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Background: Despite advances in diagnosis and treatment in lung cancer, therapies still fail to improve patient management due to resistance mechanisms and relapses. As Cancer stem cells (CSCs) directly contribute to tumor growth and therapeutic resistance, their clinical detection represents a major challenge. However specific and additional CSC markers lack. Thus, our aim was to achieve selective detection of CSCs with specific glycan patterns and assess the CSCs burden to predict the risk of relapse in NSCLC tumors. Methods: The lung CSCs detection and sorting with a lectin MIX were assessed and compared to CD133 in vitro. Then, its putative role as CSC biomarker was evaluated in vivo and its clinical significance on 221 NSCLC patients. Results: We showed a significant CSCs enrichment in the MIX+ sorted fraction compared to CD133+ cells and confirmed its high tumorigenic capacity. The MIX prognostic value on the overall survival from early stages patients was validated suggesting its potential for detecting CSCs directly linked to tumor aggressiveness. Conclusion: The MIX could be more relevant for detecting and sorting CSCs than CD133. Moreover, its prognosis value could enable clinicians to better classify early-stage patients at high risk of relapse in order to tailor therapeutic decisions. [ABSTRACT FROM AUTHOR]

Background: Fiber-matrix debonding is a precursor for transverse cracking and several other types of damage in fiber composites. However, to date, there are limited experiment-based reports that study the fundamental mechanisms of fiber-matrix debonding. Objective: This work aims to uncover the governing mechanisms of fiber-matrix interface debonding by full-field measurements supplemented by numerical simulations. In particular, the application of a dual-vision image-based characterization approach on single glass macro fiber samples is discussed and proven useful in understanding the in-plane and out-of-plane debonding characteristics at the fiber-matrix interface. Methods: Full-field strain and displacement measurements based on digital image correlation are performed on model single-fiber composites. The use of a dual-vision system allows strain measurements in the vicinity of the fiber-matrix interface, also allowing for the identification of critical strain and stress values corresponding to the initiation and propagation of debonding damage. The experimental data are used to calibrate an inverse identification approach that outputs the shape of the debonded interface along the fiber length. Results: Full-field measurements allow for establishing correlations between local and global strain fields. Observation of debonding propagation along the fiber axis seems to be representative of the crack tunneling during the early stages of the failure process, i.e., when the crack tip is subjected to opening mode only. Conclusions: Side view measurements are useful as a first-order approximation of the debonding propagation velocity along the fiber axis but fail to provide accurate measurements for the debonding shape, esp. in areas where the crack is under a dominantly shear stress state. This issue can be resolved by full-field measurements coupled with computational simulations. [ABSTRACT FROM AUTHOR]

Background/Objectives: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening event with major complications. Delayed cerebral infarct (DCI) occurs most frequently 7 days after aSAH and can last for a prolonged period. To determine the most predictive radiological scales in grading subarachnoid or ventricular haemorrhage or both for functional outcome at 3 months in a large aSAH population, we conducted a single-centre retrospective study. Methods: A 3-year single-centre retrospective cohort study of 230 patients hospitalised for aSAH was analysed. Initial computed tomography (CT) scans in patients hospitalised for aSAH were blindly assessed using eight grading systems: the Fisher grade, modified Fisher grade, Barrow Neurological Institute scale, Hijdra scale, Intraventricular Haemorrhage (IVH) score, Graeb score and LeRoux score. Results: Of 200 patients with aSAH who survived to day 7 and were included for DCI analysis, 39% of cases were complicated with DCI. The Hijdra scale was the best predictor for DCI, with a receiver operating characteristic area under the curve (ROCAUC) of 0.80 (95% confidence interval (CI), 0.74–0.85). The IVH score was the most effective grading system for predicting acute hydrocephalus, with a ROCAUC of 0.85 (95% CI, 0.79–0.89). In multivariate analysis, the Hijdra scale was the best predictor of the occurrence of DCI (hazard ratio, 1.18; 95% CI, 1.10–1.25). Conclusions: Although these results have yet to be prospectively confirmed, our findings suggest that the Hijdra scale may be a good predictor of DCI and could be useful in daily clinical practice. Clinical relevance statement: Better assessment of subarachnoid haemorrhage patients would allow for better prognostication and management of expectations, as well as referral for appropriate services and helping to appropriate use limited critical care resources. Key Points: Aneurysmal subarachnoid haemorrhage is a life-threatening event that causes severe disability and leads to major complications such as delayed cerebral infarction. Accurate assessment of the amount of blood in the subarachnoid spaces on computed tomography with the Hijdra scale can better predict the risk of delayed cerebral infarct. The Hijdra scale could be a good triage tool for subarachnoid haemorrhage patients. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cell (iPSC)-derived mesenchymal stromal cells (iMSCs) offer a promising alternative to primary mesenchymal stromal cells (MSCs) and their derivatives, particularly extracellular vesicles (EVs), for use in advanced therapy medicinal products. In this study we evaluated the immunomodulatory and regenerative potential of iMSCs as well as iMSC-EVs, alongside primary human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Our findings demonstrate that iMSCs exhibit comparable abilities to hUCMSCs in regulating lymphocyte proliferation and inducing an anti-inflammatory phenotype in monocytes. We also observed decreased TNFα levels and increased IL-10 induction, indicating a potential mechanism for their immunomodulatory effects. Furthermore, iMSC-EVs also showed effective immunomodulation by inhibiting T cell proliferation and inducing macrophage polarization similar to their parental cells. Additionally, iMSC-EVs exhibited pro-regenerative potential akin to hUCMSC-EVs in in vitro scratch assays. Notably, priming iMSCs with pro-inflammatory cytokines significantly enhanced the immunomodulatory potential of iMSC-EVs. These results underscore the considerable promise of iMSCs and iMSCs-EVs as an alternate source for MSC-derived therapeutics, given their potent immunomodulatory and regenerative properties. [ABSTRACT FROM AUTHOR]

Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer. Targeted protein degradation (TPD) can be employed to eliminate disease-causing proteins. Here, the authors present CYpHER, a TPD tool that uses molecules engineered for intracellular target release with drug recycling via transferrin receptor. CYpHER induces depletion of extracellular targets in vitro and in xenograft tumours. [ABSTRACT FROM AUTHOR]

Purpose: Survivorship from gynecologic cancers is becoming increasingly prevalent. There are significant sexual side effects that influence quality of life that would be reduced with proper intervention; however, existing literature highlights the lack of understanding of the sexual health needs within this population. Furthermore, multiple studies show that one contributing factor to sexual well-being in survivorship is provider-patient communication. The aim of this study is to explore experiences of sexual distress and survivor experiences of sexual health communication. Methods: Adult participants who had been out of active treatment for 3 months were recruited to participate in focus groups. Six focus groups (n = 32) were conducted with survivors of gynecologic cancers via Zoom. Research team members analyzed content using thematic analysis. Results: Two broad themes were identified: Experiences of provider communication and Preferences for provider communication, with subthemes nested under both. Subthemes from the Experiences theme included absent/lacking communication, negative experiences, emotional reaction to lack of communication, and feeling like sexuality was not valued. Subthemes from the Preferences theme included more conversation and open communication about sexuality, more resources/referrals, and more provider training on sexuality. Conclusion: Survivor experiences of subjective sexual health are often dependent on the type and quality of information they receive from their healthcare team during treatment. Unfortunately, the majority of participants endorsed negative or absent communication related to their sexual health needs, leading to additional distress. [ABSTRACT FROM AUTHOR]

Background: Difficulties in distinguishing fibrosis from tumor in borderline and locally advanced pancreatic adenocarcinoma (PDAC) justify surgical exploration to assess resectability. This issue is especially relevant after neoadjuvant treatments (NAT) prior to pancreaticoduodenectomy (PD) although outcomes of aborted PD are unknown. Objectives: This study aimed to evaluate early outcomes after aborted PD in patients with PDAC. Methods: Data were collected over a ten-year period, in three University Hospitals in France. Perioperative patient management was similar. The causes of intraoperative PD abortions were recorded, and outcomes of patients who underwent early (metastases, carcinomatosis) and late (following extensive vascular dissection) PD abortion were compared. Results: Of 774 PD for PDAC, 131 (17%) were aborted. 97 (74%) patients underwent early PD abortion due to carcinomatosis (n = 14; 14%), liver metastases (n = 32; 33%), aortocaval lymph node invasion (n = 28; 29%) and massive vascular extension (n = 23; 24%). Late PD abortion occurred after extensive vascular dissection in 34 (26%) patients due to invasion of the common hepatic (n = 16; 47%), superior mesenteric (n = 5; 15%) and right hepatic (n = 1; 3%) arteries and nonreconstructable venous invasion (n = 12; 35%). Patients who underwent late PD abortion had higher rates of overall morbidity (n = 22; 65% vs n = 27; 28%, p = 0.0001), severe complications (n = 14; 41% vs n = 11; 11%, p = 0.0005), mortality (n = 4; 12% vs n = 0; 0%, p = 0.003). They also had higher rates of delayed gastric emptying (n = 11; 32% vs n = 6; 6%, p = 0.0003), deep space infections (n = 10; 29% vs n = 7; 7%, p = 0.002), wound infections (n = 5; 15% vs n = 4; 4%, p = 0.05), and bleeding (n = 8; 24% vs n = 0; 0%, p < 0.0001). Conclusion: Aborted PD after extensive vascular dissection has high morbidity and mortality rates. Appropriate information and counseling should be delivered to patients with borderline/locally advanced PDAC considered for PD. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) guidelines recommend methotrexate (MTX)-anchored therapy with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs); however, tolerability issues often lead to non-adherence. Canadian data on MTX tapering and/or withdrawal following b/tsDMARD initiation are minimal. This chart review assessed frequency of MTX tapering or withdrawal following b/tsDMARD initiation and the impact on disease status in Canadian adults with RA. Methods: Eligible patients had received MTX for ≥ 3 months before b/tsDMARD initiation. The b/tsDMARD was prescribed continuously for ≥ 18 months. Patients taking > 10 mg/day oral prednisone or equivalent were excluded. Results: Eight hundred eighty-nine patients (mean baseline MTX dose 19.0 mg/week) prescribed b/tsDMARDs (tumor necrosis factor inhibitor 52.1%, Janus kinase inhibitor 18.3%, interleukin-6 inhibitor [IL-6i] 11.9%, other 17.7%) were evaluated at 22 Canadian centers. Within 2 years of b/tsDMARD initiation, MTX was tapered in 123 (13.8%) patients and discontinued in 147 (16.5%), most commonly due to planned tapering (36.6%) and patient decision (27.2%), respectively, and most commonly with IL-6i use (34.9%). The MTX dose was unchanged for 582 (65.5%) patients and increased for 37 (4.2%). Missing data limit interpretations of MTX dose effects on some secondary endpoints and challenge the assertion that a disease activity measure–based treat-to-target approach is routinely used in Canadian rheumatology practice. Conclusions: Methotrexate tapering or withdrawal occurred in 30.4% of Canadians with RA within 2 years following b/tsDMARD initiation. Baseline disease activity measures were missing from many medical records. However, for patients with baseline assessments, MTX tapering or discontinuation did not worsen disease activity. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions Level of Evidence A lack of standardization exists for functional tasks in return‐to‐activity (RTA) guidelines for adolescents with anterior cruciate ligament injury (ACLi). Identifying the variables that discern ACLi status among adolescents is a first step in the creation of such guidelines following surgical reconstruction. This study investigated the use of classification models to discern ACLi status of adolescents with and without injury using spatiotemporal variables from functional tasks typically used in RTA guidelines for adults.Sixty‐four adolescents with ACLi and 70 uninjured adolescents completed single‐limb hops, lunges, squats, countermovement jumps and drop‐vertical jumps. Jumping distances, heights, and depths were collected. Decision trees (DTs) were used to classify ACLi status and were evaluated using the F‐measure (F1), kappa statistic (ĸ) and area under the precision–recall curve (PRC). Independent t tests and effect sizes were calculated for each important classifier of the DT models.A five‐variable model classified ACLi status with an accuracy of 67.5% (F1 = 0.6842; ĸ = 0.350; PRC = 0.491) with sex as a classifier. Significant differences were found in three of the four spatiotemporal variables (p ≤ 0.002). Separate models then classified ACLi status in males and females with an accuracy of 53.3% (F1 = 0.5882; ĸ = 0.0541; PRC = 0.476) and 76.9% (F1 = 0.7692; ĸ = 0.541; PRC = 0.528), respectively, with significant differences for all variables (p ≤ 0.013).Among the DT models, females were better able to classify ACLi status compared to males, highlighting the importance of sex‐specific rehabilitation guidelines for adolescents.Level III. [ABSTRACT FROM AUTHOR]

Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both the central and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available. This paper presents the development process of the Person-Reported Ataxia Impact Scale (PRAIS), a new PROM in recessive ataxias, and the documentation of its content validity, interpretability, and construct validity (structural and discriminant). The development followed the PROMIS framework and the Food and Drug Administration guidelines. A mixed-method study design was used to develop the PROM. A systematic review of the literature, semistructured interviews, and discussion groups was conducted to constitute an item pool. Experts' consultation helped formulate items, and the questionnaire was sent online to be completed by people affected. Statistical analyses were performed to assess the structural and discriminant validity. A total of 125 people affected by recessive ataxia completed the questionnaire. The factor analysis confirmed the three components: physical functions and activities, mental functions, and social functions. The statistical analysis showed that it can discriminate between stages of mobility and level of autonomy. It showed very good levels of internal consistency (0.79 to 0.89). The Person-Reported Ataxia Impact Scale (PRAIS) is a 38-item questionnaire that assesses the manifestations and impacts of the disease according to the perception of people affected by recessive ataxia. It can be used in clinical and research settings. [ABSTRACT FROM AUTHOR]

Background: While it is increasingly acknowledged that conduct problems and peer problems often co-occur in development, less is known about the ways in which peer problems may alter the developmental course of conduct problems for distinct subgroups. Methods: Using data from a large population-based study in Norway (the Bergen Child Study/youth@hordaland; 47.4% males), we estimated group-based trajectories of conduct problems and the presence of time-varying peer problems on the developmental progression of conduct problems between seven and 19 years of age. Risk factors for group membership were also examined. Results: A 3-group model of conduct problems best fit the data (non-engagers, low-engagers, moderate-stable). The presence of peer problems increased the estimated level of conduct problems for both the low-engagers and moderate-stable groups across adolescence. No differences in conduct problems were observed when peer problems were present in childhood or preadolescence for these two groups, nor for the non-engagers group at any point. Being male, having lower perceived economic wellbeing, and lower levels of parental education predicted group membership for the moderate-stable group, whilst lower paternal education predicted membership for the low-engagers group. Conclusions: Support for developmental 'turning points' was found, suggesting that adolescence is a particularly salient time for those with conduct problems. In particular, the presence of peer problems can increase observed conduct problems at this stage in development. [ABSTRACT FROM AUTHOR]

This work focuses on dimension-reduction techniques for modelling conditional extreme values. Specifically, we investigate the idea that extreme values of a response variable can be explained by nonlinear functions derived from linear projections of an input random vector. In this context, the estimation of projection directions is examined, as approached by the extreme partial least squares (EPLS) method—an adaptation of the original partial least squares (PLS) method tailored to the extreme-value framework. Further, a novel interpretation of EPLS directions as maximum likelihood estimators is introduced, utilizing the von Mises–Fisher distribution applied to hyperballs. The dimension reduction process is enhanced through the Bayesian paradigm, enabling the incorporation of prior information into the projection direction estimation. The maximum a posteriori estimator is derived in two specific cases, elucidating it as a regularization or shrinkage of the EPLS estimator. We also establish its asymptotic behavior as the sample size approaches infinity. A simulation data study is conducted in order to assess the practical utility of our proposed method. This clearly demonstrates its effectiveness even in moderate data problems within high-dimensional settings. Furthermore, we provide an illustrative example of the method’s applicability using French farm income data, highlighting its efficacy in real-world scenarios. [ABSTRACT FROM AUTHOR]

Primary vaccination with mRNA-1273 (100-µg) was safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the previously reported, blinded Part A of the phase 3 Coronavirus Efficacy (COVE; NCT04470427) trial in adults (≥18 years) across 99 U.S. sites. The open-label (Parts B and C) primary objectives were evaluation of long-term safety and effectiveness of primary vaccination plus a 50-µg booster dose; immunogenicity was a secondary objective. Of 29,035 open-label participants, 19,609 received boosters (mRNA-1273 [n = 9647]; placebo-mRNA-1273 [n = 9952]; placebo [n = 10] groups). Booster safety was consistent with that reported for primary vaccination. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with a significant, 47.0% (95% CI : 39.0-53.9%) reduction of Omicron BA.1 incidence (24.6 [23.4 − 25.8] vs 46.4 [40.6 − 52.7]/1000 person-months). In an exploratory Cox regression model adjusted for time-varying covariates, a longer median interval between primary vaccination and boosting (mRNA-1273 [13 months] vs placebo-mRNA-1273 [8 months]) was associated with significantly lower, COVID-19 risk (24.0% [16.0% − 32.0%]) during Omicron BA.1 predominance. Boosting elicited greater immune responses against SARS-CoV-2 than primary vaccination, irrespective of prior SARS-CoV-2 infection. Primary vaccination and boosting with mRNA-1273 demonstrated acceptable safety, effectiveness and immunogenicity against COVID-19, including emergent variants. Building on evidence from the phase 3 COVE trial, the authors report the long-term safety and effectiveness of primary vaccination and boosting with mRNA-1273 against COVID-19, including during emergent variant waves. [ABSTRACT FROM AUTHOR]

Background: Practice guidelines recommend nonpharmacologic and nonopioid therapies as first-line pain treatment for acute pain. However, little is known about their utilization generally and among individuals with opioid use disorder (OUD) for whom opioid and other pharmacologic therapies carry greater risk of harm. Objective: To determine the association between a pre-existing OUD diagnosis and treatment of acute low back pain (aLBP). Design: Retrospective cohort study using 2016–2019 Medicare data. Participants: Fee-for-service Medicare beneficiaries with a new episode of aLBP. Main Measures: The main independent variable was OUD diagnosis measured prior to the first LBP claim (i.e., index date). Using multivariable logistic regressions, we assessed the following outcomes measured within 30 days of the index date: (1) nonpharmacologic therapies (physical therapy and/or chiropractic care), and (2) prescription opioids. Among opioid recipients, we further assessed opioid dose and co-prescription of gabapentin. Analyses were conducted overall and stratified by receipt of physical therapy, chiropractic care, opioid fills, or gabapentin fills during the 6 months before the index date. Key Results: We identified 1,263,188 beneficiaries with aLBP, of whom 3.0% had OUD. Two-thirds (65.8%) did not receive pain treatments of interest at baseline. Overall, nonpharmacologic therapy receipt was less prevalent and opioid and nonopioid pharmacologic therapies were more common among beneficiaries with OUD than those without OUD. Beneficiaries with OUD had lower odds of receiving nonpharmacologic therapies (aOR = 0.62, 99%CI = 0.58–0.65) and higher odds of prescription opioid receipt (aOR = 2.24, 99%CI = 2.17–2.32). OUD also was significantly associated with increased odds of opioid doses ≥ 90 morphine milligram equivalents/day (aOR = 2.43, 99%CI = 2.30–2.56) and co-prescription of gabapentin (aOR = 1.15, 99%CI = 1.09–1.22). Similar associations were observed in stratified groups though magnitudes differed. Conclusions: Medicare beneficiaries with aLBP and OUD underutilized nonpharmacologic pain therapies and commonly received opioids at high doses and with gabapentin. Complementing the promulgation of practice guidelines with implementation science could improve the uptake of evidence-based nonpharmacologic therapies for aLBP. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context. We used the mouse line carrying OPA1delTTAG mutation to investigate its impact on corneal biology. To our surprise, neither the tear film composition nor the corneal epithelial transcriptomic signature were altered upon OPA1 mutation. However, when analyzing the corneal innervation, we discovered an undersensitivity of the cornea upon the mutation, but an increased innervation volume at 3 months. Furthermore, the fibre identity changed with a decrease of the SP + axons. Finally, we demonstrated that the innervation regeneration was less efficient and less functional in OPA1+/- corneas. Altogether, our study describes the resilience of the corneal epithelial biology, reflecting the mitohormesis induced by the OPA1 mutation, and the adaptation of the corneal innervation to maintain its functionality despite its morphogenesis defects. These findings will participate to a better understanding of the mitochondrial dysfunction on peripheral innervation. [ABSTRACT FROM AUTHOR]

Background: Autologous fat grafting is a widely adopted approach to optimize outcomes in breast reconstruction and augmentation. Although fat necrosis is a well-known consequence of autologous fat grafting, it remains inconsistently defined in the literature. In late 2014, the Food and Drug Administration released a draft guidance to restrict future autologous fat grafting—a statement that was permissively modified in late 2017. In the context of evolving guidelines and autologous fat grafting outcome data, the language and descriptions of fat necrosis are inconsistent in the literature. Methods: Five databases were queried for studies reporting fat necrosis following autologous fat grafting for breast reconstruction or augmentation from inception to August 11, 2022. Studies were temporally stratified according to released FDA guidelines: pre-2015, 2015–2017, and 2018–2022. Results: Sixty-one articles met inclusion criteria. Prior to 2015, 6 of 21 studies (28.6%) offered clear definitions of fat necrosis. In contrast, the 2015–2017 period demonstrated an absence of clear fat necrosis definitions (0/13 studies, p = 0.03). Though the 2018–2022 period exhibited a rise in annual publications compared with the pre-2015 period (5.4 vs. 1.9, respectively, p = 0.04), this was not matched by a rise in clear fat necrosis reporting (14.8% studies, p = 0.45). Across all periods, only 16.4% of articles offered clear definitions, which exhibited wide heterogeneity. Conclusion: Despite the increasing popularity of autologous fat grafting, fat necrosis remains inconsistently defined and described, especially in the context of changing FDA guidelines. This limits the reliable interpretation and application of the current literature reporting fat necrosis outcomes. Level of Evidence IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Understanding the factors influencing mosquitoes' fecundity and longevity is important for designing better and more sustainable vector control strategies, as these parameters can impact their vectorial capacity. Here, we address how mating affects midgut growth in Aedes aegypti, what role Juvenile Hormone (JH) plays in this process, and how it impacts the mosquito's immune response and microbiota. Our findings reveal that mating and JH induce midgut growth. Additionally, the establishment of a native bacterial population in the midgut due to JH-dependent suppression of the immune response has important reproductive outcomes. Specific downregulation of AMPs with an increase in bacteria abundance in the gut results in increased egg counts and longer lifespans. Overall, these findings provide evidence of a cross-talk between JH response, gut epithelial tissue, cell cycle regulation, and the mechanisms governing the trade-offs between nutrition, immunity, and reproduction at the cellular level in the mosquito gut. In A. aegypti, the female mosquito midgut responds to mating and to juvenile hormone. Immune suppression in the midgut results in an increased bacteria load in mated animals. The midgut response to mating positively affects the reproductive outcome. [ABSTRACT FROM AUTHOR]

The link between childhood mental health difficulties such as conduct problems and adult political abstention has been overlooked despite early mental health difficulties potentially resulting in political self-marginalisation. Using the1970s British Cohort Study, we estimate developmental trajectories of conduct problems (i.e., from 5 to 16 years). Logistic regression, linear probability models, and propensity score matching were then conducted to test the association between trajectory group membership and voter turnout at 30, 42, and 46 years of age. Three distinct trajectories of conduct problems were identified: a normative (n = 11,871; reference group), moderate-chronic (n = 3433), and elevated-chronic (n = 250) group. Results revealed an association between conduct problems and decreased turnout. In particular the elevated-chronic group had a decreased odds of voting of 52.2%, 52.0%, and 45.7%, as compared to the normative group at 30, 42, and 46 years respectively. The moderate-chronic group had a decreased odds of voting of 24.7% as compared to the normative group at age 30 only. Matched results and linear probability models substantiated findings, suggesting (1) the importance of considering childhood factors when examining antecedents of lifelong voting behaviour, and (2) the political self-marginalisation of people with chronic childhood conduct problems more than 3 decades later. [ABSTRACT FROM AUTHOR]

Purpose: There is a growing interest in assessing the benefits of exposure to urban greenspace on mental health due to the increased urbanization of youth and concerns for their mental health. We investigated the prospective associations of residential greenspace in childhood and mental health in adolescence. Use of a well-characterized birth cohort permitted adjustment for a range of potential confounding factors including family and neighborhood characteristics in addition to prior mental health problems, and exploration of moderation effects by sex and family socioeconomic status. Methods: We analyzed longitudinal data collected from 742 urban-dwelling participants of the Quebec Longitudinal Study of Children Development. The Normalized Difference Vegetation Index (NDVI) within 250, 500, and 1000 m buffer zones surrounding the home residence was used to indicate childhood exposure to greenspace. Six self-reported mental health problems at 15/17 years were examined using the Mental Health and Social Inadaptation questionnaire: inattention, hyperactivity/impulsivity, conduct, depression, anxiety, and suicidal ideation. Results: Childhood urban greenspace was associated with lower inattention problems in both females and males. We observed a 0.14 reduced standard deviation (SD) (β = − 0.14, SE = 0.05, p < 0.01) in relation to an interquartile range (IQR) increase of NDVI (0.15) at the 250 m buffer zone, and similar results were found in 500 m and 1000 m buffer zones. These associations only slightly attenuated after adjustment for individual (sex, childhood mental health), family (family SES, maternal age at birth, parental mental health, family composition), and neighborhood (material and social deprivation) characteristics (β = − 0.13, SE = 0.06, p = 0.03). No association was found for other mental health problems, and no moderation associations of sex or family socioeconomic status were observed. Conclusion: These findings suggest that increasing residential greenspace in cities may be associated with modest benefits in attentional capacities in youth, necessitating further research to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Upadacitinib (UPA), a selective, reversible, oral Janus kinase (JAK)-1 inhibitor, was approved in 2019 in Canada for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). This phase 4 prospective study aimed to characterise the effectiveness of UPA in the real-world population of patients with RA. Methods: Adults with RA who initiated treatment with once daily UPA (15 mg) and enrolled in the Canadian Real-Life post-marketing Observational Study assessing the Effectiveness of UPadacitinib for treating rheumatoid arthritis (CLOSE-UP) and who completed a 6-month assessment as of 28 February 2023 were included. The primary endpoint of the CLOSE-UP study is the proportion of patients achieving a Disease Activity Score-28 Joint Count C-reactive protein (DAS28-CRP) < 2.6 at 6 months. Data was collected at routine visits. Data analysed and summarised descriptively for the overall interim population and for subgroups based on prior therapy included remission or low disease activity, patient-reported outcomes (PROs), and adverse events. Results: A total of 392 patients were included in the interim analysis. Overall, 63.5% (191/301) of patients achieved a DAS28-CRP score < 2.6 at month 6, with similar rates observed for all subgroups analysed according to prior therapy including those with prior JAK inhibitor exposure (range 57.4–71.0%), and in patients who received UPA monotherapy (71.6% [48/67]). Early (month 3) and sustained improvements up to 6 months were observed for all PROs. The safety profile was consistent with previous reports. Conclusion: Real-world improvements in disease activity and PROs in response to UPA treatment were consistent with clinical trial data across a range of Canadian patients with prior therapy exposure and with UPA monotherapy, with an overall favourable benefit–risk profile. Trial Registration: NCT04574492. [ABSTRACT FROM AUTHOR]

Hutchemys rememdium is a poorly understood softshell turtle (Trionychidae) from the mid Paleocene of the Williston Basin of North America previously known only from postcranial remains. A particularly rich collection of previously undescribed material from the Tiffanian 4 North American Land Mammal Age (NALMA) of North Dakota is here presented consisting of numerous shells that document new variation, some non-shell postcrania, and cranial remains, which are described based on 3D models extracted from micro-CT data. Although the observed shell variation weakens previously noted differences with the younger species Hutchemys arctochelys from the Clarkforkian NALMA, the two taxa are still recognized as distinct. Parsimony and Bayesian phylogenetic analyses reaffirm the previously challenged placement of Hutchemys rememdium within the clade Plastomenidae, mostly based on novel observations of cranial characters made possible by the new material and the micro-CT data. The new topology supports the notion that the well-ossified plastron of plastomenids originated twice in parallel near the Cretaceous/Paleogene boundary, once in the Hutchemys lineage and once in the Gilmoremys/Plastomenus lineage. Hutchemys rememdium is notable for being the only documented species of trionychid in the mid Paleocene of the Williston Basin. The presence of multiple individuals in a carbonaceous claystone indicates this taxon lived in swamps and lakes and its expanded triturating surface suggests it had a durophagous diet. [ABSTRACT FROM AUTHOR]

Hurricane Laura made landfall in southwestern Louisiana in August 2020 while the world was several months into the COVID-19 pandemic. In the present research, we examined pandemic precautionary behaviors in a sample of adults who varied in exposure and damage due to Hurricane Laura, a destructive Category 4 hurricane. A total of 127 participants responded to an online survey that assessed pandemic worry and precautionary behaviors, hurricane exposure and damage, and health-related quality of life. We found that Hurricane Laura victims neglected pandemic precautionary behaviors at significantly higher levels in the weeks immediately following Hurricane Laura than did indirectly impacted control participants, although the two comparison groups did not differ in COVID-19 worry or adherence to precautionary pandemic behavior 14–22 months after Hurricane Laura made landfall. Older age was negatively correlated with COVID-19 worry prior to Hurricane Laura, which was unexpected given that older people in general were more vulnerable to COVID-19 by their membership in a high-risk group. Future directions for research on post-disaster vulnerabilities during a global pandemic are discussed. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness. Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives. Results: Among 991 participants with a median age (interquartile range, IQR) of 62 [53–72] years and enrollment SOFA of 9 [7–11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4–2.3]), IL-8 (1.3 [1.1–1.5]), IL-10 (1.5 [1.2–1.8]), TNF-α (1.2 [1.0–1.4]), and TNFR1 (1.3 [1.1–1.6]) and lower concentrations of protein C (0.7 [0.6–0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1–1.7]), IFN-γ (1.3 [1.1–1.5]), IL-6 (2.3 [1.8–3.0]), IL-8 (1.8 [1.4–2.3]), and IL-10 (1.5 [1.2–2.0]) and lower concentrations of protein C (0.6 [0.5–0.8]) were associated with coma the following day. IL-1β, IL-12, and MMP-9 were not associated with mental status. Conclusion: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness. [ABSTRACT FROM AUTHOR]

Introduction: The MonarchE trial explored the use of abemaciclib, a CDK4/6 inhibitor, as an adjuvant treatment in high-risk early-stage luminal-like breast cancer. The study's inclusion criteria, especially the N2 status, may require revisiting surgical interventions, including invasive axillary lymph node dissection (ALND)—a procedure that current guidelines generally do not recommend. Methods: We conducted a single-centre, retrospective, observational cohort study on non-metastatic breast cancer patients managed from 2002 to 2011, at the Institut Curie. Data collection involved clinical and histological characteristics plus treatment follow-up. Results: Out of 8715 treated patients, 721 met the inclusion criteria. Overall, 12% (87) were classified as N2 (≥ 4 positive lymph nodes), thus eligible for abemaciclib per "node criterion." Tumour size, positive sentinel lymph nodes, and lobular histology showed a significant correlation with N2 status. Approximately 1000 ALNDs would be required to identify 120 N2 cases and prevent four recurrences. Conclusion: The MonarchE trial may significantly affect surgical practices due to the need for invasive procedures to identify high-risk patients for adjuvant abemaciclib treatment. The prospect of unnecessary morbidity demands less invasive N2 status determination methods. Surgical decisions must consider patient health and potential treatment benefits. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to assess whether a strategy combining spontaneous breathing trial (SBT) with both pressure support (PS) and positive end-expiratory pressure (PEEP) and extended use of post-extubation non-invasive ventilation (NIV) (extensively-assisted weaning) would shorten the time until successful extubation as compared with SBT with T-piece (TP) and post-extubation NIV performed in selected patients as advocated by guidelines (standard weaning), in difficult-to-wean patients from mechanical ventilation. Methods: The study is a single-center prospective open label, randomized controlled superiority trial with two parallel groups and balanced randomization with a 1:1 ratio. Eligible patients were intubated patients mechanically ventilated for more than 24 h who failed their first SBT using TP. In the extensively-assisted weaning group, SBT was performed with PS (7 cmH2O) and PEEP (5 cmH2O). In case of SBT success, an additional SBT with TP was performed. Failure of this SBT-TP was an additional criterion for post-extubation NIV in this group in addition to other recommended criteria. In the standard weaning group, SBT was performed with TP, and NIV was performed according to international guidelines. The primary outcome criterion was the time between inclusion and successful extubation evaluated with a Cox model with adjustment on randomization strata. Results: From May 2019 to March 2023, 98 patients were included and randomized in the study (49 in each group). Four patients were excluded from the intention-to-treat population (2 in both groups); therefore, 47 patients were analyzed in each group. The extensively-assisted weaning group had a higher median age (68 [58–73] vs. 62 [55–71] yrs.) and similar sex ratio (62% male vs. 57%). Time until successful extubation was not significantly different between extensively-assisted and standard weaning groups (median, 172 [50–436] vs. 95 [47–232] hours, Cox hazard ratio for successful extubation, 0.88 [95% confidence interval: 0.55–1.42] using the standard weaning group as a reference; p = 0.60). All secondary outcomes were not significantly different between groups. Conclusion: An extensively-assisted weaning strategy did not lead to a shorter time to successful extubation than a standard weaning strategy. Trial registration The trial was registered on ClinicalTrials.gov (NCT03861117), on March 1, 2019, before the inclusion of the first patient. https://clinicaltrials.gov/study/NCT03861117. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) antagonists are highly effective in controlling autoimmune diseases. This has led to speculation that they might also be useful in treating inflammatory placental conditions, such as chronic villitis of unknown etiology (VUE). VUE affects 10–15% of term placentas and is associated with recurrent fetal growth restriction (FGR) and pregnancy loss. We aimed to evaluate outcomes in patients with autoimmune diseases with and without anti-TNF-α biologic exposure during gestation. This retrospective cohort study compared pregnant women with autoimmune disease taking anti-TNF-α biologics (n = 89) to pregnant women with autoimmune disease but not taking a biologic (n = 53). We extracted data on all patients meeting our inclusion criteria over a 20-year period. Our primary outcome was the diagnosis of VUE by histology. Our secondary outcomes were maternal and neonatal complications such as preeclampsia, FGR, and neonatal intensive care admission. Kruskal–Wallis and chi-squared tests were performed as appropriate for statistical analysis. Maternal characteristics were comparable between groups, and there was no increase in adverse pregnancy outcomes based on anti-TNF-α treatment. Exposure to anti-TNF-α therapy had no significant effect on the incidence of VUE or other obstetric complications. Within the cohort exposed to anti-TNF-α biologics during pregnancy, the rate of VUE was 9.3%, which is comparable to the reported general population risk. Our data support the safety profile of biologic use in pregnancy. [ABSTRACT FROM AUTHOR]

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4 ± 12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6 ± 9.8 vs. 25.6 ± 8.1 mL/m2; median LAVIminimum 18.5 [13.9–24.8] vs. 14.1 [10.9–19.2] mL/m2); left atrioventricular coupling index was reduced (28.2 ± 11.5 vs. 22.7 ± 9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7–60.3] vs. 55.9 [50.3–61.1] %; active LAEF 40.2 ± 8.6 vs. 43.1 ± 7.8%). LA global longitudinal strain in the active phase was increased (16.3 ± 4.1 vs. 17.8 ± 4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling. [ABSTRACT FROM AUTHOR]

This study aims to examine the moderating role of individual (sex, symptom severity, and comorbid disorders) and familial (parental stress and parental depressive symptoms) factors on the improvement of organization, time management, and planning (OTMP) skills of youths with attention-deficit hyperactivity disorder (ADHD) following participation of families in a multimodal intervention targeting academic organizational skills. ADHD youths (M = 12.04 years, SD = 0.44; first language: 85.7% French, 11.4% English) under optimized psychostimulant treatment and their parents were randomly assigned to either an intervention group (n = 32; 21 boys and 11 girls) or a control group (n = 38; 28 boys and 10 girls). A two-dimensional questionnaire was used to measure improvement of OTMP skills: Time Management and Planning and Memorization and Material Management (MMM). Severity of inattention symptoms (p <.01) moderates MMM skills' improvement. The intervention was more efficacious in improving MMM skills of youths with more severe inattention symptoms under optimized psychostimulant treatment. No other moderating factors were observed. The intervention was effective in supporting ADHD youths improve their OTMP skills. The intervention appears to buffer the negative impact of inattention symptoms severity on MMM skills improvement. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has overturned daily routines across the entire planet. And newly arrived college students in the fall of 2019 were no exception. In addition to adjusting to the college transition, they had to cope with the multiple consequences of the pandemic's first wave (e.g., confinement, quarantine, physical distancing, remote learning, job loss). To date, it is unknown how this experience has affected students, and particularly the most vulnerable. The main objective of this study was to examine, from a stress and coping perspective, how college students with and without disability experienced the first COVID-19 wave. A longitudinal study using online surveys was conducted in a sample of 1,465 students (mean age = 18.2) attending college in the province of Québec (Canada), of whom 42% disclosed a disability (i.e., ADHD, mental health disorder, or learning problem) at college entry. Exposure to COVID-19 varied according to disability type, study region, and study program. After controlling for exposure, students' initial adjustment to college, and high school GPA, students with a disability, and particularly those presenting a mental health disorder, experienced greater stress and had greater difficulty coping with the situation compared to students without a disability. Generally, girls and students attending a college in an urban area were more affected by the pandemic. Results are discussed with a view to designing preventive measures for at-risk students who enter college during a pandemic. [ABSTRACT FROM AUTHOR]

Phase change materials (PCMs) designate materials able to store latent heat. PCMs change state from solid to liquid over a defined temperature range. This process is reversible and can be used for thermo-technical purposes. The present paper aims to study the thermal performance of an inorganic eutectic PCM integrated into the rooftop slab of a test room and analyze its potential for building thermal management. The experiment is conducted in two test rooms in Antofagasta (Chile) during summer, fall, and winter. The PCM is integrated into the rooftop of the first test room, while the roof panel of the second room is a sealed air cavity. The work introduces a numerical model, which is built using the finite difference method and used to simulate the rooms' thermal behavior. Several thermal simulations of the PCM room are performed for other Chilean locations to evaluate and compare the capability of the PCM panel to store latent heat thermal energy in different climates. Results show that the indoor temperature of the PCM room in Antofagasta varies only 21.1°C±10.6°C, while the one of the air-panel room varies 28.3°C±18.5°C. Under the experiment's conditions, the PCM room's indoor temperature observes smoother diurnal fluctuations, with lower maximum and higher minimum indoor temperatures than that of the air-panel room. Thermal simulations in other cities show that the PCM panel has a better thermal performance during winter, as it helps to maintain or increase the room temperature by some degrees to reach comfort temperatures. This demonstrates that the implementation of such PCM in the building envelope can effectively reduce space heating and cooling needs, and improve indoor thermal comfort in different climates of Chile. [ABSTRACT FROM AUTHOR]

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Arcagen (NCT02834884) is a European prospective study aiming at defining the molecular landscape of rare cancers for treatment guidance. We present data from the cohort of rare thoracic tumors. Patients with advanced pleural mesothelioma (PM) or thymic epithelial tumors (TET) underwent genomic profiling with large targeted assay [>300 genes, tumor mutational burden (TMB), microsatellite instability (MSI) status] on formalin-fixed paraffin-embedded (FFPE) or plasma samples. EORTC molecular tumor board (MTB) advised for biomarker-guided treatments. 102 patients recruited from 8 countries between July 2019 and May 2022 were evaluable: 56 with PM, 46 with TET (23 thymomas, 23 thymic carcinomas). Molecular profiling was performed on 70 FFPE samples (42 PM, 28 TET), and 32 cases on ctDNA (14 PM, 18 TET), within a median turnaround time of 8 days from sample reception. We detected relevant molecular alterations in 66 out of 102 patients (65%; 79% PM, 48% TET), 51 of 70 FFPE samples (73%; 90% PM, 46% TET), and 15 of 32 plasma samples (47%; 43% PM, 50% TET). The most frequently altered genes were CDKN2A/B, BAP1, MTAP in PM and TP53, CDKN2A/B, SETD2 in TET. The TMB was low (mean 3.2 Muts/MB), 2 PM had MSI-high status. MTB advised molecular-guided treatment options in 32 situations, for 17 PM and 15 TET patients (75% clinical trial option, 22% off-label drug or compassionate use, 3% early access program). Molecular testing and MTB discussion were feasible for patients with rare thoracic cancers and allowed the broadening of treatment options for 30% of the cases. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) organs of the human body are responsible for transporting and extracting nutrients from food and drink, as well as excreting solid waste. Biomechanical experimentation of the GI organs provides insight into the mechanisms involved in their normal physiological functions, as well as understanding of how diseases can cause disruption to these. Additionally, experimental findings form the basis of all finite element (FE) modelling of these organs, which have a wide array of applications within medicine and engineering. This systematic review summarises the experimental studies that are currently in the literature (n = 247) and outlines the areas in which experimentation is lacking, highlighting what is still required in order to more fully understand the mechanical behaviour of the GI organs. These include (i) more human data, allowing for more accurate modelling for applications within medicine, (ii) an increase in time-dependent studies, and (iii) more sophisticated in vivo testing methods which allow for both the layer- and direction-dependent characterisation of the GI organs. The findings of this review can also be used to identify experimental data for the readers' own constitutive or FE modelling as the experimental studies have been grouped in terms of organ (oesophagus, stomach, small intestine, large intestine or rectum), test condition (ex vivo or in vivo), number of directions studied (isotropic or anisotropic), species family (human, porcine, feline etc.), tissue condition (intact wall or layer-dependent) and the type of test performed (biaxial tension, inflation–extension, distension (pressure-diameter), etc.). Furthermore, the studies that investigated the time-dependent (viscoelastic) behaviour of the tissues have been presented. [ABSTRACT FROM AUTHOR]

We propose new parametrizations for neural networks in order to estimate extreme quantiles in both non-conditional and conditional heavy-tailed settings. All proposed neural network estimators feature a bias correction based on an extension of the usual second-order condition to an arbitrary order. The convergence rate of the uniform error between extreme log-quantiles and their neural network approximation is established. The finite sample performances of the non-conditional neural network estimator are compared to other bias-reduced extreme-value competitors on simulated data. It is shown that our method outperforms them in difficult heavy-tailed situations where other estimators almost all fail. Finally, the conditional neural network estimators are implemented to investigate the behavior of extreme rainfalls as functions of their geographical location in the southern part of France. The source code is available at . [ABSTRACT FROM AUTHOR]

The current study examined multi-trajectories of aggression, hyperactivity/inattention and anxious/depressed problems, along with associated risk factors for trajectory group membership, using a person-centred approach. The sample included 2,857 children (50.1% males) enrolled in the Chilean Encuesta Longitudinal de la Primera Infancia cohort. Maternal reports using the Child Behaviour Checklist (CBCL) were completed when children were three, five and eleven years old. Information on risk/protective factors was collected using maternal reports and standardised assessments when children were aged three. Group-based multi-trajectory analysis was implemented. Results indicated that a five-group model best fit the data, with co-occurring symptoms across domains for all groups. Risk factors for membership of groups with the most elevated risk profiles included child sex, maternal age, single parent status, and maternal education, whilst children's receptive language, maternal vocabulary skills, and not having early attendance in the educational system emerged as protective factors. These identified risk factors may be important targets for future intervention programmes in the Chilean context. [ABSTRACT FROM AUTHOR]

Purpose: We investigated whether caffeine consumption can enhance peak oxygen uptake ( V ˙ O 2peak ) by increasing peak ventilation during an incremental cycling test, and subsequently enhance time to exhaustion (TTE) during high-intensity cycling exercise in moderate normobaric hypoxia. Methods: We conducted a double-blind, placebo cross-over design study. Sixteen recreational male endurance athletes (age: 20 ± 2 years, V ˙ O 2peak : 55.6 ± 3.6 ml/kg/min, peak power output: 318 ± 40 W) underwent an incremental cycling test and a TTE test at 80% V ˙ O 2peak (derived from the placebo trial) in moderate normobaric hypoxia (fraction of inspired O2: 15.3 ± 0.2% corresponding to a simulated altitude of ~ 2500 m) after consuming either a moderate dose of caffeine (6 mg/kg) or a placebo. Results: Caffeine consumption resulted in a higher peak ventilation [159 ± 21 vs. 150 ± 26 L/min; P < 0.05; effect size (ES) = 0.31]. V ˙ O 2peak (3.58 ± 0.44 vs. 3.47 ± 0.47 L/min; P < 0.01; ES = 0.44) and peak power output (308 ± 44 vs. 302 ± 44 W; P = 0.02, ES = 0.14) were higher following caffeine consumption than during the placebo trial. During the TTE test, caffeine consumption enhanced minute ventilation (P = 0.02; ES = 0.28) and extended the TTE (426 ± 74 vs. 358 ± 75 s; P < 0.01, ES = 0.91) compared to the placebo trial. There was a positive correlation between the percent increase of V ˙ O 2peak following caffeine consumption and the percent increase in TTE (r = 0.49, P < 0.05). Conclusion: Moderate caffeine consumption stimulates breathing and aerobic metabolism, resulting in improved performance during incremental and high-intensity endurance exercises in moderate normobaric hypoxia. [ABSTRACT FROM AUTHOR]

In this article, we obtain explicit bounds on the uniform distance between the cumulative distribution function of a standardized sum S n of n independent centered random variables with moments of order four and its first-order Edgeworth expansion. Those bounds are valid for any sample size with n - 1 / 2 rate under moment conditions only and n - 1 rate under additional regularity constraints on the tail behavior of the characteristic function of S n . In both cases, the bounds are further sharpened if the variables involved in S n are unskewed. We also derive new Berry-Esseen-type bounds from our results and discuss their links with existing ones. Following these theoretical results, we discuss the practical use of our bounds, which depend on possibly unknown moments of the distribution of S n . Finally, we apply our bounds to investigate several aspects of the non-asymptotic behavior of one-sided tests: informativeness, sufficient sample size in experimental design, distortions in terms of levels and p-values. [ABSTRACT FROM AUTHOR]

Patients with drug-resistant essential tremor (ET) may undergo Gamma Knife stereotactic radiosurgical thalamotomy (SRS-T), where the ventro-intermediate nucleus of the thalamus (Vim) is lesioned by focused beams of gamma radiations to induce clinical improvement. Here, we studied SRS-T impacts on left Vim dynamic functional connectivity (dFC, n = 23 ET patients scanned before and 1 year after intervention), and on surface-based morphometric brain features (n = 34 patients, including those from dFC analysis). In matched healthy controls (HCs), three dFC states were extracted from resting-state functional MRI data. In ET patients, state 1 spatial stability increased upon SRS-T (F1,22 = 19.13, p = 0.004). More frequent expression of state 3 over state 1 before SRS-T correlated with greater clinical recovery in a way that depended on the MR signature volume (t6 = 4.6, p = 0.004). Lower pre-intervention spatial variability in state 3 expression also did (t6 = − 4.24, p = 0.005) and interacted with the presence of familial ET so that these patients improved less (t6 = 4.14, p = 0.006). ET morphometric profiles showed significantly lower similarity to HCs in 13 regions upon SRS-T (z ≤ − 3.66, p ≤ 0.022), and a joint analysis revealed that before thalamotomy, morphometric similarity and states 2/3 mean spatial similarity to HCs were anticorrelated, a relationship that disappeared upon SRS-T (z ≥ 4.39, p < 0.001). Our results show that left Vim functional dynamics directly relates to upper limb tremor lowering upon intervention, while morphometry instead has a supporting role in reshaping such dynamics. [ABSTRACT FROM AUTHOR]

Villitis of unknown etiology (VUE) is a prevalent inflammatory pathology of the placenta characterized by infiltration of maternal T cells and accumulation of fetal macrophages into chorionic villi. VUE is associated with a variety of adverse clinical outcomes, including fetal growth restriction and fetal demise. Evaluation of the phenotypic and functional differences between two immune cell types associated with this pathology, namely T cells and macrophages, was completed to gain a deeper understanding of the immuno-pathogenesis of VUE. GeoMx Digital Spatial Profiling was performed on placental tissue from 4 high grade VUE cases and 4 controls with no underlying pathology. Placental tissues were fluorescently labeled with CD3 and CD68 antibodies and oligo-conjugated antibodies against 48 protein targets. Overall, T cells in VUE exhibited upregulated markers of activation, memory, and antigen experience compared to controls and were altered based on placental location (villi vs. decidua). Additionally, villous macrophages in VUE upregulated costimulatory and major histocompatibility complex class I and II molecules compared to controls and macrophage subtypes in the decidua. Data herein provides new mechanistic insights into T cell and macrophage biology in VUE which contribute to this abnormal immune response to pregnancy. [ABSTRACT FROM AUTHOR]

Purpose: The Latarjet procedure is traditionally used to treat chronic anterior shoulder instability associated with glenoid bone loss. However, few series have analyzed outcomes in a female-only population. The objective of this study was to evaluate the clinical and radiological outcomes of a Latarjet bone block in this specific population. Methods: This single-center retrospective study included 15 women (mean age 35 ± 11.3; 19–60) reviewed with a minimum follow-up of 2 years. The procedure was performed using the open bone block screw technique (n = 7) or by arthroscopy with cortical button (n = 8). Clinical evaluation was based on active range of motion measurements, Rowe and Walch–Duplay scores, and subjective shoulder value (SSV). Radiographic analysis explored bone block healing at the last follow-up. Results: At a mean follow-up of 48 months (32–86), no recurrence was reported. The mean Rowe score was 91 points (70–100), Walch–Duplay 90 points (60–100), and SSV 87% (70–100). The active mobilities reached 169° (± 9°) in elevation, 57° (± 15°) in external rotation at side, and 89° (± 6°) in abduction. The return-to-sport rate was 91%. Five patients experienced persistent anterior pain, with screws requiring hardware removal in 2 (p = 0.02). Radiological assessment detected one case of nonunion (7%). Conclusion: Women treated with the Latarjet procedure experienced satisfactory midterm clinical outcomes. The arthroscopic technique using cortical button fixation seems to avoid residual anterior pain requiring hardware removal. [ABSTRACT FROM AUTHOR]

Purpose: Fracture blisters, a common soft-tissue complication of pilon fractures, are associated with post-operative wound infections, delays in definitive fixation, and alterations in surgical plan. The purpose of this study was to (1) identify the delay in surgery attributable to the presence fracture blisters and (2) investigate the relationship of fracture blisters to comorbidities and fracture severity. Methods: Patients with pilon fractures at an urban level 1 Trauma center from 2010 to 2021 were identified. The presence or absence of fracture blisters was noted, along with location. Demographic information, time from injury to external fixator placement, and time to definitive open reduction internal fixation (ORIF) were collected. Pilon fractures were classified according to AO/OTA guidelines using CT imaging and plain radiographs. Results: 314 patients with pilon fractures were available for analysis, eighty (25%) of whom were found to have fracture blisters. Patients with fracture blisters had longer time to surgery compared to those without fracture blisters (14.2 days vs 7.9 days, p < 0.001). A greater proportion of patients with fracture blisters had AO/OTA 43C fracture patterns, compared with those without fracture blisters (71.3% vs 53.8%, p = 0.03). Fractures blisters were less likely to be localized over the posterior ankle (12%, p = 0.007). Conclusion: The presence of fracture blisters in pilon fractures are associated with significant delays in time to definitive fixation and higher energy fracture patterns. Fracture blisters are less commonly located over the posterior ankle which may support the implementation of a staged posterolateral approach when managing these injures. [ABSTRACT FROM AUTHOR]

Purpose: Chimeric antigen receptor (CAR) T cells have established themselves as an effective treatment for refractory or relapsed large B cell lymphoma (LBCL). Recently, the sDmax, which corresponds to the distance separating the two farthest lesions standardized by the patient's body surface area, has appeared as a prognostic factor in LBCL. This study aimed to identify [18F]FDG-PET biomarkers associated with prognosis and predictive of adverse events in patients treated with CAR T cells. Methods: Patients were retrospectively included from two different university hospitals. They were being treated with CAR T cells for LBCL and underwent [18F]FDG-PET just before CAR T cell infusion. Lesions were segmented semi-automatically with a threshold of 41% of the maximal uptake. In addition to clinico-biological features, sDmax, total metabolic tumor volume (TMTV), SUVmax, and uptake intensity of healthy lymphoid organs and liver were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The occurrence of adverse events, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), was reported. Results: Fifty-six patients were included. The median follow-up was 9.7 months. Multivariate analysis showed that TMTV (cut-off of 36 mL) was an independent prognostic factor for PFS (p < 0.001) and that sDmax (cut-off of 0.15 m−1) was an independent prognostic factor for OS (p = 0.008). Concerning the occurrence of adverse events, a C-reactive protein level > 35 mg/L (p = 0.006) and a liver SUVmean > 2.5 (p = 0.027) before CAR T cells were associated with grade 2 to 4 CRS and a spleen SUVmean > 1.9 with grade 2 to 4 ICANS. Conclusion: TMTV and sDmax had independent prognostic values, respectively, on PFS and OS. Regarding adverse events, the mean liver and spleen uptakes were associated with the occurrence of grade 2 to 4 CRS and ICANS, respectively. Integrating these biomarkers into the clinical workflow could be useful for early adaptation of patients management. [ABSTRACT FROM AUTHOR]

The chapter deals with the design of event-triggering mechanisms (ETM) for discrete-time linear systems stabilized by neural network controllers. The proposed event-triggering mechanism is based on the use of local sector conditions related to the activation functions, to reduce the computational cost associated with the neural network evaluation. Such a mechanism avoids redundant computations by updating only a portion of the layers instead of evaluating periodically the complete neural network. Sufficient matrix inequality conditions are provided to design the parameters of the event-triggering mechanism and compute an inner-approximation of the region of attraction for the feedback system. The theoretical conditions are obtained by using a quadratic Lyapunov function and an adequate abstraction of the activation functions via generalised sector condition to decide whether the outputs of the layers should be transmitted through the network or not. Convex optimisation procedures can be associated to the theoretical conditions in order to maximise the approximation of the region of attraction or to minimise the number of updates. The advantages and the drawbacks of our approach are illustrated in an example borrowed from the literature, namely the nonlinear inverted pendulum system stabilized by a trained neural network. [ABSTRACT FROM AUTHOR]

In this chapter, we introduce some tools to analyze stability properties of discrete-time switched linear systems driven by switching signals belonging to a given.1-regular language. More precisely, we assume that the switching signals are generated by a deterministic Büchi automaton whose alphabet coincides with the set of modes of the switched system. We present the notion of ω-regular joint spectral radius (ω-RJSR), which intuitively describes the contraction of the state when the run associated with the switching signal visits an accepting state of the automaton. Then, we show how this quantity is related to the stability properties of such systems. Specifically, we show how this notion can characterize a class of stabilizing switching signals for a switched system that is unstable for arbitrary switching. Though the introduced quantity is hard to compute, we present some methods to approximate it using Lyapunov and automata-theoretic techniques. More precisely, we show how upper bounds can be computed by solving a convex optimization problem. To validate the results of our work, we finally show a numerical example related to the synchronization of oscillators over a communication network. [ABSTRACT FROM AUTHOR]

Purpose: Hip arthroplasty with metal-on-metal bearings like hip resurfacing results in the release of metallic ions. In parallel, like every metallic implant, knee arthroplasty implants undergo passive corrosion. We analyzed blood levels of cobalt and chromium ions in patients who have a hip resurfacing arthroplasty and compared them to patients who have undergone knee arthroplasty at a minimum follow-up of one year. The hypothesis was that there is no difference in the ion release between hip resurfacing and knee arthroplasty. Methods: Sixty-three patients who underwent knee arthroplasty were compared to a cohort of 132 patients who underwent hip resurfacing. The blood levels of cobalt and chromium ions were determined preoperatively and at six and 12 months postoperatively and then compared between groups. We analyzed the relationship between ion release and the change in clinical outcome scores (Harris Hip score, Oxford Hip score, Merle D'Aubigné Postel score, Oxford Knee score, International Knee Society score), the BMI, sex, physical activity, implant size and inclination of the acetabular implant (hip resurfacing patients only). Mixed linear models were used to assess the changes in ion blood levels over time. Results: The cobalt blood levels were higher in the first 6 months in the resurfacing group (0.87 ug/L vs 0.67 ug/L; p = 0.011), while it was higher in the knee arthroplasty group at 12 months (1.20 ug/L vs 1.41 ug/L; p = 0.0008). There were no significant differences in chromium levels during the follow-up period. Conclusion: The increase in metal ion release after knee arthroplasty is as high as after hip resurfacing at the one year follow-up. The monitoring of this parameter probably should not be recommended in case of good clinicals outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Our aim was to investigate the efficacy and safety of upadacitinib (UPA) in patients with either oligo- or polyarticular active psoriatic arthritis (PsA) using routine clinical practice data from an observational, prospective, multicentre study. Methods: This interim analysis contains upadacitinib efficacy and safety data from the UPJOINT study, collected from baseline to the week 24 visit with a focus on composite measures, clinical assessments and patient-reported outcomes, amongst others, including minimal disease activity (MDA), very low disease activity (VLDA), Disease Activity Index for Psoriatic Arthritis (DAPSA), Leeds Enthesitis Index (LEI), resolution of dactylitis and nail psoriasis and body surface area affected by skin psoriasis (BSA). Results: A total of 296 patients with baseline data and 192 with completed week 24 visits were included in the analysis. The proportion of patients achieving MDA increased from 2.7% at baseline to 39.1% at week 24 (95% CI 32.1, 46.3). Similarly, the number of patients in DAPSA remission (DAPSA ≤ 4) increased from 0 at baseline to 32 (16.7%) by week 24. At that time, 59.4% of the patients were either in DAPSA remission or had low disease activity (DAPSA ≤ 14). During the 24 weeks time frame, the proportion of patients with BSA ≤ 3 increased from 80.7% to 91.1%. Furthermore, at weeks 12 and 24, 45.14% and 47.19% of affected patients showed a resolution of enthesitis. Active dactylitis and nail psoriasis at baseline were reported to affect 10.5% and 22.0%, decreasing to 2.6% and 5.7% at week 24, respectively. The safety findings are consistent with the known safety profile of upadacitinib in rheumatoid arthritis and PsA; no new safety risks were identified. Conclusion: The data from this study confirm the findings of previous randomized controlled trials suggesting UPA is an effective treatment for active PsA without any new safety signals in patients from daily clinical practice. Clinical Trial Registration: ClinicalTrials.gov identifier, NCT04758117. Plain Language Summary: Upadacitinib is an antirheumatic medical therapy approved for treating psoriatic arthritis with insufficient response to previous conventional or biological therapies (DMARD-IR). Psoriatic arthritis is a chronic inflammatory disease affecting the joints, spine, tendons/entheses, skin, nails and other parts of the musculoskeletal system. Early diagnosis and treatment initiation are essential for patients with psoriatic arthritis given the potentially irreversible damage to joints, spine, and entheses and the considerable impact on quality of life. The results presented in this manuscript help clinicians evaluate whether the efficacy and the safety profile of upadacitinib found in previous clinical trials can be reproduced in patients seen in daily clinical practice. This analysis presents descriptive data on the real-world efficacy and safety of upadacitinib, measured by clinical and patient-reported outcomes assessed in four visits over 24 weeks. In summary, our findings confirm the results of previous clinical trials showing that upadacitinib effectively reduces symptom severity of PsA and substantially increases the proportion of patients achieving treatment goals relevant to clinical practice, such as remission or very low disease activity. In addition, safety data were consistent with previous studies of upadacitinib in rheumatoid arthritis or psoriatic arthritis; no new risks to the patients' safety were identified. [ABSTRACT FROM AUTHOR]

Based on self-determination theory, this study examines the relations between teachers' perception of classes' engagement, their motivating teaching practices, and students' motivation. Fifty-two physical education (PE) teachers and their 1,040 students from 52 classes participated in this study. Teachers' perception of classes' engagement was self-reported one week before their motivating teaching practices were observed. At the end of the observed lesson, students completed a questionnaire assessing their situational motivation toward PE. Results indicated that teachers' perception of class engagement predicted different dimensions of students' self-determined motivation, and that these relations were fully mediated by teachers' behaviors. More specifically, the more teachers reported high scores in class engagement, the more they displayed need-supportive behaviors that were, in turn, related to positive students' motivational outcomes. These results suggest that teachers' perception of class engagement could exacerbate motivational differences between classes. [ABSTRACT FROM AUTHOR]

Background: Brain [18F]FDG PET is used clinically mainly in the presurgical evaluation for epilepsy surgery and in the differential diagnosis of neurodegenerative disorders. While scans are usually interpreted visually on an individual basis, comparison against normative cohorts allows statistical assessment of abnormalities and potentially higher sensitivity for detecting abnormalities. Little work has been done on out-of-sample databases (acquired differently to the patient data). Combination of different databases would potentially allow better power and discrimination. We fully characterised an unpublished healthy control brain [18F]FDG PET database (Marseille, n = 60, ages 21–78 years) and compared it to another publicly available database (MRXFDG, n = 37, ages 23–65 years). We measured and then harmonised spatial resolution and global values. A collection of patient scans (n = 34, 13–48 years) with histologically confirmed focal cortical dysplasias (FCDs) obtained on three generations of scanners was used to estimate abnormality detection rates using standard software (statistical parametric mapping, SPM12). Results: Regional SUVs showed similar patterns, but global values and resolutions were different as expected. Detection rates for the FCDs were 50% for comparison with the Marseille database and 53% for MRXFDG. Simply combining both databases worsened the detection rate to 41%. After harmonisation of spatial resolution, using a full factorial design matrix to accommodate global differences, and leaving out controls older than 60 years, we achieved detection rates of up to 71% for both databases combined. Detection rates were similar across the three scanner types used for patients, and high for patients whose MRI had been normal (n = 10/11). Conclusions: As expected, global and regional data characteristics are database specific. However, our work shows the value of increasing database size and suggests ways in which database differences can be overcome. This may inform analysis via traditional statistics or machine learning, and clinical implementation. [ABSTRACT FROM AUTHOR]