Medical School Berlin

In the fight against bacterial infections, particularly those caused by multi‐resistant pathogens, the need for new antibacterials is undoubted in scientific communities. and is by now also widely perceived by the general population. However, the antibacterial research landscape has changed considerably over the past years. The majority of big pharma companies has left the field and thus, the decline in R&D on antibacterials severely impacts the drug pipeline. In past years, antibacterial research increasingly relies on smaller companies or academic research institutions, which mostly have only limited financial resources, to carry a drug discovery and development process from the beginning and through the clinical phases. This review formulates the requirements for an antibacterial in regard of targeted pathogens and resistance mechanisms. Strategies are shown for the discovery of new antibacterial structures originating from natural sources, chemical synthesis and more recent AI approaches. This is complemented by principles for the computer‐aided design of antibacterials and the refinement of a lead structure. The second part of the article comprises a compilation of promising antibacterial molecules classified according to bacterial target areas. Aspects of the origin, the antibacterial spectrum, resistance and the current development status of the presented drug molecules are highlighted.

In the fight against bacterial infections, particularly those caused by multi‐resistant pathogens, the need for new antibacterials is undoubted in scientific communities. and is by now also widely perceived by the general population. However, the antibacterial research landscape has changed considerably over the past years. The majority of big pharma companies has left the field and thus, the decline in R&D on antibacterials severely impacts the drug pipeline. In past years, antibacterial research increasingly relies on smaller companies or academic research institutions, which mostly have only limited financial resources, to carry a drug discovery and development process from the beginning and through the clinical phases. This review formulates the requirements for an antibacterial in regard of targeted pathogens and resistance mechanisms. Strategies are shown for the discovery of new antibacterial structures originating from natural sources, chemical synthesis and more recent AI approaches. This is complemented by principles for the computer‐aided design of antibacterials and the refinement of a lead structure. The second part of the article comprises a compilation of promising antibacterial molecules classified according to bacterial target areas. Aspects of the origin, the antibacterial spectrum, resistance and the current development status of the presented drug molecules are highlighted.

Background: Suicide bereavement increases the probability of adverse outcomes related to grief, social functioning, mental health, and suicidal behavior. While more support for individuals bereaved by suicide has become available, the evidence regarding its effectiveness is not straightforward. The literature suggests that identifying best-practice components is key in designing effective postvention interventions. Aims: This metareview aims to identify components of suicide bereavement interventions perceived to be effective by suicide-bereaved people. Method: The review adhered to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Systematic searches in Medline, PsycINFO, Embase, Emcare, EBM Reviews, Scopus, and Web of Science identified 11 eligible systematic reviews published between 2008 and 2023. The methodological quality was assessed using the Measurement Tool to Assess Systematic Reviews (AMSTAR-2) (PROSPERO registration CRD42023458300). Results: Our narrative synthesis reported the components perceived to be effective in relation to structure and content of interventions, facilitators, and modality (peer, group, community, online). Limitations: The quality of the included reviews varied considerably, and not all reviews reported on perceived effectiveness of interventions’ components. Meta-analysis of findings was not possible due to study heterogeneity. Conclusion: The findings provide crucial information for researchers, service providers, and policymakers to enhance the provision of evidence-based support for people bereaved by suicide.

Background : The social environment is important to consider for effective promotion of movement behaviors like increased physical activity (PA) and reduced sedentary behavior (SB); yet, it is less often considered than individual and built environments. One way to advance social environment research is to develop system maps, an innovative, participatory, action-oriented research process that actively engages stakeholders to visualize system structures and explore how systems “work.” The purpose of this research was to develop PA and SB system maps of the social environment embedded within the core/nuclear family system. Methods : The development process began with a 2-day multicountry, 16-researcher, in-person participatory workshop in August 2023, followed by multiple online follow-up consultations. Attendees contributed to the creation of the maps through shared development of critical determinants and their causal pathways. The structure of the final maps was analyzed using network analysis methods to identify indicators of centrality, and key feedback loops and areas for potential intervention were explored. Results : Key central determinants that were likely critical targets for systems intervention to produce changes in PA and SB and featured prominently in most of the reinforcing and balancing feedback loops included shared family interests, values and priorities, family logistical support, family cohesion/organization, and shared experiences. The maps also highlighted key determinants of the broader social environment external to the family. Conclusions : These system maps support current evidence on movement behaviors in family systems and socioecological theories and have the utility to galvanize future research and policy to promote PA and reduce SB.

Introduction/Background: Hypertension and hypercholesterolemia are important risk factors of endothelial dysfunction and atherosclerosis. Previous studies suggested a crosstalk between an activated renin-angiotensin-aldosterone system (RAAS), reactive oxygen species (ROS) and oxidized low-density lipoproteins (oxLDL) in atherosclerosis, but the underlying molecular mechanisms are not well understood. Research Question/Hypothesis: Can we identify novel signaling pathways controlling the molecular crosstalk of the RAAS with ROS and oxLDL in endothelial dysfunction and atherosclerosis? Methods/Approach: The impact of AT 1 R blockade on oxLDL-induced superoxide anion formation and endothelial dysfunction was studied in human umbilical artery endothelial cells and aortic rings of wild-type mice by chemiluminescence and Mulvany myograph. We cloned 5’-terminal deletions of the AT 1 R promoter and assessed the luciferase activity in human endothelial cells. Oct-1 binding to the human AT 1 R promoter region was studied by EMSA. Further assays included real-time PCR, confocal microscopy, Western blotting, G protein reporter assays, phospho-ERK1/2 antibodies and specific siRNAs. The data were validated in heart of obese C57BL/6 mice and cardiac and aortic tissue of AT 1a /AT 1b double knockout mice in vivo . Results/Data: AT 1 R promoter activation studies upon Ang II- and oxLDL-stimulation in endothelial cells revealed that Ang II and oxLDL activate AT 1 R signaling through G protein Gα 12/13 , followed by activation of ERK1/2 MAP kinases, and transcription and translation of Oct-1, resulting in up-regulation of AT 1 R, LOX-1 and NOX2 expression, which could be antagonized by specific inhibitors at each step of the identified signaling cascade. AT 1 R blockade improved oxLDL-induced endothelial dysfunction in aortic rings of wild-type mice. Male C57BL/6 mice fed a high-fat diet exhibited upregulation of Oct-1 levels in cardiac tissues, compared to normal controls, while AT 1a /AT 1b double knockout mice demonstrated downregulation of Oct-1, AT 1 R, LOX-1, and NOX2 on mRNA and protein level in cardiac and aorta tissue, thus confirming the identified signaling cascade in vivo . Conclusions: Oct-1 is an essential transcription factor for Ang II- and oxLDL-induced upregulation of AT 1 R and LOX-1 expression in endothelium, thus identifying a novel molecular cross-talk of oxLDL with ROS signaling and the RAAS contributing to development of endothelial dysfunction and atherosclerosis.

Adolescence is considered a critical period for understanding how individuals develop their self-concepts and personality dispositions, with the assumption that these changes presage important life outcomes. However, this tenet has been infrequently tested; few studies have included rigorous, frequent assessment of personality traits during adolescence, particularly from multiple rater perspectives. The current study utilizes data from the Oregon Youth Substance Use Project (OYSUP; N = 951), which followed students throughout their school years into early adulthood. Student- and teacher-reports of the Big Five personality traits were assessed yearly from grades 7 to 10, as well as drug use, well-being, and maturity outcomes later in emerging adulthood. Using latent growth curve models and true intraindividual change score models, results indicated that youth exhibited relative stability but significant trait changes on multiple domains during adolescence. Moreover, individual differences in these changes predicted likelihood for drug use and depressive symptoms later, as well as the students’ perceptions of their status as being developed adults, even when accounting for initial trait levels. Findings differed somewhat between youth- and teacher-reports of personality, with both demonstrating value for predicting young adult outcomes, indicating multiple perspectives of personality development are important.

Darknet forums dedicated to child sexual abuse material (CSAM) attract thousands of users interacting with each other through online communications. Given finite resources, law enforcement agencies seek ways to effectively prioritise their investigative efforts by identifying key-players that are central to the forum community. For the identification of such users, law enforcement agencies typically rely on the communication network that can be derived from messages posted on the public part of the forum. Many forums, however, also allow for private communications between members, raising the question to what extent relying on only a single mode of communication biases key-player identification. Using data on both public and private communications on two large-scale darknet CSAM forums, two communication networks are derived and their structures analysed. Measures of centrality robustness are applied to ascertain the level of bias introduced when determining key-players on only one of the available networks. Findings show only a minority of members to participate in forum communication, and limited overlap between participants active in public and private communications. Key-players emerging from combining the public and private communications resemble those from the public network only, suggesting that police prioritisation based on public postings only is still ‘on mark’. Members who are central to the private communications network may nevertheless be of special law enforcement interest.

Objective: With advances in techniques, arthroscopic repair of isolated subscapularis tendon tears has become increasingly popular in recent years. The aim of this study was to analyze the clinical and structural results of arthroscopic repair versus the gold standard of open repair. It is a prospective cohort study with a control group; evidence level III. Methods: In a prospective study performed at two centers, 18 patients with an isolated subscapularis tear were treated with arthroscopic repair (ARG) and 16 patients with open repair (ORG) using a uniform single-row suture anchor repair technique in both groups. The subscapularis function was assessed using specific clinical tests (belly-press and lift-off tests), strength testing and shoulder function with the use of the Constant–Murley score (CMS). Standardized magnetic resonance imaging (MRI) was used to evaluate the postoperative subscapularis muscle-tendon status. Results: At a minimum follow-up of 48 months, the CMS increased from a mean of 54 points preoperatively to a mean of 86 points postoperatively in the ARG (p < 0.01) and from 50 points to 85 points postoperatively in the ORG (p < 0.01). Specific subscapularis tests (belly-press test and lift-off test) were significantly improved from the preoperative to the postoperative status in both repair groups (p < 0.05). Despite a subscapularis tendon healing rate of over 90% on MRI scans in both repair groups, the incomplete correction of specific muscle tests was a frequent postoperative finding. Conclusions: Arthroscopic repair of isolated subscapularis tears achieved equivalent clinical and structural results compared to the gold standard of open repair.

Background Epidemiological research has failed to confirm laterality of lesion site as a neurobiological source of post-stroke psychopathology. However, acquired communication disorders have proved to be a key risk factor for depression, apart from established parameters such as pre-stroke psychopathology and physical immobility. Objectives The present work examines a new predictor of post-stroke psychopathology: psychological flexibility. This concept describes an accepting attitude toward irreversible loss following stroke while using remaining agency. Design Overall, 70 individuals engaged in a cross-sectional study conducted in the subacute stage after an ischemic or hemorrhagic event, a period with elevated prevalence of mental-health problems (2 weeks to 6 months after stroke). Methods Outcomes included standardized self-report and clinician-rated measures of depression, anxiety disorders, and general psychopathology (Beck Depression Inventory; Hospital Anxiety and Depression Scale; ICD-10 Symptom Rating; Hamilton Depression Rating Scale) alongside lack of psychological flexibility (Acceptance and Action Questionnaire II). The study design controlled for pre-stroke psychopathology and physical immobility (Barthel Index). Results Partial correlation analyses revealed a significant medium-to-large association between the entire set of clinical outcomes and lack of psychological flexibility (r ⩽ 0.62, p < 0.001). In moderator analyses, the magnitude of this association did not vary significantly with diagnosis of acquired communication disorders (i.e., aphasia, apraxia of speech or dysarthria; separately or combined). Conclusion The current results demonstrate a substantial link between post-stroke psychopathology and psychological flexibility. This finding opens new avenues for research on depression and other mental-health problems in stroke survivors with and without acquired communication disorders. Registration www.drks.de; identifier: DRKS00031204

The Strengthening the Screening of Lung Cancer in Europe (SOLACE) initiative, supported by Europe’s Beating Cancer Plan, is dedicated to advancing lung cancer screening. This initiative brings together the most extensive pan-European network of respiratory and radiology experts, involving 37 partners from 15 countries. SOLACE aims to enhance equitable access to lung cancer screening by developing targeted recruitment strategies for underrepresented and high-risk populations. Through comprehensive work packages, SOLACE integrates scientific research, pilot studies, and sustainability efforts to bolster regional and national screening efforts across EU member states. Critical relevance statement The SOLACE project aims to facilitate the optimization and implementation of equitable lung cancer screening programs across the heterogeneous healthcare landscape in EU member states. Key Points The effectiveness of lung cancer screening is supported by both scientific evidence and now increasing legislative support. SOLACE aims to develop, test, and disseminate tools to facilitate the realization of lung cancer screening at both a national and regional level. Previously underrepresented populations in lung cancer screening will be targeted by tailored recruitment strategies. SOLACE forms the first pan-European network of experts poised to drive real-world implementation of lung cancer screening.

Background One of the challenges in surgery of tumors in motor eloquent areas is the individual risk assessment for postoperative motor disorder. Previously a regression model was developed that permits estimation of the risk prior to surgery based on topographical and neurophysiological data derived from investigation with nTMS (navigated Transcranial Magnetic Stimulation). This study aims to analyze the impact of including additional neurophysiological TMS parameters into the established risk stratification model for motor outcome after brain tumor surgery. Methods Biometric and clinical data of 170 patients with glioma in motor eloquent areas were collected prospectively. In addition, the following nTMS parameters were collected bihemispherically prior to surgery: resting motor threshold (RMT), recruitment curve (RC), cortical silent period (CSP) and a nTMS based fibertracking to measure the tumor tract distance (TTD). Motor function was quantified by Medical Research Council Scale (MRCS) preoperatively, seven days and three months postoperatively. Association between nTMS parameters and postoperative motor outcome was investigated in bivariate and multivariable analyses. Results The bivariate analysis confirmed the association of RMT ratio with the postoperative motor outcome after seven days with higher rates of worsening in patients with RMT ratio > 1.1 compared to patients with RMT ratio ≤ 1.1 (31.6% vs. 15.1%, p = 0.009). Similarly, an association between a pathological CSP ratio and a higher risk of new postoperative motor deficits after seven days was observed (35.3% vs. 16.7% worsening, p = 0.025). A pathological RC Ratio was associated postoperative deterioration of motor function after three months (42.9% vs. 16.2% worsening, p = 0.004). In multiple regression analysis, none of these associations were statistically robust. Conclusions The current results suggest that the RC ratio, CSP ratio and RMT ratio individually are sensitive markers associated with the motor outcome 7 days and 3 months after tumor resection in a presumed motor eloquent location. They can therefore supply valuable information during preoperative risk–benefit-balancing. However, underlying neurophysiological mechanisms might be too similar to make the parameters meaningful in a combined model.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Background Research on circulating tumor cells (CTCs) offers the opportunity to better understand the initial steps of blood‐borne metastasis as main cause of cancer‐related deaths. Here, we have used the colon cancer CTC‐MCC‐41 and breast cancer CTC‐ITB‐01 lines, which were both established from human CTCs as permanent cell lines as models to further study CTC biology with special emphasis on anchorage‐independent survival and growth. Methods and Results Both cell lines showed a marked intrinsic plasticity to switch between suspension and adherent in vitro growth, in 2D adherent culture conditions, and established an equilibrium of both growth patterns with predominant adherent cells in the CTC‐MCC‐41 line (77%) and suspension cells in the CTC‐ITB‐01 line (85%). Western blot analysis revealed a higher expression of pERK1/2 in CTC‐ITB‐01 adherent cells compared to the suspension counterpart that suggested the involvement of kinases in this process. Subsequent functional kinome profiling identified several serine/threonine as well as tyrosine kinases that were differentially regulated in adherent and suspension CTCs. In the adherent cells of the breast cancer line CTC‐ITB‐01 the activity of MSK1, Src family kinases and the PKG family was increased compared to the suspension counterpart. In adherent cells of the colorectal CTC‐MCC‐41 line, an increased activity of TYRO3 and JAK2 was detected, whereas p38 MAPK was strongly impaired in the suspension CTC‐MCC‐41 cells. Some of the regulated kinases, which include the Src family, TYRO3, MSK1, JAK2 and p38 MAPK, have been associated with crucial cellular processes including proliferation, migration and dormancy in the past. Conclusions The investigated CTC lines exhibit a high plasticity, similar to the concept of ‘adherent‐to‐suspension transition (AST)’ that was recently suggested as a new hallmark of tumor biology by Huh et al. Moreover, we identified differentially regulated kinome profiles that may represent potential targets for future studies on therapeutic interventions.

Purpose In the 2020 emergence of SARS-CoV-2, global response lacked unified treatment and surveillance, resulting in diverse impacts due to varied healthcare resources and national guidelines. Germany and Switzerland curbed the virus initially by promptly tracking and testing, bolstered by strong governmental capacity. This study aimed to assess country-specific healthcare disparities and their impact on ICU admission rates, mechanical ventilation, and in-hospital mortality. Methods To enhance healthcare quality using real-world data, the “Initiative of Quality Medicine” (IQM) was established. Pseudonymised routine data from participating hospitals, during 01/01/2019–31/12/2022, was retrospectively analysed, focusing on patients with SARI ± SARS-CoV-2-infection (U07.1). Cohorts were matched based on various factors and multivariable analyses included logistic regression. Results 1.421.922 cases of SARI ± U07.1 involving 386 German and 41 Swiss hospitals were included. Patients in Germany were older (mean: 69.4 vs. 66.5 years) and had more comorbidities than in Switzerland (p < .001). Patients in Germany were also more likely to be treated on ICU (28% vs. 20%, OR 1.5 95% CI 1.5–1.6, p < .001) and mechanically ventilated (20% vs. 15%, OR 1.4, 95% CI 1.4–1.5, p < .001). The in-hospital mortality was significantly higher in Germany than in Switzerland (21% vs. 12%, OR 2.0, 95% CI 1.9–2.0, p < .001). Matched cohorts showed reduced differences, but Germany still exhibited higher in-hospital mortality. Discrepancies were evident in both pre-pandemic and pandemic analyses, highlighting existing disparities between both countries. Conclusion IQM data from Swiss and German hospitals reveals country-specific differences in SARI ± U07.1 outcomes, highlighting higher in-hospital mortality in Germany, with uncertain causes suggesting varied treatments and resources.

This study is the first to provide a systematic overview and taxonomy of measures assessing perceived ageism. A systematic review according to PRISMA was conducted with the aim of descriptively presenting the body of existing perceived ageism measures. Of 14,135 identified

Ketamine is a highly effective antidepressant (AD) that targets the glutamatergic system and exerts profound effects on brain circuits during negative emotional processing. Interestingly, the effects of ketamine on brain measures are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Examining the antagonistic effects of ketamine and lamotrigine on glutamate transmission holds promise to identify effects of ketamine that are mediated through changes in the glutamatergic system. Investigating this modulation in relation to both the acute and sustained effects of ketamine on functional activity and connectivity during negative emotional processing should therefore provide novel insights. 75 healthy subjects were investigated in a double-blind, single-dose, randomized, placebo-controlled, parallel-group study with three treatment conditions (ketamine, lamotrigine pre-treatment, placebo). Participants completed an emotional face viewing task during ketamine infusion and 24 h later. Acute ketamine administration decreased hippocampal and Default Mode Network (DMN) activity and increased fronto-limbic coupling during negative emotional processing. Furthermore, while lamotrigine abolished the ketamine-induced increase in functional connectivity, it had no acute effect on activity. Sustained (24 h later) effects of ketamine were only found for functional activity, with a significant reduction in the posterior DMN. This effect was blocked by pretreatment with lamotrigine. Our results suggest that both the acute increases in fronto-limbic coupling and the delayed decrease in posterior DMN activity, but not the attenuated limbic and DMN recruitment after ketamine, are mediated by altered glutamatergic transmission.

Background Men at risk for suicide are a challenging population group to reach with suicide prevention strategies. Gatekeepers hold a pivotal role in the prevention of male suicide, yet effective intervention requires them to have a level of knowledge and strategies to provide support. Aim This study aimed to examine the efficacy of an online gatekeeper program for gatekeepers in male suicide prevention, assessing knowledge, perceived preparedness, self-efficacy, and psychopathological symptoms of gatekeepers. Methods Eighty-four participants were randomized to either the intervention (n = 43) or the waitlist control group (n = 41). The intervention comprised four modules providing knowledge and strategies for addressing men in suicidal crises. Outcomes included depression (PHQ-9), distress (PSS-10), burden (BAS), involvement (IEQ), as well as gatekeeper outcomes and knowledge. Results Completer analyses revealed significant improvement of depressive symptoms (d = 0.39) and an increase in gatekeeper outcomes (d = 0.58 to d = 0.84) and knowledge (d = 0.62) from baseline to post-assessment. The effects were maintained for 3 months. No significant effects could be found for burden, distress, and involvement. Conclusions The findings indicate that a brief gatekeeper program can serve as a valuable resource. Future research should focus on examining the mental health of gatekeepers themselves and its long-term effects on intervention behavior. Trial registration German Clinical Trials Register, DRKS00030758, registered on 05.12.2022.