Heinrich Heine University Düsseldorf

Introduction This study examined psychometric properties of the Pandemic-Related Pregnancy Stress Scale (PREPS) using a Rasch Model (RM) in a large sample of pregnant women from Germany, Israel, Italy, Poland, Spain, Switzerland and the United States of America (USA). Material and methods Rasch analyses were used to analyze a sample of 7185 pregnant women who completed the PREPS during the COVID-19 pandemic onset from April to August 2020. Psychological, sociodemographic, and obstetric factors were also collected and analyzed. Results 12-item and 15-item PREPS versions showed acceptable fit indices. The separation index for persons on both versions allows to distinguish more than two levels of performance and for items (high and low performers). For items, it was above 30 and the strata value for items was above 45. The category probability curves for the 12-item version showed that threshold parameter categories showed a coherent order with the meaning of the response options. However, this did not occur in the 15-item version. The item-person map showed that each item is represented by an equal length of the segment, and its threshold parameters differ only in the stress severity values. Also, there is an overlap of items. Finally, DIF analysis showed many CC-rated items as well as many items with a BB rating could be revised. Conclusions The implications of this psychometric study lie in the importance of having accurate measures of the stress that pregnant women in various parts of the world have experienced due to the COVID-19 pandemic.

In Germany, all new drugs undergo an early benefit assessment (EBA) by the decision-making body (G-BA). Due to limited access to clinical data in pediatric healthcare since 2017, evidence transfer has allowed for data from adult studies to be used in the EBA of pediatric drugs. This study examines the acceptance of evidence transfer, aiming to understand its correlation with granted added benefit. By searching the G-BA database, relevant EBAs were identified. In addition to descriptive statistics, agreement statistics regarding binary and ordinal extent of added benefit and binary logistic regression with and without intercept were performed to investigate acceptance of evidence transfer, juxtaposing it with manufacturers’ claims, and to evaluate the impact of identified factors on evidence transfer. In 14 of 36 identified EBAs, the evidence transfer was accepted by the G-BA. They referred to four therapeutic areas, received a non-quantifiable added benefit and were subject to a pediatric investigation program. Non-quantifiable added benefit implies an added value in itself which can range from minor to major added benefit and is considering the genuine uncertainty mainly induced in theese EBAs due to evidence transfer, which is not allowing a quantification of an added benefit. The binary agreement between manufacturers’ claims and G-BA’s appraisals was less than by chance [kappa − 0.054 (− 0.158 to 0.050)] whereas the ordinal agreement became fair [kappa 0.333 (0.261–0.406)]. Congruence of the mechanism of action, alignment of disease pattern, transferability of efficacy and safety, and same comparator were fundamental for evidence transfer. Additionally, supportive evidence, therapeutic breakthroughs, and small-scale approval enhanced the acceptance of evidence transfer. The regression models yielded similar results showing different model fit and explained variance. Evidence transfer hinges upon fulfilling various minimum criteria and additional supportive evidence. Availability of study data from adult or older patients and the pediatric group under evaluation is crucial.

Background This study aims to evaluate the current rates and outcomes of minimally invasive versus open surgery for colonic diverticular disease in Germany, using a nationwide dataset. Methods We analyzed data from 36 hospitals, encompassing approximately 1.25 million hospitalizations from 1 January 2019 to 31 December 2023. Patients aged 18 years and older with colonic diverticular disease (International Classification of Diseases, Tenth Revision (ICD-10): K57.2 and K57.3) who underwent surgical treatment were included. Surgeries were classified as open or minimally invasive (laparoscopic or robotic). Outcomes such as in-hospital mortality, complications, and length of stay were assessed using multivariable logistic and linear regression models. Results Out of 1670 patients who underwent surgery for colonic diverticular disease, 63.2% had perforation and abscess. The rate of minimally invasive surgery increased from 34.6% in 2019 to 52.9% in 2023 for complicated cases and from 67.8% to 86.2% for uncomplicated cases. Open surgery was associated with higher in-hospital mortality (odds ratio (OR): 7.41; 95% CI: 2.86–19.21) and complications compared with minimally invasive surgery. The length of hospital stay was significantly longer for open surgery patients, with an increase of 4.6 days for those with perforation and abscess and 5.0 days for those without. Conclusions Minimally invasive surgery for colonic diverticular disease is increasingly preferred in Germany, especially for uncomplicated cases. However, open surgery remains common for complicated cases, but is associated with higher mortality, more complications, and longer hospital stays.

Amyloid fibrils are highly stable misfolded protein assemblies that play an important role in several neurodegenerative and systemic diseases. Although structural information of the amyloid state is now abundant, mechanistic details about the misfolding process remain elusive. Inspired by the Φ-value analysis of protein folding, we combined experiments and molecular simulations to resolve amino-acid contacts and determine the structure of the transition-state ensemble—the rate-limiting step—for fibril elongation of PI3K-SH3 amyloid fibrils. The ensemble was validated experimentally by Tanford β analysis and computationally by free energy calculations. Although protein folding proceeds on funnel-shaped landscapes, here we find that the energy landscape for the misfolding reaction consists of a large ‘golf course’ region, defined by a single energy barrier and transition state, accessing a sharply funnelled region. Thus, misfolding occurs by rare, successful monomer–fibril end collisions interspersed by numerous unsuccessful binding attempts. Taken together, these insights provide a quantitative and highly resolved description of a protein misfolding reaction.

Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with myocardial hypertrophy, fibrosis and ventricular dysfunction. Hypoxia-inducible transcription factor-1α (Hif-1α) is the central master regulators of cellular hypoxia response and associated with HCM. Yet its exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. The results show that Hif-1α protein and HIF targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a blunted the disease phenotype, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, disordered SRX/DRX state and ROS production. cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM revealed significant modulation of HIF. These results demonstrate that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the mouse model. Targeting Hif-1α might serve as a therapeutic option to mitigate HCM disease progression.

Objective Subacute thyroiditis (SAT) is a painful inflammatory disorder of the thyroid gland, which – after a phase of thyrotoxicosis – leads to transient, or less frequently permanent hypothyroidism. Apart from a strong association with specific HLA alleles, the causes are uncertain. Viral disease has been hypothesised as a trigger, with Enteroviruses, namely Echoviruses and Coxsackieviruses, showing a seasonal distribution that coincides with the incidence of SAT. In the first year of the COVID-19 pandemic, strict hygiene measures led to a sharp decline in infections and thus offered the opportunity to test this hypothesis. Methods We analysed national registry data of hospitalised patients from Germany during the years 2015 to 2022 (Federal statistical Office (Destatis), Wiesbaden, Germany) and surveillance data on infectious diseases from the same years (clinical-virology.net and RKI). Statistical analysis includes modelling of seasonality by month, polynomial autoregression and Granger causality to assess dependency of future SAT frequencies from past ones, and association of virus incidence to SAT frequency, respectively. Results Our study confirms previously described epidemiological findings with higher incidence in females and a seasonal peak in late summer coinciding with the seasonality of enteroviruses until 2019. In 2020, the pattern remained unchanged, except for the marked reduction of enteroviruses and other pathogens (except SARS-CoV-2) due to hygienic measures. Moreover, the SAT seasonality in the years 2021 and 2022 was apparently unaltered through the COVID-19 pandemic. Conclusions Our study provides strong evidence that despite their seasonal pattern, Echoviruses and Coxsackieviruses are not the cause of SAT. Moreover, no other analysed virus (including Influenza A and B, Parainfluenza, Rhinovirus, Human Coronaviruses including SARS-CoV-2) showed any association.

Depressive disorders in older people are often accompanied by thoughts of their own death and the specific wish to die. Therefore, it can be assumed that depressive older people will express the wish for assisted suicide more frequently if legal provisions have been made. The following aspects must be taken into account when examining the decision-making capacity of those affected: depressive disorders can be reversible. Severe depressive disorders can be accompanied by an impaired capacity for judgment and making decisions, which rules out the possibility of making decisions of one′s own free will. Particularly in old age, somatic comorbidities and an increased risk of loneliness are often found, which can additionally promote suicidal ideation. Without comprehensive assessments it will not be possible to clarify the actual autonomy of the will and it will be difficult to assess the permanence of the decisions made. It is also conceivable that the legal expert opinion could come to a different conclusion than the treating physician, who has followed the course of the illness during various phases of the patient′s life and observed many changes in the patients will. In summary, it is currently not clearly recognizable in what form the assessment of free will could be organized in connection with possible legal regulations on assisted suicide, as long observation periods would be required for an adequate assessment.

Zusammenfassung Zur Behandlung der Epilepsien stehen zahlreiche anfallssuppressive Medikamente (ASM) zur Verfügung, die auf Basis klinischer Studien für bestimmte Indikationen und Altersgruppen zugelassen sind. Allerdings erfordert die Vielzahl verschiedener Epilepsietypen und Syndrome häufig einen Off-label-Einsatz von ASM, wenn die Patienten unter der aktuellen Therapie nicht anfallsfrei werden oder diese nicht vertragen. Ähnliches gilt für die Verwendung von verschiedenen immunsuppressiven Medikamenten zur Therapie von Anfällen und Epilepsien, die infolge autoimmuner Enzephalitiden auftreten, mit dem Unterschied, dass hier bisher keinerlei zugelassene Substanzen existieren. Der Off-label-Use beschreibt die Anwendung eines Medikaments außerhalb der zugelassenen Indikationen, Dosierungen oder Altersgruppen. Insbesondere in der Epilepsietherapie tritt dies häufig auf, etwa bei Kindern unter dem Zulassungsalter, bei generalisierten Epilepsien oder bei entwicklungsbedingten und epileptischen Enzephalopathien. Obwohl der Off-label-Use zusätzliche Behandlungsoptionen bietet, führt es zu einigen Herausforderungen in der klinischen Praxis. Es fehlen oft klinische Daten zur Sicherheit und Wirksamkeit, was zu Unsicherheiten in Bezug auf Dosierung und Nebenwirkungen führen kann. Eine sorgfältige Aufklärung der Patienten oder ihrer Angehörigen über Nutzen und Risiken ist daher essenziell, ebenso wie eine umfassende Dokumentation der Entscheidungsfindung. Da der Off-label-Use nicht regelhaft von den Kostenträgern übernommen wird, ist – insbesondere bei kostenintensiven neueren Substanzen unter Patentschutz – eine vorherige Klärung der Kostenübernahme sinnvoll, um wirtschaftliche Risiken zu vermeiden.

Estimation of the energy of quantum many-body systems is a paradigmatic task in various research fields. In particular, efficient energy estimation may be crucial in achieving a quantum advantage for a practically relevant problem. For instance, the measurement effort poses a critical bottleneck for variational quantum algorithms. We aim to find the optimal strategy with single-qubit measurements that yields the highest provable accuracy given a total measurement budget. As a central tool, we establish tail bounds for empirical estimators of the energy. They are helpful for identifying measurement settings that improve the energy estimate the most. This task constitutes an NP-hard problem. However, we are able to circumvent this bottleneck and use the tail bounds to develop a practical, efficient estimation strategy, which we call ShadowGrouping. As the name indicates, it combines shadow estimation methods with grouping strategies for Pauli strings. In numerical experiments, we demonstrate that ShadowGrouping improves upon state-of-the-art methods in estimating the electronic ground-state energies of various small molecules, both in provable and practical accuracy benchmarks. Hence, this work provides a promising way, e.g., to tackle the measurement bottleneck associated with quantum many-body Hamiltonians.

Cerebral vasculitis is a rare but severe manifestation of neurosarcoidosis (NS) that has received little attention. The aim of the present study was to characterize clinical and diagnostic features as well as potential treatment strategies of cerebral vasculitis related to NS. We assessed 29 patients with cerebral vasculitis related to NS (15 female, mean age at time of diagnosis 45 years, SD = 11.85) among these were four new cases from our hospital records and 25 previously published cases from a systematic literature review. The demographic, clinical, and diagnostic features of those 29 patients with cerebral vasculitis related to NS were compared with a group of 73 NS patients without vasculitic involvement (37 female, mean age at time of diagnosis 47 years, SD = 14.79). Neurologic deficits and MRI abnormalities were significantly more frequent in cerebral vasculitis related to NS than in NS without vasculitic involvement. Patients with cerebral vasculitis related to NS significantly more often presented with headache, motor symptoms, and cognitive and/or behavioral changes. Non-neurologic manifestations of sarcoidosis did not significantly differ in character or frequency between both groups. Glucocorticoids in combination with methotrexate, cyclophosphamide, or infliximab were the most frequently used treatment strategies in cerebral vasculitis related to NS. Within the complex diagnostic work-up that is required in cerebral vasculitis related to NS sufficient angiographic imaging as digital subtraction angiography or MRI vessel wall imaging and tissue biopsy are of particular significance as they can detect vascular changes caused by inflammatory processes. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-024-12868-2.

Therapeutic proteins are commonly conjugated with polymers to modulate their pharmacokinetics but often lack a description of the polymer‐protein interaction. We deployed limited proteolysis mass spectrometry (LiP‐MS) to reveal the interaction of polyethylene glycol (PEG) and PEG alternative polymers with interferon‐α2a (IFN). Target conjugates were digested with the specific protease trypsin and a “heavy” ¹⁵N‐IFN wild type (IFN‐WT) for time‐resolved quantification of the cleavage dynamics. Interactions between IFN‐α2a and its high‐affinity receptor were detailed by LiP‐MS. Then, 10 kDa polymers of PEG, linear polyglycerol (LPG), and poly(2‐oxazoline) (POX) with two different cyclooctyne linkers (BCN/DBCO) were used for site‐specific bioconjugation to azide functionalized IFN‐α2a. Tryptic events at each cleavage site and in different structural environments (loops/helices) were compared. PEG and LPG were similar, and POX showed a reduced interaction profile with the IFN‐α2a surface. All‐atom molecular dynamics simulations of IFN‐DBCO‐polymer conjugates revealed distinct and transient (below 50 ns) protein‐interaction profiles for PEG, LPG, and POX. Cleavage dynamics of IFN‐polymer conjugates from the BCN handle were homogeneous, pointing to a more conserved IFN structure than DBCO‐polymer conjugates. In summary, time‐resolved LiP‐MS for quantification of cleavage events enhances the structural understanding of transient IFN‐polymer interactions, which may be extended to other bioconjugate types.

A parental cancer diagnosis can result in sudden upset and considerable strain for the entire family system. The new Familien-SCOUT intervention from the Centrum für Integrierte Onkologie Aachen, Bonn, Köln, und Düsseldorf (CIO-ABCD) cancer center network and the Aachen Caritas Association shows how multidimensional support can be designed for all family members and how the burden can be effectively reduced.

Background Dialectical behavioral therapy (DBT) and repetitive transcranial magnetic stimulation (rTMS) are both effective in treating borderline personality disorder (BPD). Impulsivity and impaired decision-making are prominent features of BPD, and therapeutic interventions targeting these symptoms could lead to significant improvements. Objective/Hypothesis We hypothesized that intermittent theta burst stimulation (iTBS), a modified rTMS protocol that targets the left dorsolateral prefrontal cortex, would enhance the therapeutic effects of DBT, leading to greater improvements in impulsivity and decision-making compared with sham stimulation. Methods We performed a single-blind, randomized, sham-controlled pilot study to evaluate the efficacy of iTBS as an add-on to an 8-week DBT program for BPD in a routine inpatient setting. A total of 53 BPD patients were randomly assigned to receive either iTBS (n = 25) or sham stimulation (n = 28) during weeks 4 to 8 of DBT, and 36 patients met the inclusion criteria for the present analysis (≥ 16 of 20 iTBS/sham sessions and assessment of delay discounting). The study endpoints were the Barratt Impulsiveness Scale-15 for impulsivity and the Monetary Choice Questionnaire for decision-making/delay discounting. Results A mixed model repeated measures analysis with a 2 × 2 factorial between-subjects design showed a significant overall improvement over time in impulsivity but not in decision-making/delay discounting. No significant differences were found between iTBS and sham, although post hoc tests revealed significant changes in impulsivity in the iTBS group (meandiff = -4.7, p = .001, Cohen’s d = 0.68) but not in the sham group (meandiff = -2.1, p = .077, d = 0.31). Conclusions iTBS may offer long-term benefits as an add-on treatment to DBT for impulsivity in BPD, suggesting the need for further investigation in larger-scale studies. Trial registration Registered at drks.de (no. DRKS00020413) on January 13, 2020.