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Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fabrice Balavoine has patent issued to Assignee. Delphine Compere has patent issued to Assignee. Catherine Llorens-Cortes has patent issued to Assignee. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Importance: International guidelines lack consistency in their recommendations regarding routine imaging in the follow-up after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). Consequently, follow-up strategies differ between centers worldwide., Objective: To compare clinical outcomes, including recurrence-focused treatment and survival, in patients with PDAC recurrence who received symptomatic follow-up or routine imaging after pancreatic resection in international centers affiliated with the European-African Hepato-Pancreato-Biliary Association (E-AHPBA)., Design, Setting, and Participants: This was a prospective, international, cross-sectional study. Patients from a total of 33 E-AHPBA centers from 13 countries were included between 2020 and 2021. According to the predefined study protocol, patients who underwent PDAC resection and were diagnosed with disease recurrence were prospectively included. Patients were stratified according to postoperative follow-up strategy: symptomatic follow-up (ie, without routine imaging) or routine imaging., Exposures: Symptomatic follow-up or routine imaging in patients who underwent PDAC resection., Main Outcomes and Measures: Overall survival (OS) was estimated with Kaplan-Meier curves and compared using the log-rank test. To adjust for potential confounders, multivariable logistic regression was used to evaluate the association between follow-up strategy and recurrence-focused treatment. Multivariable Cox proportional hazard analysis was used to study the independent association between follow-up strategy and OS., Results: Overall, 333 patients (mean [SD] age, 65 [11] years; 184 male [55%]) with PDAC recurrence were included. Median (IQR) follow-up at time of analysis 2 years after inclusion of the last patient was 40 (30-58) months. Of the total cohort, 98 patients (29%) received symptomatic follow-up, and 235 patients (71%) received routine imaging. OS was 23 months (95% CI, 19-29 months) vs 28 months (95% CI, 24-30 months) in the groups who received symptomatic follow-up vs routine imaging, respectively (P = .01). Routine imaging was associated with receiving recurrence-focused treatment (adjusted odds ratio, 2.57; 95% CI, 1.22-5.41; P = .01) and prolonged OS (adjusted hazard ratio, 0.75; 95% CI, 0.56-.99; P = .04)., Conclusion and Relevance: In this international, prospective, cross-sectional study, routine follow-up imaging after pancreatic resection for PDAC was independently associated with receiving recurrence-focused treatment and prolonged OS.

Collagen is a key component of the extracellular matrix (ECM) and well-oriented domains of collagen are important for mimicking the local cell environment in vitro . While there has been significant attention directed towards the alignment of collagen, formation of large-scale oriented domains remains a key challenge. Type I collagen self-assembles to form liquid crystalline (LC) mesophases in acidic conditions at concentrations above 100 mg mL -1 . The LC mesophase provides an efficient platform for large-scale alignment and patterning of collagen coated substrates. However, there still exist challenges related to solubilizing and processing of collagen at such high concentrations in order to replicate the native ECM. In this contribution, we report on centimeter-scale alignment in collagen-coated glass substrates using solutions that are well below the LC-forming concentrations. Importantly, we are also able to extend this method to macroscopic 3-D LC-collagen hydrogels with programmed anisotropy within them to create a mimic of the native ECM. We show that the orientation and aspect ratio of human Schwann cells are strongly coupled with the alignment of the collagen substrate/hydrogel. We use a simple model to estimate the critical magnetic field strength needed for a given concentration of collagen to permit macroscopic alignment-enabling guidance for future studies on alignment of collagen at high concentrations.

Aedes albopictus mosquitoes face numerous anthropic stressors in urban areas. These xenobiotics not only impact mosquito physiology but also shape the composition of their microbiota, which play important roles in host physiological traits. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants known to alter mosquito metabolism, but no studies have yet investigated their impact on microbiota. Using a bespoke indoor mesocosm tailored for Ae. albopictus mosquitoes, we investigated the dynamics of bacterial communities in both mosquitoes and their larval breeding sites following chronic exposure to a cocktail of PAHs consisting of benzo[a]pyrene, benz[a]anthracene, chrysene and benzo[b]fluoranthene. Our findings showed that PAHs have a stage-specific effect on mosquito microbiota, with a higher impact in larvae than in adults, contributing to 12.5 % and 4.5 % of the PAHs-induced variations, respectively. The presence of PAHs in the treated mesocosm led to the enrichment of bacterial families and genera known for their ability to catabolize PAHs, such as Comamonadaceae and Raoultella (increasing from 19 % to 30 % and from 1.2 % to 5.6 %, respectively). Conversely, prevalent taxa found in mosquito microbiota like Wolbachia and Cedecea exhibited a reduction (decreasing from 4 % to 0.8 % and from 12.8 % to 6.4 %, respectively). This reduction could be attributed to the competitive advantage gained by PAH-degrading taxa, or it could reflect a direct sensitivity to PAH exposure. Overall, this indicates a shift in microbiota composition favoring bacteria that can thrive in a PAH-contaminated environment. PAHs persisted in the water of breeding sites only the first 45 days of the experiment. Benzo[a]pyrene and benzo[b]fluoranthene were more susceptible to bioaccumulation in larval tissues over time. Overall, this study enhances our understanding of the impact of pollution on mosquitoes and could facilitate future research on the importance of symbiosis in urban-dwelling insect disease vectors. Given the recent advancements in the generation of axenic (microbe-free) and gnotobiotic (mosquitoes with a defined or specific microbiota) mosquitoes, further studies are needed to explore how changes in microbiota composition could influence mosquito responses to pollution, particularly in relation to host fitness, immunity, and vector competence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

As full-scale detailed hemodynamic simulations of the entire vasculature are not feasible, numerical analysis should be focused on specific regions of the cardiovascular system, which requires the identification of lumped parameters to represent the patient behavior outside the simulated computational domain. We present a novel technique for estimating cardiovascular model parameters using gappy Proper Orthogonal Decomposition (g-POD). A POD basis is constructed with FSI simulations for different values of the lumped model parameters, and a linear operator is applied to retain information that can be compared to the available patient measurements. Then, the POD coefficients of the reconstructed solution are computed either by projecting patient measurements or by solving a minimization problem with constraints. The POD reconstruction is then used to estimate the model parameters. In the first test case, the parameter values of a 3-element Windkessel model are approximated using artificial patient measurements, obtaining a relative error of less than 4.2%. In the second case, 4 sets of 3-element Windkessel are approximated in a patient's aorta geometry, resulting in an error of less than 8% for the flow and less than 5% for the pressure. The method shows accurate results even with noisy patient data. It automatically calculates the delay between measurements and simulations and has flexibility in the types of patient measurements that can handle (at specific points, spatial or time averaged). The method is easy to implement and can be used in simulations performed in general-purpose FSI software., (© 2024. The Author(s).)

Objective: Few studies have considered the neural underpinnings of binge eating disorder (BED) in children, despite clinical and subclinical symptom presentation occurring in this age group. Symptom presentation at this age is of clinical relevance, as early onset of binge eating is linked to negative health outcomes. Studies in adults have highlighted dysfunction in the frontostriatal reward system as a potential candidate for binge eating pathophysiology, although the exact nature of such dysfunction is currently unclear., Method: Data from 83 children (mean age 9.9 years, SD = 0.60) with symptoms of BED (57% girls) and 123 control participants (mean age 10.0 years, SD = 0.60) (52% girls) were acquired from the 4.0 baseline release of the Adolescent Brain Cognitive Development Study. Task-based graph theoretic techniques were used to analyze data from anticipation trials of the monetary incentive delay task. Network and nodal properties were compared between groups., Results: The BED-S group showed alterations in topological properties associated with the frontostriatal subnetwork, such as reduced nodal efficiency in the superior frontal gyrus, nucleus accumbens, putamen, and in normal sex-difference patterns of these properties, such as diminished girls-greater-than-boys pattern of betweenness-centrality in nucleus accumbens observed in controls., Conclusion: Distinct network properties and sex-difference patterns in preadolescent children with BED-S suggest dysregulation in the reward system compared to those of matched controls. For the first time, these results quantify this dysregulation in terms of systems-level properties during anticipation of monetary reward and significantly inform the early and sex-related brain markers of BED symptoms., Plain Language Summary: Binge eating disorder is the most common eating disorder. One factor that may contribute to binge eating is dysregulation of the reward system in the brain. This study analyzed brain activity during anticipation of monetary rewards in 83 youth with and 123 children without binge eating disorder symptoms from the Adolescent Brain Cognitive Development Study. The authors found specific alterations in the frontostriatal system, responsible for reward processing, in children with binge eating disorder symptoms, compared to the control group, suggesting dysregulation of the reward system., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

From 2014-2023, infectious bronchitis virus (IBV) was detected in 6,589 samples from Canada, and partial nucleotide (nt) sequences of the IBV spike protein ( S ) gene were determined for 1,678 samples. Based on their S gene nt sequence identities and origin, Canadian IBVs could be classified into 4 groups: 1) 50.3% were variant viruses related to strains described in the United States; 2) 45.6% were vaccine-like viruses; 3) 2.1% were Eurasian viruses; 4) 2.0% were Canadian variants. Outbreaks with IBVs related to strains CAL1734/04, 4/91, and DMV/1639/11 were often associated with more severe disease in all chicken commodity groups. With the emergence of numerous IBV strains, the severity of infection and number of affected flocks increased. Outbreaks with various IBV strains overlapped in their emergence, peaked, and regressed, but the introduction of DMV/1639/11 has resulted in a continuous field challenge since its first detection in 2015., Competing Interests: Declaration of conflicting interestsWe declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The heterotrimeric G-protein α subunit, Gα olf , acts to transduce extracellular signals through G-protein coupled receptors (GPCRs) and stimulates adenylyl cyclase mediated production of the second messenger cyclic adenosine monophosphate. Numerous mutations in the GNAL gene, which encodes Gα olf , have been identified as causative for an adult-onset dystonia. These mutations disrupt GPCR signaling cascades in in vitro assays through several mechanisms, and this disrupted signaling is hypothesized to lead to dystonic motor symptoms in patients. However, the cells and circuits that mutations in GNAL corrupt are not well understood. Published patterns of Gα olf expression outside the context of the striatum are sparse, conflicting, often lack cell type specificity, and may be confounded by expression of the close GNAL homolog of GNAS. Here, we use RNAScope in-situ hybridization to quantitatively characterize Gnal mRNA expression in brain tissue from wildtype C57BL/6J adult mice. We observed widespread expression of Gnal puncta throughout the brain, suggesting Gα olf is expressed in more brain structures and neuron types than previously accounted for. We quantify transcripts at a single cell level, and use neuron type specific markers to further classify and understand patterns of GNAL expression. Our data suggests that brain regions classically associated with motor control, initiation, and regulation show the highest expression of GNAL, with Purkinje Cells of the cerebellum showing the highest expression of any neuron type examined. Subsequent conditional Gnal knockout in Purkinje cells led to markedly decreased intracellular cAMP levels and downstream cAMP-dependent enzyme activation. Our work provides a detailed characterization of Gnal expression throughout the brain and the biochemical consequences of loss of Gα olf signaling in vivo in neurons that highly express Gnal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patients with pancreatic ductal adenocarcinoma present early postoperative systemic metastases, despite complete oncological resection. The aim of this study was to assess two pancreatoduodenectomy approaches with regard to intraoperative circulating tumour cells and cluster mobilization and their potential association with the development of distant metastasis., Methods: Patients with periampullary tumours who underwent open pancreatoduodenectomy were randomly allocated to either the no-touch approach or the superior mesenteric artery approach. A total of four intraoperative portal vein samples (at the beginning of the intervention, after portal vein disconnection from the tumour, after tumour resection, and before abdominal closure) were collected to measure circulating tumour cells and cluster numbers. Primary outcomes were the intraoperative number of circulating tumour cells and cluster mobilization. Further, their potential impact on 3-year distant metastasis disease-free survival and overall survival was assessed., Results: A total of 101 patients with periampullary tumours were randomized (51 in the superior mesenteric artery group and 50 in the no-touch group) and 63 patients with pancreatic ductal adenocarcinoma (34 in the superior mesenteric artery group and 29 in the no-touch group) were analysed. Circulating tumour cells and cluster mobilization were similar in both the no-touch group and the superior mesenteric artery group at all time points. There were no significant differences between surgical groups with regard to the median metastasis disease-free survival (12.4 (interquartile range 6.1-not reached) months in the superior mesenteric artery group and 18.1 (interquartile range 12.1-not reached) months in the no-touch group; P = 0.730). Patients with intraoperative cluster mobilization from the beginning to the end of surgery developed significantly more distant metastases within the first year after surgery (P = 0.023). Two intraoperative factors (the superior mesenteric artery approach (P = 0.025) and vein resection (P < 0.001)) were predictive factors for cluster mobilization., Conclusion: Patients undergoing pancreatoduodenectomy using either the no-touch approach or the superior mesenteric artery approach had similar circulating tumour cells and cluster mobilization and similar overall survival and metastasis disease-free survival. A high intraoperative cluster dissemination during pancreatoduodenectomy was a predictive factor for early metastases in patients with pancreatic ductal adenocarcinoma., Registration Number: NCT03340844 (http://www.clinicaltrials.gov)-CETUPANC trial., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

How landscape composition and configuration impact the distribution of multi-vector and multi-host mosquito vector-borne disease systems, such as West Nile virus (WNV), remains challenging because of complex habitat and resource requirements by hosts and vectors that affect transmission opportunities. We examined correlations between landscape composition and configuration and 2018 WNV sentinel chicken seroconversion in Florida, USA across the state and within five National Oceanic Atmospheric Administration (NOAA) bioclimatic regions to understand strength and variation of landscape effects during an elevated transmission year. Although few landscape studies have examined WNV in Florida, we expected higher percentages of residential or medium-developed landscapes and more fragmented landscapes would be positively correlated with WNV seroconversion owing to the main mosquito vector habitats and avian host distributions. However, we expected to find variation in the importance of forest, wetland, and agriculture landscapes across bioclimatic regions in the state. WNV seroconversion rates were calculated using Florida 2018 Department of Health WNV sentinel chicken seroconversion data from 187 flocks maintained by mosquito control programs. Percent land cover and edge density metrics were calculated for multiple land cover classes and within multiple buffer distances from chicken coops using 2019 National Land Cover Data. We used binomial generalized linear mixed effects models to calculate the importance of landscape metrics to WNV seroconversion. We found no statewide predictors of seroconversion, but as expected, the importance of landscape varied across regions. In the north-central part of the state, we found higher seroconversion in less populated suburban areas while higher seroconversion in south-central Florida was correlated with fragmented forested areas within 0.5 km of coops and intact woody wetland areas within 2 km of coops. This work corroborates previous findings that consistent landscape predictors of WNV are difficult to identify across broader geographic areas and sets the stage for additional work that incorporates climate and landscapes interactions for a greater understanding of WNV ecology in this geographic region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tavares et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Asian tiger mosquito Aedes albopictus is well adapted to urban environments and takes advantage of the artificial containers that proliferate in anthropized landscapes. Little is known about the physicochemical, pollutant, and microbiota compositions of Ae. albopictus-colonized aquatic habitats and whether these properties differ with noncolonized habitats. We specifically addressed this question in French community gardens by investigating whether pollution gradients (characterized either by water physicochemical properties combined with pollution variables or by the presence of organic molecules in water) influence water microbial composition and then the presence/absence of Ae. albopictus mosquitoes. Interestingly, we showed that the physicochemical and microbial compositions of noncolonized and colonized waters did not significantly differ, with the exception of N2O and CH4 concentrations, which were higher in noncolonized water samples. Moreover, the microbial composition of larval habitats covaried differentially along the pollution gradients according to colonization status. This study opens new avenues on the impact of pollution on mosquito habitats in urban areas and raises questions on the influence of biotic and abiotic interactions on adult life-history traits and their ability to transmit pathogens to humans., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Midline incision for extra-corporeal anastomosis is common with traditional laparoscopic right hemicolectomy. Incisional hernias develop in up to 20% of these patients within a year adding considerable morbidity and healthcare costs. Robotic assisted surgery (RAS) improves technical ease of intra-corporeal anastomosis, preventing midline extraction but its benefit over laparoscopy remains debated. We aimed to determine if robotic assisted surgery and Pfannenstiel extraction decreased the rate of radiologically detected incisional hernias compared to standard laparoscopy with extra-corporeal anastomosis. The secondary outcomes aimed to evaluate incidence of port site hernias in 8 mm robotic ports for which routine closure is not followed. Our single centre retrospective cohort study included patients who had minimally invasive right hemicolectomy and had cross-sectional imaging at least 1-year later. Patient demographics, body mass index, history of smoking or previous surgery was recorded. At imaging, evidence of new extraction site or port site-site hernia, contents and clinical impact was noted. A total of 100 patients (50 robotic and 50 laparoscopic) were included. Baseline characteristics appeared equally distributed. 16% (8 patients) who had laparoscopic surgery developed midline extraction site hernias which was significantly higher to RAS group (0 patients). 3 patients developed hernias at the site of robotic ports and this was more commonly at the right iliac fossa port. RAS, by simplifying intra-corporeal anastomosis has potential to eliminate incisional hernias, particularly when Pfannenstiel extraction is used. The potential for 8 mm robotic ports to develop clinically significant hernias cannot be ignored and meticulous closure can prevent patient harm., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Introduction: Despite a longstanding Israel Ministry of Health recommendation that all healthcare personnel (HCP) receive a seasonal influenza vaccine, vaccine uptake among HCP remains below the country's target of 60% coverage. To understand factors related to vaccine hesitancy, we used data from a prospective three-year (2016-2019) influenza vaccine effectiveness study among Israeli HCP to examine knowledge, attitudes, and practices (KAP) about influenza vaccination and their association with vaccine uptake., Methods: At the start of each influenza season, all participating HCP completed a questionnaire that included questions about socio-demographic and occupational characteristics, health status, and KAP related to seasonal influenza vaccination. We extracted vaccination history from electronic medical records and employee vaccination registries. We used logistic regression models to identify demographic and occupational factors, and KAP about influenza vaccination, associated with receipt of vaccination., Result: A total of 2,126 HCP were enrolled and had available data on vaccination history. Their median age was 42 years [IQR 35-52], and 73 % self-identified as female. Influenza vaccine uptake in 2016, 2017 and 2018 was 46 %, 48 % and 47 %, respectively. Overall, 36 % of HCP had received an influenza vaccine in ≥ 4 of the eight years prior. HCP aged 35-49 years were less likely to receive influenza vaccine compared to HCP aged ≥ 50 years (OR: 0.81 [95 % CI: 0.67-0.98]). Nurses and allied personnel were less likely to receive influenza vaccine compared to physicians (OR: 0.63 [95 % CI: 0.50-0.78] and OR: 0.53 [95 % CI: 0.40-0.70], respectively). The emotional benefit of vaccination (e.g., anticipating regret if not vaccinated) and the perception of vaccine safety were factors associated with vaccine uptake (OR: 7.60 [95 % CI: 6.27-9.22] and OR: 3.43 [95 % CI:2.91-4.03], respectively)., Conclusion: Among HCP at two hospitals in Israel, less than half received an annual influenza vaccine. Older HCP, physicians, and those who reported the emotional benefit of vaccination or agreed that influenza vaccines are safe were more likely to be vaccinated. Future influenza vaccination campaigns could focus on these demographic groups and tailor messages emphasizing the emotional benefits of vaccination and vaccine safety to increase seasonal influenza vaccine uptake among HCP in Israel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Introduction: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous., Methods: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data., Results: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10 -8 ). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10 -9 ). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10 -8 )., Discussion: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD., Highlights: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The first search for the Z boson decay to ττμμ at the CERN LHC is presented, based on data collected by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 138  fb^{-1}. The data are compatible with the predicted background. For the first time, an upper limit at the 95% confidence level of 6.9 times the standard model expectation is placed on the ratio of the Z→ττμμ to Z→4μ branching fractions. Limits are also placed on the six flavor-conserving four-lepton effective-field-theory operators involving two muons and two tau leptons, for the first time testing all such operators.

Background: Clostridioides difficile infection (CDI) may be misdiagnosed if testing is performed in the absence of signs or symptoms of disease. This study sought to support appropriate testing by estimating the impact of signs, symptoms, and healthcare exposures on pre-test likelihood of CDI., Methods: A panel of fifteen experts in infectious diseases participated in a modified UCLA/RAND Delphi study to estimate likelihood of CDI. Consensus, defined as agreement by >70% of panelists, was assessed via a REDCap survey. Items without consensus were discussed in a virtual meeting followed by a second survey., Results: All fifteen panelists completed both surveys (100% response rate). In the initial survey, consensus was present on 6 of 15 (40%) items related to risk of CDI. After panel discussion and clarification of questions, consensus (>70% agreement) was reached on all remaining items in the second survey. Antibiotics were identified as the primary risk factor for CDI and grouped into three categories: high-risk (likelihood ratio [LR] 7, 93% agreement among panelists in first survey), low-risk (LR 3, 87% agreement in first survey), and minimal-risk (LR 1, 71% agreement in first survey). Other major factors included new or unexplained severe diarrhea (e.g., ≥ 10 liquid bowel movements per day; LR 5, 100% agreement in second survey) and severe immunosuppression (LR 5, 87% agreement in second survey)., Conclusion: Infectious disease experts concurred on the importance of signs, symptoms, and healthcare exposures for diagnosing CDI. The resulting risk estimates can be used by clinicians to optimize CDI testing and treatment., Competing Interests: All authors report no conflicts of interest related to this article. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention., (© The Author(s) 2024.)

Objectives: To assess the acceptance and intention to use physiological sensor shirt among older patients in healthcare, as well as to identify the factors that encourage a positive attitude towards its adoption., Methods: Cross-sectional study using questionnaires addressed to patients between 60 and 85years of age, administered via face-to-face interviews to determine intention to use a shirt with physiological sensors. The extended version of the Technology Acceptance Model (TAM) questionnaire was used in conjunction with administration of the quality of life and perceived stress scales., Results: Forty-eight patients participated in the study, 54.2% were male with a mean age of 70.5years. The mean scores for attitude towards use and intention to use were 3.9 (SD: 0.8) and 3.3 (SD: 0.8), respectively, out of a maximum of 5. The willingness to use the device was positive in 72.9% of patients The patients intending to use wearable technology (n=35) scored significantly higher than those unwilling to wear the shirt (n=13) on perceived ubiquity (P=.031), perceived ease of use (P=.002), and perceived utility (P=.007)., Conclusions: In a sample of independent older adults from the healthcare sector, a high willingness to use a shirt with physiological sensors was found. Through the TAM questionnaire, ubiquity, perceived ease of use, and perceived usefulness were identified as key factors predisposing its adoption., (Copyright © 2024 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: This study aimed to measure patient-reported health-related quality of life amongst post-partum women in Queensland, Australia., Methods: Patient-reported health-related quality of life data was prospectively collected from 134 post-partum women using the EQ-5D-5L at weekly intervals during the first six weeks following birth. Data across the five health domains of the EQ-5D-5L was converted to a single health utility value to represent overall health status. Linear mixed modelling and regression analysis were used to examine changes in utility over the first six weeks post-birth and determine associations between utility and clinical and demographic characteristics of post-partum women., Findings: Gestation at birth and weeks post-partum were significantly associated with utility values when considered in a multivariate linear mixed model. Mean utility values increased by 0.01 for every week increase in gestation at birth, and utility values were 0.70 at one week post-partum and increased to 0.85 at six weeks post-partum, with the largest increase occurring between one- and two-weeks post-birth. When controlling for variables that were found to predict utility values across the first six weeks post-partum, no single state of health predicted utility values at one-week post-partum., Conclusions: Maternity services can use our data and methods to establish norms for their own service, and researchers and maternity services can partner to conduct cost-effectiveness analysis using our more relevant utility values than what is currently available. Time since birth and gestational age of the woman's baby should be considered when selecting post-partum health state utility values for maternity services cost-effectiveness analyses., Competing Interests: Authors EM and JT previously worked for the health service involved in this study. Employment with the health service was not related to this study and the health service did not fund this study. EM and JT were not employed at the time of data collection or manuscript preparation. MB works for the health service involved in this study. MB’s employment enabled participants to be informed of the study and opportunity to participate. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Martin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Urbanization is creating a new global biome, in which cities and suburbs around the world often resemble each other more than the local natural areas they replaced. But while urbanization can profoundly affect ecology at local scales, we know little about whether it disrupts large-scale ecological patterns. Here we test whether urbanization disrupts a macroecological pattern central to ecological and evolutionary theory: the increase in seed predation intensity from high to low latitudes. Across 14,000 km of latitude spanning the Americas, we compared predation intensity on two species of standardized experimental seeds in urbanized and natural areas. In natural areas, predation on both seed species increased fivefold from high latitudes to the tropics, one of the strongest latitudinal gradients in species interactions documented so far. Surprisingly, latitudinal gradients in predation were equally strong in urbanized areas despite significant habitat modification. Nevertheless, urbanization did affect seed predation. Compared with natural areas, urbanization reduced overall predation and vertebrate predation, did not affect predation by invertebrates in general, and increased predation by ants. Our results show that macroecological patterns in predation intensity can persist in urbanized environments, even as urbanization alters the relative importance of predators and potentially the evolutionary trajectory of urban populations., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Intestinal mucormycosis is a rare manifestation of the Mucor fungus, associated with high mortality and typically found in immunocompromised patients, though it has also been described in immunocompetent individuals. The mode of acquisition is digestive. It usually presents as abdominal pain, with ischemia and intestinal perforation, and the diagnosis is often histopathological after surgical resection. We present the case of a 54-year-old female patient with recurrent acute myeloid leukemia undergoing treatment with daunorubicin-cytarabine and experiencing febrile neutropenia. She developed patchy and progressive intestinal ischemia that evolved into intestinal necrosis, which was treated with antifungal medications and surgery. Examination of the surgical specimen revealed aseptate wide hyphae with branching at right angles, suggestive of Mucor fungus. This is a rare but highly mortal pathology in which clinical, radiological, and surgical suspicion is essential for early diagnosis and treatment, thus improving the patient's prognosis.

Objective: To explore the experiences of clinician and management stakeholders involved in a rural/metropolitan collaborative mental health disaster response to the 2019-2020 Black Summer bushfires in the Snowy Valleys region of southern New South Wales (NSW), Australia., Setting: A mental health and drug health service in the Snowy Valleys region of rural NSW in collaboration with a mental health service from metropolitan Sydney, NSW., Participants: Mental health clinicians and managers from a rural health district (n = 6) and a metropolitan health district (n = 8) involved in a collaborative disaster response to the 2019-2020 Black Summer bushfire disaster in the Snowy Valleys region of southern NSW, Australia., Design: An interpretive qualitative study design using semi-structured individual interviews, with transcripts analysed using Reflexive Thematic Analysis., Results: Thematic findings on participant experiences are presented under three organising constructs of before (stepping up and jumping right in), during (finding a rhythm of working together), and after (profound personal and professional impacts) the mental health disaster response., Conclusion: Participant experiences had shared and distinct components before, during and after the mental health disaster response, culminating in profound personal and professional impacts. Findings highlight positive aspects and challenges for clinicians participating in a rural/metropolitan collaborative mental health disaster response. The findings of this study contribute new knowledge about experiences of mental health clinicians participating in a disaster response after bushfires, from dual perspectives of members of a bushfire-affected community and those responding from outside a bushfire-affected community, which may inform ongoing planning of responses to disaster in Australia., (© 2024 National Rural Health Alliance Ltd..)

Attention-deficit/hyperactivity disorder (ADHD) is among the most prevalent, inheritable, and heterogeneous childhood-onset neurodevelopmental disorders. Children with a hereditary background of ADHD have heightened risk of having ADHD and persistent impairment symptoms into adulthood. These facts suggest distinct familial-specific neuropathological substrates in ADHD that may exist in anatomical components subserving attention and cognitive control processing pathways during development. The objective of this study is to investigate the topological properties of the gray matter (GM) structural brain networks in children with familial ADHD (ADHD-F), non-familial ADHD (ADHD-NF), as well as matched controls. A total of 452 participants were involved, including 132, 165 and 155 in groups of ADHD-F, ADHD-NF and typically developed children, respectively. The GM structural brain network was constructed for each group using graph theoretical techniques with cortical and subcortical structures as nodes and correlations between volume of each pair of the nodes within each group as edges, while controlled for confounding factors using regression analysis. Relative to controls, children in both ADHD-F and ADHD-NF groups showed significantly higher nodal global and nodal local efficiencies in the left caudal middle frontal gyrus. Compared to controls and ADHD-NF, children with ADHD-F showed distinct structural network topological patterns associated with right precuneus (significantly higher nodal global efficiency and significantly higher nodal strength), left paracentral gyrus (significantly higher nodal strength and trend toward significantly higher nodal local efficiency) and left putamen (significantly higher nodal global efficiency and trend toward significantly higher nodal local efficiency). Our results for the first time in the field provide evidence of familial-specific structural brain network alterations in ADHD, that may contribute to distinct clinical/behavioral symptomology and developmental trajectories in children with ADHD-F., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: The primary aim of this study was to compare how eyecare professionals in disparate regions of the world diagnose and manage Demodex blepharitis. A secondary aim was to explore interprofessional differences in diagnostic and management practices., Methods: Ophthalmologists and optometrists from India and Australia/New Zealand, were invited to complete an online survey on Demodex blepharitis. Clinical practice patterns relating to patients with Demodex blepharitis, with details of how they investigate and manage Demodex blepharitis in clinical practice, were collected along with clinician demographics and general perceptions on eyelid health. Mann-Whitney U, and Fisher's exact tests were used for statistical analysis., Results: A total of 261 eyecare professionals completed the survey, comprising 207 from India (84% optometrists) and 54 from Australia and New Zealand (91% optometrists). Almost 70% of practitioners across the 3 countries recognized Demodex blepharitis as a cause of ocular discomfort, yet only 45% reported attempting to identify Demodex in their patients. There were significant differences noted in clinical practice between those in Australasia and India. Perceived prevalence of Demodex blepharitis also differed (60% in Australasia vs 27% in India; p<0.01), as well as, the choice of slit lamp magnification used to detect the mites (25x in Australasia vs 16x in India; p = 0.02), preferred treatment option to manage Demodex blepharitis (tea tree oil in Australasia vs Standard lid hygiene in India; p = 0.01), treatment duration (from 3-4 weeks to over 12 weeks in Australasia vs 3-4 weeks in India; p = 0.02) and treatment application frequency (once daily in Australasia vs twice daily in India; p = 0.01)., Conclusions: This study highlights differences in clinical evaluation and treatment practices between eyecare professionals in India and Australasia. Overall, practitioners in Australia and New Zealand were more evidence-based in their investigation and management. However, in both regions, interprofessional differences in perceived optimal treatment duration and frequency were reported., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Sharma et al.)

The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia in mouse models of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treated with BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model., Competing Interests: Two patents WO 2011 144725 A2 and WO 2016 156531 A1 related to BL001 have been published of which GB and C-VN are inventors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cobo-Vuilleumier, Lorenzo, Martin Vazquez, López Noriega, Nano, Piemonti, Martín and Gauthier.)

Caveolae are small membrane pits with fundamental roles in mechanotransduction. Several studies have shown that caveolae flatten out in response to increased membrane tension, thereby acting as a mechanosensitive membrane reservoir that buffers acute mechanical stress. Caveolae have also been implicated in the control of RhoA/ROCK-mediated actomyosin contractility at the rear of migrating cells. However, how membrane tension controls the organisation of caveolae and their role in mechanotransduction remains unclear. To address this, we systematically quantified protein-protein interactions of caveolin-1 in migrating RPE1 cells at steady state and in response to an acute increase in membrane tension using biotin-based proximity labelling and quantitative mass spectrometry. Our data show that caveolae are highly enriched at the rear of migrating RPE1 cells and that membrane tension rapidly and reversibly disrupts the caveolar protein coat. Membrane tension also detaches caveolin-1 from focal adhesion proteins and several mechanosensitive regulators of cortical actin including filamins and cortactin. In addition, we present evidence that ROCK and the RhoGAP ARHGAP29 associate with caveolin-1 in a manner dependent on membrane tension, with ARHGAP29 influencing caveolin-1 Y14 phosphorylation, caveolae rear localisation, and RPE1 cell migration. Taken together, our work uncovers a membrane tension-sensitive coupling between caveolae and the rear-localised F-actin cytoskeleton. This provides a framework for dissecting the molecular mechanisms underlying caveolae-regulated mechanotransduction pathways., Competing Interests: EM, RG, GD, AL No competing interests declared, (© 2024, Martin, Girardello et al.)

The presubiculum is part of the parahippocampal cortex and plays a fundamental role for orientation in space. Many principal neurons of the presubiculum signal head direction, and show persistent firing when the head of an animal is oriented in a specific preferred direction. GABAergic neurons of the presubiculum control the timing, sensitivity and selectivity of head directional signals from the anterior thalamic nuclei. However, the role of vasoactive intestinal peptide (VIP) expressing interneurons in the presubicular microcircuit has not yet been addressed. Here, we examined the intrinsic properties of VIP interneurons as well as their input connectivity following photostimulation of anterior thalamic axons. We show that presubicular VIP interneurons are more densely distributed in superficial than in deep layers. They are highly excitable. Three groups emerged from the unsupervised cluster analysis of their electrophysiological properties. We demonstrate a frequency dependent recruitment of VIP cells by thalamic afferences and facilitating synaptic input dynamics. Our data provide initial insight into the contribution of VIP interneurons for the integration of thalamic head direction information in the presubiculum., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Contact precautions for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have limited data on efficacy and have been associated with patient harm. Still, a 2015 Society for Healthcare Epidemiology of America (SHEA) Research Network (SRN) survey showed only 7% of hospitals discontinued routine MRSA/VRE contact precautions. The study objectives were to identify the current proportion of hospitals that have discontinued routine MRSA/VRE contact precautions and motivations for change., Design: An online survey was conducted of the SRN on current use and views of contact precautions for MRSA/VRE in each facility. An initial survey followed by 2 reminders was sent between 5/18/2021 and 6/9/2021., Participants: SRN facilities., Results: The response rate was 43% (37/87) of facilities surveyed and 35% of respondents were not routinely using contact precautions for MRSA and VRE. The most frequently reported reason for discontinuing contact precautions was research on the safety of discontinuing contact precautions without an increase in healthcare-associated infections (reported for 92% of facilities for MRSA and 100% for VRE). Of those using contact precautions, the most frequently reported reason to continue was a lack of safety data for discontinuation (MRSA 58% and VRE 46%). Most of those continuing contact precautions were interested in using contact precautions differently in their facility (MRSA 63% and VRE 58%)., Conclusions: Over one in three healthcare facilities surveyed do not use contact precautions for MRSA or VRE. Most facilities choosing to continue contact precautions are interested in a different implementation strategy., Competing Interests: All authors report no conflicts of interest relevant to this article. D.M. does receive funding from government agencies to conduct research (CDC, NIH, AHRQ, and VA HSRD). E.M. receives CDC funding for other contact precautions research., (© The Author(s) 2024.)

This study evaluates the use of poly(vinyl alcohol), collagen, and chitosan blends for developing a microneedle patch for the delivery of meloxicam (MEL). Results confirm successful MEL encapsulation, structural integrity, and chemical stability even after ethylene oxide sterilization. Mechanical testing indicates the patch has the required properties for effective skin penetration and drug delivery, as demonstrated by load-displacement curves showing successful penetration of pig ear surfaces at 3N of normal load. In vitro imaging confirms the microneedle patch penetrates the pig's ear cadaver skin effectively and uniformly, with histological evaluation revealing the sustained presence and gradual degradation of microneedles within the skin. Additionally, in vitro drug diffusion experiments utilizing ballistic gel suggest that microneedles commence dissolution almost immediately upon insertion into the gel, steadily releasing the drug over 24 h. Furthermore, the microneedle patch demonstrates ideal drug release capabilities, achieving nearly 100% release of meloxicam content from a single patch within 18 h. Finally, in vivo studies using pigs demonstrate the successful dissolution and transdermal drug delivery efficacy of biodegradable microneedle patches delivering meloxicam in a porcine model, with over 70% of microneedles undergoing dissolution after 3 days. While low detectable meloxicam concentrations were observed in the bloodstream, high levels were detected in the ear tissue, confirming the release and diffusion of the drug from microneedles. This work highlights the potential of microneedle patches for controlled drug release in veterinary applications.

During neuronal development, neurons undergo significant microtubule reorganization to shape axons and dendrites, establishing the framework for efficient wiring of the nervous system. Previous studies from our laboratory demonstrated the key role of kinesin-1 in driving microtubule-microtubule sliding, which provides the mechanical forces necessary for early axon outgrowth and regeneration in Drosophila melanogaster. In this study, we reveal the critical role of kinesin-5, a mitotic motor, in modulating the development of postmitotic neurons. Kinesin-5, a conserved homotetrameric motor, typically functions in mitosis by sliding antiparallel microtubules apart in the spindle. Here, we demonstrate that the Drosophila kinesin-5 homolog, Klp61F, is expressed in larval brain neurons, with high levels in ventral nerve cord (VNC) neurons. Knockdown of Klp61F using a pan-neuronal driver leads to severe locomotion defects and complete lethality in adult flies, mainly due to the absence of kinesin-5 in VNC motor neurons during early larval development. Klp61F depletion results in significant axon growth defects, both in cultured and in vivo neurons. By imaging individual microtubules, we observe a significant increase in microtubule motility, and excessive penetration of microtubules into the axon growth cone in Klp61F -depleted neurons. Adult lethality and axon growth defects are fully rescued by a chimeric human- Drosophila kinesin-5 motor, which accumulates at the axon tips, suggesting a conserved role of kinesin-5 in neuronal development. Altogether, our findings show that at the growth cone, kinesin-5 acts as a brake on kinesin-1-driven microtubule sliding, preventing premature microtubule entry into the growth cone. This regulatory role of kinesin-5 is essential for precise axon pathfinding during nervous system development.

Objectives: Antihistamines have been reported to be linked with less pain in osteoarthritis. We aimed to estimate associations between antihistamine use and three outcomes: prevalent osteoarthritis, current joint pain, and developing osteoarthritis., Methods: We included 25 003 participants of EpiHealth - a cohort of persons aged 45 to 75 from Malmö/Uppsala in Sweden. Participants self-reported the presence of allergy, joint pain and osteoarthritis at a study visit between years 2010 and 2016. Further, we obtained data about diagnoses of allergy and osteoarthritis from health-care registers (primary, specialist and inpatient care). Exposure was prescribed dispensed antihistamines (H1-antagonists) during ~6 years preceding the EpiHealth visit retrieved from the Prescribed Drugs Register. The outcomes were osteoarthritis (any location) or pain in knees/hips/hands-wrists at the examination (cross-sectional) and future incident diagnosis of osteoarthritis (longitudinal, in a cohort free of osteoarthritis at EpiHealth). We report risk ratios (95% confidence intervals [CI]) from logistic regression and hazard ratios (HR) from Cox regression, from models adjusted for age, sex, body mass index, allergy and use of healthcare. We used prescribed dispensed penicillin as negative control., Results: The associations between use of antihistamines and osteoarthritis/joint pain at EpiHealth were 1.13 (95%CI 1.06, 1.20) and 1.02 (0.99, 1.05), respectively. The HR of future incident osteoarthritis diagnosis with use of antihistamines was 1.15 (1.03, 1.28). The association (HR) between penicillin use and future incident osteoarthritis diagnosis was 1.16 (1.07, 1.25)., Conclusions: In a large population-based observational cohort, use of antihistamines was neither associated with less joint pain/osteoarthritis nor lower risk of future osteoarthritis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The advent of highly effective and well-tolerated direct-acting antiviral therapy has made it more feasible to transplant hepatitis C virus (HCV)-infected organs into HCV-negative recipients. This case report presents the outcomes of 4 patients who underwent multivisceral transplantation from HCV-nucleic acid test (NAT)-viremic donors, with 1 recipient also requiring a kidney transplant. All recipients received posttransplant direct-acting antiviral therapy with sofosbuvir/velpatasvir (SOF/VEL [Epclusa]). By the fourth week of therapy, none of the recipients exhibited detectable viral loads, and all achieved sustained virologic response at 12 weeks. Allograft function for HCV D+/R- recipients remained excellent throughout follow-up. One recipient died from posttransplant lymphoproliferative disorder and another developed end-stage renal disease; both outcomes were ostensibly unrelated to HCV-donor status. The other 2 patients are progressing well without any evidence of allograft rejection., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

MYSM1 deficiency causes inherited bone marrow failure syndrome (IBMFS). We have previously identified an IBMFS patient with a homozygous pathogenic variant in MYSM1 who recovered from cytopenia due to spontaneous correction of one MYSM1 variant in the haematopoietic compartment, an event called somatic genetic rescue (SGR). The study of the genetic and biological aspects of the patient's haematopoietic/lymphopoietic system over a decade after SGR shows that one genetically corrected haematopoietic stem cell (HSC) can restore a healthy and stable haematopoietic system. This supports in vivo gene correction of HSCs as a promising treatment for IBMFS, including MYSM1 deficiency., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Schizophrenia is characterized by a loss of network features between cognition and reward sub-circuits (notably involving the mesolimbic system), and this loss may explain deficits in learning and cognition. Learning in schizophrenia has typically been studied with tasks that include reward related contingencies, but recent theoretical models have argued that a loss of network features should be seen even when learning without reward. We tested this model using a learning paradigm that required participants to learn without reward or feedback. We used a novel method for capturing higher order network features, to demonstrate that the mesolimbic system is heavily implicated in the loss of network features in schizophrenia, even when learning without reward., Methods: fMRI data (Siemens Verio 3T) were acquired in a group of schizophrenia patients and controls (n=78; 46 SCZ, 18 ≤ Age ≤ 50) while participants engaged in associative learning without reward-related contingencies. The task was divided into task-active conditions for encoding (of associations) and cued-retrieval (where the cue was to be used to retrieve the associated memoranda). No feedback was provided during retrieval. From the fMRI time series data, network features were defined as follows: First, for each condition of the task, we estimated 2 nd order undirected functional connectivity for each participant (uFC, based on zero lag correlations between all pairs of regions). These conventional 2 nd order features represent the task/condition evoked synchronization of activity between pairs of brain regions. Next, in each of the patient and control groups, the statistical relationship between all possible pairs of 2 nd order features were computed. These higher order features represent the consistency between all possible pairs of 2 nd order features in that group and embed within them the contributions of individual regions to such group structure., Results: From the identified inter-group differences (SCZ ≠ HC) in higher order features, we quantified the respective contributions of individual brain regions. Two principal effects emerged: 1) SCZ were characterized by a massive loss of higher order features during multiple task conditions (encoding and retrieval of associations). 2) Nodes in the mesolimbic system were over-represented in the loss of higher order features in SCZ, and notably so during retrieval., Discussion: Our analytical goals were linked to a recent circuit-based integrative model which argued that synergy between learning and reward circuits is lost in schizophrenia. The model's notable prediction was that such a loss would be observed even when patients learned without reward. Our results provide substantial support for these predictions where we observed a loss of network features between the brain's sub-circuits for a) learning (including the hippocampus and prefrontal cortex) and b) reward processing (specifically constituents of the mesolimbic system that included the ventral tegmental area and the nucleus accumbens. Our findings motivate a renewed appraisal of the relationship between reward and cognition in schizophrenia and we discuss their relevance for putative behavioral interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Martin, Chowdury, Kopchick, Thomas, Khatib, Rajan, Zajac-Benitez, Haddad, Amirsadri, Robison, Thakkar, Stanley and Diwadkar.)

Significance: When using lissamine green for bulbar conjunctival evaluation, the most staining was observed with two applications of the same strip in the same eye, wetted with a drop of saline. The first application was 5 seconds after wetting the strip, and the second was 1 minute later, followed by immediate viewing. This suggests that bulbar staining should be viewed before the lid wiper region., Purpose: This study aimed to optimize the assessment of lissamine green staining of the bulbar conjunctiva by investigating the application technique and subsequent observation period., Methods: Twenty-two participants with dry eye (as defined by the Tear Film and Ocular Surface Society Dry Eye Workshop II) were recruited to trial five application methods in randomized order: (1) application immediately after wetting a single strip, (2) application 5 seconds after wetting a single strip, (3) application 10 seconds after wetting a single strip, (4) consecutive single application of sodium fluorescein followed by lissamine green 5 seconds after wetting, and (5) two applications using the same lissamine green strip 5 seconds after wetting, 1 minute apart. Slit-lamp photography of the conjunctiva was performed immediately following application and at 30, 60, 90, and 300 seconds after application. Three experienced (masked) practitioners independently quantified the visible punctate spots and graded the staining intensity within the images in a random order., Results: Values for punctate spot count ( F = 6.29, p<0.0001) and lissamine green staining intensity ( F = 6.29, p<0.0001) varied significantly between the different application methods. Using two applications of the same lissamine green strip, 1 minute apart, in the same eye resulted in the greatest values for both punctate spot count and lissamine green staining intensity. Lissamine green staining decreased with time for both spot count ( F = 18.87, p<0.0001) and lissamine green staining intensity ( F = 11.33, p<0.0001), with the most staining found immediately after application followed by a gradual decline. There was no evidence of any interaction effect between time and application method for either measure (p>0.05 for both)., Conclusions: The optimal approach for assessing bulbar conjunctival lissamine green staining involves two applications of a whole infused drop resting on the same strip for 5 seconds, applied 1 minute apart. The ocular surface should be viewed immediately after application to maximize the conjunctival staining observed., Competing Interests: Conflict of Interest Disclosure: The authors declare no competing or commercial interests with any of the materials used in this study. There are no financial disclosures to declare., (Copyright © 2024 American Academy of Optometry.)

The translocator protein TSPO is an evolutionary conserved mitochondrial protein overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) is a neurodegenerative disease due to GAA expansions in the FXN gene leading to decreased expression of frataxin, a mitochondrial protein involved in the biosynthesis of iron-sulfur clusters. We previously reported that Tspo was overexpressed in a Drosophila model of this disease generated by CRISPR/Cas9 insertion of approximately 200 GAA in the intron of fh, the fly frataxin gene. Here, we describe a new Drosophila model of FA with 42 GAA repeats, called fh-GAAs. The smaller expansion size allowed to obtain adults exhibiting hallmarks of the FA disease, including short lifespan, locomotory defects and hypersensitivity to oxidative stress. The reduced lifespan was fully rescued by ubiquitous expression of human FXN, confirming that both frataxins share conserved functions. We observed that Tspo was overexpressed in heads and decreased in intestines of these fh-GAAs flies. Then, we further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-PET results., Methods: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [ 18 F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m 2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m 2 intravenously once every 3 weeks and vinorelbine 30 mg/m 2 intravenously on day 1 and 60 mg/m 2 orally [or 30 mg/m 2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m 2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m 2 intravenously and vinorelbine 20 mg/m 2 intravenously on day 1 and 40 mg/m 2 orally (or 20 mg/m 2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing., Findings: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [ 18 F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment)., Interpretation: A thoracic radiotherapy boost, based on interim [ 18 F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [ 18 F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC., Funding: Programme Hospitalier de Recherche Clinique National 2014., Competing Interests: Declaration of interests EM declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian Medical Systems, AstraZeneca, MSD, Janssen, and Sanofi; support for attending meetings or travel, or both, from Ipsen, Janssen, and AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca and Janssen. IB-R declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis 3A and Curium; payment for expert testimony from Curium; and support for attending meetings or travel, or both, from Novartis 3A. CLP declares payment or honoraria to her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca and Amgen; support for attending meetings or travel, or both, paid to her institution from Janssen and Roche; and participation on a data safety monitoring board or advisory board paid to her institution for AstraZeneca, Varian, MSD, and Roche. EG-L declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, and Takeda; and support for attending meetings or travel, or both, from Takeda, MSD, AstraZeneca, and Roche. CA-V declares support for attending meetings or travel, or both, from Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie; and participation on a data safety monitoring board or advisory board for Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie. ALan and EA are employees of the French Intergroup (Intergroupe Francophone de Cancérologie Thoracique). GZ declares consulting fees paid to his institution from AstraZeneca, BMS, Takeda, and Roche; payment or honoraria to his institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Inventiva, BMS, and Pfizer; support for attending meetings or travel, or both, from Roche, BMS, Abbvie, Pfizer, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services to his institution by Foundation Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

An 8-year-old American Quarter Horse gelding was treated with extracorporeal hemoperfusion (HP) therapy for treatment of Clostridioides difficile (C. difficile) colitis-induced systemic inflammatory response syndrome (SIRS). The gelding developed C. difficile associated peracute colitis and severe SIRS as evidenced by a positive fecal C. difficile PCR and tachypnea, tachycardia, fever, neutropenia, altered mucous membrane color, and hyperlactatemia. Concurrent acute kidney injury in the horse limited the use of routine anti-inflammatory and anti-lipopolysaccharide treatments, including flunixin meglumine and polymyxin B, because of potential for nephrosis. Extracorporeal HP therapy was performed twice within 48 hours of the onset of severe SIRS during which the horse's physical examination variables stabilized. The horse was euthanized after 4 days because of laminitis. These findings support further investigation of extracorporeal HP therapy as an adjunctive treatment for severe SIRS/sepsis in horses., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background/objectives: Artificial intelligence can assist with ocular image analysis for screening and diagnosis, but it is not yet capable of autonomous full-spectrum screening. Hypothetically, false-positive results may have unrealized screening potential arising from signals persisting despite training and/or ambiguous signals such as from biomarker overlap or high comorbidity. The study aimed to explore the potential to detect clinically useful incidental ocular biomarkers by screening fundus photographs of hypertensive adults using diabetic deep learning algorithms., Subjects/methods: Patients referred for treatment-resistant hypertension were imaged at a hospital unit in Perth, Australia, between 2016 and 2022. The same 45° colour fundus photograph selected for each of the 433 participants imaged was processed by three deep learning algorithms. Two expert retinal specialists graded all false-positive results for diabetic retinopathy in non-diabetic participants., Results: Of the 29 non-diabetic participants misclassified as positive for diabetic retinopathy, 28 (97%) had clinically useful retinal biomarkers. The models designed to screen for fewer diseases captured more incidental disease. All three algorithms showed a positive correlation between severity of hypertensive retinopathy and misclassified diabetic retinopathy., Conclusions: The results suggest that diabetic deep learning models may be responsive to hypertensive and other clinically useful retinal biomarkers within an at-risk, hypertensive cohort. Observing that models trained for fewer diseases captured more incidental pathology increases confidence in signalling hypotheses aligned with using self-supervised learning to develop autonomous comprehensive screening. Meanwhile, non-referable and false-positive outputs of other deep learning screening models could be explored for immediate clinical use in other populations., (© 2024. The Author(s).)

Background: Rapid Start ensures that persons with HIV initiate antiretroviral therapy in less than seven days after diagnosis. Benefits of Rapid Start include timely linkage to medical care, viral suppression in a shorter time and improved retention to medical care. Despite these benefits, there is a slow uptake of Rapid Start, in New Jersey., Objective: Identify barriers to Rapid Start among New Jersey providers., Methods: An electronic survey, consisting of 28 questions, with the following domains was administered to New Jersey providers, using Qualtrics: provider and practice characteristics (10), knowledge (1), barriers (8) and attitudes to diverse patient types (9). The results were analyzed using descriptive statistics due to small numbers over strata. Approval to conduct the survey was obtained from the William Paterson University Institutional Review Board., Results: There were 69 responses to the survey. Providers were at least 45 years old (48%), female (44/60, 73%), nurse practitioners or physician assistants (41/59, 69%). Overall, 44/63 (70%) providers did not correctly identify that integrase inhibitors had the lowest prevalence of transmitted drug resistance. Newly diagnosed patients were referred for medical care in 37 (65%) of the medical sites. Only providers from Ryan White (federally funded clinics for persons with HIV) (64%) and non-Ryan White (73%) public sites reported co-located HIV testing sites. Seventy percent of medical sites offered same-day medical appointments. However, a lower proportion of private (62%), public Ryan White (55%), and other medical sites (36%) offered same-day appointments compared to public non-Ryan White sites (82%). Despite having staff available 40 h per week (91%), only 55% of Ryan White sites offered extended office hours in the early morning, evenings, or on Saturdays. When compared to providers in public non-Ryan White sites, a lower proportion of providers in Ryan White sites were comfortable doing Rapid Start either on the day of or within one week of diagnosis, 82% and 72%, respectively, or starting antiretroviral therapy before genotype results were available, 55% and 46%, respectively. Overall, providers were not comfortable with Rapid Start for persons engaging in condomless sex (60%)., Conclusions: Policy and administrative decisions are needed to eliminate barriers at the clinic level. An HIV clinical scholar program, to increase providers knowledge, may increase uptake of Rapid Start.

Background: Lung cancer is the most common cause of cancer death in the UK resulting in 21% of all cancer deaths. In 2016, local lung cancer surgery services required improvement due to under-representation in cancer resections and resource scarcity during the pandemic, which affected critical care bed availability and extended postoperative stays. The aim of this service improvement was to increase the number of lung cancer resection; develop minimally invasive techniques and reduce the use of Critical Care Unit beds by 35% (a subsequent goal)., Methods: A five-year plan, guided by Kotter's 8-step change model, was initiated to address these issues. This model promotes sustainable change by setting clear goals, effective communication, and stakeholder involvement. Initial changes included hiring a thoracic surgeon experienced in uniportal video assisted thoracoscopy and enhanced recovery protocols. The team grew to three thoracic surgeons by 2020. The service increased operating theatre days and adopted new postoperative practices to reduce complications and hospital stays. Lung Cancer Multidisciplinary Team Meetings were consistently covered by thoracic surgeons, ensuring comprehensive care. Data on surgical activity were collected from departmental databases and national audits, with internal audits conducted regularly. Statistical significance was tested using chi-square tests with P values <0.05., Results: The number of surgical procedures more than doubled, with primary lung cancer resections increasing nearly three-fold from 12.8% to 29.8% over six years. Postoperative complications and mortality rates remained low. Critical care bed usage dropped significantly during the pandemic, with new protocols enabling safe recovery in general surgical areas., Conclusions: The successful expansion of thoracic surgical services was attributed to the dedicated minimally invasive surgeons, enhanced recovery measures, and skilled staff. The change model facilitated efficient and dynamic progress. With the introduction of lung cancer screening programs, the demand for surgical services is expected to rise. The effective change model will be re-applied to meet this demand. The organizational change model, focused on patients and staff, achieved sustained quality improvement in lung cancer care despite challenging conditions like the coronavirus disease 2019 pandemic., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1537/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background: Despite the widespread use of the phrase "harm reduction" and the proliferation of programs based on its principles during the current opioid epidemic, what it means in practice is not universally agreed upon. Harm reduction strategies have expanded from syringe and needle exchange programs that emerged in the mid-1980s primarily in response to the HIV epidemic, to include medication for opioid use disorder, supervised consumption rooms, naloxone distribution, and drug checking technologies such as fentanyl test strips. Harm reduction can often be in tension with abstinence and recovery models to address substance use, and people who use drugs may also hold competing views of what harm reduction means in practice. Street-based outreach workers are increasingly incorporated into harm reduction programs as part of efforts to engage with people more fully in various stages of drug use and nonuse., Method: This paper explores how peer outreach workers, called "members," in a street-based naloxone distribution program define and practice harm reduction. We interviewed 15 members of a street-based harm reduction organization in an urban center characterized by an enduring opioid epidemic. Inductive data analysis explored harm reduction as both a set of principles and a set of practices to understand how frontline providers define and enact them., Results: Analysis revealed that when members talked about their work, they often conceptualized harm reduction as a collection of ways members and others can "save lives" and support people who use drugs. They also framed harm reduction as part of a "path toward recovery." This path was complicated and nonlinear but pursued a common goal of life without drug use and its residual effects. These findings suggest the need to develop harm reduction programs that incorporate both harm reduction and recovery to best meet the needs of people who use drugs and align with the value systems of implementers., (© 2024. The Author(s).)

Objective: To describe the results of the application of a Machine Learning (ML) model to predict in-hospital cardiac arrests (ICA) 24 hours in advance in the hospital wards., Design: Retrospective observational cohort study., Setting: Hospital Wards., Patients: Data were extracted from the hospital's Electronic Health Record (EHR). The resulting database contained a total of 750 records corresponding to 620 different patients (370 patients with ICA and 250 control), between may 2009 and december 2021., Interventions: No., Main Variables of Interest: As predictors of ICA, a set of 28 variables including personal history, vital signs and laboratory data was employed., Models: For the early prediction of ICA, predictive models based on the following ML algorithms and using the mentioned variables, were developed and compared: K Nearest Neighbours, Support Vector Machine, Multilayer Perceptron, Random Forest, Gradient Boosting and Custom Ensemble of Gradient Boosting estimators (CEGB)., Experiments: Model training and evaluation was carried out using cross validation. Among metrics of performance, accuracy, specificity, sensitivity and AUC were estimated., Results: The best performance was provided by the CEGB model, which obtained an AUC = 0.90, a specificity = 0.84 and a sensitivity = 0.81. The main variables with influence to predict ICA were level of consciousness, haemoglobin, glucose, urea, blood pressure, heart rate, creatinine, age and hypertension, among others., Conclusions: The use of ML models could be of great support in the early detection of ICA, as the case of the CEGB model endorsed, which enabled good predictions of ICA., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Phosphorus-based stimuli-responsive hydrogels have potential in a wide range of applications due to their ionizable phosphorus groups, biocompatibility, and tunable swelling capacity utilizing hydrogel design parameters and external stimuli. In this study, poly(2-methacryloyloxyethyl phosphate) (PMOEP) hydrogels were synthesized via aqueous activators regenerated by electron transfer atomic transfer radical polymerization using ascorbic acid as the reducing agent. Swelling and deswelling behaviors of PMOEP hydrogels were examined in different salt solutions, pH conditions, and temperatures. The degree of swelling in salt solutions followed CaCl 2 < MgCl 2 < KCl < NaCl with a decrease in swelling rate at higher concentrations until reaching a saturation point. In water, the degree of swelling increased significantly around neutral pH and remained constant at basic pH values. The effects of polymerization conditions, including pH, temperature (30, 40, 50 °C), and MOEP concentration (40, 50, 60% v/v MOEP/H 2 O), on the hydrogel swelling behavior in various salt solutions were also investigated. PMOEP hydrogels showed a decrease in the degree of swelling as the pH was increased above the native pH of the monomer solution. Scanning electron microscopy and energy-dispersive spectroscopy were utilized to examine the microstructure and chemical composition of the dried hydrogel after salt solution swelling. Cytotoxicity testing using rat bone marrow stem cells confirmed the biocompatibility of the PMOEP hydrogels. A unique feature of this effort was evaluation of these phosphate hydrogels for use in expansion microscopy where a significant twofold enhancement in cellular expansion capacity was showcased utilizing 4T1 mouse breast cancer cells. This comprehensive study provides valuable insights into the stimuli-responsive behavior and expansion characteristics of phosphate hydrogels, highlighting their potential in diverse biomedical applications., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: Intravenous vitamin C was administered following hematopoietic stem cell transplant to mitigate nonrelapse mortality (NRM) in a Phase II clinical trial., Methods: Patients with advanced hematologic malignancies received IV vitamin C, 50 mg/kg/day, in three divided doses on days 1-14 after HSCT, followed by 500 mg bid oral until 6 months., Results: All patients enrolled (55) were deficient in vitamin C at day 0 and had restoration to normal levels. Vitamin C recipients had a trend for lower nonrelapse mortality (NRM, 11% vs. 25%, p -value = 0.07) compared with propensity score-matched historical controls. A similar trend toward improved survival was observed (82% vs. 62% p  = 0.06), with no attributable grade 3 and 4 toxicities to vitamin C., Conclusion: In patients undergoing allogeneic HSCT, repletion of vitamin C is feasible and may reduce NRM and improve overall survival. Randomized trials in large uniform cohorts of patients are needed to confirm the utility of this easily available and inexpensive therapy., Competing Interests: The authors have no conflict of interest to disclose., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Supportive care (SC) refers to the prevention and management of complications of cancer and its treatment. While it has long been recognized as an important cancer care delivery component, a high proportion of patients face unaddressed SC needs, calling for innovative approaches to deliver SC., Objective: The objective of this master protocol is to evaluate the implementation of different integrated proactive SC pathways across the cancer care continuum in our institution (Gustave Roussy, Villejuif, France). Pathways studied in this master protocol may occur shortly after diagnosis to prevent treatment-related burden; during treatment to monitor the onset of toxicities and provide timely symptom management; and after treatment to improve rehabilitation, self-management skills, and social reintegration., Methods: This study is guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. The primary objective is to evaluate the impact of SC pathways on patients' distress and unmet needs after 12 weeks, measured by the National Comprehensive Cancer Network's Distress Thermometer and Problem List. Secondary objectives will focus on the pathways (macrolevel) and each SC intervention (microlevel), evaluating their reach (administrative data review of the absolute number and proportion of clinical and sociodemographic characteristics of patients included in the pathways); short-term and long-term efficacy through their impact on quality of life (EQ-5D-5L and the 30-item European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) and symptom burden (MD Anderson Symptom Inventory, Hospital Anxiety and Depression Scale, Insomnia Severity Index, and 22-item European Organization for Research and Treatment of Cancer Sexual Health Questionnaire); adoption by patients and providers (administrative data review of SC referrals and attendance or use of SC strategies); barriers to and leverage for implementation (surveys and focus groups with patients, providers, and the hospital organization); and maintenance (cost-consequence analysis). Pilot evaluations with a minimum of 70 patients per pathway will be performed to generate mean Distress Thermometer scores and SDs informing the calculation of formal sample size needed for efficacy evaluation (cohorts will be enriched accordingly)., Results: The study was approved by the ethics committee, and as of February 2024, a total of 12 patients were enrolled., Conclusions: This study will contribute toward innovative models of SC delivery and will inform the implementation of integrated SC pathways of care., Trial Registration: ClinicalTrials.gov NCT06479057; https://clinicaltrials.gov/study/NCT06479057., International Registered Report Identifier (irrid): PRR1-10.2196/52841., (©Maria Alice Franzoi, Arnaud Pages, Loula Papageorgiou, Antonio Di Meglio, Ariane Laparra, Elise Martin, Aude Barbier, Nathalie Renvoise, Johanna Arvis, Florian Scotte, Ines Vaz-Luis. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.08.2024.)

The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow some physical crosstalk across regulatory domains, which is at odds with the specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites cooperatively foster the robust insulation of regulatory domains. By genetically dissecting a couple of representative loci in mouse embryonic stem cells, we show that CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), while developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the insulation of regulatory domains, which in turn might help interpreting the pathological consequences of certain structural variants., (© 2024. The Author(s).)

The study aimed to: (1) compare the occurrence of postoperative respiratory difficulties (PRD) following primary cleft palate repair (CPR) in infants with an isolated cleft palate (iCP) and infants with Robin sequence (RS), and (2) describe the possible benefit of preoperative analysis with palatal plate in infants with RS. All consecutive infants with an iCP and infants with RS who underwent CPR between January 2009 and June 2022 in the Wilhelmina Children's Hospital were retrospectively reviewed. A total of 127 infants were included of which 74 infants with an iCP and 53 infants with RS. The group of infants with RS consisted of 35 infants with non-isolated RS (niRS) and 18 infants with isolated RS (iRS). Significant more PRD were seen in infants with RS compared to infants with an iCP (14/53 versus 9/74; p = 0.04). Especially infants with niRS have a significant higher risk of developing PRD in comparison with infants with an iCP (OR = 4.16, 95% CI [1.17-15.99], p = 0.031). The preoperative palatal plate screening in infants with RS (n = 25) did not show abnormalities and had no effect on the perioperative policy. Within the limitations of this study it seems that infants with niRS are more prone to develop PRD following primary CPR when compared to infants with iRS or an iCP. No clear benefit was found in postponing surgery until 12 months or later in infants with RS to avoid PRD. The preoperative palatal plate screening did not demonstrate signs of UAO in infants with RS that developed PRD. These findings suggest that preoperative analysis with palatal plate has a low predictive value., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: It is well-known that right ventricle-to-pulmonary artery homograft conduit durability is worse for smaller conduits and smaller/younger patients. However, there is limited literature on age and conduit-size specific outcomes, or on the role of conduit oversizing. Methods: Patients diagnosed with tetralogy of Fallot and major aortopulmonary collateral arteries undergoing right ventricular outflow tract (RVOT) reconstruction with a valved aortic homograft conduit from November 2001 through March 2023, at our institution were included. Conduits were grouped and evaluated by diameter, diameter Z-score, and patient age at implant. The primary time-related outcome was freedom from RVOT reintervention. Factors associated with freedom from time-related outcomes were assessed with univariable Cox regression analysis. Results: A total of 863 RVOT conduits were implanted in 722 patients. On multivariable analysis, younger age, male sex, Alagille syndrome, smaller diameter of the conduit, and smaller Z-score were associated with shorter freedom from reintervention. Among patients with smaller diameter conduits, larger Z-scores were associated with longer freedom from conduit reintervention ( P  < .001). Transcatheter interventions were commonly used to extend conduit lifespan across ages and conduit sizes. Conclusions: Larger conduit diameter, older age, and higher conduit Z-score were associated with longer freedom from reintervention in patients undergoing RVOT reconstruction in this cohort. Oversizing of conduits, even beyond a Z-score of 4, is generally appropriate., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In this study, we investigate the influence of cold-plasma-induced enhanced performance and efficiency of SAPO-34 membranes in the separation of CO 2 and CH 4 mixtures. Placing the herein presented research in a broader context, we aim to address the question of whether cold plasma can significantly impact the membrane performance. We subjected SAPO-34 membranes to plasma mild disturbances and analyzed their performance in separating CO 2 and CH 4 . Our findings reveal a notable enhancement in membrane efficiency and sustained performance when exposed to cold plasma. The pulsed plasma separation displayed improved structural integrity, and the experimental results indicated that the linear structure of CO₂ facilitates the distortion of electron clouds in response to the electric field, a property known as polarizability, which aids in effective separation. Plausible mechanistic insight indicated that the intermolecular forces facilitated an integral role in SAPO-34 membranes exhibiting strong electrostatic interactions. In conclusion, our research highlights the potential of cold plasma as a promising technique for improving the performance of SAPO-34 membranes in gas mixtures at atmospheric pressures, providing valuable insights for optimizing membrane technology in carbon capture and gas separation applications.