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Abstract Background Premature birth and/or low birthweight have long-lasting effects on cognition. The purpose of the present systematic review is to examine whether the effects of prematurity and/or low birth weight on neurodevelopmental outcomes differ between males and females. Methods Web of Science, Scopus, and Ovid MEDLINE were searched for studies of humans born premature and/or of low birthweight, where neurodevelopmental phenotypes were measured at 1 year of age or older. Studies must have reported outcomes in such a way that it was possible to assess whether effects were greater in one sex than the other. Risk of bias was assessed using both the Newcastle–Ottawa scale and the National Institutes of Health Quality assessment tool for observational cohort and cross-sectional studies. Results Seventy-five studies were included for descriptive synthesis, although only 24 presented data in a way that could be extracted for meta-analyses. Meta-analyses found that severe and moderate prematurity/low birthweight impaired cognitive function, and severe prematurity/low birthweight also increased internalizing problem scores. Moderate, but not severe, prematurity/low birthweight significantly increased externalizing problem scores. In no case did effects of prematurity/low birthweight differ between males and females. Heterogeneity among studies was generally high and significant, although age at assessment was not a significant moderator of effect. Descriptive synthesis did not identify an obvious excess or deficiency of male-biased or female-biased effects for any trait category. Individual study quality was generally good, and we found no evidence of publication bias. Conclusions We found no evidence that the sexes differ in their susceptibility to the effects of severe or moderate prematurity/low birthweight on cognitive function, internalizing traits or externalizing traits. Result heterogeneity tended to be high, but this reflects that one sex is not consistently more affected than the other. Frequently stated generalizations that one sex is more susceptible to prenatal adversity should be re-evaluated.

Abstract Catheter ablation is the most effective treatment for atrial fibrillation (AF). Electrical pulmonary veins isolation (PVI) forms the cornerstone ablation strategy. Radiofrequency (RF) in combination with 3D mapping system is the traditional ablation approach to treat AF. As a single-shot ablation system, cryoballoon (CB) has been an established ablation modality to facilitate PVI procedure. As a novel non-thermal single-shot ablation technology, pulsed field ablation (PFA) has its unique biophysical profile. Recent studies have demonstrated that PFA allows for efficient and durable PVI. However, the manipulation of single-shot ablation catheter may be different from the conventional point-by-point RF ablation catheter; ablation catheter with fixed size may have practical difficulties in variable anatomy and different clinical scenarios. The present article focuses on the technical aspects, describes the procedural approaches and illustrates the practical techniques of using CB and PFA for PVI, ultimately with the purpose to facilitate the ablation procedure and improve the patients’ clinical outcome.

Abstract Background HIV remains one of the most important health issues worldwide, with almost 40 million people living with HIV. Although patients develop antibodies against the virus, its high mutation rate allows evasion of immune responses. Some patients, however, produce antibodies that are able to bind to, and neutralise different strains of HIV. One such ‘broadly neutralising’ antibody is ‘N6’. Identified in 2016, N6 can neutralise 98% of HIV-1 isolates with a median IC50 of 0.066 µg/mL. This neutralisation breadth makes N6 a very promising therapeutic candidate. Results N6 was expressed in a glycoengineered line of N. benthamiana plants (pN6) and compared to the mammalian cell-expressed equivalent (mN6). Expression at 49 mg/kg (fresh leaf tissue) was achieved in plants, although extraction and purification are more challenging than for most plant-expressed antibodies. N-glycoanalysis demonstrated the absence of xylosylation and a reduction in α(1,3)-fucosylation that are typically found in plant glycoproteins. The N6 light chain contains a potential N-glycosylation site, which was modified and displayed more α(1,3)-fucose than the heavy chain. The binding kinetics of pN6 and mN6, measured by surface plasmon resonance, were similar for HIV gp120. pN6 had a tenfold higher affinity for FcγRIIIa, which was reflected in an antibody-dependent cellular cytotoxicity assay, where pN6 induced a more potent response from effector cells than that of mN6. pN6 demonstrated the same potency and breadth of neutralisation as mN6, against a panel of HIV strains. Conclusions The successful expression of N6 in tobacco supports the prospect of developing a low-cost, low-tech production platform for a monoclonal antibody cocktail to control HIV in low-to middle income countries. Graphic abstract

Abstract Background Males and females may experience different effects of early-life adversity on life-long health. One hypothesis is that male foetuses invest more in foetal growth and relatively less in placental growth, and that this makes them susceptible to poor nutrition in utero, particularly if nutrition is reduced part-way through gestation. Objectives Our objectives were to examine whether (1) food and/ or protein restriction in rats and mice has consistent sex-dependent effects, (2) sex-dependency differs between types of outcomes, and (3) males are more severely affected when restriction starts part-way through gestation. Data sources PubMed and Web of Science were searched to identify eligible studies. Study eligibility criteria Eligible studies described controlled experiments that restricted protein or food during gestation in rats or mice, examined physiological traits in offspring from manipulated pregnancies, and tested whether effects differed between males and females. Results Our search identified 292 articles, of which the full texts of 72 were assessed, and 65 were included for further synthesis. A majority (50) used Wistar or Sprague-Dawley rats and so these were the primary focus. Among studies in which maternal diet was restricted for the duration of gestation, no type of trait was consistently more severely affected in one particular sex, although blood pressure was generally increased in both sexes. Meta-analysis found no difference between sexes in the effect of protein restriction throughout gestation on blood pressure. Among studies restricting food in the latter half of gestation only, there were again few consistent sex-dependent effects, although three studies found blood pressure was increased in males only. Meta-analysis found that food restriction in the second half of gestation increased adult blood pressure in both sexes, with a significantly greater effect in males. Birthweight was consistently reduced in both sexes, a result confirmed by meta-analysis. Conclusions We found little support for the hypotheses that males are more affected by food and protein restriction, or that effects are particularly severe if nutrition is reduced part-way through gestation. However, less than half of the studies tested for sex by maternal diet interactions to identify sex-dependent effects. As a result, many reported sex-specific effects may be false positives.

Abstract Background Maternal nutrition during pregnancy has life-long consequences for offspring. However, the effects of maternal overnutrition and/ or obesity on fetal growth remain poorly understood, e.g., it is not clear why birthweight is increased in some obese pregnancies but not in others. Maternal obesity is frequently studied using rodents on high-fat diets, but effects on fetal growth are inconsistent. The purpose of this review is to identify factors that contribute to reduced or increased fetal growth in rodent models of maternal overnutrition. Methods We searched Web of Science and screened 2173 abstracts and 328 full texts for studies that fed mice or rats diets providing ~ 45% or ~ 60% calories from fat for 3 weeks or more prior to pregnancy. We identified 36 papers matching the search criteria that reported birthweight or fetal weight. Results Studies that fed 45% fat diets to mice or 60% fat diets to rats generally did not show effects on fetal growth. Feeding a 45% fat diet to rats generally reduced birth and fetal weight. Feeding mice a 60% fat diet for 4–9 weeks prior to pregnancy tended to increase in fetal growth, whereas feeding this diet for a longer period tended to reduce fetal growth. Conclusions The high-fat diets used most often with rodents do not closely match Western diets and frequently reduce fetal growth, which is not a typical feature of obese human pregnancies. Adoption of standard protocols that more accurately mimic effects on fetal growth observed in obese human pregnancies will improve translational impact in this field.

Abstract Tree frogs have the remarkable ability to attach to smooth, rough, dry, and wet surfaces using their versatile toe pads. Tree frog attachment involves the secretion of mucus into the pad-substrate gap, requiring adaptations towards mucus drainage and pad lubrication. Here, we present an overview of tree frog attachment, with focus on (i) the morphology and material of the toe pad; (ii) the functional demands on the toe pad arising from ecology, lifestyle, and phylogenetics; (iii) experimental data of attachment performance such as adhesion and friction forces; and (iv) potential perspectives on future developments in the field. By revisiting reported data and observations, we discuss the involved mechanisms of attachment and propose new hypotheses for further research. Among others, we address the following questions: Do capillary and hydrodynamic forces explain the strong friction of the toe pads directly, or indirectly by promoting dry attachment mechanisms? If friction primarily relies on van der Waals (vdW) forces instead, how much do these forces contribute to adhesion in the wet environment tree frogs live in and what role does the mucus play? We show that both pad morphology and measured attachment performance suggest the coaction of several attachment mechanisms (e.g. capillary and hydrodynamic adhesion, mechanical interlocking, and vdW forces) with situation-dependent relative importance. Current analytical models of capillary and hydrodynamic adhesion, caused by the secreted mucus and by environmental liquids, do not capture the contributions of these mechanisms in a comprehensive and accurate way. We argue that the soft pad material and a hierarchical surface pattern on the ventral pad surface enhance the effective contact area and facilitate gap-closure by macro- to nanoscopic drainage of interstitial liquids, which may give rise to a significant contribution of vdW interactions to tree frog attachment. Increasing the comprehension of the complex mechanism of tree frog attachment contributes to a better understanding of other biological attachment systems (e.g. in geckos and insects) and is expected to stimulate the development of a wide array of bioinspired adhesive applications.

Abstract Background Pregnancy-associated plasma protein-A2 (PAPP-A2) is consistently upregulated in the placentae of pregnancies complicated by preeclampsia and fetal growth restriction. The causes and significance of this upregulation remain unknown, but it has been hypothesized that it is a compensatory response to improve placental growth and development. We predicted that, if the upregulation of PAPP-A2 in pregnancy complications reflects a compensatory response, then deletion of Pappa2 in mice would exacerbate the effects of a gene deletion previously reported to impair placental development: deficiency of matrix metalloproteinase-9 (MMP9). Methods We crossed mice carrying deletions in Pappa2 and Mmp9 to produce pregnancies deficient in one, both, or neither of these genes. We measured pregnancy rates, number of conceptuses, fetal and placental growth, and the histological structure of the placenta. Results We found no evidence of reduced fertility, increased pregnancy loss, or increased fetal demise in Mmp9 −/− females. In pregnancies segregating for Mmp9, Mmp9 −/− fetuses were lighter than their siblings with a functional Mmp9 allele. However, deletion of Pappa2 did not exacerbate or reveal any effects of Mmp9 deficiency. We observed some effects of Pappa2 deletion on placental structure that were independent of Mmp9 deficiency, but no effects on fetal growth. At G16, male fetuses were heavier than female fetuses and had heavier placentae with larger junctional zones and smaller labyrinths. Conclusions Effects of Mmp9 deficiency were not exacerbated by the deletion of Pappa2. Our results do not provide evidence that upregulation of placental PAPP-A2 represents a mechanism to compensate for impaired fetal growth.

Abstract Background Maternal and neonatal outcomes are influenced by the nature of antenatal care. Standard pregnancy care is provided on an individual basis, with one-on-one appointments between a client and family doctor, midwife or obstetrician. A novel, group-based antenatal care delivery model was developed in the United States in the 1990s and is growing in popularity beyond the borders of the USA. The purpose of this study was to evaluate outcomes in clients receiving interprofessional group perinatal care versus interprofessional individual care in a Canadian setting. Methods Clients attending the South Community Birth Program (SCBP), an interprofessional, collaborative, primary care maternity program, offering both individual and group care, were invited to participate in the study. Pregnancy knowledge and satisfaction scores, and perinatal outcomes were compared between those receiving group versus individual care. Chi-square tests, general linear models and logistic regression were used to compare the questionnaire scores and perinatal outcomes between cohorts. Results Three hundred three clients participated in the study. Group care was comparable to individual care in terms of mode of birth, gestational age at birth, infant birth weight, breastfeeding rates, pregnancy knowledge, preparedness for labour and baby care, and client satisfaction. The rates of adverse perinatal outcomes were extremely low amongst SCBP clients, regardless of the type of care received (preterm birth rates ~5%). Breastfeeding rates were very high amongst all study participants (> 78% exclusive breastfeeding), as were measures of pregnancy knowledge and satisfaction. Conclusions This is the first Canadian study to compare outcomes in clients receiving interprofessional group care versus individual care. Our observation that interprofessional group care outcomes and satisfaction were as good as interprofessional individual care has important implications for the antenatal care of clients and for addressing the projected maternity provider crisis facing Canada, particularly in small and rural communities. Further study of group-based care including not only client satisfaction, but also provider satisfaction, is needed. In addition, research into the role of interprofessional care in meeting the needs and improving perinatal outcomes of different populations is necessary.

Abstract Background Physical activity reduces colorectal cancer risk, yet the diurnal timing of physical activity in colorectal cancer etiology remains unclear. Methods This study used 24-h accelerometry time series from UK Biobank participants aged 42 to 79 years to derive circadian physical activity patterns using functional principal component analysis. Multivariable Cox proportional hazard models were used to examine associations with colorectal cancer risk. Results Among 86,252 participants (56% women), 529 colorectal cancer cases occurred during a median 5.3-year follow-up. We identified four physical activity patterns that explained almost 100% of the data variability during the day. A pattern of continuous day-long activity was inversely associated with colorectal cancer risk (hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.89–0.99). A second pattern of late-day activity was suggestively inversely related to risk (HR = 0.93, 95% CI = 0.85–1.02). A third pattern of early- plus late-day activity was associated with decreased risk (HR = 0.89, 95% CI = 0.80–0.99). A fourth pattern of mid-day plus night-time activity showed no relation (HR = 1.02, 95% CI = 0.88–1.19). Our results were consistent across various sensitivity analyses, including the restriction to never smokers, the exclusion of the first 2 years of follow-up, and the adjustment for shift work. Conclusions A pattern of early- plus late-day activity is related to reduced colorectal cancer risk, beyond the benefits of overall activity. Further research is needed to confirm the role of activity timing in colorectal cancer prevention.

Abstract Background Non-suicidal self-injury (NSSI) is of high clinical relevance due to its high prevalence and negative long-term implications. In 2016, the German consensus-based clinical guidelines for diagnostic, assessment and treatment of NSSI in childhood and adolescence were published. However, research indicates that clinical guidelines are often poorly implemented in clinical practice. One crucial part of this process is the training of healthcare professionals to transfer knowledge and capacities to bring guideline recommendations into clinical practice. Methods The effect of three different dissemination strategies (printed educational material, e-learning, and blended-learning) on the NSSI guidelines´ recommendations was examined among 671 physicians and psychotherapists via an online-survey. The quasi-experimental study included three measurement points (before the training, after the training, 3-month follow-up) and mixed effects models were used to test for changes in knowledge, competences and attitudes toward NSSI and treatment. Moreover, the transfer of gained competences to practical work and user satisfaction were reviewed. Results With all three training formats, the intended changes of the outcome variables could be observed. Hereby, the printed educational material condition showed the lowest improvement in the scores for the ‘negative attitudes toward NSSI and those who self-injure’. The training effect remained stable throughout the follow-up measurement. The highest application rate of acquired intervention techniques in clinical practice was reported for the blended-learning condition. For all three training strategies, user satisfaction was high and evaluation of training quality was positive, with printed educational material receiving the lowest and blended-learning the highest evaluations. Conclusions In summary, all three training formats were perceived to be of high quality and seem to be suited to cover the needs of a heterogeneous group of physicians and psychotherapists. The choice of training method could be driven by considering which training goals are desired to be achieved and by the benefit-cost ratio allowing for tailored training approaches.

Abstract Background Mental health problems, such as depression, have a high prevalence in young people. However, the majority of youths suffering from depression do not seek professional help. This study aimed to compare help-seeking behavior, intentions and perceived barriers between youthswith different levels of depressive symptoms. Methods This cross-sectional study is part of a large-scale, multi-center project. Participants were n = 9509 youths who were recruited in German schools and completed a baseline screening questionnaire. Based on their depressive symptoms, youths were allocated to the following three subgroups: (a) without depressive symptoms, (b) with subclinical symptoms, (c) with clinical symptoms (measured by PHQ-A). Quantitative analyses compared previous help-seeking behavior, help-seeking intentions and perceived barriers (Barriers questionnaire) between these subgroups. An additional exploratory qualitative content analysis examined text answers on other perceived barriers to help-seeking. Results Participants were mostly female (n = 5575, 58.6%) and 12 to 24 years old (M = 15.09, SD 2.37). Participants with different levels of depressive symptoms differed significantly in help-seeking behavior, intentions and perceived barriers. Specifically, participants with clinical depressive symptoms reported more previous help-seeking, but lower intentions to seek help compared to participants without symptoms (all p

Abstract Background The current study evaluated the stepped care approach applied in AtR!Sk; a specialized outpatient clinic for adolescents with BPD features that offers a brief psychotherapeutic intervention (Cutting Down Program; CDP) to all patients, followed by a more intensive Dialectical Behavioral Therapy for Adolescents (DBT-A) for those whose symptoms persist. Methods The sample consisted of 127 patients recruited from two AtR!Sk clinics. The number of BPD criteria, psychosocial functioning, severity of overall psychopathology, number of days with non-suicidal self-injury (NSSI; past month), and the number of suicide attempts (last 3 months) were assessed at clinic entry (T0), after CDP (T1), and at 1- and 2-year follow-up (T2, T3). Based on the T1 assessment (decision criteria for DBT-A: ≥ 3 BPD criteria & ZAN-BPD ≥ 6), participants were allocated into three groups; CDP only (n = 74), CDP + DBT-A (eligible and accepted; n = 36), CDP no DBT-A (eligible, but declined; n = 17). Results CDP only showed significantly fewer BPD criteria (T2: β = 3.42, p

Abstract Background Home treatment in child and adolescent psychiatry offers an alternative to conventional inpatient treatment by involving the patient’s family, school, and peers more directly in therapy. Although several reviews have summarised existing home treatment programmes, evidence of their effectiveness remains limited and data synthesis is lacking. Methods We conducted a meta-analysis on the effectiveness of home treatment compared with inpatient treatment in child and adolescent psychiatry, based on a systematic search of four databases (PubMed, CINAHL, PsychINFO, Embase). Primary outcomes were psychosocial functioning and psychopathology. Additional outcomes included treatment satisfaction, duration, costs, and readmission rates. Group differences were expressed as standardised mean differences (SMD) in change scores. We used three-level random-effects meta-analysis and meta-regression and conducted both superiority and non-inferiority testing. Results We included 30 studies from 13 non-overlapping samples, providing data from 1795 individuals (mean age: 11.95 ± 2.33 years; 42.5% female). We found no significant differences between home and inpatient treatment for postline psychosocial functioning (SMD = 0.05 [− 0.18; 0.30], p = 0.68, I 2 = 98.0%) and psychopathology (SMD = 0.10 [− 0.17; 0.37], p = 0.44, I 2 = 98.3%). Similar results were observed from follow-up data and non-inferiority testing. Meta-regression showed better outcomes for patient groups with higher levels of psychopathology at baseline and favoured home treatment over inpatient treatment when only randomised controlled trials were considered. Conclusions This meta-analysis found no evidence that home treatment is less effective than conventional inpatient treatment, highlighting its potential as an effective alternative in child and adolescent psychiatry. The generalisability of these findings is reduced by limitations in the existing literature, and further research is needed to better understand which patients benefit most from home treatment. Trial registration Registered at PROSPERO (CRD42020177558), July 5, 2020.

Abstract Background Heme-incorporating peroxygenases are responsible for electron transport in a multitude of organisms. Yet their application in biocatalysis is hindered due to their challenging recombinant production. Previous studies suggest Komagataella phaffi to be a suitable production host for heme-containing enzymes. In addition, co-expression of helper proteins has been shown to aid protein folding in yeast. In order to facilitate recombinant protein expression for an unspecific peroxygenase (AnoUPO), we aimed to apply a bi-directionalized expression strategy with Komagataella phaffii. Results In initial screenings, co-expression of protein disulfide isomerase was found to aid the correct folding of the expressed unspecific peroxygenase in K. phaffi. A multitude of different bi-directionalized promoter combinations was screened. The clone with the most promising promoter combination was scaled up to bioreactor cultivations and compared to a mono-directional construct (expressing only the peroxygenase). The strains were screened for the target enzyme productivity in a dynamic matter, investigating both derepression and mixed feeding (methanol-glycerol) for induction. Set-points from bioreactor screenings, resulting in the highest peroxygenase productivity, for derepressed and methanol-based induction were chosen to conduct dedicated peroxygenase production runs and were analyzed with RT-qPCR. Results demonstrated that methanol-free cultivation is superior over mixed feeding in regard to cell-specific enzyme productivity. RT-qPCR analysis confirmed that mixed feeding resulted in high stress for the host cells, impeding high productivity. Moreover, the bi-directionalized construct resulted in a much higher specific enzymatic activity over the mono-directional expression system. Conclusions In this study, we demonstrate a methanol-free bioreactor production strategy for an unspecific peroxygenase, yet not shown in literature. Hence, bi-directionalized assisted protein expression in K. phaffii, cultivated under derepressed conditions, is indicated to be an effective production strategy for heme-containing oxidoreductases. This very production strategy might be opening up further opportunities for biocatalysis.

Abstract Background Disordered eating behaviors (DEBs), a risk factor for the development of eating disorders (EDs), are prevalent in young people and different DEBs frequently co-occur. Previous studies on DEB-patterns have largely used traditional retrospective questionnaires to assess DEBs. In addition, most previous studies did not specifically exclude individuals with clinical EDs, which limits current knowledge concerning purely subclinical patterns of DEBs. In the present study, we aimed to explore phenotypes and group sizes of subclinical patterns of DEBs reported in everyday life via smartphone-based ecological momentary assessment (EMA) in adolescents and young adults from the general population without lifetime EDs. In secondary analyses, we further aimed to investigate whether DEB-patterns would be associated with additional previously identified risk factors for ED-development. Methods EMA was conducted in a community sample of 14–21-year-olds from Dresden, Germany, over four days for up to eight times a day and covered engagement in four DEBs: skipping eating, restrained eating, eating large amounts of food, and loss-of-control eating. Data were analyzed from N = 966 individuals without lifetime EDs with an EMA compliance rate of at least 50% (81.9% of the total sample; average compliance: 84.6%). Latent profile analyses were performed to identify subclinical patterns of DEBs, stratified by sex. Associations between symptomatic profiles and ED-risk factors were tested via regression analyses. Results Based on theoretical deliberations, statistical indices, interpretability, and parsimony, a three-profile solution, namely no DEBs, high-mixed DEBs, and low-mixed DEBs, was selected for both sexes. Both symptomatic profiles in both sexes were associated with more unfavorable manifestations in additional ED risk factors compared to the no DEBs profile, with the highest number of associations being observed in the female high-mixed profile. Conclusions The present findings suggest that problematic manifestations of DEBs in young people may occur even in the absence of an ED diagnosis and that they are associated with additional risk factors for EDs, warranting increased efforts in targeted prevention, early identification and intervention in order to counteract symptom progression.

Abstract Introduction/aim Radiological imaging is crucial in modern clinical practice and requires thorough and early training. An understanding of cross-sectional imaging is essential for effective interpretation of such imaging. This study examines the extent to which completing an undergraduate ultrasound course has positive effects on the development of visual-spatial ability, knowledge of anatomical spatial relationships, understanding of radiological cross-sectional images, and theoretical ultrasound competencies. Material and methods This prospective observational study was conducted at a medical school with 3rd year medical students as part of a voluntary extracurricular ultrasound course. The participants completed evaluations (7-level Likert response formats and dichotomous questions “yes/no”) and theoretical tests at two time points (T1 = pre course; T2 = post course) to measure their subjective and objective cross-sectional imaging skills competencies. A questionnaire on baseline values and previous experience identified potential influencing factors. Results A total of 141 participants were included in the study. Most participants had no previous general knowledge of ultrasound diagnostics (83%), had not yet performed a practical ultrasound examination (87%), and had not attended any courses on sonography (95%). Significant subjective and objective improvements in competencies were observed after the course, particularly in the subjective sub-area of “knowledge of anatomical spatial relationships” (p = 0.009). Similarly, participants showed improvements in the objective sub-areas of “theoretical ultrasound competencies” (p

Abstract Background Despite the introduction of dimensional conceptualisations of personality functioning in the latest classification systems, such as Criterion A of the Alternative Model of Personality Disorders in the DSM-5, heterogeneous clinical presentation of personality pathology remains a challenge. Relatedly, the latent structure of personality pathology as assessed by the Semi-Structured Interview for Personality Functioning DSM-5 (STiP-5.1) has not yet been comprehensively examined in adolescents. Therefore, this study aimed to examine the latent structure of the STiP-5.1, and, based on those findings, to describe any unique clinical profiles that might emerge. Methods The final sample comprised 502 participants aged 11–18 years consecutively recruited from a specialised personality disorder outpatient service, as well as general day clinic and inpatient wards at the University Hospital University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Bern, Switzerland. Participants were assessed using the STiP-5.1, as well as a battery of other psychological measures by clinical psychologists or trained doctoral students. Variations of Factor Analysis, Latent Class Analysis and Factor Mixture Models (FMM) were applied to the STiP-5.1 to determine the most appropriate structure. Results The best fitting model was an FMM comprising four-classes and two factors (corresponding to self- and interpersonal-functioning). The classes differed in both overall severity of personality functioning impairment, and in their scores and clinical relevance on each element of the STiP-5.1. When compared to the overall sample, classes differed in their unique clinical presentation: class 1 had low impairment, class 2 had impairments primarily in self-functioning with high depressivity, class 3 had mixed levels of impairment with emerging problems in identity and empathy, and class 4 had severe overall personality functioning impairment. Conclusions A complex model incorporating both dimensional and categorical components most adequately describes the latent structure of the STiP-5.1 in our adolescent sample. We conclude that Criterion A provides clinically useful information beyond severity (as a dimensional continuum) alone, and that the hybrid model found for personality functioning in our sample warrants further attention. Findings can help to parse out clinical heterogeneity in personality pathology in adolescents, and help to inform early identification and intervention efforts.

Abstract Background Dysphagia, with its negative impact on life expectancy and quality of life, is a major side effect of head and neck squamous cell carcinoma (HNSCC). In a typical Head and Neck Cancer Center, more than half of patients are affected. Improving treatment, and ideally prevention respectively prehabilitation, therefore seems more than desirable. Methods The study is planned as a monocentric, prospective, outcome-blinded, randomized interventional study comparing an advanced phoniatric-logopedic prehabilitation with a control (standard of care). Seventy patients (30 control group, 30 intervention group, 10 drop-out rate of 15%) with an initial diagnosis of invasive HNSCC and curative treatment intention will be included over a period of 17 months. In addition to the previous standard, both groups will undergo both detailed subjective assessment of swallowing function and quality of life by means of various questionnaires and objective analyses by bioelectrical impedance measurements and phoniatric endoscopic swallowing examinations. In the intervention group, risk-related nutritional counseling (face-to-face) and phoniatric-logopedic prehabilitation are provided: detailed counseling with video demonstration and exercises to strengthen and improve the range of motion of the oral, pharyngeal, and laryngeal muscles (guided by exercise diary). Controls are performed at 6 weeks, 3 and 6 months, and 9 or 12 months after the end of therapy during the regular tumor follow-up. Primary study endpoints are swallowing function and emotional distress at 6 weeks of control visit. Discussion Prehabilitation measures have already proven successful in other patient groups, e.g., transplant patients. In the field of head and neck oncology, interest in such concepts has increased significantly in recent years. However, usually, only subgroups, e.g., patients with swallowing problems after radiochemotherapy alone, are in focus. Our study aims to investigate the general benefit of prehabilitation with regard to swallowing function, which is so important for protection of aspiration and quality of life. Trial registration German Clinical Trials Register DRKS00029676 . International Clinical Trials Registry Platform DRKS00029676 . Registered on 19 July 2022.

Abstract Background Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would be warranted, for example to monitor the effects of future Notch-targeting therapies and to learn whether altered Notch signalling is an off-target effect of current breast cancer therapies. In this report, we have established such a classifier. Methods To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated or reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by γ-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent datasets. Results An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2), and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions The 20-gene transcriptional signature will be a valuable tool to evaluate the response of future Notch-targeting therapies for breast cancer, to learn about potential effects on Notch signalling from conventional breast cancer therapies and to better stratify patients for therapy considerations.

Abstract Background Allocation of scarce organs for transplantation is ethically challenging. Artificial intelligence (AI) has been proposed to assist in liver allocation, however the ethics of this remains unexplored and the view of the public unknown. The aim of this paper was to assess public attitudes on whether AI should be used in liver allocation and how it should be implemented. Methods We first introduce some potential ethical issues concerning AI in liver allocation, before analysing a pilot survey including online responses from 172 UK laypeople, recruited through Prolific Academic. Findings Most participants found AI in liver allocation acceptable (69.2%) and would not be less likely to donate their organs if AI was used in allocation (72.7%). Respondents thought AI was more likely to be consistent and less biased compared to humans, although were concerned about the “dehumanisation of healthcare” and whether AI could consider important nuances in allocation decisions. Participants valued accuracy, impartiality, and consistency in a decision-maker, more than interpretability and empathy. Respondents were split on whether AI should be trained on previous decisions or programmed with specific objectives. Whether allocation decisions were made by transplant committee or AI, participants valued consideration of urgency, survival likelihood, life years gained, age, future medication compliance, quality of life, future alcohol use and past alcohol use. On the other hand, the majority thought the following factors were not relevant to prioritisation: past crime, future crime, future societal contribution, social disadvantage, and gender. Conclusions There are good reasons to use AI in liver allocation, and our sample of participants appeared to support its use. If confirmed, this support would give democratic legitimacy to the use of AI in this context and reduce the risk that donation rates could be affected negatively. Our findings on specific ethical concerns also identify potential expectations and reservations laypeople have regarding AI in this area, which can inform how AI in liver allocation could be best implemented.

Abstract Background Point-of-care Ocular Ultrasound (POCOUS) has gained importance in emergency medicine and intensive care in recent years. This work aimed to establish and evaluate a dedicated ultrasound education program for learning POCOUS-specific skills during medical studies at a university hospital. Methods The blended learning-based program (6 teaching units) based on recent scientific publications and recommendations was developed for students in the clinical part of their medical studies. Experts and trainers consisted of physicians from the Ear-Nose-Throat, radiology, ophthalmology and neurology specialties as well as university educational specialists. Lecture notes containing digital video links for preparation was produced as teaching material. In total, 33 students participated in the study. The education program, including the teaching materials, motivation and subjective gain in competency, was evaluated with the aid of a questionnaire (7-point Likert response format). Objective learning success was assessed on the basis of pre- and post-tests. These covered the skill areas: “anatomical basics”, “ultrasound basics”, “understanding of cross-sectional images”, “normal findings” and “pathology recognition”. Results In the objective assessment of image interpretation, the participants improved significantly (p

Abstract Background The human placenta, a tissue with a lifespan limited to the period of pregnancy, is exposed to varying shear rates by maternal blood perfusion depending on the stage of development. In this study, we aimed to investigate the effects of fluidic shear stress on the human trophoblast transcriptome and metabolism. Results Based on a trophoblast cell line cultured in a fluidic flow system, changes caused by shear stress were analyzed and compared to static conditions. RNA sequencing and bioinformatics analysis revealed an altered transcriptome and enriched gene ontology terms associated with amino acid and mitochondrial metabolism. A decreased GLUT1 expression and reduced glucose uptake, together with downregulated expression of key glycolytic rate-limiting enzymes, hexokinase 2 and phosphofructokinase 1 was observed. Altered mitochondrial ATP levels and mass spectrometry data, suggested a shift in energy production from glycolysis towards mitochondrial oxidative phosphorylation. This shift in energy production could be supported by increased expression of glutamic-oxaloacetic transaminase variants in response to shear stress as well as under low glucose availability or after silencing of GLUT1. The shift towards amino acid metabolic pathways could be supported by significantly altered amino acid levels, like glutamic acid, cysteine and serine. Downregulation of GLUT1 and glycolytic rate-limiting enzymes, with concomitant upregulation of glutamic-oxaloacetic transaminase 2 was confirmed in first trimester placental explants cultured under fluidic flow. In contrast, high fluid shear stress decreased glutamic-oxaloacetic transaminase 2 expression in term placental explants when compared to low flow rates. Placental tissue from pregnancies with intrauterine growth restriction are exposed to high shear rates and showed also decreased glutamic-oxaloacetic transaminase 2, while GLUT1 was unchanged and glycolytic rate-limiting enzymes showed a trend to be upregulated. The results were generated by using qPCR, immunoblots, quantification of immunofluorescent pictures, padlock probe hybridization, mass spectrometry and FRET-based measurement. Conclusion Our study suggests that onset of uteroplacental blood flow is accompanied by a shift from a predominant glycolytic- to an alternative amino acid converting metabolism in the villous trophoblast. Rheological changes with excessive fluidic shear stress at the placental surface, may disrupt this alternative amino acid pathway in the syncytiotrophoblast and could contribute to intrauterine growth restriction.

Abstract Background The benefit of physical activity (PA) for increasing longevity is well-established, however, the impact of diurnal timing of PA on mortality remains poorly understood. We aimed to derive circadian PA patterns and investigate their associations with all-cause mortality. Methods We used 24 h PA time series from 96,351 UK Biobank participants aged between 42 and 79 years at accelerometry in 2013–2015. Functional principal component analysis (fPCA) was applied to obtain circadian PA patterns. Using multivariable Cox proportional hazard models, we related the loading scores of these fPCs to estimate risk of mortality. Results During 6.9 years of follow-up, 2,850 deaths occurred. Four distinct fPCs accounted for 96% of the variation of the accelerometry data. Using a loading score of zero (i.e., average overall PA during the day) as the reference, a fPC1 score of + 2 (high overall PA) was inversely associated with mortality (Hazard ratio, HR = 0.91; 95% CI: 0.84–0.99), whereas a score of -2 (low overall PA) was associated with higher mortality (1.69; 95% CI: 1.57–1.81; p for non-linearity

Abstract Introduction Total hip (THA) and knee arthroplasty (TKA) are surgical interventions for patients with primary and posttraumatic osteoarthritis. The present clinical investigation compared gender differences in THA and TKA. Methods Data from 419 patients following primary THA and TKA were collected. The occurrence of systemic and surgery-related complications, the units of blood transfused, and the change in Hb were investigated. Hb was collected preoperatively and at 1, 2, 4 and 7 days postoperatively. Statistical analysis was performed using the software IBM SPSS 28. Results There was no significant difference in surgery-related and general complications in men between THA and TKA. A significant difference between THA and TKA in systemic complications in women was observed. No significant difference between THA and TKA in related to surgery-related complications was evidenced. In men, no difference in Hb progression was observed. In women, a significant Hb drop was evidenced (p = 0.03). The rate of blood transfusion units in women was significantly greater in TKA than in THA (p = 0.001). No statistically significant difference was observed in men in the rate of transfusion between THA and TKA. Conclusion Perioperative care should be organized differently for women and men. Furthermore, a differentiation between the procedures for each sex could prevent the occurrence of perioperative complicated courses.

Abstract Background Early detection and intervention of borderline personality disorder (BPD) in adolescence has become a public health priority. Theoretical models emphasize the role of social interactions and transgenerational mechanisms in the development of the disorder suggesting a closer look at caregiver-child relationships. Methods The current study investigated mother-adolescent interactions and their association with adolescent BPD traits by using a case–control design. Thirty-eight adolescent patients with ≥ 3 BPD traits and their mothers (BPD-G) were investigated in contrast to 35 healthy control dyads (HC-G). Maternal, adolescent and dyadic behavior was coded using the Coding Interactive Behavior Manual (CIB) during two interactions: a fun day planning and a stress paradigm. Additional effects of maternal and/or adolescent early life maltreatment (ELM) on behavior were also explored. Results BPD-G displayed a significantly lower quality of maternal, adolescent and dyadic behavior than the HC-G during both interactions. Maternal and adolescent behavior was predicted by BPD traits alone, whilst dyadic behavior was also influenced by general adolescent psychopathology. Exploratory analyses of CIB subscales showed that whilst HC-G increased their reciprocal behavior during stress compared to the fun day planning, BPD-G dyads decreased it. Maternal ELM did not differ between groups or have any effect on behavior. Adolescent ELM was correlated with behavioral outcome variables, but did not explain behavioral outcomes above and beyond the effect of clinical status. Discussion/Conclusion Our data suggest a stronger focus on parent–child interactions in BPD-specific therapies to enhance long-term treatment outcomes in adolescent BPD patients. Further research employing study designs that allow the analyses of bidirectional transactions (e.g. longitudinal design, behavioral microcoding) is needed.

Abstract Background Externalizing behavior problems are related to social maladjustment. Evidence indicates associations between prenatal stress and child behavioral outcomes. It remains unclear how psychological distress vs. biological correlates of stress (cortisol) differentially predict externalizing behavior, and how their effects might differ as a function of child sex. Method 108 pregnant women from the community collected salivary cortisol and reported their perceived stress during each trimester of pregnancy. At child age 9 years (M = 9.01, SD = 0.55), 70 mothers and children reported on child behavior. Structural equation modelling was used to analyze how cortisol levels and perceived stress during pregnancy predicted current child externalizing behavior, considering the moderating effect of child sex. Results Perceived stress predicted higher externalizing behavior in boys (β = 0.42, p = 0.009) and lower externalizing behavior in girls (β = − 0.56, p = 0.014). Cortisol predicted lower externalizing behavior in boys (β = − 0.81, p

Abstract Background A thorough knowledge of sonography is essential in clinical practice. Therefore, sonography training is increasingly incorporated into the medical school curriculum, entailing different course models. The question arises which model is most effective to convey sustained sonographic skills. Methods Two different peer-assisted learning (PAL) sonography course models were developed as part of a clinical prospective study. The course content was based on the national resident curriculum of the German Society for Ultrasound in Medicine (DEGUM). Model A consists of a 10-week course and model B of a two-day compact course. Each model entailed 20 teaching units (TU). A script was used to prepare for each unit. Two modified OSCE exams of the ultrasound skills (max = 50 points per exam) were performed during the last teaching unit to assess the competence level. For subjective self-assessment and model evaluation, a questionnaire with a 7-point Likert scale was employed. Results A total of 888 students of the 3rd year participated as part of a voluntary elective in the study (744 in model A and 144 in model B). In the exams, participants in model A (median 43 points) scored significantly higher than those in model B (median 39; p

Abstract Background Despite large morphological differences between the nervous systems of lower animals and humans, striking functional similarities have been reported. However, little is known about how these functional similarities translate to cognitive similarities. As a first step towards studying the cognitive abilities of simple nervous systems, we here characterize the ongoing electrophysiological activity of the planarian Schmidtea mediterranea. One previous report using invasive microelectrodes describes that the ongoing neural activity is characterized by a 1/fx power spectrum with the exponent ‘x’ of the power spectrum close to 1. To extend these findings, we aimed to establish a recording protocol to measure ongoing neural activity safely and securely from alive and healthy planarians under different lighting conditions using non-invasive surface electrodes. Results As a replication and extension of the previous results, we show that the ongoing neural activity is characterized by a 1/fx power spectrum, that the exponent ‘x’ in living planarians is close to 1, and that changes in lighting induce changes in neural activity likely due to the planarian photophobia. Conclusions We confirm the existence of continuous EEG activity in planarians and show that it is possible to noninvasively record this activity with surface wire electrodes. This opens up broad possibilities for continuous recordings across longer intervals, and repeated recordings from the same animals to study cognitive processes.

Abstract Background Associations between parent and child cortisol levels (“cortisol synchrony”) are often reported and positive synchrony may mark dyadic regulation on a physiological level. Although dyadic behavior during interaction and adolescent borderline personality disorder (BPD) traits are linked with individual and dyadic regulatory capacities, little is known about how both factors influence parent-adolescent cortisol synchrony. We hypothesized that cortisol synchrony would differ depending on behavioral synchrony, i.e., smooth reciprocal dyadic interaction patterns, adolescent BPD traits, and their interactions. Methods Multilevel state-trait modeling was implemented to investigate associations between concurrent mother-adolescent state cortisol and mother-adolescent average cortisol levels in a community sample of 76 mother-adolescent dyads. Three saliva samples were collected across interaction paradigms. Behavioral synchrony was observed, and adolescent BPD traits were evaluated using clinical interviews. Results First, behavioral synchrony and absence of BPD traits were linked with positive associations between adolescent and maternal state cortisol (positive synchrony), BPD traits with negative associations (negative synchrony). When interaction effects were examined, results were more nuanced. In low-risk dyads (higher behavioral synchrony, no BPD traits) asynchrony was found. When risk (BPD traits) and resource (higher behavioral synchrony) were combined, synchrony was positive. Lastly, in high-risk dyads (lower behavioral synchrony, adolescent BPD traits), negative synchrony was observed. Average adolescent and maternal cortisol levels were consistently positively associated in dyads with higher risk. Conclusions Positive dyadic interaction patterns are associated with positive state cortisol synchrony in mother-adolescent dyads and could buffer the effect of BPD traits, possibly supporting the process of physiological regulation.

Abstract Background The yeast Komagataella phaffii (Pichia pastoris) is routinely used for heterologous protein expression and is suggested as a model organism for yeast. Despite its importance and application potential, no reference gene for transcript analysis via RT-qPCR assays has been evaluated to date. In this study, we searched publicly available RNASeq data for stably expressed genes to find potential reference genes for relative transcript analysis by RT-qPCR in K. phaffii. To evaluate the applicability of these genes, we used a diverse set of samples from three different strains and a broad range of cultivation conditions. The transcript levels of 9 genes were measured and compared using commonly applied bioinformatic tools. Results We could demonstrate that the often-used reference gene ACT1 is not very stably expressed and could identify two genes with outstandingly low transcript level fluctuations. Consequently, we suggest the two genes, RSC1, and TAF10 to be simultaneously used as reference genes in transcript analyses by RT-qPCR in K. phaffii in future RT-qPCR assays. Conclusion The usage of ACT1 as a reference gene in RT-qPCR analysis might lead to distorted results due to the instability of its transcript levels. In this study, we evaluated the transcript levels of several genes and found RSC1 and TAF10 to be extremely stable. Using these genes holds the promise for reliable RT-qPCR results.

Abstract Background Vascular surgery of the inguinal area can be complicated by persistent lymphatic fistulas. Rapid and effective treatment is essential to prevent infection, sepsis, bleeding, and possible leg amputation. Current data on irradiation of lymphatic fistulas lack recommendation on the appropriate individual and total dose, the time of irradiation, and the target volume. Presumably, a dose of 0.3–0.5 to 1–12 Gy should be sufficient for the purpose. Currently, radiotherapy is a “can” recommendation, with a level 4 low evidence and a grade C recommendation, according to the DEGRO S2 guidelines. As part of a pilot study, we analyzed the impact and limitations of low-dose radiation therapy in the treatment of inguinal lymphatic fistulas. Patients and methods As a part of an internal quality control project, patients with lymphatic fistulas irradiated in the groin area after vascular surgery for arterial occlusive disease (AOD) III-IV, repair of pseudo aneurysm or lymph node dissection due to melanoma were selected, and an exploratory analysis on retrospectively collected data performed. Results Twelve patients (10 males and 2 females) aged 62.83 ± 12.14 years underwent open vascular reconstruction for stage II (n = 2), III (n = 1), and IV (n = 7) arterial occlusive disease (AOD), lymph node dissection for melanoma (n = 1) or repair of a pseudoaneurysm (n = 1). Surgical vascular access was obtained through the groin and was associated with a persistent lymphatic fistula, secreting more than 50 ml/day. Patients were irradiated five times a week up to a maximum of 10 fractions for the duration of the radiation period. Fraction of 0.4 Gy was applied in the first 7 cases, while 5 patients were treated with a de-escalating dose of 0.3 Gy. There was a resolution of the lymphatic fistula in every patient without higher grade complications. Conclusion Low-dose irradiation of the groin is a treatment option for persistent lymphatic fistula after inguinal vascular surgery.

Abstract Background Phosphorus (P) is an essential macronutrient required for plant metabolism and growth. Its acquisition by plants depends on the availability of dissolved P in the rhizosphere and on the characteristics of P uptake mechanisms such as root-system architecture (RSA). Compared to other crops, potato (Solanum tuberosum L.) has a relatively poor P acquisition efficiency. This is mainly due to its shallow and sparsely branched root system, resulting in a rather limited exploitable soil volume. Information about potato genotypes with RSA traits suitable to improve adaptation to nutrient scarcity is quite rare. Aim of this study is to assess phenotypic variation of RSA in a potato diversity set and its reactions to P deficiency. Results Only one out of 22 RSA-traits showed a significant increase under low-P conditions. This indicates an overall negative effect of P scarcity on potato root growth. Differences among genotypes, however, were statistically significant for 21 traits, revealing a high variability in potato RSA. Using a principal component analysis (PCA), we were able to classify genotypes into three groups with regard to their root-system size. Genotypes with both small and large root systems reacted to low-P conditions by in- or decreasing their relative root-system size to medium, whereas genotypes with an intermediate root system size showed little to no changes. Conclusions We observed a huge variation in both the potato root system itself and its adaptation to P deficiency. This may enable the selection of potato genotypes with an improved root-zone exploitation. Eventually, these could be utilized to develop new cultivars adapted to low-P environments with better resource-use efficiencies.

Abstract Background Vaccination against SARS-CoV-2 has been the main tool to contain the pandemic. The rush development of the 3 vaccines and their expedited approval have led to inoculation of millions of patients around the world, leading to a containment of the disease. Despite continuous viral mutations and the identification of weaker variants, the severity of the infections has been mild, with many patients being either asymptomatic or recovering at home. Currently the focus has shifted from the host of organ damage related to the infection to potential side effects of the vaccine. Myocarditis has been reported as one of the potential side effects from the mRNA vaccine, affecting young healthy individuals. Up to September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty© were registered in young adults by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty© or mRNA-1237 Moderna, Spikevax©). Patients and methods Eight patients between 13 and 56 years of age, vaccinated with either BNT162b2 or mRNA-1273 mRNA vaccine between January and August 2021 developed cardiac side effects shortly after either their first or second dose of the vaccine. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after the onset of symptoms, with further investigations in severe cases. Symptoms were defined as dyspnea, chest pain and cardiac arrhythmia as determined by electrocardiography. Results Eight patients (5 males and 3 females) developed cardiac symptoms compatible with myocarditis, according to the CDC criteria, shortly after SARS-CoV-2 mRNA vaccination. Three patients (2 males, 1 female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within 7 days from the symptom onset. Conclusions Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients.

Abstract Background Risk literacy, i.e., the ability to calculate and apply risk parameters, represents a key competence for risk communication and medical decision making. However, risk literacy is reportedly low in medical students. The successful acquisition of statistical competencies is often difficult, and can be hampered by emotional learning obstacles, calling for interventions to support learning. In this cluster-randomized study, we aimed to translate findings from placebo research to medical education. Specifically, we tested if the acquisition of risk literacy during a seminar unit can be facilitated by positive expectations, induced by a positive and non-threatening framing of the content and learning goals. Methods The study took place during a mandatory 2.5-h seminar on “risk literacy” for 2nd year medical students. The seminar teaches both statistical knowledge and its application in patient communication. To test the effects of expectations on risk literacy acquisition, the (otherwise identical) seminar was framed either as “communication training” (positive framing condition) or “statistics seminar” (negative framing condition). All N = 200 students of the semester were invited to participate, and cluster-randomized to the positive or negative framing condition (4 seminar groups each condition). Risk literacy was assessed with the “Quick Risk Test” (QRT) at the beginning and end of the seminar, along with statistics anxiety and subjective learning success using questionnaires. Results Data from N = 192 students were included. At the end of the seminar, risk literacy was increased in both framing conditions, with a significantly greater increase in QRT scores in the positive framing condition. Statistics anxiety was significantly decreased in both framing conditions, with no evidence of group differences. Subjective learning success was overall high and comparable between groups. Conclusions Supporting our hypothesis, positive framing led to a significantly greater increase in risk literacy (i.e., in QRT scores). Our data offer first support that positive framing of learning goals may help to facilitate the acquisition of statistical knowledge. Expectation-orientated interventions may thus offer a feasible tool to optimize learning settings and framing of learning objectives in medical statistics courses.

Abstract Purpose During the severe acute respiratory syndrome coronavirus 2 pandemic, several patient groups are at particular risk. Mortality is higher among cancer patients and may be increased further by thromboembolic events, which are more common in coronavirus 2019 patients according to recent publications. We discuss the association of gynecologic malignancies, Severe acute respiratory syndrome coronavirus 2, and thromboembolism by reporting a case study and summarizing available literature. Case report A 71-year-old Caucasian patient with ovarian cancer receiving first-line chemotherapy was diagnosed with deep vein thrombosis and pulmonary embolism. Routine screening revealed infection with severe acute respiratory syndrome coronavirus 2 in absence of specific symptoms. After uneventful recovery, oncologic treatment could be continued a few weeks later. Methods We performed a systematic review of the literature on PubMed following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The search included articles ahead of print, published between 1 December 2019 and 1 June 2020. Cross-searches were conducted on all relevant articles. Results We identified five articles meeting the defined criteria, including two retrospective studies, a review, a position paper, as well as a letter to the editor. Conclusion Cancer patients infected with severe acute respiratory syndrome coronavirus 2 have a relatively poor outcome, which may partially be due to a higher rate of thromboembolic events. Thromboprophylaxis is recommended, and scoring systems are helpful in early detection. In cancer patients with severe acute respiratory syndrome coronavirus 2, individual risk for thromboembolic events should be taken into account when considering interruption versus continuation of antitumoral therapy. However, further data and studies are required.

Abstract Background To establish effective infection control protocols, understanding pathogen transmission pathways is essential. Non-infectious surrogate tracers may safely explore these pathways and challenge pre-existing assumptions. We used silica nanoparticles with encapsulated DNA (SPED) for the first time in a real-life hospital setting to investigate potential transmission routes of vancomycin-resistant enterococci in the context of a prolonged outbreak. Methods The two study experiments took place in the 900-bed University Hospital Zurich, Switzerland. A three-run ‘Patient experiment’ investigated pathogen transmission via toilet seats in a two-patient room with shared bathroom. First, various predetermined body and fomite sites in a two-bed patient room were probed at baseline. Then, after the first patient was contaminated with SPED at the subgluteal region, both patients sequentially performed a toilet routine. All sites were consequently swabbed again for SPED contamination. Eight hours later, further spread was tested at predefined sites in the patient room and throughout the ward. A two-run ‘Mobile device experiment’ explored the potential transmission by mobile phones and stethoscopes in a quasi-realistic setting. All SPED contamination statuses and levels were determined by real-time qPCR. Results Over all three runs, the ‘Patient experiment’ yielded SPED in 59 of 73 (80.8%) predefined body and environmental sites. Specifically, positivity rates were 100% on subgluteal skin, toilet seats, tap handles, and entertainment devices, the initially contaminated patients’ hands; 83.3% on patient phones and bed controls; 80% on intravenous pumps; 75% on toilet flush plates and door handles, and 0% on the initially not contaminated patients’ hands. SPED spread as far as doctor’s keyboards (66.6%), staff mobile phones (33.3%) and nurses’ keyboards (33.3%) after eight hours. The ‘Mobile device experiment’ resulted in 16 of 22 (72.7%) positive follow-up samples, and transmission to the second patient occurred in one of the two runs. Conclusions For the first time SPED were used to investigate potential transmission pathways in a real hospital setting. The results suggest that, in the absence of targeted cleaning, toilet seats and mobile devices may result in widespread transmission of pathogens departing from one contaminated patient skin region.

Abstract Introduction Patient suicidality is a frequently experienced topic for psychotherapists. Especially adolescents with borderline personality pathology (BPP) often exhibit suicidal tendencies. Previous research which examined therapists’ countertransference towards suicidal patients suggested that therapists are negatively affected and distressed by them. We hypothesize that this emotional response of the therapists is related to specific sessions in which suicidality came up as a topic. Accordingly, the objective of this study consists in examining therapists’ emotional state on a session level of analysis. Methods The sample consisted of N = 21 adolescents (age 13–19 years) with BPD or subthreshold BPD. Therapists’ emotional states were measured in n = 418 sessions using the Session Evaluation Questionnaire. Principal component analysis was used to reduce dimensionality of the therapist response. The emotional states were compared depending on whether suicidality has been addressed in the session (SS) or not (NSS). Results Two components could be identified. Firstly, therapists were more aroused, excited, afraid, angry and uncertain after SS than after NSS. Secondly, therapists were more aroused, excited, definite and pleased after SS than after NSS. Discussion: Suicidality does not always have to be a burden for therapists: Both a “distress” and an “eustress” component occur in this context from which the latter is supposed to help clinicians master a difficult situation. Since countertransference feelings are often not fully conscious, it is necessary to do research on therapists’ emotional states after sessions in which suicidality is addressed. This is crucial to both prevent the therapeutic process from being endangered and preserve clinicians’ mental health. Clinical implications and limitations are discussed.

Abstract Background There is a lack of studies examining psychosocial functioning in patients with non-suicidal self-injury (NSSI), especially in adolescents, and rates of impaired functioning in existing literature vary considerably. These variations may be attributable to further risk factors that influence psychosocial functioning. Thus, the aim of the study was to examine whether adolescent NSSI patients with childhood maltreatment (CM), a known risk factor for lower psychosocial functioning, may differ from adolescent NSSI patients without CM, and whether these differences may be explained by the severity of comorbid disorders. Specifically, we examined whether severity of borderline personality disorder (BPD), depression and posttraumatic stress disorder may explain differences in psychosocial functioning in NSSI patients with and without CM. Methods Data of 368 adolescents with NSSI disorder from an outpatient clinic were analyzed using structural equation modeling. Clinicans’ rating of the Global Assessment of Functioning Scale (GAF) was collected, in addition to clinical interviews. Results Results indicate that GAF scores were lower among NSSI patients with CM and that the difference in psychosocial functioning between these groups was explained by BPD and depression severity. Conclusions Psychosocial functioning in NSSI patients varies depending on whether they have experienced CM or not. Specifically, these differences seem to be attributable to higher BPD and depression severity in adolescent NSSI patients with CM. Clinicians should ensure to assess CM and focus on BPD and depression severity in this population. Treatment of BPD and depression may notably reduce psychosocial impairment in NSSI patients with CM.

Abstract Resistance to CD19-directed immunotherapies in lymphoblastic leukemia has been attributed, among other factors, to several aberrant CD19 pre-mRNA splicing events, including recently reported excision of a cryptic intron embedded within CD19 exon 2. While “exitrons” are known to exist in hundreds of human transcripts, we discovered, using reporter assays and direct long-read RNA sequencing (dRNA-seq), that the CD19 exitron is an artifact of reverse transcription. Extending our analysis to publicly available datasets, we identified dozens of questionable exitrons, dubbed “falsitrons,” that appear only in cDNA-seq, but never in dRNA-seq. Our results highlight the importance of dRNA-seq for transcript isoform validation.

Abstract Background Metastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma. Case presentation We present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body. Conclusions Renal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.

Abstract Background The speckled-pelage brush-furred rats (Lophuromys flavopunctatus group) have been difficult to define given conflicting genetic, morphological, and distributional records that combine to obscure meaningful accounts of its taxonomic diversity and evolution. In this study, we inferred the systematics, phylogeography, and evolutionary history of the L. flavopunctatus group using maximum likelihood and Bayesian phylogenetic inference, divergence times, historical biogeographic reconstruction, and morphometric discriminant tests. We compiled comprehensive datasets of three loci (two mitochondrial [mtDNA] and one nuclear) and two morphometric datasets (linear and geometric) from across the known range of the genus Lophuromys. Results The mtDNA phylogeny supported the division of the genus Lophuromys into three primary groups with nearly equidistant pairwise differentiation: one group corresponding to the subgenus Kivumys (Kivumys group) and two groups corresponding to the subgenus Lophuromys (L. sikapusi group and L. flavopunctatus group). The L. flavopunctatus group comprised the speckled-pelage brush-furred Lophuromys endemic to Ethiopia (Ethiopian L. flavopunctatus members [ETHFLAVO]) and the non-Ethiopian ones (non-Ethiopian L. flavopunctatus members [NONETHFLAVO]) in deeply nested relationships. There were distinctly geographically structured mtDNA clades among the NONETHFLAVO, which were incongruous with the nuclear tree where several clades were unresolved. The morphometric datasets did not systematically assign samples to meaningful taxonomic units or agree with the mtDNA clades. The divergence dating and ancestral range reconstructions showed the NONETHFLAVO colonized the current ranges over two independent dispersal events out of Ethiopia in the early Pleistocene. Conclusion The phylogenetic associations and divergence times of the L. flavopunctatus group support the hypothesis that paleoclimatic impacts and ecosystem refugia during the Pleistocene impacted the evolutionary radiation of these rodents. The overlap in craniodental variation between distinct mtDNA clades among the NONETHFLAVO suggests unraveling underlying ecomorphological drivers is key to reconciling taxonomically informative morphological characters. The genus Lophuromys requires a taxonomic reassessment based on extensive genomic evidence to elucidate the patterns and impacts of genetic isolation at clade contact zones.

Abstract Background The heterogeneous presentation of borderline personality disorder (BPD) represents a clinical challenge. There is an ongoing scientific debate whether the heterogeneity can best be understood in terms of qualitative (categorical) or quantitative (dimensional) differences between individuals. The present study examined the latent structure of BPD in adolescents. Methods Five-hundred and six outpatients aged 12 to 17 years with risk-taking and/or self-harming behavior were assessed at baseline and one-year follow-up. Latent class analysis (corresponding with the categorical approach), factor analysis (corresponding with the dimensional approach), and factor mixture models (allowing for both categorical and dimensional aspects) were applied to the DSM-IV BPD criteria. Results The best fitting model distinguished between a majority class with high probabilities for all BPD criteria (“borderline group”) and a minority class with high probabilities for the impulsivity and anger criteria only (“impulsive group”). Sex significantly affected latent class membership, and both a latent factor and age explained within-class variability. The borderline group primarily consisted of females, frequently reported adverse childhood experiences, scored high on the emotion dysregulation and inhibitedness personality traits, and was associated with internalizing psychopathology. In contrast, the impulsive group primarily consisted of males, scored high on the dissocial behavior personality trait, and was associated with externalizing psychopathology. After one year, the two groups showed similar clinical improvement. Conclusions The study provides evidence for two distinct subgroups of adolescents with BPD features that resemble the subtypes of the ICD-10 emotionally unstable personality disorder. More research is needed to further investigate the diagnostic stability of the two groups over time and potential differential treatment indications.

Abstract Background There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required. Methods We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients. Results Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction. Conclusions The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation.

Abstract Background Explanations for the ecological dominance of ants generally focus on the benefits of division of labour and cooperation during foraging. However, the principal innovation of ants relative to their wasp ancestors was the evolution of a new phenotype: a wingless worker caste optimized for ground labour. Ant workers are famous for their ability to lift and carry heavy loads, but we know surprisingly little about the morphological basis of their strength. Here we examine the consequences of the universal loss of flight in ant workers on skeletomuscular adaptations in the thorax for enhanced foraging on six legs. Results Using X-ray microcomputed tomography and 3D segmentation, we compared winged queens and wingless workers in Euponera sikorae (subfamily Ponerinae) and Cataglyphis savignyi (subfamily Formicinae). Workers are characterized by five major changes to their thorax: i) fusion of the articulated flight thorax (queens) into a rigid box optimized to support the muscles that operate the head, legs and abdomen, ii) redesign of internal cuticular structures for better bracing and muscle attachment, iii) substantial enlargement of the neck muscles for suspending and moving the head, iv) lengthening of the external trochanter muscles, predominant for the leg actions that lift the body off the ground, v) modified angle of the petiole muscles that are key for flexion of the abdomen. We measured volumes and pennation angles for a few key muscles to assess their increased efficacy. Our comparisons of additional workers across five genera in subfamilies Dorylinae and Myrmicinae show these modifications in the wingless thorax to be consistent. In contrast, a mutillid wasp showed a different pattern of muscle adaptations resulting from the lack of wing muscles. Conclusions Rather than simply a subtraction of costly flight muscles, we propose the ant worker thorax evolved into a power core underlying stronger mandibles, legs, and sting. This contrasts with solitary flightless insects where the lack of central place foraging generated distinct selective pressures for rearranging the thorax. Stronger emphasis is needed on morphological innovations of social insects to further our understanding of the evolution of social behaviours.

Abstract Background The increase in antimicrobial resistance is of worldwide concern. Surrogate tracers attempt to simulate microbial transmission by avoiding the infectious risks associated with live organisms. We evaluated silica nanoparticles with encapsulated DNA (SPED) as a new promising surrogate tracer in healthcare. Methods SPED and Escherichia coli were used to implement three experiments in simulation rooms and a microbiology laboratory in 2017–2018. Experiment 1 investigated the transmission behaviour of SPED in a predefined simulated patient-care scenario. SPED marked with 3 different DNA sequences (SPED1-SPED3) were introduced at 3 different points of the consecutive 13 touch sites of a patient-care scenario that was repeated 3 times, resulting in a total of 288 values. Experiment 2 evaluated SPED behaviour following hand cleaning with water and soap and alcohol-based handrub. Experiment 3 compared transfer dynamics of SPED versus E. coli in a laboratory using a gloved finger touching two consecutive sites on a laminate surface after a first purposefully contaminated site. Results Experiment 1: SPED adhesiveness on bare skin after a hand-to-surface exposure was high, leading to a dissemination of SPED1–3 on all consecutive surface materials with a trend of decreasing recovery rates, also reflecting touching patterns in concordance with contaminated fingers versus palms. Experiment 2: Hand washing with soap and water resulted in a SPED reduction of 96%, whereas hand disinfection led to dispersal of SPED from the palm to the back of the hand. Experiment 3: SPED and E. coli concentration decreased in parallel with each transmission step – with SPED showing a trend for less reduction and variability. Conclusions SPED represent a convenient and safe instrument to simulate pathogen spread by contact transmission simultaneously from an infinite number of sites. They can be further developed as a central asset for successful infection prevention in healthcare.