which are important for developing robust physiologically based pharmacokinetic models for predicting AO-mediated metabolism in children.

A Near-Infrared Luminescent Cr(III) N-Heterocyclic Carbene Complex.

Photoluminescent coordination complexes of Cr(III) are of interest as near-infrared spin-flip emitters. Here, we explore the preparation, electrochemistry, and photophysical properties of the first two examples of homoleptic N-heterocyclic carbene complexes of Cr(III), featuring 2,6-bis(imidazolyl)pyridine (ImPyIm) and 2-imidazolylpyridine (ImPy) ligands. The complex [Cr(ImPy)3]3+ displays luminescence at 803 nm on the microsecond time scale (13.7 µs) from a spin-flip doublet excited state, which transient absorption spectroscopy reveals to be populated within several picoseconds following photoexcitation. Conversely, [Cr(ImPyIm)2]3+ is nonemissive and has a ca. 500 ps excited-state lifetime.

Molecular phylogenetic analyses support the validity of Ceratiomyxa porioides (Amoebozoa, Eumycetozoa) at species level.

The frequently encountered macroscopic slime molds of the genus Ceratiomyxa have long been recognized by mycologists and protistologists for hundreds of years. These organisms are amoebozoan amoebae that live and grow inside and on the surface of decaying wood. When conditions are favorable, they form subaerial sporulating structures called fruiting bodies which take on a variety of forms. These forms are typically some arrangement of column and/or branches, but one is uniquely poroid, forming folds instead. Originally, this poroid morphology was designated as its own species. However, it was not always clear what significance fruiting body morphology held in determining species. Currently, Ceratiomyxa fruticulosa var. porioides, the poroid form, is considered a taxonomic variety of Ceratiomyxa fruticulosa based on morphological designation alone. Despite its long history of observation and study, the genus Ceratiomyxa has been paid little molecular attention to alleviate these morphological issues. We have obtained the first transcriptomes of the taxon C. fruticulosa var. porioides and found single gene phylogenetic and multigene phylogenomic support to separate it from C. fruticulosa. This provides molecular evidence that fruiting body morphology does correspond to species level diversity. Therefore, we formally raise Ceratiomyxa porioides to species level.

Critical appraisal of surgical margins according to KRAS status in liver resection for colorectal liver metastases: Should surgical strategy be influenced by tumor biology?

BACKGROUND: KRAS mutation is a negative prognostic factor for colorectal liver metastases. Several studies have investigated the resection margins according to KRAS status, with conflicting results. The aim of the study was to assess the oncologic outcomes of R0 and R1 resections for colorectal liver metastases according to KRAS status. METHODS: All patients who underwent resection for colorectal liver metastases between 2010 and 2015 with available KRAS status were enrolled in this multicentric international cohort study. Logistic regression models were used to investigate the outcomes of R0 and R1 colorectal liver metastases resections according to KRAS status: wild type versus mutated. The primary outcomes were overall survival and disease-free survival. RESULTS: The analysis included 593 patients. KRAS mutation was associated with shorter overall survival (40 vs 60 months; P = .0012) and disease-free survival (15 vs 21 months; P = .003). In KRAS-mutated tumors, the resection margin did not influence oncologic outcomes. In multivariable analysis, the only predictor of disease-free survival and overall survival was primary tumor location (P = .03 and P = .03, respectively). In KRAS wild-type tumors, R0 resection was associated with prolonged overall survival (74 vs 45 months, P < .001) and disease-free survival (30 vs 17 months, P < .001). The multivariable model confirmed that R0 resection margin was associated with prolonged overall survival (hazard ratio = 1.43, 95% confidence interval: 1.01-2.03) and disease-free survival (hazard ratio = 1.42; 95% confidence interval: 1.06-1.91). CONCLUSIONS: KRAS-mutated colorectal liver metastases showed more aggressive tumor biology with inferior overall survival and disease-free survival after liver resection. Although R0 resection was not associated with improved oncologic outcomes in the KRAS-mutated tumors group, it seems to be of paramount importance for achieving prolonged long-term survival in KRAS wild-type tumors.

A Lung Cancer Mouse Model Database.

Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.

NPEPPS Is a Druggable Driver of Platinum Resistance.

There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations. SIGNIFICANCE: Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.

Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.