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Generalized epilepsy (GE) encompasses a heterogeneous group of hyperexcitability disorders that clinically manifest as seizures. At the whole-brain level, distinct seizure patterns as well as interictal epileptic discharges (IEDs) reflect key signatures of hyperexcitability in magneto- and electroencephalographic (M/EEG) recordings. Moreover, it had been suggested that aperiodic activity, specifically the slope of the 1/ ƒ x decay function of the power spectrum, might index neural excitability. However, it remained unclear if hyperexcitability as encountered at the cellular level directly translates to putative large-scale excitability signatures, amenable to M/EEG. In order to test whether the power spectrum is altered in hyperexcitable states, we recorded resting-state MEG from male and female GE patients ( n  = 51; 29 females; 28.82 ± 12.18 years; mean ± SD) and age-matched healthy controls ( n  = 49; 22 females; 32.10 ± 12.09 years). We parametrized the power spectra using FOOOF ("fitting oscillations and one over f ") to separate oscillatory from aperiodic activity to directly test whether aperiodic activity is systematically altered in GE patients. We further identified IEDs to quantify the temporal dynamics of aperiodic activity around overt epileptic activity. The results demonstrate that aperiodic activity indexes hyperexcitability in GE at the whole-brain level, especially during epochs when no IEDs were present ( p  = 0.0130; d  = 0.52). Upon IEDs, large-scale circuits transiently shifted to a less excitable network state ( p  = 0.001; d  = 0.68). In sum, these results uncover that MEG background activity might index hyperexcitability based on the current brain state and does not rely on the presence of epileptic waveforms., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Kopf et al.)

Background: Bolus administration of adrenaline during cardiopulmonary resuscitation (CPR) results in only short-term increases in systemic and cerebral perfusion pressure (CePP) with unclear effects on cerebral oxygenation. The aim of this study was to investigate the effects of bolus compared to continuous adrenaline administration on cerebral oxygenation in a porcine CPR model., Methods: After five minutes of cardiac arrest, mechanical CPR was performed for 15 min. Adrenaline (45 μg/kg) was administered either as a bolus every five minutes or continuously over the same period via an infusion pump. Main outcome parameter was brain tissue oxygen tension (P bt O 2 ), secondary outcome parameters included mean arterial pressure (MAP), intracranial pressure (ICP), CePP and cerebral regional oxygen saturation (rSO 2 ) as well as arterial and cerebral venous blood gases., Results: During CPR, mean MAP (45 ± 8 mmHg vs. 38 ± 8 mmHg; p  = 0.0827), mean ICP (27 ± 7 mmHg vs. 20 ± 7 mmHg; p  = 0.0653) and mean CePP (18 ± 8 mmHg vs. 18 ± 8 mmHg; p  = 0.9008) were similar in the bolus and the continuous adrenaline group. Also, rSO 2 (both 24 ± 6 mmHg; p  = 0.9903) and cerebral venous oxygen saturation (18 ± 12% versus 27.5 ± 12%; p  = 0.1596) did not differ. In contrast, relative P bt O 2 reached higher values in the continuous group after five minutes of CPR and remained significantly higher than in the bolus group until the end of resuscitation., Conclusion: Continuous administration of adrenaline improved brain tissue oxygen tension compared with bolus administration during prolonged CPR., 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).)

The current meta-analysis examined the mediating role of sensitive-responsive parenting in the relationship between depression in mothers and internalizing and externalizing behavior in children. A systematic review of the path of maternal sensitive responsiveness to child psychopathology identified eligible studies. Meta-analytic structural equation modelling (MASEM) allowed for the systematic examination of the magnitude of the indirect effect across 68 studies ( N  = 15,579) for internalizing and 92 studies ( N  = 26,218) for externalizing psychopathology. The synthesized sample included predominantly White, English-speaking children (age range = 1 to 205 months; M age  = 66 months; 47% female) from Western, industrialized countries. The indirect pathway was small in magnitude and similar for externalizing ( b  = .02) and internalizing psychopathology ( b  = .01). Moderator analyses found that the indirect pathway for externalizing problems was stronger when mother-child interactions were observed during naturalistic and free-play tasks rather than structured tasks. Other tested moderators were not significant.

Chronic noncommunicable diseases are a global health problem causing increased rates of mortality and sick leaves, which can be reduced by controlling dyslipidemia and hyperglycemia. Experimental and clinical studies have demonstrated the antidiabetic, lipid-lowering, antiobesogenic, anti-inflammatory, and antihypertensive properties of cinnamon; therefore, its use in yogurt can help reverse the effects of these diseases. Our study aims to evaluate the effect of a microencapsulated aqueous extract of cinnamon ( Cinnamomum zeylanicum ) (MCE Cz) incorporated in a yogurt drink on metabolic syndrome (MS) in a rabbit ( Oryctolagus cuniculus ). Physicochemical, microbiological, and proximal chemical characterization; total phenol, flavonoid, and 2,2-diphenyl-1-picrylhydrazil activity quantification; intestinal bioaccessibility; sensory analysis; MS induction through diet; and treatment with 5, 10, and 20 mg/kg of flavonoids contained in the MCE Cz were performed to help evaluate morphological, biochemical, and lipid peroxidation measurements in the liver and heart. The results show that the addition of MCE Cz in the yogurt modified the yogurt texture, increased its adhesiveness and firmness, and imparted a characteristic cinnamon color and biological value by providing intestinally bioaccessible antioxidants with antioxidant potential by reducing lipoperoxidation in the liver and heart after treatment. MCE Cz reduced the weight of the animals by up to 38.5% and the abdominal circumference by 29%. Biochemically, it decreased glucose levels by 24.38%, total cholesterol levels by 69.2%, triglyceride levels by 72.69%, and low-density lipoprotein levels by 89.25%; it increased high-density lipoprotein levels by 67.08%. Therefore, adding MCE Cz in doses of 5 and 10 mg of flavonoids in drinkable yogurt can be an alternative to preparing functional foods with physicochemical attributes and biological properties that can be consumed at all stages of life without undesirable effects. Moreover, it can act as a potential adjuvant in the treatment of comorbidities related to MS.

3-tolunitrile (3-TN) can form three different dimers, which differ in the relative orientation of the methyl groups. We determined the geometry changes of two of these conformers of 3-TN upon electronic excitation via a Franck-Condon fit of the vibronic intensities in the fluorescence emission spectra. Both aromatic rings expand upon electronic excitation, showing a delocalized one-photon excitation of the cluster. The conformer with the smaller center-of-mass distance shows an unusual order of the split components of the electronic origin. We attribute this changed order to the stronger charge transfer contributions to the splitting and a partial breakdown of the point dipole approximation, made in the Frenkel type interaction., (© 2024 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Background: Breast cancer is the leading cause of death from cancer in women and is a major public health problem worldwide. Despite the lower incidence rates of breast cancer in resource-limited settings, especially sub-Saharan Africa, there is a higher mortality rate compared to high-resource countries where the disease has a higher incidence. This makes breast cancer the second deadliest cancer in African women. These poor results reflect the weakness in public health policies. The aim of this paper is to contribute to the effective control of breast cancer by designing a framework for a comprehensive and systemic analysis of these policies in Sub-Saharan Africa., Methods: This research is based on a literature review that adopted a systematic approach followed by a modified policy Delphi involving breast cancer experts in Sub-Saharan Africa. We included narrative reviews and systematic reviews/meta-analyses published between 2015 and 2022 as well as official documents in the analysis. We integrated the World Health Organization's health system building blocks with Walt and Gilson's policy analysis triangle to analyse the information collected and develop our analytical framework., Results: A total of 22 reviews and documents were included in the study. Sixteen breast cancer experts from Sub-Saharan Africa participated in the first Delphi round, and nine participated in the second round. The different components identified for a comprehensive and systemic analysis of effective breast cancer policies can be classified into policy content divided according to the health system building blocks and related policy processes; individual, organized national and international policy stakeholders; and policy contexts., Conclusion: This study enabled the design of a framework suitable for the comprehensive and systemic analysis of breast cancer control policies in Sub-Saharan Africa. This framework can be used as a checklist for stakeholders to guide the planning, implementation and evaluation of policies and specific breast cancer control programmes at the national and facility levels., (© 2024. The Author(s).)

Blood clot formation, a crucial process in hemostasis and thrombosis, has garnered substantial attention for its implications in various medical conditions. Microscopic examination of blood clots provides vital insights into their composition and structure, aiding in the understanding of clot pathophysiology and the development of targeted therapeutic strategies. This study explores the use of topological data analysis (TDA) to assess plasma clot characteristics microscopically, focusing on the identification of the elements components, holes and Wasserstein distances. This approach should enable researchers to objectively classify fibrin networks based on their topologic architecture. We tested this mathematical characterization approach on plasma clots formed in static conditions from porcine and human citrated plasma samples, where the effect of dilution and direct thrombin inhibition was explored. Confocal microscopy images showing fluorescence labeled fibrin networks were analyzed. Both treatments resulted in visual differences in plasma clot architecture, which could be quantified using TDA. Significant differences between baseline and diluted samples, as well as blood anticoagulated with argatroban, were detected mathematically. Therefore, TDA could be indicative of clots with compromised stability, providing a valuable tool for thrombosis risk assessment. In conclusion, microscopic examination of plasma clots, coupled with Topological Data Analysis, offers a promising avenue for comprehensive characterization of clot microstructure. This method could contribute to a deeper understanding of clot pathophysiology and thereby refine our ability to assess clot characteristics., (© 2024. The Author(s).)

Background: Normothermic machine perfusion (NMP) of liver grafts has been shown to reduce intraoperative catecholamine consumption and the need for allogenic blood products after reperfusion compared with organs undergoing classical static cold storage (SCS). This study aimed to investigate the effects of an NMP phase after SCS (NMP after SCS) of liver grafts in terms of postreperfusion hemodynamics and transfusion requirements., Methods: Eighteen recipients of NMP after SCS grafts were matched according to recipient age, donor age, and model for end-stage liver disease score in a 1:2 ratio with recipients of an SCS graft. Postreperfusion hemodynamics and the need for catecholamines, blood products, and clotting factors were compared., Results: After reperfusion of the organ, patients in the NMP after SCS group showed significantly reduced transfusion requirements for packed red blood cells and platelet concentrates compared with patients of the SCS group ( P  < 0.001 and P  = 0.018, respectively). In addition, patients in the NMP after SCS group received less fibrinogen concentrate (NMP after SCS group 0 [0-1.5] g versus SCS group 2 [0-4] g; P  = 0.0163). No differences in postreperfusion hemodynamics could be detected between groups., Conclusions: This retrospective analysis shows that NMP reduces postreperfusion requirements of red blood cells, platelet concentrates, and fibrinogen concentrate even if installed after a phase of organ SCS, because it may be practiced on most centers where NMP is available., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Hemodynamic instability after liver graft reperfusion increases recipient morbidity after liver transplantation. The etiologies of hemodynamic disturbances appear to be multifactorial and are poorly understood. Normothermic machine perfusion (NMP) provides an opportunity to analyze graft quality prior to transplantation. In the present study, we aim to investigate the influence of interleukin-6 (IL-6) levels during NMP on postreperfusion hemodynamics of the recipient., Methods: Consecutive NMP-liver transplants at a single-center were prospectively analyzed. Perfusate samples were collected at the beginning, after 6 h, and at the end of perfusion and analyzed for IL-6 levels. Mean arterial pressure (MAP) and catecholamine consumption during surgery were recorded. IL-6 levels at the end of NMP were correlated to donor and perfusion characteristics as well as changes in MAP and catecholamine requirements during the anhepatic and reperfusion phase., Results: IL-6 perfusate measurements were assessed in 77 livers undergoing NMP and transplantation. Donor age, sex, cold ischemic time, and NMP time did not correlate with IL-6 levels. Perfusates of donation after circulatory death grafts showed higher IL-6 levels at the end of NMP than donation after brain death grafts. However, IL-6 levels at the end of NMP correlated with catecholamine requirements and MAP in the reperfusion phase. Per log10 increase in IL-6 levels, an increase of 42% points in administered catecholamine dose was observed, despite MAP being decreased by 3.6% points compared to baseline values., Conclusions: IL-6 levels may be a predictor for recipient hemodynamic instability during liver reperfusion. Larger studies are needed to confirm this finding., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

To ensure the best quality bread, it is important to consider the speed of digestion of starch and proteins, as well as how time fermentation and storage time influence the rate of starch digestion and the texture of the bread. This study compared the effect of fermentation time and days of storage on the texture, physicochemical, protein and starch digestibility of sourdough bread. Texture profile analysis showed that the fermentation time in recently baked sourdough bread affects hardness, chewiness, and springiness. The electrophoretic profile showed a decrease in band thickness with increase in fermentation time, consistent with a higher percentage of protein digestion. While fermentation time did not significantly affect rapidly digestible starch (RDS) and slowly digestible starch (SDS), storage time resulted in a decrease in RDS and an increase in SDS. Sourdough breads had higher levels of resistant starch (RS). The digestibility characteristics of protein and starch, as well as texture properties, are significantly influenced by fermentation and storage time. The evidence suggests that sourdough bread has the potential to improve the digestion of protein and to effectively regulate the glycemic response, which is due to its higher levels of SDS and RS., (© 2024 Wiley Periodicals LLC.)

Background: In nursing education, bridging the gap between theoretical knowledge and practical skills is crucial for developing competence in clinical practice. Nursing students encounter challenges in acquiring these essential skills, making self-efficacy a critical component in their professional development. Self-efficacy pertains to individual's belief in their ability to perform tasks and overcome challenges, with significant implications for clinical skills acquisition and academic success. Previous research has underscored the strong link between nursing students' self-efficacy and their clinical competence. Technology has emerged as a promising tool to enhance self-efficacy by enabling personalized learning experiences and in-depth discussions. However, there is a need for a comprehensive literature review to assess the existing body of knowledge and identify research gaps., Objective: The aim of this study is to systematically map and identify gaps in published studies on the use of technology-supported guidance models to stimulate nursing students' self-efficacy in clinical practice., Methods: This scoping review followed the framework of Arksey and O'Malley and was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). A systematic, comprehensive literature search was conducted in ERIC, CINAHL, MEDLINE, Embase, PsycINFO, and Web of Science for studies published between January 2011 and April 2023. The reference lists of the included papers were manually searched to identify additional studies. Pairs of authors screened the papers, assessed eligibility, and extracted the data. The data were thematically organized., Results: A total of 8 studies were included and four thematic groups were identified: (1) technological solutions for learning support, (2) learning focus in clinical practice, (3) teaching strategies and theoretical approaches for self-efficacy, and (4) assessment of self-efficacy and complementary outcomes., Conclusions: Various technological solutions were adopted in the guidance models to stimulate the self-efficacy of nursing students in clinical practice, leading to positive findings. A total of 7 out of 8 studies presented results that were not statistically significant, highlighting the need for further refinement of the applied interventions. Nurse educators play a pivotal role in applying learning strategies and theoretical approaches to enhance nursing students' self-efficacy, but the contributions of nurse preceptors and peers should not be overlooked. Future studies should consider involving users in the intervention process and using validated instruments tailored to the studies' intervention objectives, ensuring relevance and enabling comparisons across studies., (©Paula Bresolin, Simen A Steindal, Hanne Maria Bingen, Jaroslav Zlamal, Jussara Gue Martini, Eline Kaupang Petersen, Andréa Aparecida Gonçalves Nes. Originally published in JMIR Nursing (https://nursing.jmir.org), 08.03.2024.)

Background: Aim of this study was to evaluate feasibility and effects of individualised flow-controlled ventilation (FCV), based on compliance guided pressure settings, compared to standard of pressure-controlled ventilation (PCV) in a porcine intra-abdominal hypertension (IAH) model. The primary aim of this study was to investigate oxygenation. Secondary aims were to assess respiratory and metabolic variables and lung tissue aeration., Methods: Pigs were randomly assigned to FCV (n = 9) and PCV (n = 9). IAH was induced by insufflation of air into the abdomen to induce IAH grades ranging from 0 to 3. At each IAH grade FCV was undertaken using compliance guided pressure settings, or PCV (n = 9) was undertaken with the positive end-expiratory pressure titrated for maximum compliance and the peak pressure set to achieve a tidal volume of 7 ml/kg. Gas exchange, ventilator settings and derived formulas were recorded at two timepoints for each grade of IAH. Lung aeration was assessed by a computed tomography scan at IAH grade 3., Results: All 18 pigs (median weight 54 kg [IQR 51-67]) completed the observation period of 4 h. Oxygenation was comparable at each IAH grade, but a significantly lower minute volume was required to secure normocapnia in FCV at all IAH grades (7.6 vs. 14.4, MD - 6.8 (95% CI - 8.5 to - 5.2) l/min; p < 0.001). There was also a significant reduction of applied mechanical power being most evident at IAH grade 3 (25.9 vs. 57.6, MD - 31.7 (95% CI - 39.7 to - 23.7) J/min; p < 0.001). Analysis of Hounsfield unit distribution of the computed tomography scans revealed a significant reduction in non- (5 vs. 8, MD - 3 (95% CI - 6 to 0) %; p = 0.032) and poorly-aerated lung tissue (7 vs. 15, MD - 6 (95% CI - 13 to - 3) %, p = 0.002) for FCV. Concomitantly, normally-aerated lung tissue was significantly increased (84 vs. 76, MD 8 (95% CI 2 to 15) %; p = 0.011)., Conclusions: Individualised FCV showed similar oxygenation but required a significantly lower minute volume for CO 2 -removal, which led to a remarkable reduction of applied mechanical power. Additionally, there was a shift from non- and poorly-aerated lung tissue to normally-aerated lung tissue in FCV compared to PCV., (© 2024. The Author(s).)

Objective: In paediatric oncology, little is known about trajectories of illness perceptions and their longitudinal associations with health-related quality of life (HRQoL). Therefore, the aim of this study was to investigate changes in illness perceptions in children and parents over a one-year-period and to investigate predictive value of child's and parent's illness perceptions during acute treatment for child's HRQoL 1 year later., Methods: N = 65 child-parent-dyads participated in a longitudinal study (retention rate: 80.2%). Children were 4-18 years of age and underwent acute cancer treatment at baseline. Children and parents reported on their own illness perceptions (Illness-Perception-Questionnaire-Revised), as well as on the child's HRQoL (KINDL-R) at baseline and one-year-follow-up. Paired-samples t-tests were calculated to investigate changes over time. A hierarchical multiple regression analysis was performed to investigate predictive value of child's and parent's illness perceptions for child's HRQoL., Results: Child's HRQoL t(63) = -6.73, p < 0.001, their perceptions of coherence (i.e. understanding; t(54) = -2.36, p = 0.022) and consequences of their illness (t(54) = 2.86, p = 0.006), and parent's perception of cyclical trajectory (t(61) = 2.06, p = 0.044) improved from baseline to 1-year-follow-up. All other illness perceptions remained stable. Exploratory post-hoc analyses showed differences in the pattern of change in age-, gender-, and diagnosis-specific subgroups. After controlling for baseline levels of HRQoL, child's perceptions of symptoms and consequences were independent predictors of their HRQoL 1 year later (R 2  = 0.396, F(2,52) = 10.782, p < 0.001), whereas no parent's illness perceptions added predictive value., Conclusion: In paediatrics, child's and parent's illness perceptions should be assessed. Our findings highlight the importance of illness perceptions as potential modifiable variables in interventions to improve child's HRQoL., (© 2024 The Authors. Psycho‐Oncology published by John Wiley & Sons Ltd.)

Background: Illness perceptions comprise assumptions about symptoms, timeline, consequences, controllability, and emotional responses to an illness. Recent evidence shows that illness perceptions are associated with coping and well-being. So far, assessment in paediatric care was based on parental report only, since no instrument for the direct assessment of young children was available. We aim to describe the development (incl. indication and contraindication) of an innovative puppet interview to assess illness perceptions in children with cancer from the age of four years. Moreover, we investigate longitudinal trajectories and examine psychometric properties., Methods: The puppet interview was developed based on the Illness-Perception-Questionnaire-Revised and the Berkeley-Puppet-Interview. Longitudinal trajectories and psychometric properties were examined in a sample of patient-parent dyads (N = 75) in a prospective longitudinal study in acute treatment with a 1-year follow-up (study 1: n T1  = 41, n T2  = 27) and in a cross-sectional study in follow-up care (study 2, n = 34)., Results: The puppet interview is comprehensible and well-received by children in acute treatment and follow-up care. There were significant differences in perceptions of a chronic timeline (U = 301.00, p = .008), consequences (U = 251.00, p = .008), and emotional representations (U = 244.50, p = .020) between children in acute treatment and children in follow-up care. Over the course of one year, children in acute treatment perceived more symptoms as part of their illness (M T1  = 3.6, SD T1  = 2.9, M T2  = 4.5, SD T2  = 3.1, n = 27, Z = -2.603, p = .009). We found expected intercorrelations between illness perception dimensions, e.g. between perception of consequences and emotional representations (r τ  = .27, p = .033), and between perception of a chronic timeline and consequences (r τ  = .38, p = .001). Moreover, we found confirming results regarding construct validity, as child's perceptions of symptoms correlated with their self-rated HRQoL (r τ  = -.32, p adj.  = .014). Also parent-rated subscale on illness-specific aspects of child's HRQoL correlated with child's perception of symptoms (r τ  = -.26, p adj.  = .016), cyclicity (r τ  = -.28, p adj.  = .016), and consequences (r τ  = -.34, p adj.  = .014). Acceptable internal consistency was shown for the dimensions timeline-acute/chronic and personal control., Conclusions: Parental report can now be complemented by a self-report of illness perceptions in children aged four years and older. This will allow for the further adaptation of medical and psychosocial care during and after acute cancer treatment., Trial Registration: The study has been pre-registered at the German Clinical Trials Register (registered 30/06/2020; DRK-S00022034) and at the Open Science Foundation ( https://osf.io/7xr6z )., (© 2024. The Author(s).)

Background: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features., Methods: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites ( N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPI bipolar )., Results: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11-0.361) and a balanced accuracy of 63.1% (95% CI 55.9-70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI -0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6-67.8). BARS and EPI bipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance., Conclusions: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long‑term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk., Competing Interests: Declaration of Competing Interest JM, KLB, CB, KL, CS, JM, GJ, AJF, ML, AB, AR, SM, TS, TK, IF, AJ, UD, SKÖ, PFP, LMH, PR, SB, PM, BM and AP state to have no conflict of interest. SKS has received author's and advisory honoraria from Takeda/Shire and Medice Arzneimittel Pütter GmbH in the last 3 years. AR serves on advisory boards and receives speaker's honoraria from Medice, Shire/Takeda, Janssen, neuraxpharm, Servier and SAGE. MB has received grant support from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the European Commission. He served as a consultant to GH Research, Janssen-Cilag, neuraxpharm, Novartis, Shire International, Sunovion, and Takeda, and received fees from Aristo, Hexal, Janssen-Cilag, and Sunovion. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic., (Copyright © 2023. Published by Elsevier B.V.)

Study Objective: Multifactorial comparison of flow-controlled ventilation (FCV) to standard of pressure-controlled ventilation (PCV) in terms of oxygenation in cardiac surgery patients after chest closure., Design: Prospective, non-blinded, randomized, controlled trial., Setting: Operating theatre at an university hospital, Austria., Patients: Patients scheduled for elective, open, on-pump, cardiac surgery., Interventions: Participants were randomized to either individualized FCV (compliance guided end-expiratory and peak pressure setting) or control of PCV (compliance guided end-expiratory pressure setting and tidal volume of 6-8 ml/kg) for the duration of surgery., Measurements: The primary outcome measure was oxygenation (PaO 2 /FiO 2 ) 15 min after intraoperative chest closure. Secondary endpoints included CO 2 -removal assessed as required minute volume to achieve normocapnia and lung tissue aeration assessed by Hounsfield unit distribution in postoperative computed tomography scans., Main Results: Between April 2020 and April 2021 56 patients were enrolled and 50 included in the primary analysis (mean age 70 years, 38 (76%) men). Oxygenation, assessed by PaO 2 /FiO 2 , was significantly higher in the FCV group (n = 24) compared to the control group (PCV, n = 26) (356 vs. 309, median difference (MD) 46 (95% CI 3 to 90) mmHg; p = 0.038). Additionally, the minute volume required to obtain normocapnia was significantly lower in the FCV group (4.0 vs. 6.1, MD -2.0 (95% CI -2.5 to -1.5) l/min; p < 0.001) and correlated with a significantly lower exposure to mechanical power (5.1 vs. 9.8, MD -5.1 (95% CI -6.2 to -4.0) J/min; p < 0.001). Evaluation of lung tissue aeration revealed a significantly reduced amount of non-aerated lung tissue in FCV compared to PCV (5 vs. 7, MD -3 (95% CI -4 to -1) %; p < 0.001)., Conclusions: In patients undergoing on-pump, cardiac surgery individualized FCV significantly improved oxygenation and lung tissue aeration compared to PCV. In addition, carbon dioxide removal was accomplished at a lower minute volume leading to reduced applied mechanical power., Competing Interests: Declaration of Competing Interest Tom Barnes has filed patent applications on calculating and displaying dissipated energy and differentiating airway and tissue resistance and is a paid consultant to Ventinova Medical. Dietmar Enk represents the inventor of EVA and FCV technology (Ventrain, Tritube, Evone), receives royalties for EVA and FCV technology (Ventrain, Tritube, Evone), has filed patent applications on calculating and displaying dissipated energy and differentiating airway and tissue resistance and is a paid consultant to Ventinova Medical. The remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many articles described a massive decline in surgical procedures during the COVID-19 pandemic waves. Especially the reduction in oncologic and emergency procedures led to the concern that delays and cancelling surgical activity might lead to a substantial increase in preventable deaths., Methods: Overall numbers and types of surgery were analysed in a tertiary hospital in Austria during the winter period (October-April) from 2015/16 to 2021/22. The half-years 2019/20, 2020/21 and 2021/22 were defined as pandemic half-years and were compared with the mean results of the previous, four, pre-pandemic half-years., Results: A reduction was found for overall numbers and elective surgeries during 2019/20 (4.62%; p < 0.0001 and 12.14; p < 0.0001 respectively) and 2021/22 (14.94%; p < 0.0001 and 34.27; p < 0.0001 respectively). Oncologic surgery increased during 2021/22 (- 12.59%; p < 0.0001) and remained unchanged during the other periods. Emergency surgeries increased during 2019/20 (- 6.97%; p < 0.0001) and during 2021/22 (- 9.44%; p < 0.0001) and remained unchanged during 2020/21., Conclusions: The concern that the pandemic led to a decrease in oncologic and emergency surgeries cannot be supported with the data from our hospital. A flexible, day-by-day, resource allocation programme with central coordination adhering to hospital resilience recommendations may have helped to adapt to the impact of the COVID-19 pandemic during the first three pandemic half-years., (© 2023. Society of Surgical Oncology.)

Organ transplant patients who must undergo nontransplant surgical interventions can be challenging for the anesthesiologists in charge. On the one hand, it is important to carefully monitor the graft function in the perioperative period with respect to the occurrence of a possible rejection reaction. On the other hand, the ongoing immunosuppression may have to be adapted to the perioperative requirements in terms of the active substance and the route of administration, the resulting increased risk of infection and possible side effects (e.g., myelosuppression, nephrotoxicity and impairment of wound healing) must be included in the perioperative treatment concept. Furthermore, possible persistent comorbidities of the underlying disease and physiological peculiarities as a result of the organ transplantation must be taken into account. Support can be obtained from the expertise of the respective transplantation center., (© 2023. The Author(s).)

Objective: To assess the relationship between the site, ischaemia, neuropathy, bacterial infection, area, depth (SINBAD) score and major adverse foot events in patients with diabetes and foot ulcers., Methods: For this retrospective ancillary study, patients (n = 537) followed for a diabetic foot ulcer (DFU) in six French hospitals were included between 1 February 2019 and 17 March 2019, and between 1 February 2020 and 17 March 2020. The SINBAD score was assessed at inclusion. The frequency of a composite outcome consisting of eight major adverse foot events (MAFE) was assessed after 5-6 months of follow-up: hospitalisation for DFU, septic surgery, revascularisation, minor amputation, major amputation, death, secondary infection and ulcer recurrence. A logistical regression explored the link between the SINBAD score and MAFE and each of its component., Results: A low SINBAD score (from 0 to 3) was observed in 61% of patients and a high (from 4 to 6) in 39%. MAFE occurred in, respectively, 24% and 28% of these patients. Multivariate analyses showed a significant relationship between the SINBAD score and MAFE, with the continuous SINBAD score: odds ratio (OR) 1.72 [95% CI (1.51-1.97)] or dichotomic SINBAD score (values: 0-3 and 4-6): OR 3.71 [95% CI (2.54-5.42)]. The SINBAD score (continuous or dichotomic) at inclusion was also significantly associated with six out of the eight components of the MAFE., Conclusions: The SINBAD score is a useful tool for predicting major adverse foot events., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Many viral infections, including the COVID-19 infection, are associated with the hindrance of blood oxygenation due to the accumulation of fluid, inflammatory cells, and cell debris in the lung alveoli. This condition is similar to Acute Respiratory Distress Syndrome (ARDS). Mechanical positive-pressure ventilation is often used to treat this condition, even though it might collapse pulmonary capillaries, trapping red blood cells and lowering the lung's functional capillary density. We posit that the hyperosmotic-hyperoncotic infusion should be explored as a supportive treatment for ARDS. As a first step in verifying the feasibility of this ARDS treatment, we model the dynamics of alveolar fluid extraction by osmotic effects. These are induced by increasing blood plasma osmotic pressure in response to the increase of blood NaCl concentration. Our analysis of fluid drainage from a plasma-filled pulmonary alveolus, in response to the intravenous infusion of 100 ml of 1.28 molar NaCl solution, shows that alveoli empty of fluid in approximately 15 min. These modeling results are in accordance with available experimental and clinical data; no new data were collected. They are used to calculate the temporal change of blood oxygenation, as oxygen diffusion hindrance decreases upon absorption of the alveolar fluid into the pulmonary circulation. Our study suggests the extraordinary speed with which beneficial effects of the proposed ARDS treatment are obtained and highlight its practicality, cost-efficiency, and avoidance of side effects of mechanical origin., 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 © 2023 Li, Martini, Intaglietta and Tartakovsky.)

DBR1 encodes the only known human lariat debranching enzyme and its deficiency has been found to cause an autosomal recessive inborn error of immunity characterized by pediatric brainstem viral-induced encephalitis (MIM 619441). We describe a distinct allelic disorder caused by a founder recessive DBR1 variant in four families (DBR1(NM&#95;016216.4):c.200A > G (p.Tyr67Cys)). Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. Patient-derived fibroblasts displayed the characteristic accumulation of intron lariats in their RNA as revealed by targeted and untargeted analysis, in addition to a marked reduction of DBR1 on immunoblot analysis. We propose a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility and highlight the apparent lack of correlation with the degree of DBR1 deficiency., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nowadays, the food and health industries are generating new products with antioxidant potential; among them are those rich in phenolic compounds that have a beneficial impact on human health. Therefore, the aim of this research was to obtain different types of mixtures from Portulaca oleraceae (P), Chenopodium album (C), Opuntia oligacantha Förster var. Ulapa (O), and Amaranthus tricolor (A) and evaluate the content of total phenols, total flavonoids, and antioxidant potential in order to select the mixture with the highest content of phenolic compounds. An experimental simplex-centroid mixture design with 15 experimental treatments was used; the data were analyzed and adjusted to a quadratic model that allowed for the prediction of the content of phenols, flavonoids, and antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-Azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid) (ABTS) of different experimental mixtures. The results show that the individual components of C and P had the highest content of phenols and antioxidant potential. It was observed that the binary mixtures P-C and P-A presented values of total phenols greater than 11 mg of gallic acid equivalents g -1 DW and values of flavonoids greater than 13 mg of quercetin equivalents g -1 DW. These values were higher than those found in the individual components. The P-C mixture with an antioxidant potential of 66.0 ± 0.07 Trolox equivalents g -1 DW could be used as an additive in food or to obtain a functional food that improves the intake of antioxidant compounds in the population.

Flavonoids are a large subgroup of polyphenols known to be sourced from over 6000 natural products, including fruits, vegetables, bark, and herbs. Due to their antioxidant properties, flavonoids have been implicated as a therapy source for many diseases and conditions, including inflammation, vasculitis, venous insufficiency, and hemorrhoids. Currently, some flavonoids are being researched for their antioxidant ability concerning neuroprotection. These flavonoids can penetrate the blood-brain barrier and, depending on the specific flavonoid, retain adequate bioavailability in certain brain regions. Further data suggest that flavonoids could have a strong anti-inflammatory effect in the brain, which not only could be a robust therapeutic source for known neuroinflammatory diseases such as Alzheimer's Disease or Parkinson's Disease but also could be a therapeutic source for ischemic or hemorrhagic conditions such as a stroke. While flavonoid toxicity exists, they are relatively safe and non-invasive drugs from natural origins. As such, exploring the known mechanisms and therapies may highlight and establish flavonoid therapy as a viable source of therapy for stroke patients. As stated, many flavonoids are already being isolated, purified, and implemented in both in vitro and in vivo experiments. As these flavonoids proceed to clinical trials, it will be important to understand how they function as a therapy, primarily as antioxidants, and by other secondary mechanisms. This review aims to elucidate those mechanisms and explore the neuroprotective role of flavonoids.

Intraoperative fluid therapy is regularly used in patients undergoing cardiac surgery procedures with cardiopulmonary bypass (CPB). Although fluid administration has several advantages, it unavoidably leads to hemodilution. The hemodilution may further influence the interpretation of concentration-based laboratory parameters like hemoglobin (Hgb), platelet count (PLT) or prothrombin time (PT). These all parameters are commonly used to guide blood product substitution. To assess the impact of dilution on these values, we performed a prospective observational study in 174 patients undergoing elective cardiac surgery. We calculated the total blood volume according to Nadler's formula, and fluid therapy was correlated with a newly developed dilution coefficient formula at the end of CPB. Intravenously applied fluids were measured from the beginning of the anesthesia (baseline, T 0 ) and 15 min after the end of protamine infusion (end of CPB, T 1 ). The amount of the administered volume (crystalloids or colloids) was calculated according to the percentage of the intravascular fluid effect, and intraoperative diuresis was further subtracted. The median blood volume increased by 148% in all patients at T 1 compared to the calculated total blood volume at T 0 . This led to a dilution-dependent decrease of 38% in all three parameters (Hgb 24%, corrCoeff = 0.53; PLT 41%, corrCoeff = 0.68; PT 44%, corrCoeff = 0.54). The dilution-correlated decrease was significant for all parameters ( p < 0.001), and the effect was independent from the duration of CPB. We conclude that the presented calculation-based approach could provide important information regarding actual laboratory parameters and may help in the guidance of the blood product substitution and potential transfusion thresholds. Further research on the impact of dilution and related decision-making for blood product substitution, including its impact on morbidity and mortality, is warranted.

Background: A continuous gas flow provided by flow-controlled ventilation (FCV) facilitates accurate dynamic compliance measurement and allows the clinician to individually optimise positive end-expiratory and peak pressure settings accordingly., Objective: The aim of this study was to compare the efficiency of gas exchange and impact on haemodynamics between individualised FCV and pressure-controlled ventilation (PCV) in a porcine model of oleic acid-induced acute respiratory distress syndrome (ARDS)., Design: Randomised controlled interventional trial conducted on 16 pigs., Setting: Animal operating facility at the Medical University Innsbruck., Interventions: ARDS was induced in lung healthy pigs by intravenous infusion of oleic acid until moderate-to-severe ARDS at a stable Horowitz quotient (PaO 2 FiO 2-1 ) of 80 to 120 over a period of 30 min was obtained. Ventilation was then either performed with individualised FCV ( n  = 8) established by compliance-guided pressure titration or PCV ( n  = 8) with compliance-guided titration of the positive end-expiratory pressure and peak pressure set to achieve a tidal volume of 6 ml kg -1 over a period of 2 h., Main Outcome Measures: Gas exchange parameters were assessed by the PaO 2 FiO 2-1 quotient and CO 2 removal by the PaCO 2 value in relation to required respiratory minute volume. Required catecholamine support for haemodynamic stabilisation was measured., Results: The FCV group showed significantly improved oxygenation [149.2 vs. 110.4, median difference (MD) 38.7 (8.0 to 69.5) PaO 2 FiO 2-1 ; P  = 0.027] and CO 2 removal [PaCO 2 7.25 vs. 9.05, MD -1.8 (-2.87 to -0.72) kPa; P  = 0.006] at a significantly lower respiratory minute volume [8.4 vs. 11.9, MD -3.6 (-5.6 to -1.5) l min -1 ; P  = 0.005] compared with PCV. In addition, in FCV-pigs, haemodynamic stabilisation occurred with a significant reduction of required catecholamine support [norepinephrine 0.26 vs. 0.86, MD -0.61 (-1.12 to -0.09) μg kg -1  min -1 ; P  = 0.037] during 2 ventilation hours., Conclusion: In this oleic acid-induced porcine ARDS model, individualised FCV significantly improved gas exchange and haemodynamic stability compared with PCV., Trial Registration: Protocol no.: BMBWF-66.011/0105-V/3b/2019)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.)

Background: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample., Methods: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001., Results: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger., Conclusion: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition., (© 2023. The Author(s).)

Background: Flow-controlled ventilation (FCV) represents a novel ventilation method, which guarantees a continuous gas flow during inspiration and expiration. Long term comparison to volume- and pressure-controlled ventilation (PCV) after five- and ten hours have shown improved gas exchange parameters and lung tissue aeration. Aim of this porcine trial was to compare gas exchange parameters and lung tissue aeration in short time application of FCV compared to PCV to determine effects which will most probably pertain in short lasting procedures under general anesthesia., Methods: After induction of general anesthesia nine pigs were randomly ventilated either with compliance guided FCV settings or standard of PCV with compliance titrated positive end-expiratory pressure and peak pressure set to achieve a tidal volume of 7 mL/kg. Subsequently an arterial blood gas sample was obtained, and a computed tomography scan was performed. Afterwards, each animal was extubated and on the following day the same protocol was performed again with the alternative ventilation method., Results: Primary analysis of 18 datasets from nine animals (with paired comparison) revealed a significantly improved oxygenation with FCV compared to control (paO2 118 vs. 109, 95% CI 2 to 16 mm Hg; P=0.042). The required respiratory minute volume was significantly lower with FCV (7.4 vs. 10.8, 95% CI -4.0 to -2.9 L/min; P<0.001) to achieve similar levels of normocapnia. However, lung tissue aeration did not significantly differ between ventilation methods., Conclusions: In this short-term ventilation comparison FCV improved gas exchange parameters without differences in lung tissue aeration compared to PCV.

In pressure-controlled ventilation (PCV), a decelerating gas flow pattern occurs during inspiration and expiration. In contrast, flow-controlled ventilation (FCV) guarantees a continuous gas flow throughout the entire ventilation cycle where the inspiration and expiration phases are simply performed by a change of gas flow direction. The aim of this trial was to highlight the effects of different flow patterns on respiratory variables and gas exchange. Anesthetized pigs were ventilated with either FCV or PCV for 1 h and thereafter for 30 min each in a crossover comparison. Both ventilation modes were set with a peak pressure of 15 cmH 2 O, positive end-expiratory pressure of 5 cmH 2 O, a respiratory rate of 20/min, and a fraction of inspired oxygen at 0.3. All respiratory variables were collected every 15 min. Tidal volume and respiratory minute volume were significantly lower in FCV ( n = 5) compared with PCV ( n = 5) animals [4.6 vs. 6.6, MD -2.0 (95% CI -2.6 to -1.4) mL/kg; P < 0.001 and 7.3 vs. 9.5, MD -2.2 (95% CI -3.3 to -1.0) L/min; P = 0.006]. Notwithstanding these differences, CO 2 -removal as well as oxygenation was not inferior in FCV compared with PCV. Mechanical ventilation with identical ventilator settings resulted in lower tidal volumes and consecutive minute volume in FCV compared with PCV. This finding can be explained physically by the continuous gas flow pattern in FCV that necessitates a lower alveolar pressure amplitude. Interestingly, gas exchange was comparable in both groups, which is suggestive of improved ventilation efficiency at a continuous gas flow pattern. NEW & NOTEWORTHY This study examined the effects of a continuous (flow-controlled ventilation, FCV) vs. decelerating (pressure-controlled ventilation, PCV) gas flow pattern during mechanical ventilation. It was shown that FCV necessitates a lower alveolar pressure amplitude leading to reduced applied tidal volumes and consequently minute volume. Notwithstanding these differences, CO 2 -removal as well as oxygenation was not inferior in FCV compared with PCV, which is suggestive of improved gas exchange efficiency at a continuous gas flow pattern.

Purpose of Review: Telepsychiatry practiced by psychiatrists is evidence-based, regulated, private, and effective in diverse settings. The use of telemedicine has grown since the COVID-19 pandemic as people routinely obtain more healthcare services online. At the same time, there has been a rapid increase in the number of digital mental health startups that offer various services including online therapy and access to prescription medications. These digital mental health firms advertise directly to the consumer primarily through digital advertising. The purpose of this narrative review is to contrast traditional telepsychiatry and the digital mental health market related to online therapy., Recent Findings: In contrast to standard telepsychiatry, most of the digital mental health startups are unregulated, have unproven efficacy, and raise concerns related to self-diagnosis, self-medicating, and inappropriate prescribing. The role of digital mental health firms for people with serious mental illness has not been determined. There are inadequate privacy controls for the digital mental health firms, including for online therapy. We live in an age where there is widespread admiration for technology entrepreneurs and increasing emphasis on the role of the patient as a consumer. Yet, the business practices of digital mental health startups may compromise patient safety for profits. There is a need to address issues with the digital mental health startups and to educate patients about the differences between standard medical care and digital mental health products., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI ( n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPI bipolar . We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Background: Children diagnosed with cancer are at increased risk for the development of psychosocial problems. Currently, no qualitative and quantitative tests are available to measure their need for psychosocial follow-up care. The NPO-11 screening was developed to tackle this issue., Patients and Methods: 11 dichotomous items were generated to measure self- and parent-reported fear of progression, sadness, avolition, self-esteem problems, school and vocational problems, somatic complaints, emotional withdrawal, social disintegration, pseudo-maturity, parent-child conflicts, and parental conflicts. Data from N=101 parent-child dyads were obtained to validate the NPO-11., Results: Self- and parent-reported items showed few missing values and response frequencies without floor or ceiling effects. Inter-rater reliability was fair to moderate. Factor analysis confirmed a single-factor model and therefore an overall NPO-11 sum score. Self- and parent-reported sum scores had sufficient to good reliability and large correlations with health-related quality of life., Conclusion: The NPO-11 is a screening for psychosocial needs in pediatric follow-up care with good psychometric properties. It may help to plan diagnostics and interventions for patients transitioning from in-patient to out-patient treatment., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Background: The association between mode of delivery (MOD) and parent-infant-bonding has only been studied in mothers and findings have been inconclusive. The aim of this study was to prospectively investigate how MOD relates to postpartum parent-infant-bonding in both mothers and fathers and whether these associations are mediated by birth experience., Methods: This study is part of the prospective cohort study "Dresden Study on Parenting, Work, and Mental Health" (DREAM). Our sample comprised N = 1,780 participants who completed quantitative questionnaires during pregnancy as well as 8 weeks and 14 months postpartum. MOD was dummy coded, contrasting spontaneous vaginal delivery against vaginal delivery induced by drugs, operative vaginal delivery, planned, and unplanned cesarean section. Parent-infant bonding and birth experience were assessed using validated scales. A moderated mediation analysis based on ordinary least square (OLS) regression and bootstrapped estimates was conducted, considering relevant confounding variables., Results: Compared to spontaneous vaginal delivery, all categories of MOD predicted more negative birth experiences in both parents. A more positive birth experience predicted stronger parent-infant-bonding at 8 weeks, but not at 14 months postpartum. Mothers who delivered via cesarean section (planned or unplanned) reported stronger parent-infant-bonding at 8 weeks and 14 months postpartum. In fathers, only unplanned cesarean section was associated with stronger parent-infant-bonding at 8 weeks postpartum. At 8 weeks postpartum, birth experience mediated the association between a vaginal delivery induced by drugs and a planned cesarean section and mother-infant-bonding and between a vaginal delivery induced by drugs, an operative vaginal delivery, and planned cesarean section and father-infant-bonding. At 14 months postpartum, birth experience mediated the association between a vaginal delivery induced by drugs, operative vaginal delivery, and planned cesarean section and parent-infant-bonding in both parents., Conclusions: The results emphasize the importance of the birth experience for parent-infant-bonding in both mothers and fathers. Further research should address the mechanisms by which parents with an unplanned cesarean section establish stronger parent-infant-bonding compared to parents whose baby was delivered via spontaneous vaginal delivery, despite their overall more negative birth experiences., (© 2023. The Author(s).)

Background: Genetic alterations in lymphatic development can lead to microcystic lymphatic malformations (micro LMs). LMs can have both microcystic and macrocytic components or be exclusively one or the other. LMs can result in serious, sometimes life-threatening, sequelae. Absent consensus guidelines, treatment has been largely empiric. Recent advances in our understanding of the pathogenesis of micro LMs have provided a foundation for novel therapeutic approaches. This review examines clinical data over the last 10 years on the role of sirolimus, an inhibitor of the PI3K/AKT/mTOR signaling pathway implicated in micro LM development, in the treatment of micro LM. Methods and Results: Systematic review of published clinical studies from January 1, 2011, to July 15, 2021, using the PubMed, Google Scholar, and Cochrane Reviews databases, and utilizing delimiters to focus specifically on sirolimus in the treatment of micro LM. A total of 16 studies were identified (13 case studies or case reviews; 3 prospective) that included 52 subjects treated with topical ( n  = 15) or oral ( n  = 37) sirolimus for micro LM. Clinically meaningful, long-term improvement (up to 3 years) was noted in 92% (46/50), mostly previously treated subjects. Sirolimus yielded improvements in key manifestations such as lymphatic leakage, bleeding, vesicle bulk, pain, and skin discoloration. Some subjects experienced a rapid onset of effect (within 2 weeks). No unexpected adverse events were seen. Conclusion: Sirolimus appears to be an effective and safe option in the management of cutaneous and complex micro LM. However, prospective, controlled trials are clearly needed to accurately elucidate the benefits and risks of sirolimus in the management of micro LM. ClinicalTrials.gov Identifier: NCT05050149.

Immunothrombosis, an excessive inflammatory response with simultaneous overactivation of the coagulation system, is a central pathomechanism in sepsis and COVID-19. It is associated with cellular activation, vascular damage, and microvascular thrombosis, which can lead to multiple organ failure and death. Here, we characterized factors related to immunothrombosis in plasma samples from 78 sepsis patients. In the course of routine clinical testing, SARS-CoV-2 was detected in 14 of these patients. Viral infection was associated with a higher mortality. Both, COVID-19 negative and COVID-19 positive sepsis patients showed increased levels of effectors of immunothrombosis, including platelet factor 4, D-dimer, nucleosomes, citrullinated histone H3, high mobility group box-1 protein, as well as phosphatidylserine-expressing platelet-derived extracellular vesicles, compared to healthy controls ( n = 25). Using a 27-plex cytokine bead array, we found that Interleukin (IL)-1ra, IL-6, IL-8, IL-13, tumor necrosis factor (TNF)-α, interferon inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and granulocyte-colony stimulating factor (G-CSF) were elevated in both, COVID-19 negative and COVID-19 positive sepsis patients, as compared to healthy controls. SARS-CoV-2 infection was associated with elevated levels of IP-10, MCP-1, and IL-13, while all other mediators widely overlapped between COVID-19 negative and COVID-19 positive patients.

Background: Although psychotherapy is an important pillar in the treatment of bipolar disorders, alongside pharmacotherapy, non-drug and complementary procedures, there is no up to date evidence synthesis for inpatient psychotherapeutic treatment and work with caregivers., Objective: To review and evaluate the current study situation on evidence-based inpatient psychotherapy for bipolar disorders., Material and Methods: 1.Summary of the evidence for inpatient psychotherapy in adolescents and adults with bipolar disorders from current review articles and guidelines (German S3 guidelines, Australian, Canadian, and British NICE guidelines). 2. Systematic literature search (PRISMA) in Cochrane trials and Medline (via PubMed). 2a. Identification of original articles using the following search term: "bipolar fft" OR "bipolar ipsrt" OR "bipolar cbt" OR "bipolar cognitive remediation" OR "bipolar psychotherapy inpatient". 2b. Screening of n = 942 publications on the following inclusion criteria: randomized controlled efficacy trials, inpatient treatment/recruitment in the inpatient setting, adolescent or adult patients with bipolar disorder or caregivers., Results: The guidelines recommend a combination of pharmacotherapy and psychotherapy for the treatment of patients with bipolar disorders (so far no evidence-based presentation of inpatient psychotherapy). The results from reviews and original papers are heterogeneous. Recently described evidence-based psychotherapeutic approaches for inpatient treatment are family focused therapy (FFT), interpersonal and social rhythm therapy (IPSRT) and psychoeducation., Conclusion: Although the current evidence is heterogeneous and further systematic studies are necessary, the results indicate that psychotherapy should be started or initiated in the inpatient setting with inclusion of caregivers., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: This study examines the role of illness perceptions and fear of progression (FoP) in paediatric cancer patients and their parents for patient's health-related quality of life (HRQoL), controlling for sociodemographic and medical variables. 4-18-year-old patients in acute treatment or follow-up care and one parent were examined., Methods: N = 46 patient-parent dyads in acute treatment and n = 84 dyads in follow-up care completed measures on illness perceptions (Illness-Perceptions-Questionnaire for 12-18-year-old patients and parents or as age-adapted puppet interview for 4-11-year-old patients) and FoP (Fear-of-Progression-Questionnaire for 7-18-year-old patients and parents). Patients also completed the KINDL-R to measure HRQoL. Hierarchical multiple regression analyses were calculated., Results: In acute treatment, patient's perceptions of symptoms and cyclicity of their illness explained variation in their HRQoL in addition to sociodemographic and medical variables. In follow-up care, patient's FoP and parent's perception of consequences explained additional variation in patient's HRQoL. Overall, sociodemographic and medical variables explained less variation in HRQoL in follow-up care than in acute treatment., Conclusions: Our results stress the importance of psychological factors for the well-being of paediatric cancer patients, particularly in follow-up care, where sociodemographic and medical variables play a lesser role. We recommend screening for illness perceptions and FoP during and after acute treatment to support patients and parents. Furthermore, standardized interventions focussed on changing maladaptive illness perceptions should be developed and evaluated. As parents' perceptions, thoughts, and feelings may also play an important role for the well-being of the patients, interventions should be family-focussed and include parents. Trial registration The study has been pre-registered at the German Clinical Trials Register (registered 30/06/2020; DRKS00022034) and at the Open Science Framework ( https://osf.io/3uwrx )., (© 2023. The Author(s).)

Purpose: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified., Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes., Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect., Conclusion: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome., Competing Interests: Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs clinical microarray analysis and other genomic studies (exome sequencing, genome sequencing) for patient and family care. N.A.M.A. is a paid consultant for Noor Diagnostics and Discovery, which performs genetic and genomic studies (exome sequencing, genome sequencing) for patient and family care. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Tyrol, a province of Austria with about 760,000 inhabitants, was one of the first regions in Europe, along with northern Italy, to be affected by the pandemic spread of the coronavirus in spring 2020. A lockdown with far-reaching restrictions in all areas of life occurred from 16 March 2020. Restrictions were imposed in the areas of gastronomy, trade and free mobility as well as in recreational sports. The ski resorts were closed and due to the strong winter tourism in Tyrol, this meant that about 340,000 people left the region. In the province of Tyrol comprehensive emergency medical care is provided by 13 ground-based emergency medical systems (NEF) in combination with air rescue (16 emergency medical helicopters, some of which are seasonal). Normally, this system provides emergency medical care for approx. 1 million people; however, in spring 2020 during the first lockdown, the number of people to be cared for was approx. 30% less. In order to protect the emergency medical teams as best as possible from infections and thus the system from failures, the Integrated Control Center Tyrol (Landesleitstelle Tirol GmbH) adapted the release order for emergency medical resources. The aim of the study is to describe the influence of the pandemic in spring 2020 on the emergency medical services in Tyrol in comparison to the three preceding years., Methods: A retrospective survey of all emergency helicopter missions and ground-based emergency physician missions in Tyrol in the period 15 March 2020-15 May 2020, as well as in the same period of the previous years 2017-2019, was conducted. Detailed figures on medical procedures and patient-related data were collected from 6 ÖAMTC helicopter bases. In addition, all ground-based emergency physician missions from all 13 physician systems including appeal mission diagnoses were collected in the same period., Results: The total number of emergency helicopter missions and ground-based emergency physician missions showed a significant decrease during the observational period (67.3% and 39.8%, respectively). In the area of ground-based emergency medical resources, there was a significant increase in respiratory and CNS diseases during the observational period. The range of emergency helicopter missions showed a significant shift from sports and leisure missions to internal medicine and neurological emergencies and the duration of missions was significantly longer. The NACA score was higher with a significant decrease in NACA 3 scores in favor of NACA 4 and 5. The circulatory status of patients during the observational period was significantly more often documented as unstable. Hypertension, impending shock and circulatory arrest occurred more frequently in the trend. Cardiac massage, oxygen administration, circulatory drugs and specific monitoring were used more frequently in 2020. Analgesics were administered less frequently. In air rescue, there was no infection of rescue workers in the field., Conclusion: The first pandemic wave in Tyrol and the consecutive lockdown from 16 March 2020 had a massive impact on emergency medical care in Tyrol, both quantitatively and in terms of the spectrum of operations and emergency medical interventions. The decline in patient numbers was highly relevant, especially in air rescue and can be explained in part by the discontinuation of tourism, the general exit restrictions and the restrictive disengagement order. This decline primarily affected patients in the NACA 3 category and the analgesic administration measure. The patients treated had a higher NACA score and the emergency procedures were more extensive during the observational period. The measures to protect the emergency helicopter team from infections were presumably successful as no infections occurred., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)