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The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline 1a was orally efficacious in Plasmodium berghei -infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a . The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a , is twice as potent as 1a . Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a , 1m , 42a , and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

Alterations in interoception have been linked to psychopathology. Recent findings suggest that both the attention to and the accuracy of, interoceptive perceptions may be oppositely related to subclinical symptomatology. Thus, providing well-validated tools that tap into these interoceptive processes is crucial for understanding the relation between interoceptive processing and subclinical psychopathology. In the current study ( N  = 642), we aimed to (1) validate the German version of the Interoceptive Attention Scale (IATS; Gabriele et al., 2022), and (2) test the differential association of self-reported interoceptive attention and accuracy with subclinical symptomatology, including alexithymia, depressive, and anxious symptomatology. We observed that a one-factor solution is a well-fitting model for the IATS. Further, the IATS showed good internal consistency, convergent, and divergent validity, but poor test-retest reliability. Self-reported interoceptive attention and accuracy were unrelated to each other. However, IATS scores were positively related to all measures of psychopathology (except depressive symptomatology), whereas self-reported interoceptive accuracy scores showed negative or nonsignificant relations with these. Our data suggest that the IATS is a good instrument to measure self-report interoceptive attention in the German population. Further, we highlight the need to distinguish between constructs of interoception to better understand the relation between interoception and psychopathology.

Background: Variant-adapted COVID-19 vaccines are recommended for patients with inflammatory bowel disease (IBD). However, many patients rely on pre-existing immunity by original vaccines or prior infections., Aim: To assess whether such immunity sufficiently combats the highly immune-evasive SARS-CoV-2 JN.1 variant., Methods: Utilising two longitudinal cohorts, we evaluated immunity against JN.1 induced by original vaccines (IBD: n = 98; healthy: n = 48), omicron breakthrough infection (IBD: n = 55; healthy: n = 57) or XBB.1.5-adapted vaccines (IBD: n = 18). Neutralisation and anti-receptor-binding domain (RBD) IgG levels against wild-type SARS-CoV-2 and JN.1 were assessed using multiplex immunoassays. Study outcomes were wild-type and JN.1 neutralisation following three doses of original mRNA vaccines, stratified by immunosuppressive therapy (primary outcome), and JN.1 neutralisation following third-dose breakthrough infection or a fourth dose of XBB.1.5-adapted mRNA vaccines (secondary outcomes)., Results: Following original vaccines, JN.1 neutralisation was lower than wild-type neutralisation in all study groups (healthy, anti-TNF and non-anti-TNF; each p < 0.001); most individuals lacked JN.1 neutralisation (healthy: 97.9%; anti-TNF: 98.3% and non-anti-TNF: 92.3%). Confounder-adjusted multivariable modelling strongly associated anti-TNF therapy with low levels of anti-JN.1-RBD IgG (fold-change 0.48 [95% CI 0.39-0.59]). JN.1 neutralisation was similar in patients with or without breakthrough infection (anti-TNF, non-anti-TNF; each p > 0.05); neutralisation failure was 100% despite breakthrough infection. XBB.1.5-adapted vaccines enhanced JN.1 neutralisation (p < 0.001) and reduced neutralisation failure rates in patients with IBD (94.4% pre-vaccination vs. 44.4% post-vaccination; p = 0.003)., Conclusions: Only variant-adapted vaccines protect against emerging SARS-CoV-2 variants. Patients with IBD and healthy individuals without recent vaccination may lack protection against the JN.1 subvariant KP.3 which causes current COVID-19 surges., (© 2024 John Wiley & Sons Ltd.)

Social prescribing has become a global phenomenon. A Delphi study was recently conducted with 48 social prescribing experts from 26 countries to establish global agreement on the definition of social prescribing. We reflect on the use and utility of the outputs of this work, and where we go from here., (© 2024. The Author(s).)

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7'-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC 50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Positional skull deformities have been on the rise for decades and can be treated with molding helmets in early childhood. Parents often fear later cosmetic stigmatization, but also a reduced quality of life (QoL) during treatment. The aim of this study was to examine therapy results in our patient collection from a new perspective. Cranial vault asymmetry (CVA), cranial vault asymmetry index (CVAI), and cranial index (CI) were compared before and after molding helmet therapy. Correction was defined by a decrease in CVA <3.5 mm and CI <90%. Subjective therapy outcome, side effects and QoL from the parents' perspective were determined using a questionnaire. There were 25 patients included. Differences between pretherapeutic and posttherapeutic CVA, CVAI, and CI were significant ( P <0.01). An objective correction according to the defined values was observed in only 12% of cases. However, 76% of parents stated that their child's skull shape was normal after therapy. There were 60 side effects reported in 23 cases. The QoL of 21 children was assessed as unimpaired during helmet therapy. Even though complete normalization was rarely observed, the parameters were significantly different after therapy, and subjective reduction in skull deformity was common., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

There is no multi-country/multi-language study testing a-priori multivariable associations between non-modifiable/modifiable factors and validated wellbeing/multidimensional mental health outcomes before/during the COVID-19 pandemic. Moreover, studies during COVID-19 pandemic generally do not report on representative/weighted non-probability samples. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is a multi-country/multi-language survey conducting multivariable/LASSO-regularized regression models and network analyses to identify modifiable/non-modifiable factors associated with wellbeing (WHO-5)/composite psychopathology (P-score) change. It enrolled general population-representative/weighted-non-probability samples (26/04/2020-19/06/2022). Participants included 121,066 adults (age=42±15.9 years, females=64 %, representative sample=29 %) WHO-5/P-score worsened (SMD=0.53/SMD=0.74), especially initially during the pandemic. We identified 15 modifiable/nine non-modifiable risk and 13 modifiable/three non-modifiable protective factors for WHO-5, 16 modifiable/11 non-modifiable risk and 10 modifiable/six non-modifiable protective factors for P-score. The 12 shared risk/protective factors with highest centrality (network-analysis) were, for non-modifiable factors, country income, ethnicity, age, gender, education, mental disorder history, COVID-19-related restrictions, urbanicity, physical disorder history, household room numbers and green space, and socioeconomic status. For modifiable factors, we identified medications, learning, internet, pet-ownership, working and religion as coping strategies, plus pre-pandemic levels of stress, fear, TV, social media or reading time, and COVID-19 information. In multivariable models, for WHO-5, additional non-modifiable factors with |B|>1 were income loss, COVID-19 deaths. For modifiable factors we identified pre-pandemic levels of social functioning, hobbies, frustration and loneliness, and social interactions as coping strategy. For P-scores, additional non-modifiable/modifiable factors were income loss, pre-pandemic infection fear, and social interactions as coping strategy. COH-FIT identified vulnerable sub-populations and actionable individual/environmental factors to protect well-being/mental health during crisis times. Results inform public health policies, and clinical practice., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in eTable 12., (Copyright © 2024. Published by Elsevier B.V.)

This retrospective monocentric cohort study analyzed patients with head and neck cancer according their nutritional status and association of percutaneous endoscopic gastrostomy (PEG) from admission to six months after treatment at a tertiary hospital in Germany from 2017 to 2019. A total of 289 patients (76.5% men; median age 62 years; 63.3% stage IV) were included. Univariate analyses and ANOVAs with repeated measures were performed to analyze differences over time. The percentage of patients requiring PEG was 14.9% (43 of 289 patients) before start of treatment (Z0), 14% (40 of 286 patients alive) after one week (Z1), 22.7% (58 of 255 patients) after six weeks (Z2) and 23% (53 of 230 patients) after six months (Z3) from the end of treatment. PEG placement was associated with alcohol or nicotine consumption, in oropharyngeal and hypopharyngeal carcinoma, squamous cell carcinoma, cancer stage III/IV, chemotherapy and impairment of food intake (all p < 0.05). Weight loss between Z1 and Z3 with PEG did not differ from patients without PEG at Z0 ( p = 0.074), although patients with PEG at Z0 had a lower mean weight at the beginning. PEG was important for a quarter of the patients alive at Z3 and helped to prevent weight loss.

Introduction: Although increasingly appreciated, little is known about the prevalence of fecal urgency, fecal incontinence and differences between patients' and physicians' perception in inflammatory bowel disease (IBD)., Methods: We performed an online patient and physician survey to evaluate the assessment, prevalence and impact of fecal urgency and incontinence in IBD., Results: A total of 593 patients (44.0% ulcerative colitis (UC), 53.5% Crohn's disease (CD), 2.2% indeterminate colitis, 2 not specified) completed the survey (65.8% females, mean age 47.1 years). Fecal urgency was often reported (UC: 98.5%, CD: 96.2%) and was prevalent even during remission (UC: 65.9%, CD: 68.5%). Fecal urgency considerably impacted daily activities (visual analog scale [VAS] 5, IQR 3-8). Yet, 22.8% of patients have never discussed fecal urgency with their physicians. Fecal incontinence was experienced by 44.7% of patients and 7.9% on a weekly basis. Diapers/pads were required at least once a month in 20.4% of patients. However, 29.7% of patients never talked with their physician about fecal incontinence. UC was an independent predictor for the presence of moderate-severe fecal urgency (OR 1.65, 95% CI 1.13-2.41) and fecal incontinence (OR 1.77, 95% CI 1.22-2.59). All physicians claimed to regularly inquire about fecal urgency and incontinence. However, the impact of these symptoms on daily activities was overestimated compared with the patient feedback (median VAS 8 vs. 5, p = 0.0113, and 9 vs. 5, p = 0.0187)., Conclusions: Fecal urgency and incontinence are burdensome symptoms in IBD, with a similar prevalence in UC and CD. A mismatch was found between the physician and patient perception. These symptoms should be addressed during outpatient visits., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: Major depressive disorders (MDD) are a leading health concern worldwide. While first line medication treatments may fall short of desired therapeutic outcomes, physical activity (PA) interventions appear to be a promising and cost-effective add-on to improve symptoms of depression. This study aimed to address challenges in the assessment of PA in inpatients treated for MDD by examining the correspondence of self-reported and accelerometer-based PA., Methods: In 178 inpatients treated for MDD (mean age: M  = 41.11 years, SD = 12.84; 45.5% female) and 97 non-depressed controls (mean age: M  = 35.24 years, SD = 13.40; 36.1% female), we assessed self-reported PA via the Simple Physical Activity Questionnaire (SIMPAQ) for one week, followed by a week where PA was monitored using an accelerometer device (Actigraph wGT3x-BT). Additionally, we examined correlations between PA levels assessed with the SIMPAQ and exercise determinants in both groups., Results: Descriptively, inpatients treated for MDD showed lower levels of light PA on accelerometer-based measures, whereas they self-reported increased levels of certain types of PA on the SIMPAQ. More importantly, there was only a small degree of correspondence between self-reported and actigraphy-based PA levels in both in patients ( r  = 0.15, p  < 0.05) and controls ( r  = 0.03, ns). Only few significant correlations were found for self-reported PA (SIMPAQ subscores) and perceived fitness, whereas self-reported PA and estimated VO 2 max were unrelated. Furthermore, only weak (and mostly statistically non-significant) correlations were found between exercise determinants and SIMPAQ-based exercise behavior in both populations., Discussion: Our findings emphasize the intricate challenges in the assessment of PA, not only in inpatients treated for MDD, but also in non-depressed controls. Our findings also underline the necessity for a diversified data assessment. Further efforts are needed to refine and improve PA questionnaires for a more accurate data assessment in psychiatric patients and healthy controls., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Schilling, Cody, Kreppke, Faude, Beck, Brand, Donath, Hatzinger, Imboden, Lang, Mans, Mikoteit, Oswald, Schweinfurth-Keck and Gerber.)

Objective: The purpose of the present study was to design the Farsi Scale of Sexual-Reproductive Needs and Concerns of never-married women over 35 and to assess its psychometric properties., Materials and Methods: This mixed method research had two phases. The first phase was qualitative (Conventional Content Analysis). We interviewed never-married Iranian women over 35; from their responses, we extracted specific statements which to be used as questionnaire items. To validate the questionnaire psychometrically, we tested its validity (face, content, and structure) and reliability (internal consistency and stability). For qualitative face validity, 15 never-married women and 5 experts commented on the style of sentences. For quantitative face validity, we used the impact score. For qualitative content validity, 15 experts commented on the items based on their appropriateness, and for quantitative content validity, we performed the Content Validity Ratio and Content Validity Index. Exploratory Factor Analysis was used to Construct Validity. To evaluate structural validity, a cross-sectional sample of 240 never-married women over the age of 35 completed the questionnaire. Cronbach's Alpha was used for internal consistency. In addition, the test-retest method and Intraclass Correlation Coefficient were used to ensure stability., Results: The Sexual-Reproductive Needs and Concerns Scale of Iranian Never-Married Women over 35 was developed with 15 items and three dimensions (Emotional burden; Sexual needs; Stigma). Cronbach's alpha for the instrument was 0.81 and the Intraclass Correlation Coefficient was 0.98., Conclusion: The results of the study showed that the developed scale has acceptable validity and reliability, and thus can be used to assess the sexual-reproductive needs and concerns of never-married Iranian women of 35 and over., Competing Interests: Conflict of Interests Authors declare no conflict of interests., (Copyright © 2024 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.)

The emergence of resistance against current antimalarial treatments has necessitated the need for the development of novel antimalarial chemotypes. Toward this goal, we recently optimised the antimalarial activity of the dihydroquinazolinone scaffold and showed it targeted PfATP4. Here, we deconstruct the lactam moiety of the tricyclic dihydroquinazolinone scaffold and investigate the structure-activity relationship of the truncated scaffold. It was shown that SAR between scaffolds was largely transferrable and generated analogues with potent asexual stage activity. Evaluation of the truncated analogues against PfATP4 mutant drug-resistant parasite strains and in assays measuring PfATP4-associated ATPase activity demonstrated retention of PfATP4 as the molecular target. Analogues exhibited activity against both male and female gametes and multidrug resistant parasites. Limited efficacy of analogues in a P. berghei asexual stage mouse model was attributed to their moderate metabolic stability and low aqueous stability. Further development is required to address these attributes toward the potential use of the dihydroquinazolinone class in a curative and transmission blocking combination antimalarial therapy., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S -WJM992, were shown to inhibit PfATP4-associated Na + -ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S -WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.

Introduction: Cannabis sativa is a highly versatile plant with a long history of cultivation and domestication. It produces multiple compounds that exert distinct and valuable therapeutic effects by modulating diverse biological systems, including the endocannabinoid system (ECS). Access to standardized, metabolically diverse, and reproducible C. sativa chemotypes and chemovars is essential for physicians to optimize individualized patient treatment and for industries to conduct drug-discovery campaigns., Objective: This study aimed to characterize and assess the phytochemical diversity of C. sativa chemotypes in diverse ecological regions of Colombia, South America., Methodology: Ten cannabinoids and 23 terpenes were measured using liquid and gas chromatography, in addition to other phenotypic traits, in 156 C. sativa plants that were grown in diverse ecological regions in Colombia, a hotspot for global biodiversity., Results: Our results reveal significant phytochemical diversity in Colombian-grown C. sativa plants, with four distinct chemotypes based on cannabinoid profile. The significant amount of usually uncommon terpenes suggests that Colombia's environments may have unique capabilities that allow the plant to express these compounds. Colombia's diverse climates offer enormous cultivation potential, making it a key player in both domestic and international medicinal and recreational C. sativa trade., Conclusion: These findings underscore Colombia's capacity to pioneer global C. sativa production diversification, particularly in South America with new emerging markets., (© 2024 John Wiley & Sons Ltd.)

The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism. Mechanisms underlying pseudohyperaldosteronism include inhibition of adrenal 11β-hydroxylase cytochrome-P450 (CYP) 11B1 and 17α-hydroxylase (CYP17A1) as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazoles have been developed. This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted liquid-chromatography-high-resolution mass-spectrometry (LC-HRMS) indicated overall patterns common to oteseconazole, quilseconazole and itraconazole, as well as similarities between VT-1598 and isavuconazole. Additionally, more specific features of the steroid signatures were observed. Targeted quantification of nine adrenal steroids in supernatants from treated H295R cells revealed an overall inhibition of adrenal steroidogenesis by the three tetrazoles, itraconazole and isavuconazole, providing an explanation for their similar steroidomic pattern. Applying recombinant enzymes indicated that this effect is not due to direct inhibition of steroidogenic enzymes because no or only weak inhibition could be observed. Moreover, oteseconazole and the two other tetrazoles did not inhibit 11β-HSD2, suggesting that they do not pose a risk of pseudohyperaldosteronism. Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia., Competing Interests: Authors TD and SB were employed by the Mycovia Pharmaceuticals Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jäger, González-Ruiz, Joos, Winter, Boccard, Degenhardt, Brand, Rudaz, Thompson and Odermatt.)

Background: Compared to civilians and non-medical personnel, military medical doctors are at increased risk for sleep disturbances and impaired psychological well-being. Despite their responsibility and workload, no research has examined sleep disturbances and psychological well-being among the medical doctors (MDs) of the Swiss Armed Forces (SAF). Thus, the aims of the proposed study are (1) to conduct a cross-sectional study (labeled 'Survey-Study 1') of sleep disturbances and psychological well-being among MDs of the SAF; (2) to identify MDs who report sleep disturbances (insomnia severity index >8), along with low psychological well-being such as symptoms of depression, anxiety and stress, but also emotion regulation, concentration, social life, strengths and difficulties, and mental toughness both in the private/professional and military context and (3) to offer those MDs with sleep disturbances an evidence-based and standardized online interventional group program of cognitive behavioral therapy for insomnia (eCBTi) over a time lapse of 6 weeks (labeled 'Intervention-Study 2')., Method: All MDs serving in the SAF ( N  = 480) will be contacted via the SAF-secured communication system to participate in a cross-sectional survey of sleep disturbances and psychological well-being ('Survey-Study 1'). Those who consent will be provided a link to a secure online survey that assesses sleep disturbances and psychological well-being (depression, anxiety, stress, coping), including current working conditions, job-related quality of life, mental toughness, social context, family/couple functioning, substance use, and physical activity patterns. Baseline data will be screened to identify those MDs who report sleep disturbances (insomnia severity index >8); they will be re-contacted, consented, and randomly assigned either to the eCBTi or the active control condition (ACC) ('Intervention-Study 2'). Individuals in the intervention condition will participate in an online standardized and evidence-based group intervention program of cognitive behavioral therapy for insomnia (eCBTi; once the week for six consecutive weeks; 60-70 min duration/session). Participants in the ACC will participate in an online group counseling (once the week for six consecutive weeks; 60-70 min duration/session), though, the ACC is not intended as a bona fide psychotherapeutic intervention. At the beginning of the intervention (baseline), at week 3, and at week 6 (post-intervention) participants complete a series of self-rating questionnaires as for the Survey-Study 1, though with additional questionnaires covering sleep-related cognitions, experiential avoidance, and dimensions of self-awareness., Expected Outcomes: Survey-Study 1: We expect to describe the prevalence rates of, and the associations between sleep disturbances (insomnia (sleep quality); sleep onset latency (SOL); awakenings after sleep onset (WASO)) and psychological well-being among MDs of the SAF; we further expect to identify specific dimensions of psychological well-being, which might be rather associated or non-associated with sleep disturbances.Intervention-Study 2: We expect several significant condition-by-time-interactions. Such that participants in the eCBTi will report significantly greater improvement in sleep disturbances, symptoms of depression, anxiety, stress reduction both at work and at home (family related stress), and an improvement in the overall quality of life as compared to the ACC over the period of the study., Conclusion: The study offers the opportunity to understand the prevalence of sleep disturbances, including factors of psychological well-being among MDs of the SAF. Further, based on the results of the Intervention-Study 2, and if supported, eCBTi may be a promising method to address sleep disturbances and psychological well-being among the specific context of MDs in the SAF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sadeghi-Bahmani, Rigotti, Stanga, Lang, Blais, Kelley and Brand.)

Sublingual allergen immunotherapy (SLIT) is an emerging treatment option for allergic asthma and a potential disease-modifying strategy for asthma prevention. The key cellular events leading to such long-term tolerance remain to be fully elucidated. We administered prophylactic SLIT in a mouse model of house dust mite (HDM)-driven allergic asthma. HDM extract was sublingually administered over 3 weeks followed by intratracheal sensitization and intranasal challenges with HDM. Prophylactic SLIT prevented allergic airway inflammation and hyperreactivity with a low lab-to-lab variation. The HDM-specific T helper (Th)2 (cluster of differentiation 4 Th) response was shifted by SLIT toward a regulatory and Th17 response in the lung and mediastinal lymph node. By using Derp1-specific cluster of differentiation 4 + T cells (1-DER), we found that SLIT blocked 1-DER T cell recruitment to the mediastinal lymph node and dampened IL-4 secretion following intratracheal HDM sensitization. Sublingually administered Derp1 protein activated 1-DER T cells in the cervical lymph node via chemokine receptor7 + migratory dendritic cells (DC). DCs migrating from the oral submucosa to the cervical lymph node after SLIT-induced Foxp3 + regulatory T cells. When mice were sensitized with HDM, prior prophylactic SLIT increased Derp1 specific regulatory T cells (Tregs) and lowered Th2 recruitment in the lung. By using Foxp3-diphtheria toxin receptor mice, Tregs were found to contribute to the immunoregulatory prophylactic effect of SLIT on type 2 immunity. These findings in a mouse model suggest that DC-mediated functional Treg induction in oral mucosa draining lymph nodes is one of the driving mechanisms behind the disease-modifying effect of prophylactic SLIT., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background : Almost by default, young adult students are at increased risk of suffering from mental health issues, and this holds particularly true for medical students. Indeed, compared to the general population and non-medical students, medical students report higher scores for symptoms of depression. For Swiss medical students, research on the associations between psychiatric characteristics and symptoms of depression and insomnia, including cognitive-emotional processes and social activity, has been lacking so far. Given this, the aims of the present study were to relate self-declared psychiatric characteristics to symptoms of depression, insomnia, emotion regulation, and social activity. Methods : A total of 575 medical students (mean age: 22.4 years; 68.9% females) completed an online survey covering sociodemographic information (age and gender), study context (year of study), self-declared psychiatric characteristics and symptoms of depression, insomnia, emotion regulation (cognitive reappraisal vs. emotion suppression), and social activity. Data on insomnia sum scores and categories of historical samples (862 non-medical students and 533 police and emergency response service officers) were used for comparison. Results : Of the 575 participants, 190 participants (33%) self-declared psychiatric issues, such as major depressive disorder; anxiety disorders, including PTSD and adjustment disorders; eating disorders; ADHD; or a combination of such psychiatric issues. Self-reporting a psychiatric issue was related to higher symptoms of depression and insomnia and lower symptoms of social activity and cognitive reappraisal (always with significant p -values and medium effect sizes). Compared to historical data for non-medical students and police and emergency response service officers, medical students reported higher insomnia scores. In a regression model, current self-declared psychiatric issues, female gender, higher scores for insomnia, and lower scores for social activity were associated with higher scores for depression. Conclusions : Among a sample of Swiss medical students, the occurrence of self-declared psychiatric issues was associated with higher scores for depression and insomnia and lower cognitive reappraisal and social activity. Further, insomnia scores and insomnia categories were higher when compared to non-medical students and to police and emergency response service officers. The data suggest that medical schools might introduce specifically tailored intervention and support programs to mitigate medical students' mental health issues. This holds particularly true for insomnia, as standardized and online-delivered treatment programs for insomnia (eCBTi) are available.

Introduction: The first-line treatment for opioid dependence is opioid agonist treatment (OAT) with oral opioids. However, in some cases, treatment with intravenous diacetylmorphine (IV-DAM) is indicated. Research on neurocognitive impairments and treatment effects of OAT - particularly with IV-DAM - on neurocognitive functioning, is scarce. The current study is the first to investigate the neurocognitive performance of individuals on OAT with IV-DAM. Using a prospective study design with two timepoints of measurement, the first aim was to assess the nature and extent of neurocognitive functioning in individuals with opioid dependence by comparing participants' neurocognitive performance with normative data of the general population on admission to treatment (baseline) and after an initial three-month period of OAT (study end). The second aim was to examine whether and to what extent neurocognitive performance would improve after three months on OAT. The third aim was to investigate whether, and if so, to what extent the treatment method (IV-DAM vs. oral opioids) would lead to higher neurocognitive improvements at study end., Methods: Forty-seven opioid-dependent individuals (baseline; 33 individuals at study end) participated in this study (mean age: 34.3 years; 27.7% female). Participants underwent neuropsychological testing with a battery of 12 tests covering different neurocognitive domains, including attention, memory, and executive functions., Results: Compared to normative data, opioid-dependent individuals showed impairments in almost every test both at baseline and at study end. At baseline, neurocognitive performance did not differ between individuals receiving IV-DAM or oral opioids for OAT. Compared to baseline, the neurocognitive performance did neither improve nor deteriorate after three months of treatment with neither IV-DAM nor oral opioids. However, a trend towards improvement was found for the memory domain., Discussion: Given that neurocognitive impairments should be considered in treatment planning and therapeutic interventions. Since a reduced cognitive performance may affect both the treatment outcome and the therapeutic relationship unfavorably, specific neurocognitive training at the beginning of treatment should be considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chamakalayil, Stohler, Moldovanyi, Gerber, Brand and Dürsteler.)

Subepithelial gastric tumors are a diagnostic challenge. Endoscopic ultrasound allows differentiation. Lesions originating from the submucosal layer can be resected using endoscopic submucosal dissection (ESD). Surgery or endoscopic full-thickness resection (EFTR) techniques are alternatives. We present a patient with an 11 × 8 mm submucosal tumor in the gastric antrum suggestive of a gastrointestinal stromal tumor, originating from the muscularis propria. Eventually endoscopic resection was performed, combining ESD and EFTR (hybrid ESD-EFTR). Contrary to expectations, histology revealed a gastric schwannoma. This case illustrates an efficient and safe endoscopic hybrid technique for the removal of submucosal gastric lesions., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background : For military leaders, military values and virtues are important psychological prerequisites for successful leadership and for ethical and moral military behavior. However, research on predictors of military values and virtues is scarce. Given this background, we investigated whether Organizational Citizenship Behavior (OCB), resilience, and vulnerable narcissism might be favorably or unfavorably associated with military values and virtues, and whether vulnerable narcissism could moderate the association between the OCB-by-resilience-interaction, and military virtues. Methods : A total of 214 officer cadets (mean age: 20.75 years; 96.8% males) of the Swiss Armed Forces (SAF) volunteered to take part in this cross-sectional study. They completed a booklet of self-rating scales covering dimensions of military values and military virtues, OCB, resilience, and vulnerable narcissism. Results : Higher scores for military virtues were associated with higher scores for military values, OCB, and resilience, and with lower scores for vulnerable narcissism. Multiple regression models showed that higher scores for OCB and resilience were associated with military values and virtues. Vulnerable narcissism moderated the association between military virtues, and the OCB-by-resilience-interaction: the higher the vulnerable narcissism, the more the OCB-by-resilience-interaction was associated with lower scores for military virtues. Conclusions : Among cadets of the SAF, the associations between military values, military virtues, OCB, and resilience were highly intertwined, while vulnerable narcissism appeared to attenuate the association between military virtues, OCB, and resilience.

Introduction: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS) is a national cohort that was established in 2015 with the aim of improving quality of care of affected adults with eosinophilic esophagitis (EoE). Between 2020 and 2022, paper questionnaires were gradually replaced by fully electronic data capture using Research Electronic Data Capture (REDCap ® ) software. We aim to provide an update of the SEECS 8 years after its launch., Methods: The SEECS prospectively includes adults (≥18 years of age) with EoE as well as patients with gastroesophageal reflux disease (GERD) and healthy control subjects (HC). Upon inclusion and follow-up (typically once every 12-18 months), patients and physicians complete REDCap ® questionnaires, which are available in German, French, and English. Patient-reported outcomes (PROs) and biologic findings are assessed on the same day using validated instruments (EEsAI PRO for symptoms; EoE-QoL-A for QoL; EREFS for endoscopic activity; modified EoE-HSS for histologic activity). The SEECS biobank includes biosamples from patients with EoE, GERD, and HC., Results: As of July 2023, the SEECS included 778 patients (716 [92%] with EoE, 29 [3.8%] with GERD, and 33 [4.2%] HC; 559/778 [71.9%] were male). Mean age ± SD (years) at enrollment according to diagnosis was as follows: EoE 41.9 ± 12.9, GERD 53.6 ± 16.4, HC 51.7 ± 17.2. Concomitant GERD was found in 200 patients (27.9%) of the EoE cohort. Concomitant allergic disorders (asthma, rhinoconjunctivitis, eczema) were present in 500 EoE patients (74.4%). At inclusion, 686 (95.8%) of EoE patients were on ongoing treatment (orodispersible budesonide tablet [Jorveza ® ] in 281 patients [41%]; budesonide or fluticasone syrup or swallowed powder in 290 patients [42.3%]; proton-pump inhibitors in 162 patients [23.6%]; elimination diets in 103 patients [15%]; and esophageal dilation at last visit in 166 patients [24.2%]). A total of 8,698 biosamples were collected, of which 1,395 (16%) were used in the framework of translational research projects., Conclusion: SEECS continuously grows and is operational using fully electronic data capture. SEECS offers up-to-date epidemiologic and real-world clinical efficacy data on EoE and promotes clinical and translational research., Competing Interests: Jeanine Wakim has no relevant financial, professional, or personal relationships to disclose. Ekaterina Safroneeva reports (i) consulting fees from Avir Pharma, Inc., Aptalis Pharma, Inc., Celgene Corp., Novartis, AG, and Regeneron Pharmaceuticals Inc.; (ii) being an employee of Tillotts Pharma AG. Catherine Saner has no relevant financial, professional, or personal relationships to disclose. Jean-Benoit Rossel has no relevant financial, professional, or personal relationships to disclose. Sven Trelle has no relevant financial, professional, or personal relationships to disclose. Marcel Zwahlen has no relevant financial, professional, or personal relationships to disclose. Luc Biedermann received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Andrea Kreienbuehl has no relevant financial, professional, or personal relationships to disclose. Thomas Greuter received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Philipp Schreiner received consulting fees and/or speaker fees from Dr. Falk Pharma, GmbH, Takeda, Regerenon-Sanofi Pharmaceuticals, AbbVie, Janssen-Cilag, Receptos-Celgene-BMS. Peter Netzer has no relevant financial, professional, or personal relationships to disclose. Annett Franke has no relevant financial, professional, or personal relationships to disclose. Stephan Brand has no relevant financial, professional, or personal relationships to disclose. Chantal Hasler has no relevant financial, professional, or personal relationships to disclose. Patrick Aepli has no relevant financial, professional, or personal relationships to disclose. Emanuel Burri has no relevant financial, professional, or personal relationships to disclose. Achim Weber has no relevant financial, professional, or personal relationships to disclose. Christine Sempoux has no relevant financial, professional, or personal relationships to disclose. Ruggero Biral has no relevant financial, professional, or personal relationships to disclose. Wolfram Jochum has no relevant financial, professional, or personal relationships to disclose. Joachim Diebold has no relevant financial, professional, or personal relationships to disclose. Niels Willi has no relevant financial, professional, or personal relationships to disclose. Alex Straumann received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals. Alain Schoepfer received consulting fees and/or speaker fees and/or research grants from Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Receptos-Celgene-BMS, Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis, AG, Switzerland, and Regeneron-Sanofi Pharmaceuticals., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Recently updated COVID-19 mRNA vaccines encode the spike protein of the omicron subvariant XBB.1.5 and are recommended for patients with inflammatory bowel disease (IBD) on immunosuppressive treatment. Nonetheless, their immunogenicity in patients with IBD against rapidly expanding virus variants remains unknown. This prospective multicenter cohort study is the first study to investigate the immunogenicity of XBB.1.5-adapted vaccines in patients with IBD. Systemic and mucosal antibodies targeting the receptor-binding domains (RBDs) of the omicron subvariants XBB.1.5, EG.5.1, and BA.2.86, as well as their neutralization were quantified before and two to four weeks after vaccination with monovalent XBB.1.5-adapted mRNA vaccines. Vaccination increased levels of serum anti-RBD IgG targeting XBB.1.5, EG.5.1, and BA.2.86 (1.9-fold, 1.8-fold, and 2.6-fold, respectively) and enhanced corresponding neutralization responses (2.3-fold, 3.1-fold, and 3.5-fold, respectively). Following vaccination, anti-TNF-treated patients had reduced virus neutralization compared to patients on treatments with other cellular targets. 11.1% and 16.7% of patients lacked EG.5.1 and BA.2.86 neutralization, respectively; all these patients received anti-TNF treatment. At mucosal sites, vaccination induced variant-specific anti-RBD IgG but failed to induce RBD-targeting IgA. Our findings provide a basis for future vaccine recommendations while highlighting the importance of frequent booster vaccine adaptation and the need for mucosal vaccination strategies in patients with IBD.

Objectives: In a time of exponential growth of new evidence supporting clinical decision-making, combined with a labor-intensive process of selecting this evidence, methods are needed to speed up current processes to keep medical guidelines up-to-date. This study evaluated the performance and feasibility of active learning to support the selection of relevant publications within medical guideline development and to study the role of noisy labels., Design: We used a mixed-methods design. Two independent clinicians' manual process of literature selection was evaluated for 14 searches. This was followed by a series of simulations investigating the performance of random reading versus using screening prioritization based on active learning. We identified hard-to-find papers and checked the labels in a reflective dialogue., Main Outcome Measures: Inter-rater reliability was assessed using Cohen's Kappa (ĸ). To evaluate the performance of active learning, we used the Work Saved over Sampling at 95% recall (WSS@95) and percentage Relevant Records Found at reading only 10% of the total number of records (RRF@10). We used the average time to discovery (ATD) to detect records with potentially noisy labels. Finally, the accuracy of labeling was discussed in a reflective dialogue with guideline developers., Results: Mean ĸ for manual title-abstract selection by clinicians was 0.50 and varied between - 0.01 and 0.87 based on 5.021 abstracts. WSS@95 ranged from 50.15% (SD = 17.7) based on selection by clinicians to 69.24% (SD = 11.5) based on the selection by research methodologist up to 75.76% (SD = 12.2) based on the final full-text inclusion. A similar pattern was seen for RRF@10, ranging from 48.31% (SD = 23.3) to 62.8% (SD = 21.20) and 65.58% (SD = 23.25). The performance of active learning deteriorates with higher noise. Compared with the final full-text selection, the selection made by clinicians or research methodologists deteriorated WSS@95 by 25.61% and 6.25%, respectively., Conclusion: While active machine learning tools can accelerate the process of literature screening within guideline development, they can only work as well as the input given by human raters. Noisy labels make noisy machine learning., (© 2024. The Author(s).)

Over 300 million individuals worldwide suffer from major depressive disorder (MDD). Individuals with MDD are less physically active than healthy people which results in lower cardiorespiratory fitness (CRF) and less favorable perceived fitness compared with healthy controls. Additionally, individuals with MDD may show autonomic system dysfunction. The purpose of the present study was to evaluate the CRF, perceived fitness and autonomic function in in-patients with MDD of different severity compared with healthy controls. We used data from 212 in-patients (age: 40.7 ± 12.6 y, 53% female) with MDD and from 141 healthy controls (age: 36.7 ± 12.7 y, 58% female). We assessed CRF with the Åstrand-Rhyming test, self-reported perceived fitness and autonomic function by heart rate variability (HRV). In specific, we used resting heart rate, time- and frequency-based parameters for HRV. In-patients completed the Beck Depression Inventory-II (BDI-II) to self-assess the subjectively rated severity of depression. Based on these scores, participants were grouped into mild, moderate and severe MDD. The main finding was an inverse association between depression severity and CRF as well as perceived fitness compared with healthy controls. Resting heart rate was elevated with increasing depression severity. The time-based but not the frequency-based autonomic function parameters showed an inverse association with depression severity. The pattern of results suggests that among in-patients with major depressive disorder, those with particularly high self-assessed severity scores show a lower CRF, less favorable perceived fitness and partial autonomic dysfunction compared to healthy controls. To counteract these conditions, physical activity interventions may be effective., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. The PACINPAT trial is funded by the Swiss National Science Foundation (grant number: 321003B-179353). The authors JB, MH, CI, UEL, SM, TM, AO, AR and NS supported the patient screening and recruitment processes on the four study sites. JNK and RC recruited the participants and collected the data. EHT, LD, AE, SB, LZ and MG offered thematic support. JNK and OF were responsible for conceptualizing the manuscript. JNK conducted the statistical analyses. JNK wrote the first draft of the manuscript with assistance of OF. All listed co-authors read, contributed to and approved the final manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cover crops and flower strips are used in agricultural fields as part of integrated pest management strategies. However, their potential as secondary hosts of soilborne pathogens such as Sclerotinia sclerotiorum in oilseed rape cultivation is not fully comprehended. In the current study, we evaluated the effect of pathogen virulence on the development of Sclerotinia stem/leaf rot and sclerotia production in 33 plant species from 11 botanical families using two S. sclerotiorum isolates. Furthermore, the effect of sclerotial size on carpogenic germination was studied. Results showed that the pathogen's virulence significantly affected the occurrence and development of Sclerotinia stem/leaf rot and the subsequent production of sclerotia. Among all plant species tested, 26 were more susceptible to the highly aggressive S . sclerotiorum isolate, which produced more and bigger sclerotia in 17 species than the less aggressive isolate. Moreover, a stronger positive correlation was found between the relative lesion length of plants inoculated with the highly aggressive isolate and the number of sclerotia produced by this isolate (Spearman's rank correlation coefficient [ r s ] = 0.572; P = 0.004). Additionally, we found that larger and heavier sclerotia produced stipes and apothecia earlier and at a greater rate than smaller ones. The heavyweight class had the highest carpogenic germination rate (82.4%), followed by the average (67.2%) and lightweight classes (59.5%). Our findings highlight the need for further investigation into the potential risks associated with cover crops, weeds, and flower strips as secondary hosts of soilborne pathogens in agricultural fields., Competing Interests: The author(s) declare no conflict of interest.

International studies measuring wellbeing/multidimensional mental health before/ during the COVID-19 pandemic, including representative samples for >2 years, identifying risk groups and coping strategies are lacking. COH-FIT is an online, international, anonymous survey measuring changes in well-being (WHO-5) and a composite psychopathology P-score, and their associations with COVID-19 deaths/restrictions, 12 a-priori defined risk individual/cumulative factors, and coping strategies during COVID-19 pandemic (26/04/2020-26/06/2022) in 30 languages (representative, weighted non-representative, adults). T-test, χ 2 , penalized cubic splines, linear regression, correlation analyses were conducted. Analyzing 121,066/142,364 initiated surveys, WHO-5/P-score worsened intra-pandemic by 11.1±21.1/13.2±17.9 points (effect size d=0.50/0.60) (comparable results in representative/weighted non-probability samples). Persons with WHO-5 scores indicative of depression screening (<50, 13% to 32%) and major depression (<29, 3% to 12%) significantly increased. WHO-5 worsened from those with mental disorders, female sex, COVID-19-related loss, low-income country location, physical disorders, healthcare worker occupations, large city location, COVID-19 infection, unemployment, first-generation immigration, to age=18-29 with a cumulative effect. Similar findings emerged for P-score. Changes were significantly but minimally related to COVID-19 deaths, returning to near-pre-pandemic values after >2 years. The most subjectively effective coping strategies were exercise and walking, internet use, social contacts. Identified risk groups, coping strategies and outcome trajectories can inform global public health strategies., Competing Interests: Declaration of competing interest Conflict of interest statements of all authors are detailed in eTable 8., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Replacing crude oil as the primary industrial source of carbon-based chemicals has become crucial for both environmental and resource sustainability reasons. In this scenario, wood arises as an excellent candidate, whilst depolymerization approaches have emerged as promising strategies to unlock the lignin potential as a resource in the production of high-value organic chemicals. However, many drawbacks, such as toxic solvents, expensive catalysts, high energy inputs, and poor product selectivity have represented major challenges to this task. Herein, we present an unprecedented approach using electrocatalysis for the simultaneous depolymerization and dearomatization of lignin in aqueous medium under ambient conditions. By employing water/sodium carbonate as a solvent system, we demonstrated a pathway for selectively depolymerizing lignin under reductive electrochemical conditions using carbon as an electrocatalyst. After reductive electrocatalysis, the presence of aromatic compounds was no longer detected via nuclear magnetic resonance (NMR) spectroscopy. Further characterization by NMR, FTIR spectroscopy, and mass spectrometry revealed the major presences of sodium levulinate, sodium 4-hydroxyvalerate, sodium formate, and sodium acetate as products. By achieving a complete dearomatization, valuable aliphatic intermediates with enhanced reactivity were selectively obtained, opening new avenues for further synthesis of many different organic chemicals, and contributing to a more sustainable and circular economy., (© 2024 Wiley-VCH GmbH.)

We examined the cognitive processes underlying the comprehension of reduced word pronunciation variants in natives and advanced learners of French. In a passive listening visual world task, participants heard sentences containing either a reduced or a full form and saw pictures representing the target word, a phonological competitor and two neutral distractors. After each sentence they saw a picture and had to decide whether it matched the content of that sentence. Eye movements and EEG were recorded simultaneously. Because the two recordings offer complementary information about cognitive processes, we developed methods for analysing the signals in combination. We found a stronger effect of reduction on phonetic processing and semantic integration in learners than in natives, but the effects are different from the N100/N400 and P600 effects found in previous research. Time-locking EEG signals on fixation moments in the eye movements offers a window onto the time course of semantic integration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Malaria is a devastating disease that causes significant morbidity worldwide. The development of new antimalarial chemotypes is urgently needed because of the emergence of resistance to frontline therapies. Independent phenotypic screening campaigns against the Plasmodium asexual parasite, including our own, identified the aryl amino acetamide hit scaffold. In a prior study, we identified the STAR-related lipid transfer protein (PfSTART1) as the molecular target of this antimalarial chemotype. In this study, we combined structural elements from the different aryl acetamide hit subtypes and explored the structure-activity relationship. It was shown that the inclusion of an endocyclic nitrogen, to generate the tool compound WJM-715, improved aqueous solubility and modestly improved metabolic stability in rat hepatocytes. Metabolic stability in human liver microsomes remains a challenge for future development of the aryl acetamide class, which was underscored by modest systemic exposure and a short half-life in mice. The optimized aryl acetamide analogs were cross resistant to parasites with mutations in PfSTART1, but not to other drug-resistant mutations, and showed potent binding to recombinant PfSTART1 by biophysical analysis, further supporting PfSTART1 as the likely molecular target. The optimized aryl acetamide analogue, WJM-715 will be a useful tool for further investigating the druggability of PfSTART1 across the lifecycle of the malaria parasite., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Brad Sleebs reports financial support was provided by National Health and Medical Research Council. Susan Charman reports financial support was provided by National Health and Medical Research Council. Paul Gilson reports financial support was provided by National Health and Medical Research Council. Alan Cowman reports financial support was provided by National Health and Medical Research Council. William Nguyen reports financial support was provided by National Health and Medical Research Council. Tania de Koning Ward reports financial support was provided by National Health and Medical Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cell surface biomarkers are fundamental for specific characterization of human pluripotent stem cells (hPSCs). Importantly, they can be applied for hPSC enrichment and/or purification but also to remove potentially teratoma-forming hPSCs from differentiated populations before clinical application. Several specific markers for hPSCs are glycoconjugates comprising the glycosphingolipid (GSL)-based glycans SSEA-3 and SSEA-4. We applied an analytical approach based on multiplexed capillary gel electrophoresis coupled to laser-induced fluorescence detection to quantitatively assess the GSL glycome of human embryonic stem cells and human induced pluripotent stem cells as well as during early stages of differentiation into mesoderm, endoderm, and ectoderm. Thereby, we identified the GSL lacto-N-tetraosylceramide (Lc4-Cer, Galβ1-3GlcNAcβ1-3Galβ1-4Glc-Cer), which comprises a terminal type 1 LacNAc (T1LN) structure (Galβ1-3GlcNAc), to be rapidly decreased upon onset of differentiation. Using a specific antibody, we could confirm a decline of T1LN-terminating glycans during the first four days of differentiation by live-cell staining and subsequent flow cytometry. We could further separate T1LN-positive and T1LN-negative cells out of a mixed population of pluripotent and differentiated cells by magnetic activated cell sorting. Notably, not only the T1LN-positive but also the T1LN-negative population was positive for SSEA-3, SSEA-4, and SSEA-5 while expression of nuclear pluripotency markers OCT4 and NANOG was highly reduced in the T1LN-negative population, exclusively. Our findings suggest T1LN as a pluripotent stem cell-specific glycan epitope that is more rapidly down-regulated upon differentiation than SSEA-3, SSEA-4, and SSEA-5., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Scientific evidence and everyday experience show that sleep disturbances and self-regulation as a proxy of stress reactivity are linked. Particular personality traits such as neuroticism, internalizing and externalizing problems are also associated with sleep disturbances. Here, we combined self-regulation and personality traits and associated these variables with subjective sleep disturbances. Methods: A total of 846 adults (mean age: 33.7 years; 78.7% females) completed questionnaires covering sleep disturbances, self-regulation and personality traits. Results: Higher scores for sleep disturbances were associated with higher scores for externalization, internalization, and instability and with lower scores for stability (all trait variables) and with poorer self-regulation (state variable). The regression model showed that higher scores for externalization and internalization (traits), and lower scores for self-regulation (state) predicted higher scores for sleep disturbance. Next, self-regulation had both a direct effect on sleep disturbance, and an indirect effect via personality traits. Conclusions: Sleep disturbances were related to both state (i.e., self-regulation) and trait (e.g., internalization and instability) dimensions. The current data analysis leapfrogs the state-trait dichotomy discussion and reconciles the state-and-trait approach in the prediction of poor sleep, though self-regulation appeared to have both direct and indirect effects on sleep disturbances.

Major depressive disorder (MDD) is an increasingly common psychiatric illness associated with a high risk of insufficient physical activity, which in turn is associated with negative mental and physical health outcomes. Theory-based, individually tailored, in-person and remote physical activity counseling has the potential to increase physical activity levels in various populations. Given this, the present study investigated the effect of such a physical activity intervention on the physical activity behavior of in-patients with MDD. This was a multi-center, two-arm randomized controlled trial including initially insufficiently physically active adult in-patients with MDD from four study sites in Switzerland. The sample consisted of 220 participants (M age  = 41 ± 12.6 years, 52% women), 113 of whom were randomized to the intervention group and 107 to the control group. The main outcome, moderate-to-vigorous physical activity (MVPA), was assessed at three time points via hip-worn accelerometer. According to accelerometer measures, there was no significant difference in minutes spent in MVPA over a 12-month intervention period when comparing the intervention with the control group (β = -1.02, 95% CI = -10.68 to 8.64). Higher baseline physical activity significantly predicted physical activity at post and follow-up. This study showed that it is feasible to deliver an individually tailored, theory-based physical activity counseling intervention to in-patients with MDD, however yielding no significant effects on accelerometer-based MVPA levels. Further efforts are warranted to identify efficacious approaches.Trial registration: ISRCTN, ISRCTN10469580, registered on 3rd September 2018, https://www.isrctn.com/ISRCTN10469580 ., (© 2024. The Author(s).)

Background: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT)., Objective: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT., Methods: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort., Results: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p = 0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p = 0.006) for subjects with a higher number of elevated T2 biomarkers., Conclusions: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype., Trial Registration Number: NCT01433523., Competing Interests: Competing interests: IH is an employee of ALK-Abelló A/S. KB has acted as a paid consultant for ALK-Abelló A/S, AstraZeneca, Boehringer Ingelheim and Sanofi. TS is an employee of ALK-Abelló A/S. SB was an employee of ALK-Abelló A/S when data analysis took place. MHS receives grant support via Imperial College London from the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases, Medical Research council, ALK-Abelló A/S, Regeneron, and serves as a consultant for Allergy Therapeutics, Angany, and UCB. EDB is a member of the Science Committee and Board of GINA. He reports personal fees from ALK-Abelló A/S in relation to the current submission, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Novartis, Orion, Regeneron and Sanofi Genzyme, outside the submitted work. EB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme, and has served as a paid consultant for ALK-Abelló A/S, AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, Regeneron, Sanofi Genzyme and TEVA, outside the submitted work. PSA is an employee of ALK-Abelló A/S., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is sufficient evidence that the index-finger-to-ring-finger-ratio (2D:4D-ratio) is associated with testosterone and estrogen exposure during the fetal stage. More specifically, a lower 2D:4D-ratio (that is; a shorter index finger, compared to a longer ring finger) was associated with a prenatally higher testosterone and lower estrogen exposure during the first trimester of the fetal stage. At a behavioral level, among adults, a lower 2D:4D-ratio was associated with a higher competitive performance among both female and male professional athletes, and with personality traits such as higher scores for mental toughness, dark triad traits, and aggressive behavior, and internet use disorder. Here, we tested, if 2D:4D-ratios differed among three clinical samples of individuals with amphetamine use disorder (AUD), antisocial personality disorder (ASPD), or both AUD and ASPD (AUD + ASPD), and when compared to healthy controls., Method: The sample consisted of 44 individuals (mean age: 32.95 years; 22.7% females) diagnosed either with AUD (n = 25), ASPD (n = 10) or both AUD + ASPD (n = 9), and of 36 healthy controls (mean age: 23.28; 25% females). After a thorough clinical assessment, participants provided the scans of their right-hand palm to measure the lengths of their index finger and ring finger. Further, participants with AUD, ASPD and both AUD + ASPD completed a series of self-rating questionnaires on Dark Triad traits, narcissism sensitivity, and intolerance of uncertainty., Results: Compared to healthy controls, participants with AUD, ASPD, or AUD + ASPD showed statistically significantly lower 2D:4D-ratios. Participants with AUD + ASPD showed statistically significantly lowest 2D:4D-ratios, compared to participants with AUD and compared to healthy controls. For the clinical sample, a lower 2D:4D-ratio was associated with higher Dark Triad traits. 2D:4D-ratios were unrelated to narcissism sensitivity or intolerance of uncertainty. Higher scores for Dark Triad traits were associated with higher scores for narcissism sensitivity and intolerance of uncertainty., Conclusions: Compared to healthy controls, individuals with amphetamine use disorder and concomitant antisocial personality disorder (AUD + ASPD) appeared to have been exposed to particularly high prenatal testosterone and particularly low estrogen concentrations, which, at a behavioral level, might have led to a fast life history for immediate resource acquisition., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Within the UK, there is a goal that research is embedded into everyday healthcare practice. Currently education provided to students at pre-registration level is theoretical, with little focus on clinical research delivery., Aims: The paper's aim is to report on the development and evaluation of a pre-registration clinical research resource for nursing and midwifery students with direct application to clinical settings and patient care outcomes., Methods: An initial survey assessed whether the learning resource was useful for nursing pre-registration students. Based on the findings, alongside expert stakeholder input, adaptations were made to the learning resources and a second survey re-evaluated the learning resources. Survey findings were analysed using descriptive statistics. Free text responses were thematically grouped., Results: Ninety-seven pre-registration nursing students responded. Most students agreed that they had enjoyed using the resources, had improved understanding of clinical research, anticipated being actively involved in research and would consider a future clinical research role., Conclusions: The learning resources can help overcome barriers to research engagement by nurses and midwives. The results demonstrate that research can be incorporated into clinical, educational and academic roles, highlighting their worth in supporting the clinical research workforce., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Calcium signaling has essential roles in the neurodevelopmental processes and pathophysiology of related disorders for instance autism spectrum disorder (ASD)., Methods and Results: We compared expression of SLC1A1, SLC25A12, RYR2 and ATP2B2, as well as related long non-coding RNAs, namely LINC01231, lnc-SLC25A12, lnc-MTR-1 and LINC00606 in the peripheral blood of patients with ASD with healthy children. Expression of SLC1A1 was lower in ASD samples compared with control samples (Expression ratio (95% CI) 0.24 (0.08-0.77), adjusted P value = 0.01). Contrary, expression of LINC01231 was higher in cases compared with control samples (Expression ratio (95% CI) 25.52 (4.19-154), adjusted P value = 0.0006) and in male cases compared with healthy males (Expression ratio (95% CI) 28.24 (1.91-418), adjusted P value = 0.0009). RYR2 was significantly over-expressed in ASD children compared with control samples (Expression ratio (95% CI) 4.5 (1.16-17.4), adjusted P value = 0.029). Then, we depicted ROC curves for SLC1A1, LINC01231, RYR2 and lnc-SLC25A12 transcripts showing diagnostic power of 0.68, 0.75, 0.67 and 0.59, respectively., Conclusion: To sum up, the current study displays possible role of calcium related genes and lncRNAs in the development of ASD., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)