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Summary: Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61–79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53–68). OS was 46.5% (95% CI, 40.6%–53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus

AimThe anticholinergic properties of medications are associated with poorer cognitive performance in schizophrenia. Numerous scales have been developed to assess anticholinergic burden and yet, there is no consensus indicating which anticholinergic burden scale is more relevant for patients with schizophrenia. We aimed to identify valid scales for estimating the risk of iatrogenic cognitive impairment in schizophrenia.MethodsWe identified 27 scales in a literature review. The responses to neuropsychological tests of 839 individuals with schizophrenia or schizoaffective disorder in the FACE-SZ database were collected between 2010 and 2021. We estimated the association between objective global cognitive performance and the 27 scales, the number of psychotropic drugs, and chlorpromazine and lorazepam equivalents in bivariable regressions in a cross-sectional design. We then adjusted the bivariable models with covariates: the predictors significantly associated with cognitive performance in multiple linear regressions were considered to have good concurrent validity to assess cognitive performance.ResultsEight scales, the number of psychotropic drugs, and drug equivalents were significantly associated with cognitive impairment. The number of psychotropic drugs, the most convenient predictor to compute, was associated with worse executive function (Standardized β = −0.12, p = .004) and reasoning (Standardized β = −0.08, p = .037).ConclusionAnticholinergic burden, the number of psychotropic drugs, and drug equivalents were weakly associated with cognition, thus suggesting that cognitive impairment in schizophrenia and schizoaffective disorder is explained by factors other than medication. The number of psychotropic drugs was the most parsimonious method to assess the risk of iatrogenic cognitive impairment.

The multinucleon transfer (MNT) reaction approach was successfully employed for the first time to measure the isomeric ratios (IRs) of 211Po isomer (25/2+) and its ground state (9/2+) at the IGISOL facility using a 945 MeV 136Xe beam impinged on 209Bi and natPb targets. The dominant production of isomers compared to the corresponding ground states was consistently revealed in the α-decay spectra. Deduced IR of 211Po populated through the 136Xe+natPb reaction was found to have an enhancement of ≈1.8-times than that observed for the 136Xe+209Bi. State-of-the-art Langevin-type model calculations have been utilized to estimate the spin distribution of an MNT residue. The computations qualitatively corroborate with the considerable increase in the IRs of 211Po produced from 136Xe+natPb compared to 136Xe+209Bi. Theoretical investigations indicate a weak dependence of target spin on the IRs. The enhancement of the 211Po isomer in the 136Xe+natPb over 136Xe+209Bi can be attributed to the different proton (p)-transfer production routes. Estimations demonstrate an increment in the angular momentum transfer, favorable for isomer production, with increasing projectile energy. Comparative analysis reveals the two entrance channel parameters, projectile mass and p-transfer channels, strongly influencing the population of the high-spin isomer of 211Po (25/2+). This letter reports the first experimental and theoretical study on the IRs of nuclei formed from two different p-transfer channels via two independent MNT reactions.

ABSTRACT Introduction: the simulation in minimally invasive surgery is fundamental for surgeon in training to learning and training skills, especially in pediatrics, due to the particularities, reduced spaces, specific and rare procedures. The aim of this study was to propose an adapted series of exercises and to simply evaluate the performance of pediatric surgery residents in the initial implementation of a training program. Method: seven basic skills exercises in video surgery, based on series and programs already published and using low-cost materials, were performed by six residents in 2 moments, with an interval of 15 days and evaluated by simple instrument. Results: there was no difficulty with models. Considering the individual averages of the seven exercises together in the two moments, five of the six residents increased the score in the second moment. The average score per exercise increased in five of the seven tasks. Despite the small number of participants and repetition, it has already been possible to observe a trend of better performance with decreased time of all residents after a single repetition. All considered the exercises capable of training essential skills of the specialty, with simple and inexpensive materials. Conclusion: given the challenges of simulated training in pediatric video surgery, it is known the benefit of a continuous program, with exercises that can simulate real situations. A pre-established schedule, more participants and repetitions, supervision of experienced surgeons and validated instruments are fundamental to evaluate surgeons in training and show statistical benefits of simulated exercises in this series.

BackgroundAbout 10–20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.MethodsWe conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.ResultsPancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.ConclusionDonor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

BackgroundThe rise of digital health services, especially following the outbreak of COVID-19, has led to a need for health literacy policies that respond to people’s needs. Spain is a country with a highly developed digital health infrastructure, but there are currently no tools available to measure digital health literacy fully. A well-thought-through questionnaire with strong psychometric properties such as the eHealth Literacy Questionnaire (eHLQ) is important to assess people’s eHealth literacy levels, especially in the context of a fast-growing field such as digital health. ObjectiveThis study aims to adapt the eHLQ and gather evidence of its psychometric quality in 2 of Spain’s official languages: Spanish and Catalan. MethodsA systematic cultural adaptation process was followed. Data from Spanish-speaking (n=400) and Catalan-speaking (n=400) people were collected. Confirmatory factor analysis was used to confirm the previously established factor structure. For reliability, the Cronbach α and categorical ω were obtained for every subscale. Evidence of convergent and discriminant validity was provided through the correlation with the total score of the eHealth Literacy Scale. Evidence based on relations to other variables was evaluated by examining extreme values for educational level, socioeconomic level, and use of technology variables. ResultsRegarding the confirmatory factor analysis, the 7-factor correlated model and the 7 one-factor models had adequate goodness-of-fit indexes for both Spanish and Catalan. Moreover, measurement invariance was established between the Spanish and Catalan versions. Reliability estimates were considered adequate as all the scales in both versions had values of >0.80. For convergent and discriminant validity evidence, the eHealth Literacy Scale showed moderate correlation with eHLQ scales in both versions (Spanish: range 0.57-0.76 and P

Summary: Background: No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods: 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings: 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4–25.5] and 45.9 [IQR:37.9–53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p ≤ 0.0001. The risk of VF was particularly high among the youngest children (2–5 years), adolescents (13–17 years) and young adults (18–24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6–12 and 13–17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation: P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding: Inserm - ANRS MIE.

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

The EZ-FET is a device with simplified architecture and processing that enables fast electrical characterization of semiconductor films on insulators (SOI) with only two lithography levels and using regular process steps. For low temperature SOI substrates characterization, the EZ-FET must be processed at a low temperature, including the junctions formation, i.e., the dopant activation process. Two EZ-FET dopant activation approaches using nanosecond laser annealing at low thermal budget are presented in this work. The first is the classical process of partial source and drain amorphization followed by their recrystallization. The second is a simplified process consisting of full source and drain amorphization followed by recrystallization. Both approaches are evaluated through the analysis of the electrical behaviors of the resulting structures.

In this study freeze-drying and oven-drying (at 50 and 65 °C) were applied for the preparation of dried pumpkin waste. The effect of drying methods on physical properties (moisture content, water activity, hygroscopicity, water solubility, bulk and tapped density, flowability and colour), content of bioactive compounds (carotenoids and phenolics) and antioxidant activity were investigated. Also, the influence of one-year storage at –20 °C on the bioactive compounds content and the antioxidant activity of dried pumpkin waste was examined. Results indicated that drying method showed a significant impact on the investigated characteristics. Bioactive compounds content and antioxidant activity by DPPH test of freeze-dried were higher than of oven-dried pumpkin waste, while higher antioxidant activity in reducing power assay was determined by oven-dried pumpkin waste. An artificial neural network model was developed, for the anticipation of antioxidant activity according to bioactive compounds content (phenolics and carotenoids), in oven-dried (at 50 and 65 °C) and in freeze-dried pumpkin waste after one-year storage. These models showed good prediction properties (the r2 value during training cycle for output variables was 0.999). It was demonstrated that pumpkin waste is potentially an important source of bioactive compounds, which can be used after extraction in suitable forms in the development of functional food products.

Abstract Bile acids (BA) are key for liver regeneration and injury. This study aims at analyzing the changes in the BA pool induced by ischemia-reperfusion (IRI) and investigates the impact of hypothermic oxygenated perfusion (HOPE) on the BA pool compared to static cold storage (SCS). In a porcine model of IRI, liver grafts underwent 30 min of asystolic warm ischemia followed by 6 h of SCS (n = 6) ± 2 h of HOPE (n = 6) and 2 h of ex-situ warm reperfusion. The BA pool in bile samples was analyzed with liquid chromatography coupled with tandem mass spectrometry. We identified 16 BA and observed significant changes in response to ischemia-reperfusion, which were associated with both protective and injury mechanisms. Second, HOPE-treated liver grafts exhibited a more protective BA phenotype, characterized by a more hydrophilic BA pool compared to SCS. Key BA, such as GlycoCholic Acid, were identified and were associated with a decreased transaminase release and improved lactate clearance during reperfusion. Partial Least Square-Discriminant Analysis revealed a distinct injury profile for the HOPE group. In conclusion, the BA pool changes with liver graft IRI, and preservation with HOPE results in a protective BA phenotype compared to SCS.

Insect pollinators affect pollen transfer dynamics, with consequences for pollen movement and the genetic structure of plant populations. Pollen transfer dynamics has not been previously examined in flowers with a tripping mechanism. Here we examine whether pollen accumulated on a bee’s body increases with the number of Medicago sativa L. flowers tripped by Bombus impatiens Cresson during a foraging bout, while controlling for bee body size and number of visited flowers. In a second experiment, we determine whether the number of revisits to a tripped flower increases pollen deposition onto the stigmas. We set up three M. sativa plants with a controlled number of racemes in a greenhouse room, and followed individual bees as they foraged, recording each plant, raceme, and flower visited. For pollen accumulated, we collected bees at the end of their foraging bout and counted pollen grains on their body. For pollen deposition, we collected flowers with between 0 and 6 revisits and counted the pollen grains on the stigmas. The number of pollen grains on a bee’s body increased with the number of flowers tripped in a foraging bout, but was not affected by the number of flowers visited or the size of individual bees. The number of pollen grains deposited on a stigma did not increase with the number of revisits to a tripped flower. This latter result contrasts with plants without a tripping mechanism where the number of visits increases pollen deposition and seed set. Tripping affects pollen transfer dynamics and we discuss how its effect may vary with the mode of tripping.

Abstract Background Worldwide, > 1.3 million adults are diagnosed with a gynecologic cancer each year, affecting their wellbeing and quality of life. This manuscript describes the protocol for a study that sought to assess the feasibility, acceptability, and fidelity of a community-based co-created yoga program and proposed evaluative methods, and estimate program effects on self-reported outcomes. Methods Using a multiple baseline single-subject research design with a follow-up phase (ABA), quantitative and qualitative data were collected from program participants and the instructor. Participants were randomly assigned to varying baseline lengths and completed weekly surveys for 3–5 weeks pre-program. Then, participants engaged in a bi-modal 12-week hatha yoga program consisting of 2 60-min group classes a week, with optional supplemental features (January–April, 2023). Participants completed surveys after classes 1, 12, and 24. All yoga classes were audio- and video-recorded. Post-program, participants completed surveys 1, 4, and 8 weeks after the last class and took part in a semi-structured interview 1 week after to discuss program acceptability, suitability, relevance, and potential benefits. Feasibility outcomes (i.e., recruitment, retention, and program adherence rates, engagement with optional program features) were tracked by the instructor assistant and study team during the study. The yoga instructor was interviewed about their experience delivering the program 2 weeks after the last class. Planned analysis Feasibility outcomes will be analyzed using descriptive statistics. Interview transcripts will be coded using reflexive thematic analysis. Class recordings will be coded using duration and frequency coding. Survey responses for self-reported outcomes will be analyzed visually and using multilevel modeling. Expected outcomes Data will help determine refinements, if any, required to the program and instructor guidebook, implementation approach, and proposed evaluation methods before scale-up projects and definitive trials are started. Trial registration ClinicalTrials.gov NCT05610982. November 3, 2022.

Abstract One of the primary drivers behind adolescents engaging in risk-taking behaviors is the pursuit of status. This study examines how activism and radicalism mediate the relation between the search for status and risk-taking behaviors, moderated by sex. A total of 482 participants, with an average age of 17.97 (SD = 1.83), reported their levels of status-seeking, activism, radicalism, and engagement in risk-taking behaviors. The study revealed an indirect effect of seeking status on risk-taking behaviors through the mechanisms of activism and radicalism. Furthermore, sex moderated the relation between status, activism and radicalism, and risk-taking behaviors. In both girls and boys, activism correlated with reduced engagement in risk-taking, while radicalism correlated with increased engagement. In terms of sex differences, both activism and radicalism showed a more pronounced effect in boys than in girls. These findings highlight the role of political mobilization on the relation between the pursuit of status and engagement in risk-taking.

Abstract The development of innovative solutions for the conservation and the protection of historic aircraft is a recent and important issue raised in the cultural heritage field and represents the goal of the PROCRAFT (Protection and Conservation of Heritage Aircraft) project. Assessing and documenting the constituent materials as well as their degradation state is necessary to determine and understand factors inducing aluminium alloy corrosion, in order to develop tailored conservation treatments and identify effective protective coatings. The first step of the project was the identification of the constituent materials of aircraft wrecks. Al-Cu-Mg alloys—Duralumin and Super Duralumin, with a higher content of Mg—were the most employed alloys for structural and non-structural parts. These materials undergo a wide range of alterations, amongst which pitting, exfoliation and galvanic corrosion. In the present work, results of the characterisation of wrecks from a North American Republic P-47D Thunderbolt, crashed in Italy in 1945, are reported and compared to wrecks from a French Breguet 765 Sahara n°504 64-PH, built in 1958. The constituent alloys resulted to be similar to the modern 2024 and 2017A alloy. In order to assess the representativeness of these modern alloys in simulating the corrosion behaviour of the historic ones, exfoliation susceptibility (ASTM G34) as well as non-destructive and destructive electrochemical tests in 0.1 M NaCl were carried out on both historic and modern alloys. These results contributed to the selection of representative substrates for the development of protective coatings as well as to the expansion of the dataset on composition and microstructure of historic Al alloys for aircraft.

A gossip protocol is a procedure by which a device disseminates its rumor to all devices on a network. The traditional definition of the gossip problem states that, in a system with $n$ interconnected devices where each of them only knows initially its own rumor, after a known finite time of message exchange, all devices learn the $n$ rumors. This definition considers synchronous systems where devices cannot fail. Gossip-based protocols can be very useful in Internet of Things (IoT) networks as a means of disseminating information. Thus, we have reformulated the problem to expand the spectrum of networks in which the gossip technique can be applied, including asynchrony and device failures, very common features in current IoT newtwoks. Gossiping consumes valuable memory and battery resources in devices. This can be particularly problematic for small IoT devices that operate with reduced memory in remote or inaccessible locations, where battery replacement or recharging is difficult. To address these issues, two efficient gossip protocols are presented, so that the efficiency and longevity of IoT devices is not compromised. The first protocol (battery-efficient protocol) allows to reduce battery consumption while still having a good time performance, but needs quadratic memory, like traditional versions. The second protocol (memory-optimal protocol) only needs linear memory to store and manage the rumors, and is capable of significantly reducing the number of messages sent, while obtaining similar (or, in many cases, better) performance than the first protocol. Both protocols are formally proved to be correct, and upper and lower limits of their number of messages sent are determined. These theoretical limits, however, differ so much among them that they do not permit to guess the number of messages that a real case may require. Hence, the practical performance of both protocols is assessed with experiments.

Este artículo tiene como objetivo exponer los regímenes laborales de género en el capitalismo, a efecto de explicar la masculinización del privilegio en el ámbito laboral. El artículo emplea una metodología ajustada al análisis de textos tanto teóricos como empíricos. Análisis, interpretación y transformación de los regímenes de producción de la diferencia sexual que esencializan, mediante la ecuación naturaleza=heterosexualidad, la identidad sexo-genérica y las prácticas heteronormativas que rigen las organizaciones laborales. This article aims to expose gender labor regimes in capitalism, in order to explain the masculinization of privilege in the workplace. The article uses a methodology adjusted to the analysis of both theoretical and empirical texts. Analysis, interpretation, and transformation of the regimes of production of sexual difference that essentialize, through the equation nature=heterosexuality, sex-gender identity and the heteronormative practices that govern labor organizations.

Abstract This paper highlights the efficacy of the finite element method with embedded strong discontinuities in modeling discontinuities in porous media, specifically in the geomechanical behavior of Naturally Fractured Reservoirs (NFRs). The approach considers hydromechanical coupling and offers low computational cost. NFRs account for a significant portion of global reserves, representing approximately 60% of global oil reserves and 40% of gas reserves. Given that flow in NFRs is more complex than in conventional reservoirs due to the presence of multiple fractures, it's crucial to understand how pressure variations or effective stress during operations impact fracture closure and permeability of these reservoirs. To analyze this behavior, numerical simulation results using the proposed method were compared, under different liquid pressure depletion values, with the approach proposed by Oda, which is commonly used in commercial software for calculating fracture permeability tensors. This approach was enriched with Barton's fracture closure formulation and updates on rock matrix porosity and permeability. Four simulations were conducted: Firstly, a hypothetical scenario consistent with Oda's assumptions, where fractures are interconnected and span the entire grid cell, to validate the numerical hydromechanical model; subsequently, three representative sections of a Brazilian pre-salt carbonate reservoir were selected. The study confirms the efficacy of the technique of embedded strong discontinuities in calculating equivalent permeabilities in NFRs, considering geomechanical effects, especially in cells with high fracture frequencies and intensities. Furthermore, the relevance of analyzing the geomechanical behavior in NFRs is emphasized.

Abstract Adeno-associated viral (AAV) vector-mediated retinal gene therapy is an active field of both pre-clinical as well as clinical research. As with other gene therapy clinical targets, novel bioengineered AAV variants developed by directed evolution or rational design to possess unique desirable properties, are entering retinal gene therapy translational programs. However, it is becoming increasingly evident that predictive preclinical models are required to develop and functionally validate these novel AAVs prior to clinical studies. To investigate if, and to what extent, primary retinal explant culture could be used for AAV capsid development, this study performed a large high-throughput screen of 51 existing AAV capsids in primary human retina explants and other models of the human retina. Furthermore, we applied transgene expression-based directed evolution to develop novel capsids for more efficient transduction of primary human retina cells and compared the top variants to the strongest existing benchmarks identified in the screening described above. A direct side-by-side comparison of the newly developed capsids in four different in vitro and ex vivo model systems of the human retina allowed us to identify novel AAV variants capable of high transgene expression in primary human retina cells.

Objectives: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). Methods: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. Results: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P

Abstract Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10–80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.

Abstract Background Endometrial cancer is the most common gynaecological tumour in developed countries and disease burden is expected to increase over the years. Identifying modifiable risk factors may help developing strategies to reduce the expected increasing incidence of these neoplasms. Objective This study evaluates the association between occupational exposure to pesticides and endometrial cancer using data from a recent case-control study in Spain. Methods The analyses included data from 174 consecutive incident endometrial cancer cases and 216 hospital controls frequency-matched by age. Data were collected through structured epidemiological questionnaires and exposure to pesticides was assessed using a Spanish job-exposure matrix (MatEmESp). Results Overall, 12% of controls and 18% of cases were occupationally exposed to pesticides. We observed a positive association between occupational exposure to pesticides and endometrial cancer (OR = 2.08; 95% CI = 1.13–3.88 compared to non-exposed). In general, exposures that occurred farther in the past were significantly associated with endometrial cancer. Exposure to insecticides, fungicides and herbicides were positively associated with endometrial cancer (OR = 2.08; 95% CI = 1.13–3.88, OR = 4.40; 95% CI = 1.65–13.33, and OR = 5.25; 95% CI = 1.84–17.67, respectively). The agricultural, poultry and livestock activities scenario was associated with endometrial cancer (OR = 4.16; 95% CI = 1.59–12.32), while the cleaning exposure scenario was not (OR = 1.22; 95% CI = 0.55–2.67). Conclusions Assessment of occupational exposure to pesticides assessed using a Spanish job-exposure matrix revealed a positive association with endometrial cancer. The elucidation of the role of pesticide compounds on endometrial cancer should shed a light on the aetiology of this tumour.

Abstract The low-temperature alteration (

Abstract Introduction The first complete long-acting antiretroviral therapy (ART) regimen, cabotegravir + rilpivirine long-acting (CAB + RPV LA) injectable, was approved in the US for HIV-1 treatment in individuals on a stable antiretroviral regimen with a viral load

Abstract Large salt lakes are long-term witnesses to climatic conditions and land use in their basins. The majority are experiencing a drastic drop in water levels due to climate change and human impact. Endoreic Lake Urmia (NW Iran), the sixth largest salt lake worldwide, is a striking example of this decline. Quantification of the relative contributions of natural variability and human impact on the lake's water supply is therefore essential. Here we present isotopic and radiocarbon analyses of surface and groundwater from the Shahr Chay River catchment, entering Lake Urmia on its western shore, and radiocarbon dating of a sedimentary core. Lake Urmia behaves like a large saltwater wedge almost entirely fed by the river and shallow groundwater. This leads to trapping of residual brines and formation of CH4 and secondary CO2 greenhouse gases, impacting sediment geochemical records and corresponding time scales for paleoenvironmental reconstructions. We conclude that (1) salt lakes functioning like a saline wedge, allowing organic matter oxidation, could contribute to increasing methane sources or reducing carbon sinks globally, and (2) endoreic basins worldwide need to be monitored before aridification-related salinization leads to the establishment of a saline wedge precluding any possibility of return to an equilibrium state.

Abstract Background Cholelithiasis is an uncommon and mainly incidental finding in dogs; current literature on this topic is scarce in cats. Hypothesis Report prevalence, clinical presentation, management, and outcome of cholelithiasis in cats. Animals Ninety‐eight cats with cholelithiasis. Methods Retrospective multicenter case series. Electronic databases from 3 hospitals were searched for cats diagnosed with cholelithiasis by ultrasonography (US). Cholelithiasis was classified as incidental (IC) or symptomatic (SC) depending on clinicopathological signs, biliary tract US appearance, and presence of another disease potentially explaining the clinical presentation. Multivariate analysis was used to investigate factors associated with clinical expression of cholelithiasis and, within the SC group, survival. Results The observed prevalence of cholelithiasis was 0.99% (95% confidence interval [CI], 0.79%‐1.19%) among cats that underwent abdominal US. Cholelithiasis was classified as IC in 41% and SC in 59%. Choleliths found in multiple locations within the biliary tract (odds ratio [OR], 8.11; 95% CI, 2.32‐34.15; P = .001) or associated with US signs of obstruction (OR, 18.47; 95% CI, 2.13‐2413.34; P = .004) were significantly associated with SC. Concurrent hepatobiliary diseases were suspected or confirmed in 83% of cases with SC. Forty‐three cats (74%) with SC survived to discharge. Biliary tract obstruction (BTO) was negatively associated with survival (OR, 13.87; 95% CI, 1.54‐124.76; P = .001). None of the cats with IC that had available follow‐up (47%) developed clinicopathological signs related to cholelithiasis. Conclusions and Clinical Importance Cholelithiasis is uncommon and can be asymptomatic in cats. Symptomatic cholelithiasis frequently is associated with another hepatobiliary disease or BTO or both. Biliary tract obstruction is associated with poorer outcome.

Abstract Background The Laval-ROSA Transilab is a living lab that aims to support the Laval Integrated Health and Social Services Centres (Quebec, Canada) in consolidating the Quebec Alzheimer Plan. It aims to improve care transitions between different settings (Family Medicine Groups, home care, and community services) and as such improve the care of people living with dementia and their care partners. Four transition-oriented innovations are targeted. Two are already underway and will be co-evaluated: A) training of primary care professionals on dementia and interprofessional collaboration; B) early referral process to community services. Two will be co-developed and co-evaluated: C) developing a structured communication strategy around the dementia diagnosis disclosure; D) designation of a care navigator from the time of dementia diagnosis. The objectives are to: 1) co-develop a dashboard for monitoring transitions; 2) co-develop and 3) co-evaluate the four targeted innovations on transitions. In addition, we will 4) co-evaluate the impact and implementation process of the entire Laval-ROSA Transilab transformation, 5) support its sustainability, and 6) transfer it to other health organizations. Methods Multi-methods living lab approach based on the principles of a learning health system. Living labs are open innovation systems that integrate research co-creation and knowledge exchange in real-life settings. Learning health systems centers care improvement on developing the organization's capacity to learn from their practices. We will conduct two learning cycles (data to knowledge, knowledge to practice, and practice to data) and involve various partners. We will use multiple data sources, including health administrative databases, electronic health records data, surveys, semi-structured interviews, focus groups, and observations. Discussion Through its structuring actions, the Laval-ROSA Transilab will benefit people living with dementia, their care partners, and healthcare professionals. Its strategies will support sustainability and will thus allow for improvements throughout the care continuum so that people can receive the right services, at the right time, in the right place, and from the right staff.

Recent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC.