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Access to dangerous goods training for firefighters in remote areas is limited for financial and logistical reasons. Virtual reality (VR) is a promising solution for this challenge as it is cost-effective, safe, and allows to simulate realistic scenarios that would be dangerous or difficult to implement in the real world. However, rigorous evaluations of VR training tools for first responders are still scarce. In this exploratory user study, a simple VR training tool involving two dangerous goods scenarios was developed. In each scenario, trainees learned how to safely approach a jackknifed truck with a trailer and how to collect and communicate information about the transported materials. The tool was tested with a group of 24 professional firefighter trainees (n = 22) and instructors (n = 2), who each completed the two training scenarios. The main goal of the study was to assess the usability of the VR tool in the given scenarios. Participants provided feedback on cybersickness, perceived workload, and usability. They also filled out a knowledge test before and after the VR training and gave feedback at the end of the study. The VR tool recorded task completion duration and participants' navigation and use of tools events. Overall, the tool provided good usability, acceptance, and satisfaction. However, a wide range in individuals' responses was observed. In addition, no post-training improvement in participants' knowledge was found, likely due to the already high level of knowledge pre-training. Future directions for improving the VR tool, general implications for other VR training tools, and suggestions for future research are discussed.

Abstract Background Mental health presentations account for a considerable proportion of paramedic workload; however, the decision-making involved in managing these cases is poorly understood. This study aimed to explore how paramedics perceive their clinical decision-making when managing mental health presentations. Methods A qualitative descriptive study design was employed. Overall, 73 paramedics participated in semi structured interviews, and data were analyzed from transcribed interviews in NVivo. Results Four themes emerged that reflected participants’ perceptions: the assessment process, experience, the use of documents and standard procedures, and consultation with other healthcare providers. There were conflicting perceptions about the clinical decision-making process, with perception of role having a potential impact. The dual process theory of clinical decision-making, which includes both analytical and intuitive approaches, was evident in the decision-making process. Conclusion Incorporating dual process theory into education and training, which highlights the strengths and weaknesses of analytical and intuitive decision-making, may reduce clinical errors made by cognitive bias. To further support clinical decision-making, additional education and training are warranted to promote critical thinking and clarify the scope of practice and roles when attending to mental health-related presentations.

Abstract Background This study aims to evaluate the impact of Quebec’s first hospital-at-home-inspired mobile Seniors’ Clinic, the “Clinique des Ainés (CDA)”, on frail older adults’ returns to the Emergency Department (ED), mortality, and hospital Length Of Stay (LOS) and rehospitalizations. Methods Design: Quasi-experimental pre-post implementation cohort study. Population: Patients aged ≥ 75 years admitted to the short-term geriatric unit after an ED consultation (control) or included by the CDA (intervention). Outcomes: return to ED (RtoED), mortality, ED & hospital LOS, and rehospitalizations. Statistical analyses: Multivariable regression modelling. Results Overall, 891 patients were included. At the intervention site (CDA) (n = 437), RtoED were similar at 30 (17.5% & 19.5%, p = 0.58), 90 (34.4% & 37.3%, p = 0.46) and 180 days (47.2% & 54.0%, p = 0.07) in the pre and post-implementation phases. No mortality differences were found. The hospitalization LOS was significantly shorter (28.26 and 14.22 days, p

ABSTRACT Measuring boundary layer stratification, wind shear, and turbulence remains challenging for wind resource assessment. In particular, larger eddy scales have the greatest impact on turbine load fluctuations, and there are few in situ methods to observe them adequately. Satellite remote sensing using synthetic aperture radar (SAR) is an alternative approach. In this study, eddy‐related signatures in 704 high‐resolution images are related to stratification through a bulk Richardson number ( Ri) measured by a buoy near Martha's Vineyard, the US epicenter of offshore wind. Variations in SAR‐observed atmospheric boundary layer eddies, or lack of them, correspond to specific Ri regimes. Accounting for strong vertical wind shear, typically under stable stratification, is critical for energy production and turbine loads, and SAR directly identifies these conditions by the absence of energetic eddies. SAR also provides a regional climatology of atmospheric stratification for offshore wind assessment, complementing other observations, and with potential application worldwide.

Abstract Background The Leishmania genome harbors formerly active short interspersed degenerated retroposons (SIDERs) representing the largest family of repetitive elements among trypanosomatids. Their substantial expansion in Leishmania is a strong predictor of important biological functions. In this study, we combined multilevel bioinformatic predictions with high-throughput genomic and transcriptomic analyses to gain novel insights into the diversified roles retroposons of the SIDER2 subfamily play in Leishmania genome evolution and expression. Results We show that SIDER2 retroposons form various evolutionary divergent clusters, each harboring homologous SIDER2 sequences usually located nearby in the linear sequence of chromosomes. This intriguing genomic organization underscores the importance of SIDER2 proximity in shaping chromosome dynamics and co-regulation. Accordingly, we show that transcripts belonging to the same SIDER2 cluster can display similar levels of expression. SIDER2 retroposons are mostly transcribed as part of 3'UTRs and account for 13% of the Leishmania transcriptome. Genome-wide expression profiling studies underscore SIDER2 association generally with low mRNA expression. The remarkable link of SIDER2 retroposons with downregulation of gene expression supports their co-option as major regulators of mRNA abundance. SIDER2 sequences also add to the diversification of the Leishmania gene expression repertoire since ~ 35% of SIDER2-containing transcripts can be differentially regulated throughout the parasite development, with a few encoding key virulence factors. In addition, we provide evidence for a functional bias of SIDER2-containing transcripts with protein kinase and transmembrane transporter activities being most represented. Conclusions Altogether, these findings provide important conceptual advances into evolutionary innovations of transcribed extinct retroposons acting as major RNA cis-regulators.

Abstract Background Selection of the most promising radiotracer candidates for radiolabeling is a difficult step in the development of radiotracer pharmaceuticals, especially for the brain. Mass spectrometry (MS) is an alternative to study ex vivo the characteristics of candidates, but most MS studies are complicated by the pharmacologic doses injected and the dissection of regions to study candidate biodistribution. In this study, we tested the ability of a triple quadrupole analyzer (TQ LC–MS/MS) to quantify low concentrations of a validated precursor of a radiotracer targeting the DAT (LBT-999) in dissected regions. We also investigated its biodistribution on brain slices using MS imaging with desorption electrospray ionization (DESI) coupled to time-of-flight (TOF) vs. TQ mass analyzers. Results TQ LC–MS/MS enabled quantification of LBT-999 injected at sub-tracer doses in dissected striata. DESI-MS imaging (DESI-MSI) with both analyzers provided images of LBT-999 biodistribution on sagittal slices that were consistent with positron emission tomography (PET). However, the TOF analyzer only obtained biodistribution images at a high injected dose of LBT-999, while the TQ analyzer provided biodistribution images at lower injected doses of LBT-999 with a better signal-to-noise ratio. It also allowed simultaneous visualization of endogenous metabolites such as dopamine. Conclusions Our results show that LC-TQ MS/MS in combination with DESI-MSI can provide important information (biodistribution, specific and selective binding) that can facilitate the selection of the most promising candidates for radiolabeling and support the development of radiotracers.

Abstract Background Treatment persistence among patients with psoriatic arthritis (PsA) is essential for achieving optimal treatment outcomes. Guselkumab, a fully human interleukin-23p19-subunit inhibitor, was approved by the United States (US) Food and Drug Administration for the treatment of active PsA in July 2020, with a dosing regimen of 100 mg at week 0, week 4, then every 8 weeks. In the Phase 3 DISCOVER-1 and DISCOVER-2 studies of patients with active PsA, 94% of guselkumab-randomized patients completed treatment through 1 year and 90% did so through 2 years (DISCOVER-2). Real-world evidence is needed to compare treatment persistence while following US prescribing guidelines (i.e., on-label persistence) for guselkumab versus subcutaneous (SC) tumor necrosis factor inhibitors (TNFis). Methods Adults with PsA receiving guselkumab or their first SC TNFi (i.e., adalimumab, certolizumab pegol, etanercept, or golimumab) between 14 July 2020 and 31 March 2022 were identified in the IQVIA PharMetrics® Plus database (first claim defined the treatment start date [index date]). Baseline characteristics and biologic use (biologic-naïve/biologic-experienced) were assessed during the 12-month period preceding the index date. Baseline characteristics were balanced between cohorts using propensity-score weighting based on the standardized mortality ratio approach. The follow-up period spanned from the index date until the earlier of the end of continuous insurance eligibility or end of data availability. On-label persistence, defined as the absence of treatment discontinuation (based on a gap of 112 days for guselkumab or 56 days for SC TNFi) or any dose escalation/reduction during follow-up, was assessed in the weighted treatment cohorts using Kaplan-Meier (KM) curves. A Cox proportional hazards model, further adjusted for baseline biologic use, was used to compare on-label persistence between the weighted cohorts. Results The guselkumab cohort included 526 patients (mean age 49.8 years; 61.2% female) and the SC TNFi cohort included 1953 patients (mean age: 48.5 years; 60.2% female). After weighting, baseline characteristics were well balanced with a mean follow-up of 12.3–12.4 months across cohorts; 51.5% of patients in the guselkumab cohort and 16.7% in the SC TNFi cohort received biologics in the 12-month baseline period. Respective rates of treatment persistence at 3, 6, 9, and 12 months were 91.2%, 84.1%, 75.9%, and 71.5% for the guselkumab cohort versus 77.3%, 61.6%, 50.0%, and 43.7% for the SC TNFi cohort (all log-rank p

Abstract We construct classical curvature spinors in topologically massive gauge theory and topologically massive gravity, expressed in terms of massive three-particle amplitudes. We show that when the amplitudes double copy, the curvature spinors associated with particular solutions satisfy the Cotton double copy, the three-dimensional cousin of the Weyl double copy. Furthermore, we show that under certain circumstances the Cotton double copy can be derived via a dimensional reduction of the Weyl double copy.

Dietary supplementation with n-3 polyunsaturated fatty acids improves cognitive performance in several animal models of Alzheimer's disease (AD), an effect often associated with reduced amyloid-beta and/or tau pathologies. However, it remains unclear to what extent eicosapentaenoic (EPA) provides additional benefits compared to docosahexaenoic acid (DHA). Here, male and female 3xTg-AD mice were fed for 3 months (13–16 months of age) the following diets: (1) control (no DHA/EPA), (2) DHA (1.1g/kg) and low EPA (0.4g/kg), or (3) DHA (0.9g/kg) with high EPA (9.2g/kg). The DHA and DHA + EPA diets respectively increased DHA by 19% and 8% in the frontal cortex of 3xTg-AD mice, compared to controls. Levels of EPA, which were below the detection limit after the control diet, reached 0.14% and 0.29% of total brain fatty acids after the DHA and DHA + EPA diet, respectively. DHA and DHA + EPA diets lowered brain arachidonic acid levels and the n-6:n-3 docosapentaenoic acid ratio. Brain uptake of free 14C-DHA measured through intracarotid brain perfusion, but not of 14C-EPA, was lower in 3xTg-AD than in NonTg mice. DHA and DHA + EPA diets in 3xTg-AD mice reduced cortical soluble phosphorylated tau (pS202) (−34% high-DHA, −34% DHA + EPA, P

Gene therapies delivered through a single administration have revolutionized treatment possibilities for many patients living with serious or fatal conditions such as spinal muscular atrophy, hemophilia and sickle cell disease. However, shadowing the excitement about the transformational potential of many gene therapies has been widespread concern about the combination of uncertainty in the durability of their benefits over the long term and the short-term financial shock of high prices. As the healthcare payment ecosystem prepares for the growing number of gene therapies entering the market, three key interconnected challenges must be addressed: determining a fair price, managing clinical uncertainty and managing short-term budget impacts. This paper identifies specific policy reforms and market-based tools to help the US health system address these challenges to achieve more equitable and affordable access for patients to the growing number of gene therapies expected to be approved in the coming years.

BackgroundT-cell–redirecting therapies, such as bispecific antibodies and chimeric antigen receptor T-cells, exploit the cytotoxic capabilities of the immune system to destroy cells expressing specific surface antigens, including malignant cells. These therapies have demonstrated unprecedented rates, depth, and duration of responses in relapsed and refractory multiple myeloma. However, there are significant challenges in implementing these therapies into practice, which require multidisciplinary and multicenter coordination and significant healthcare resources to effectively manage these patients. So far, there are no Canadian guidelines for the effective implementation and use of T-cell–redirecting therapies.MethodsThis consensus statement was developed based on three advisory meetings held in March, July, and November 2023. During these meetings, a panel of Canadian subject matter experts and representation from Myeloma Canada gathered to discuss the optimal procedures for the use of T-cell–redirecting therapies in the treatment of multiple myeloma. Members of the panel performed a thorough review of randomized clinical trials, real-world data, and other current literature, and provided their up-to-date clinical experience with T-cell–redirecting therapies in Canadian practice settings. Subsequently, asynchronous working groups were appointed to develop unified criteria for patient selection, appraise referral pathways, and devise strategies for management of short-term and long-term adverse events arising from the use of T-cell–redirecting therapies in multiple myeloma.ResultsHere, we present recommendations for optimizing patient selection, referral pathways, and adverse event management in the Canadian practice setting. These recommendations are relevant for hematologists/oncologists, oncology nurses, pharmacists, nurse practitioners, physician assistants, and other providers who treat patients with multiple myeloma, as well as individuals with multiple myeloma and their care partners. These recommendations will be of interest to clinicians who treat patients with MM at community clinics and hospitals and who may be interested in referring patients for T-cell–redirecting therapy.

Microbubble (MB)-assisted ultrasound (US) is an innovative modality for the non-invasive, targeted, and efficient delivery of therapeutic molecules into the brain. Previously, we reported the first metabolomic signature of blood–brain barrier opening (BBBO) induced by MB-assisted US. In the present study, the neurometabolic consequences of acoustically-mediated BBBO on cerebral tissue were investigated using multimodal metabolomics approaches. Sinusoid US waves (1 MHz, peak negative pressure 0.6 MPa, burst length 10 ms, total treatment time 30 s, MB bolus dose 0.7 × 105 MBs/g) were applied on the rats’ right striatum (ipsilateral side). Brain was collected and both striata were then dissected 3 h, 2 days, and 1 week after BBBO. After tissue preparation, the samples were analyzed using nuclear magnetic resonance spectrometry (NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Our findings showed a slight disruption of metabolic pathways in contralateral striata of animals. Analyses of metabolic pathways indicated changes in amino acid metabolisms. In addition, tryptophan derivate dosages revealed the perturbation of a central metabolite of the kynurenine pathway (i.e., 3-hydroxy-kynurenine). In conclusion, the acoustically-mediated BBBO of the ipsilateral cerebral hemisphere induced significant change in metabolism of contralateral one.

**Background:** Bacillus Calmette-Guérin (BCG) can reduce recurrence and delay progression among patients with high-risk non–muscle invasive bladder cancer (NMIBC), but is associated with a substantial emotional, physical, and social burden. **Objectives:** This study evaluated the adequacy of first-line intravesical BCG treatment among high-risk NMIBC patients in the United States, including the subgroup with carcinoma in situ (CIS) of the bladder. **Methods:** Adults with high-risk NMIBC treated with BCG were selected from de-identified MarketScan® Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Adequacy of BCG induction and maintenance was evaluated from the first BCG claim until the end of the patient’s observation, using a previously published claims-based algorithm (induction: ≥5 instillations within 70 days; induction and maintenance: ≥7 instillations within 274 days of first instillation) and a definition based on the landmark Southwest Oncology Group (SWOG) trial (induction: ≥5 instillations without gaps >7 days; followed by ≥2 instillations at month 3, 6, and every 6 months thereafter). Proportions of patients with adequate BCG induction and maintenance were reported overall and compared between those with and without CIS. **Results:** Of 5803 high-risk NMIBC patients treated with first-line BCG (mean age, 67.3 years; 20.6% female), 930 (16.0%) had CIS. After first-line BCG, 56.6% received another treatment. Although 86.9% had adequate BCG induction based on the claims-based algorithm (SWOG, 73.6%), only 41.5% had adequate BCG induction and maintenance (SWOG, 1.6%). Similar trends were observed for patients with and without CIS, with higher adherence to guidelines for patients with CIS (adequate induction using claims-based algorithm: 90.3% vs 86.2%; adequate induction and maintenance: 50.8% vs 39.7%, all _P_

Synthetic biology is a growing field with an increasing number of successful applications. Yet, synthetic biology (SynBio) education initiatives are underreported and disconnected from each other. In this review we survey the literature on SynBio education and stratify this body of work into three categories: classroom activities, course designs, and program-level curricula-planning. For each category, we discuss the methods used to assess students’ experiences and achievement of learning objectives. Throughout, we identify trends and opportunities for further development in SynBio education. We determined that the design of low-cost education kits is a growing opportunity to support student learning at the level of classroom activities. In support of that work, we present a mapping of published education kits onto Bloom’s taxonomy, taking into account increasing accumulation of knowledge through continued experience. We further found that project-based learning is used widely and has proven effective in course designs. To facilitate such activities, we provide a high-level guide for the conversion of a didactic course into a project-based learning course. Further, we note that, currently, programs are delivered primarily at the graduate level, taking inspiration from traditional degree programs while incorporating interdisciplinary training. Finally, we find that design-based research may provide an effective framework for an iterative, mixed-method study design. To support such efforts, we provide a schematic overview of design-based research and its application to a learning progression for interdisciplinary skills. We conclude with a discussion of specific learning concepts that may be useful to SynBio educators and education researchers.

Synaptic loss is intrinsically linked to Alzheimer's disease (AD) neuropathology and symptoms, but its direct impact on clinical symptoms remains elusive. The postsynaptic protein Shank3 (SH3 and multiple ankyrin repeat domains) is of particular interest, as the loss of a single allele of the SHANK3 gene is sufficient to cause profound cognitive symptoms in children. We thus sought to determine whether a SHANK3 deficiency could contribute to the emergence or worsening of AD symptoms and neuropathology. We first found a 30%-50% postmortem loss of SHANK3a associated with cognitive decline in the parietal cortex of individuals with AD. To further probe the role of SHANK3 in AD, we crossed male and female 3xTg-AD mice modelling Aβ and tau pathologies with Shank3a-deficient mice (Shank3Δex4-9). We observed synergistic deleterious effects of Shank3a deficiency and AD neuropathology on object recognition memory at 9, 12, and 18 months of age and on anxious behavior at 9 and 12 months of age in hemizygous Shank3Δex4-9-3xTg-AD mice. In addition to the expected 50% loss of Shank3a, levels of other synaptic proteins, such as PSD-95, drebrin, and homer1, remained unchanged in the parietotemporal cortex of hemizygous Shank3Δex4-9 animals. However, Shank3a deficiency increased the levels of soluble Aβ42 and human tau at 18 months of age compared with 3xTg-AD mice with normal Shank3 expression. The results of this study in human brain samples and in transgenic mice are consistent with the hypothesis that Shank3 deficiency makes a key contribution to cognitive impairment in AD.SIGNIFICANCE STATEMENT Although the loss of several synaptic proteins has been described in Alzheimer's disease (AD), it remains unclear whether their reduction contributes to clinical symptoms. The results of this study in human samples show lower levels of SHANK3a in AD brain, correlating with cognitive decline. Data gathered in a novel transgenic mouse suggest that Shank3a deficiency synergizes with AD neuropathology to induce cognitive impairment, consistent with a causal role in AD. Therefore, treatment aiming at preserving Shank3 in the aging brain may be beneficial to prevent AD.

Abstract Background The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups’ own genotype. Conclusions These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or “healthy” microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. Video Abstract

ObjectiveTo test associations of candidate obesity-related single nucleotide polymorphisms (SNPs) and obesity polygenic risk scores (PRS) with neural reward reactivity to food cues.MethodsAfter consuming a pre-load meal, 9–12-year-old children completed a functional magnetic resonance imaging (fMRI) paradigm with exposure to food and non-food commercials. Genetic exposures included FTO rs9939609, MC4R rs571312, and a pediatric-specific obesity PRS. A targeted region-of-interest (ROI) analysis for 7 bilateral reward regions and a whole-brain analysis were conducted. Independent associations between each genetic factor and reward responsivity to food cues in each ROI were evaluated using linear models.ResultsAnalyses included 151 children (M = 10.9 years). Each FTO rs9939609 obesity risk allele was related to a higher food-cue-related response in the right lateral hypothalamus after controlling for covariates including the current BMI Z-score (p

Background: Data on the predictors of nonmedical problems (NMP) in older adults attending the emergency department (ED) for low acuity conditions is lacking and could help rapid identification of patients with NMP and integration of these needs into care planning. Objectives: To determine the prevalence and predictors of NMP among older adults attending EDs for low acuity conditions. Methods: Prospective cohort study in eight EDs (May–August 2021). We included cognitively intact ≥65 years old adults assigned a low triage acuity (3–5) using the CTAS. A questionnaire focusing on 11 NMP was administered. We used multiple logistic regression to identify predictors of NMP. Results: Among the 1,061 participants included, the mean age was 77.1 ± 7.6, majority were female, and 41.6 % lived alone. At least one NMP was reported by 704 persons. Prevalence of each NMP: outdoor (41.1 %) and indoor (30.2 %) mobility issues, difficult access to dental care (35.1 %), transportation (4.1 %) and medication (5.4 %), loneliness (29.5 %), food insecurity (10.3 %), financial difficulties (9.5 %), unsafe living situation (4.1 %), physical/psychological violence (3.4 %), and abuse/neglect (3.3 %). Predictors of NMP were: age (OR 1.04 for each additional year), living alone (OR 2.20), pre-existing mental health conditions (OR 3.12), heart failure (OR 1.42), recent surgery/admission (OR 1.75), memory decline (OR 2.76), no family physician (OR 1.74) and consulting for a fall/functional decline (OR 2.48). Conclusions: Nonmedical problems are frequent among older adults. We need to implement holistic ED processes that integrate these problems into care planning.

ObjectiveWe leveraged an observational, repeated-measures study to examine the within-child associations between sleep quality and emotional self-regulation, controlling for between-child effects.MethodsChildren aged 3–5 years and one parent each were recruited from the community in northern New England between 2019 and 2022. Parents completed online surveys at baseline and 2, 4, and 6 months post-baseline. Child sleep quality was measured with the validated Children's Sleep Habits Questionnaire modified for preschoolers; higher scores indicate worse sleep quality (range 32–96). Child emotional self-regulation was measured with the validated Child Social Behavior Questionnaire; higher scores indicate better emotional self-regulation (range 1–7). Adjusted mixed-effects linear regression was used to model the associations between nighttime sleep quality (exposure) and emotional self-regulation (outcome) measured at each of the four study time points while disaggregating the between- and within-child effects.ResultsChildren (n = 91) were largely white, non-Hispanic (88.7%), and from a higher social-economic status. Sleep quality scores averaged 38.9 (SD: 6.6) at baseline; 23.1% of children had scores >41, which is considered evidence of significant sleep problems. Emotional self-regulation scores averaged 4.2 (SD: 1.0). There was a significant within-child association between sleep quality and emotional self-regulation. Specifically, a decrease in sleep quality at any one time point, relative to each child's mean sleep quality, related to worse emotional self-regulation [standardized beta, βs = −0.31; 95% CI (0.53, −0.09)]; the between-child effect was not significant. Results were consistent when limited to children with complete data at all study visits (n = 78).ConclusionsThe findings support a causal, within-child association between sleep quality and emotional self-regulation in preschool-aged children, with effects evident over 6 months.

BackgroundThe current literature inadequately addresses the extent to which remote monitoring should be integrated into care models for chronic respiratory diseases (CRDs). ObjectiveThis study examined a remote monitoring program (RMP) in cystic fibrosis (CF) by exploring experiences, future perspectives, and use behavior over 3 years, with the aim of developing future directions for remote monitoring in CRDs. MethodsThis was a mixed methods, multicenter, observational study in 5 Dutch CF centers following a sequential explanatory design. Self-designed questionnaires using the technology acceptance model were sent out to people with CF who had a minimum of 12 months of experience with the RMP and local health care professionals (HCPs). Questionnaire outcomes were used to inform semistructured interviews with HCPs and people with CF. Qualitative findings were reported following the COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist. Anonymous data on use frequency of all people with CF were analyzed. ResultsBetween the second quarter of 2020 and the end of 2022, a total of 608 people with CF were enrolled in the program, and a total of 9418 lung function tests and 2631 symptom surveys were conducted. In total, 65% (24/37) of HCPs and 89% (72/81) of people with CF responded to the questionnaire, and 7 HCPs and 12 people with CF participated in semistructured interviews. Both people with CF and HCPs were positive about remote monitoring in CF care and found the RMP a good addition to daily care (people with CF: 44/72, 61%; HCPs: 21/24, 88%). Benefits ranged from supporting individual patients to reducing health care consumption. The most valued monitoring tool was home spirometry by both people with CF (66/72, 92%) and HCPs (22/24, 92%). Downsides included the potential to lose sight of patients and negative psychosocial effects, as 17% (12/72) of people with CF experienced some form of stress due to the RMP. A large majority of people with CF (59/72, 82%) and HCPs (22/24, 92%) wanted to keep using the RMP in future, with 79% (19/24) of HCPs and 75% (54/72) of people with CF looking forward to more replacement of in-person care with digital care during periods of well-being. Future perspectives for the RMP were centered on creating hybrid care models, personalizing remote care, and balancing individual benefits with monitoring burden. ConclusionsRemote monitoring has considerable potential in supporting people with CF and HCPs within the CF care model. We identified 4 practice-based future directions for remote monitoring in CF and CRD care. The strategies, ranging from patient driven to prediction driven, can help clinicians, researchers, and policy makers navigate the rapidly changing digital health field, integrate remote monitoring into local care models, and align remote care with patient and clinician needs.

IntroductionWe examined the relationship between current tobacco use and functionally important respiratory symptoms.MethodsLongitudinal cohort study of 16 295 US adults without COPD in Waves 2-3 (W2-3, 2014-2016) of the Population Assessment of Tobacco and Health Study. Exposure-Ten mutually exclusive categories of tobacco use including single product, multiple product, former, and never use (reference). Outcome-Seven questions assessing wheezing/cough were summed to create a respiratory symptom index; cutoffs of ≥2 and ≥3 were associated with functional limitations and poorer health. Multivariable regressions examined both cutoffs cross-sectionally and change over approximately 12 months, adjusting for confounders.ResultsAll tobacco use categories featuring cigarettes (>2/3's of users) were associated with higher risk (vs. never users) for functionally important respiratory symptoms at W2, for example, at symptom severity ≥ 3, risk ratio for exclusive cigarette use was 2.34 [95% CI, 1.92, 2.85] and for worsening symptoms at W3 was 2.80 [2.08, 3.76]. There was largely no increased symptom risk for exclusive use of cigars, smokeless tobacco, hookah, or e-cigarettes (adjustment for pack-years and marijuana attenuated the cross-sectional e-cigarette association from 1.53(95% CI 0.98, 2.40) to 1.05 (0.67, 1.63); RRs for these products were also significantly lower compared to exclusive use of cigarettes. The longitudinal e-cigarette-respiratory symptom association was sensitive to the respiratory index cutoff level; exclusive e-cigarette use was associated with worsening symptoms at an index cutoff ≥ 2 (RR = 1.63 [1.02, 2.59]) and with symptom improvement at an index cutoff of ≥ 3 (RR = 1.64 [1.04, 2.58]).ConclusionsPast and current cigarette smoking drove functionally important respiratory symptoms, while exclusive use of other tobacco products was largely not associated. However, the relationship between e-cigarette use and symptoms was sensitive to adjustment for pack-years and symptom severity.ImplicationsHow noncigarette tobacco products affect respiratory symptoms is not clear; some studies implicate e-cigarettes. We examined functionally important respiratory symptoms (wheezing/nighttime cough) among US adults without COPD. The majority of adult tobacco users smoke cigarettes and have higher risk of respiratory symptoms and worsening of symptoms, regardless of other products used with them. Exclusive use of other tobacco products (e-cigarettes, cigars, smokeless, hookah) was largely not associated with functionally important respiratory symptoms and risks associated with their use was significantly lower than for cigarettes. The association for e-cigarettes was greatly attenuated by adjustment for cigarette pack-years and sensitive to how symptoms were defined.

Abstract Background and Aims Chlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis. Methods This study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis. Results With a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34–0.95 for the highest vs. lowest tertile, p = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations. Conclusion According to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver. Trial registration ClinicalTrials.gov Identifier: NCT03373396.

Abstract Background Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need of more specific therapeutic strategies. The drivers of malignancy in this disease are CD4+ follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option. Methods To reveal the prominent metabolic pathways used by the AITL lymphoma cells, we relied on metabolomic and proteomic analysis of murine AITL (mAITL) T cells isolated from our established mAITL model. We confirmed these results using AITL patient and healthy T cell expression data. Results Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with a fatty acid oxydation inhibitor, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chokα confirmed the importance of the phosphatidylcholine production pathway in neoplastic CD4 + T cells, nearly eradicating mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1high neoplastic cells. Conclusion Our results suggest that interfering with choline metabolism in AITL reveals a specific metabolic vulnerability and might represent a new therapeutic strategy for these patients.