Rwanda reported its first Marburg virus disease (MVD) outbreak in September 2024. This study presents an assessment of Rwanda's National Reference Laboratory Operational Capacity during the 2024 Marburg Virus Disease Outbreak Response. The assessment was conducted using the World Health Organization laboratory assessment tool for viral haemorrhagic fever (VHF) diagnostic capacity. This was complemented by an evaluation of various laboratory quality indicators like the turnaround time (TAT). Data were collected through direct observation, documents' review, and interviews with laboratory staff. Descriptive analysis of key response activities and observations was conducted using Microsoft Office (Excel). Also, the map of testing sites was drawn using QGIS 3.40.0 software. The NRL's response to the MVD outbreak achieved an overall score of 98%. All components scored 100% except for the quality of the laboratory system, which scored 89% due to the lack of External Quality Assessment (EQA) for MVD. Key achievements during the outbreak response included (i) reduction in the turnaround time (TAT) from sample reception to releasing results from 24 to 7 h, (ii) the recruitment of more laboratory staff supporting sample collection, transportation, testing and results reporting, (ii) creation of five new MVD testing sites, (iii) training of laboratory staff, (iv) digitalization of the laboratory flow, and (v) establishing a 24/7 telephone line for easy communication with laboratories on MVD suspected samples being processed. The strong performance of the NRL highlights its robust laboratory system, which allowed effective testing of MVD suspected cases. We recommend implementing an EQA scheme for VHF diagnostics in Rwanda, including the MVD. Also, improving measures for biosafety, biosecurity, and infection prevention and control in all health facilities would reduce the risk of such infections in the future.
Marburg virus (MARV), a highly pathogenic member of the Filoviridae family, causes severe hemorrhagic fever with a high case fatality rate and currently lacks effective therapeutics. The viral entry process, mediated by the interaction between the MARV glycoprotein (GP) and host receptor C-type lectin domain family 4 member M (CLEC4M) (L-SIGN), represents a critical target for early-stage intervention. The active compounds from BindingDB and the decoy from DUDE were used. The RDKit was used for feature engineering. Machine learning models were trained on an initial dataset consisting of 56 active chemicals and 1232 decoys. Among the tested algorithms, the Random Forest model demonstrated superior performance, achieving the highest discriminative ability (AUC = 0.93, MCC = 0.88) on the test set. Virtual screening of 11,032 phytochemicals resulted in 120 predicted actives, of which 42 compounds satisfied drug-likeness criteria. Subsequent molecular docking identified three lead compounds (PubChem IDs: 42608095, 5281601, and 11243993) with moderate-to-promising binding affinities (-6.3 to -6.5 kcal/mol) toward the CLEC4M binding site. ADMET analysis revealed favorable pharmacokinetic and toxicity profiles for the selected lead compounds. DFT calculations of the three compounds highlighted their electronic stability and reactive nature, indicating that PubChem IDs 42608095 and 5281601 possess particularly stable electronic properties conducive to favorable target interactions. Combining machine learning models with molecular docking and Molecular Dynamics (MD) simulations worked well in finding promising phytochemical inhibitors. The MM/GBSA binding free energy calculations further confirmed binding affinities, with values of -10.83 and -11.08 kcal/mol, respectively, suggesting favorable complex stability. These findings provide a pathway for developing new antiviral agents against MARV, pending further experimental validation and optimization.
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The occurrence of attention deficit hyperactivity disorder (ADHD) and ADHD-typical symptomatology in children is unevenly distributed depending on sociodemographic and regional factors. The aim of this study was to analyze their distribution and their association with elevated hyperactivity. For this purpose, cross-sectional data were collected during the school entry examinations 2023/2024 using the Strengths and Difficulties Questionnaire (SDQ) in the Hessian districts of Marburg-Biedenkopf and Fulda (total n=2,832 children; total population of both districts: 465,088 [1]) and analyzed descriptively as well as using bivariate and multivariate methods with regard to sociodemographic and regional predictors of elevated hyperactivity. Overall, 7.2% of the children showed an elevated hyperactivity level; male sex, lower subjective socioeconomic status (SES), and urban residence were significantly associated with the occurrence of ADHD-typical symptomatology. Das Auftreten einer Aufmerksamkeitsdefizit-/ Hyperaktivitätsstörung (ADHS) und ADHS-typischer Symptomatik bei Kindern und Jugendlichen variiert in Abhängigkeit von soziodemografischen und regionalen Faktoren. Ziel dieser Studie war es, die Verteilung von auffälliger Hyperaktivität und die Zusammenhänge mit soziodemografischen und regionalen Faktoren im Rahmen von Schuleingangsuntersuchungen zu analysieren. Dazu wurden 2023/2024 in den hessischen Landkreisen Marburg-Biedenkopf und Fulda Querschnittsdaten, mittels des Strengths and Difficulties Questionnaire (SDQ), erhoben (n=2832 Kinder; Gesamtpopulation der beiden Landkreise: 465 088 [1]). Die Daten wurden deskriptiv sowie bi- und multivariat analysiert, um soziodemografische und regionale Prädiktoren für ein erhöhtes Hyperaktivitätslevel zu identifizieren. 7,2% der Kinder zeigten gemäß SDQ ein auffälliges Hyperaktivitätslevel; männliches Geschlecht, ein niedriger subjektiver sozioökonomischer Status (SES) und eine städtische Urbanität waren signifikant mit dem Auftreten ADHS-typischer Symptomatik assoziiert.
The Covid-19 pandemic highlighted a critical lesson for global health systems: effective preparedness depends on timely access to reliable and interconnected health data. Across many countries, fragmented information systems limited the rapid exchange and use of data needed for outbreak detection, response, and decision-making. In Uganda, the recurrent emergence of infectious disease outbreaks, including Ebola, Marburg virus disease, and cholera, has reinforced the importance of resilient and interoperable health information systems. Although substantial progress has been made in strengthening disease surveillance and response mechanisms, persistent challenges continue to affect the country's capacity to generate and utilize high-quality data during public health emergencies. This study combined a review of published and grey literature with qualitative inquiry to explore existing challenges in Uganda's health data ecosystem. Six key informants with expertise in health information systems, disease surveillance, and outbreak response participated in in-depth interviews to provide insights into current gaps and potential solutions. The findings revealed several interconnected challenges, including fragmented and poorly integrated information systems, limited access to critical digital infrastructures, incomplete digitalization of data collection processes, and weaknesses in data quality and accessibility. These challenges often result in delays in data sharing and evidence-based decision-making during outbreaks. Participants noted that many of these barriers are well recognized and can be addressed through targeted and relatively modest investments. Key recommendations included accelerating the integration of existing health information platforms, expanding end-to-end digital data collection, increasing investments in health information systems, and strengthening coordination among government agencies and development partners. Strengthening Uganda's preparedness for future epidemics requires sustained commitment to interoperable health information systems and high-quality data management. Building on the strong foundations already established through collaboration with partners such as World Health Organization and Africa Centres for Disease Control and Prevention, targeted investments and enhanced governance mechanisms could address the most pressing system gaps. Advancing these efforts will improve the availability and use of quality health data, enabling more effective surveillance, faster outbreak response, and greater resilience against future public health threats.
Several viruses belonging to the order Mononegavirales are recognized as highly pathogenic in humans and are often associated with lethal disease outcomes. Prominent examples include human respiratory syncytial virus (HRSV), Ebola virus (EBOV), rabies virus (RABV), and Marburg virus (MARV). In addition to their clinical severity, these viruses are considered potential biological threats due to their high transmissibility and virulence. In this study, we performed a metatranscriptomic analysis of Culex and Anopheles mosquitoes collected at the DBB (Diretoria de Biodiversidade e Biotecnologia), São Paulo, Brazil. Our analysis revealed viral sequences associated with two families within Mononegavirales: Lispiviridae and Rhabdoviridae. Phylogenetic analysis of the Lispiviridae sequences identified six variants, designated CxLispV-SP_03, CxLispV-SP_09, CxLispV-SP_12, CxLispV-SP_13, CxLispV-SP_14, and CxLispV-SP_15, that formed a strongly supported monophyletic clade with Canya virus, suggesting the discovery of a putative novel viral lineage. Examination of RNA-dependent RNA polymerase (RdRp) domains in these sequences confirmed the presence of essential catalytic motifs. In contrast, the detected rhabdoviruses exhibited greater genomic structural heterogeneity, including the presence of accessory protein domains. Pairwise comparisons based on RdRp amino acid identity delineated four distinct groups among these sequences, pointing to substantial evolutionary divergence within the sampled rhabdovirus diversity. Together, these findings contribute to the growing characterization of mosquito-associated mononegaviruses and provide a genomic foundation to support future surveillance efforts and public health risk assessments related to vector-borne viruses.
Transcatheter edge-to-edge mitral valve repair (M-TEER) represents an effective treatment modality for high-grade mitral valve regurgitation. The right ventricle (RV) to pulmonary artery (PA) coupling ratio has been indicated as a marker of right ventricular dysfunction (RVD), but evidence among M-TEER patients remains inconsistent to date due to divergent definitions. We therefore aimed to shed light on the impact of RV-PA uncoupling on survival following M-TEER. Data from all patients who underwent M-TEER and provided sufficient echocardiographic data were investigated. RV-PA uncoupling was defined as the ratio of tricuspid annular pulse systolic excursion (TAPSE) and to the Doppler echocardiographic-derived pulmonary artery systolic pressure (D-PASP) < 0.37 mm/mmHg. The difference in long-term survival between patients with and without RV-PA uncoupling were analyzed via the Kaplan-Meier method, and independent predictors of mortality were identified via uni- and multivariable Cox regression analyses. A total of 158 patients were eligible for analysis, and RV-PA uncoupling was present in 32.3% of the patients (51/158). Patients with RV-PA uncoupling presented significantly advanced congestive heart failure stages. While M-TEER was performed equally safely in patients with RV-PA uncoupling (odds ratio for procedural success: 0.95, 95% confidence interval [CI] 0.29-2.77, p = 0.9), their long-term survival three years after M-TEER was significantly worse (50.9% (26/51) vs. 61.7% (66/107), p = 0.01). In this regard, a TAPSE/D-PASP ratio < 0.37 mm/mmHg proved to be a more consistent discriminator of long-term survival than a TAPSE < 18 mm alone. RV-PA uncoupling, defined as a TAPSE/D-PASP ratio of < 0.37 mm/mmHg, is a feasible and reproducible parameter, which also serves as a marker for advanced congestive heart failure and worse survival outcomes.
Growing evidence has linked bullous pemphigoid (BP) to immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, the immunological features of ICI-associated BP (ICI-BP) are not yet fully elucidated. In order to characterize the humoral response in ICI BP patients and investigate whether their epitope profile differs from idiopathic BP (IBP), 53 ICI-BP patients were enrolled, immunologically characterized and compared with 59 IBP patients. ICI-BP had a distinctive IgG humoral profile, with reduced reactivity toward BP230 and recognition of multiple BP180 epitopes beyond the immunodominant extracellular noncollagenous 16A domain (NC16A). Specifically, reactivity to BP180 ectodomain was present in 94% of ICI-BP and 78% of IBP (p=0.044). Moreover, BP180 C-terminal epitope was more frequently targeted in ICI-BP than IBP (72% vs 41%, p=0.002). Notably, the combined use of an in-house BP180 ectodomain ELISA and the commercial BP180 test increased diagnostic sensitivity from 83% to 100%. Enhanced IgG reactivity toward nonimmunodominant epitopes, and especially C-terminal epitope recognition, characterize the humoral immune response in ICI-BP. Our data suggest that combining NC16A and fulllength BP180 ectodomain ELISAs may help reduce diagnostic delay in ICI-BP patients, in whom a timely diagnosis is crucial to appropriately manage the disease and ultimately avoid discontinuation of cancer therapy.
Parkinson's disease (PD) exhibits a characteristic posterior-to-anterior gradient of striatal dopamine loss, yet the underlying upstream mechanisms remain unclear. We combined in vivo ¹⁸F-FPCIT dopamine transporter (DaT) PET/MRI, quantitative susceptibility mapping, and diffusion MRI tractography in 48 PD patients and 10 healthy controls to test whether substantia nigra pars compacta (SNc) iron and microstructural disruption mediate posterior putaminal vulnerability. PD patients showed marked posterior putamen (pPut) DaT reduction (~60%) and elevated SNc iron. SNc iron negatively correlated with striatal DaT availability, and nigrostriatal pathways to the pPut exhibited higher axial diffusivity. Serial mediation analyses demonstrated that SNc iron indirectly impaired striatal DaT function via reduced SNc DaT binding. Putaminal DaT-SBR robustly discriminated PD from controls (AUC 0.93-0.96), exceeding caudate performance. Transgenic and α-synuclein preformed fibril mouse models provided qualitative anatomical support. These findings identify SNc iron-related degeneration as a key driver of posterior striatal vulnerability in PD.
Research in multilingualism has provided evidence for brain structural differences between monolinguals and bilinguals. Less is known about speakers who, apart from a standard language, also show competence in a variety (dialect) of this language ("bidialectals"). In these populations, cultural differences are minimized and language competence can be compared against a common ground. We hypothesize that bidialectals show brain-structural differences to non-bidialectals, and capitalize on one of the world's largest dialect corpus available for German. A competent dialect group (N = 26) and a group without dialect competence (N = 23) were compared by using brain structural measures, including gray matter volume (GMV) and cortical thickness (CT). Results demonstrate a whole-brain group difference, seen for CT in right orbitofrontal cortex, and for GMV in bilateral middle temporal gyrus and bilateral insula. Notably, CT in right fusiform cortex as well as GMV in bilateral middle temporal gyrus and right insula co-varied with dialect competence differently for the two groups. The structural differences and covariations with dialect competence are discussed on the background of code switching and language control. The findings suggest that dialect competence may shape brain structure in ways similar to bilingualism.
This study examined the role of perceived stress in intervention-related change during a mindfulness-based intervention (MBI) for emotional distress across two randomized controlled trials. In Study 1, 636 participants (Mage = 31.06, SDage = 9.54; 83.18% female) with high psychological distress were randomized to an MBI group (N = 318) or a Waitlist control group (N = 318), measuring perceived stress, anxiety and depression at baseline and postintervention. Study 2 randomized 607 participants (Mage = 30.13, SDage = 8.15; 82.08% female) with high psychological distress to an MBI group (N = 304) or a Waitlist control group (N = 303), with the same measurements at baseline, Week 3, Week 5 and postintervention. In both studies, linear mixed-effects models showed greater reductions in all variables in the intervention group than in the Waitlist control group. In Study 1, simple mediation analyses showed changes in perceived stress accounted for part of the intervention-related reductions in anxiety and depression. In Study 2, parallel process latent growth curve models indicated that changes in perceived stress accounted for substantial proportions of the intervention effects on anxiety and depression. Random intercept cross-lagged panel models further suggested that perceived stress functioned as a temporally prior process particularly for subsequent depression, whereas the temporal association with anxiety was more bidirectional. Perceived stress may represent an important process underlying the MBI effects on emotional distress, especially in reducing depression. Early reductions in perceived stress may help identify subsequent improvement in anxiety and depression. Trial Registration: Study1: Chinese Clinical Trial Registry number: ChiCTR2200057398. Study2: Clinical Trials number: NCT06035003.
An enantioselective total synthesis of voratin C is reported. Key steps include a ketalization through an epoxide-opening cascade to construct the spiroketal core. An enriched Sharpless dihydroxylation, followed by a stereospecific diol-to-epoxide conversion, furnished the key epoxide intermediate. The carbon skeleton of the natural product was assembled in a cross-olefin metathesis between a vinylpyridine and a C10-C18 alkene fragment. The C3 stereocenter was established via an enantioselective Cu-mediated conjugate reduction of an acrylonitrile.
Oxygen supplementation triggers inflammation and disrupts alveolar and microvascular growth in preterm infants, often leading to bronchopulmonary dysplasia (BPD). The autonomic nervous system (ANS) is critical in lung tissue homeostasis and repair. The sympathetic co-neurotransmitter neuropeptide Y (NPY) emerges as a central regulator of the ANS-organ interface with immune-modulatory function. Here, we studied sympathetic nervous system (SNS) signaling and the contribution of NPY to a hyperoxia-based model of BPD. To this end, neonatal wild-type (WT) and NPY knockout mice (NPY-/-) were exposed to 85% O2 (HYX) or 21% O2 (NOX) from birth to postnatal day 14. Prolonged hyperoxia caused a 7-fold increase of tyrosine hydroxylase (TH) protein, an enzyme characteristic for the SNS, and NPY mRNA (> 40-fold) in neonatal WT lungs. The analysis of lung scRNA-seq revealed an upregulation of NPY in alveolar macrophages of WTHYX when compared to WTNOX. In contrast, NPY-/- HYX showed lower amount of TH than WTHYX, indicating reduced sympathetic-associated signaling. Quantitative histomorphometry demonstrated an aggravated hyperoxia-induced alveolar growth arrest and septal thickening in NPY-/- HYX, whereas vascular muscularization and proliferation of vascular smooth muscle cells (SMC) were attenuated compared to WTHYX. Additionally, NPY-/- HYX were protected from hyperoxia-induced CD68+ macrophage recruitment, despite exhibiting higher lung expression of Il6 (20-fold) and Il1b (4-fold) than WTHYX. In summary, our data demonstrate a dual role of NPY in neonatal lungs in response to hyperoxia, preserving alveolarization while promoting immune cell recruitment and vascular muscularization, highlighting the importance of ANS-lung interface in lung maturation and injury.
Post-infectious syndromes like Long COVID and ME/CFS lead to disability and economic losses globally, especially in lower-income countries. These involve complex multisystem issues such as immune disturbances, inflammation, autonomic dysregulation, vascular problems, altered metabolism, and tissue damage. Re-infections increase the risk of disability and complications. Healthcare delays diagnosis and neglects long-term effects. We propose a three-part healthcare approach: primary care screening with digital tools, regional testing centers, and specialized Centers of Excellence for complex cases. An integrated infrastructure with registries, patient data, and wearables supports personalized care and surveillance. Policies should include disability benefits, rehab, infection control, and innovative funding. Healthcare must be accessible via mobile and community efforts, integrated into pandemic plans. The goal is to reduce morbidity and improve socioeconomic resilience.
Perfectionism at work is widespread and there is an ongoing debate on its relationship with work performance. Whereas most recent meta-analytic evidence suggests that perfectionistic concerns are unrelated to work performance, perfectionistic strivings showed a positive association with overall work performance. Keeping up with theoretical developments in perfectionism research, the present study draws on the Model of Excellencism and Perfectionism to provide a more nuanced perspective on how perfectionistic strivings relate to both in-role (goal attainment, in-role behavior) and extra-role performance (organizational citizenship behavior directed toward others, innovative work behavior). Multiple regression analyses based on two-wave survey data (N = 223) showed that excellencism was uniquely positively related to goal attainment, in-role behavior, and organizational citizenship behavior directed toward others. In contrast, perfectionism only showed a unique positive relationship with innovative work behavior. These findings highlight the importance of distinguishing between excellencism and perfectionism as well as between in-role and extra-role performance when investigating the perfectionism-work performance relationship. While they indicate that perfectionism can be beneficial for innovative work behavior, they also cast further doubt on its benefits for other kinds of work performance.
Point-of-care Ultrasound (POCUS) is increasingly introduced in obstetrics and gynecology as a focused bedside extension of conventional ultrasound, although evidence on its implementation in routine care remains limited. This study examined physicians' attitudes towards POCUS, their perceived diagnostic confidence across different clinical scenarios, and their preference for POCUS compared with standard ultrasound devices. These outcomes were assessed during early implementation in routine care accompanied by structured training. In this prospective, longitudinal implementation study, 22 physicians from a university department of gynecology and obstetrics evaluated standard ultrasound devices at baseline (T0a), completed a structured hands-on POCUS training, and assessed POCUS immediately after training (T0b) and after 2 weeks (T1), 1 month (T2), and 3 months (T3) of clinical use. Evaluations were conducted using repeated quantitative surveys. Outcomes were attitude (4 items, 7-point Likert), perceived diagnostic confidence in obstetric and gynecologic scenarios (17 items, 7-point Likert), and device preference (7-point Likert and dichotomous). Quantitative analyses included descriptive statistics, paired tests, mixed-effects models, and non-parametric sensitivity analyses. Attitude toward POCUS was significantly more favorable than attitude toward standard devices at baseline (T0a 3.69 vs. T0b 5.83; p < .001) and remained high throughout follow-up. Perceived diagnostic confidence for POCUS was not higher immediately after training but increased significantly over time in both obstetrics and gynecology after independent clinical use (both p < .001). Highest confidence was observed in focused bedside scenarios relevant to rapid orientation and immediate decision-making, including fetal vitality assessment, placental localization, amniotic fluid assessment, postvoid residual urine measurement, and urinary tract obstruction, whereas confidence remained lower for more complex applications such as cervical length assessment, Doppler-based examinations, and fetal growth restriction. Preference for POCUS was already high at baseline and remained stable over time. POCUS showed high acceptance in gynecologic and obstetric care from early implementation to routine use. Its clinical relevance appears greatest for focused mobile use and rapid bedside decision-making. These findings were observed during early implementation and support the role of POCUS as a complement to comprehensive ultrasound. German Registry of Clinical Trials; registration number: DRKS 00036941; date of registration: July 16, 2025; title: GO-POCUS: Point-Of-Care UltraSound in Gynecology and Obstetrics: Attitude and Perceived Diagnostic Confidence among Physicians.
Next-generation phenotyping (NGP) tools, such as GestaltMatcher, have revolutionized the diagnosis of rare genetic disorders through computational facial analysis. While NGP has been widely integrated into differential diagnosis workflows, its application in variant reclassification within the ACMG framework remains underexplored. We applied GestaltMatcher to a 4-year-old patient with an undiagnosed neurodevelopmental disorder, suspected Mowat-Wilson syndrome (MWS), and a de novo ZEB2 variant. In addition to facial image analysis, we used the PEDIA framework, integrating Human Phenotype Ontology (HPO) terms and simulated exome data to refine variant prioritization. Bayesian likelihood modeling was used to establish Gestalt score thresholds for PP4 evidence levels (supporting, moderate, strong, and very strong). Brain MRI analysis was also performed to assess structural abnormalities characteristic of MWS. GestaltMatcher ranked MWS as the top differential diagnosis, and PEDIA integration further confirmed ZEB2 as the most likely disease-causing gene. Three of the patient's 4 facial images met the PP4 moderate threshold, while one met PP4 supporting. MRI analysis revealed subtle corpus callosum thinning, consistent with MWS. In addition, an exploratory case of an infant with molecularly confirmed MWS demonstrated the capability of GestaltMatcher to prioritize the diagnosis solely based on infant facial features. This study highlights the potential of NGP-driven facial phenotyping and multimodal integration in dysmorphology. The results support the broader application of AI-assisted phenotyping to improve diagnostic accuracy, particularly in neurodevelopmental disorders with distinct facial features.
Acoustic metamaterials offer enhanced control over sound waves, enabling the design of innovative structures for diverse applications. In this work, we investigate the impact of measurement uncertainties on the sound absorption performance of three-dimensionally printed acoustic metamaterials in an impedance tube. Two representative types, the Helmholtz resonator and coiled-up space structure, are fabricated in multiple variations and characterized experimentally and numerically. The influence of factors such as printing-induced surface texture/roughness, infill density, assembly errors, and air gaps between the tube inner wall and the sample is systematically analyzed. Rather than providing a quantitative evaluation, the work characterizes observed sources and effects of uncertainty and examines how design parameters influence measurement outcomes. The results reveal that surface roughness, assembly, and tube-sample air gap can significantly distort the measured response. Notably, layer height and assembly-induced gaps can be treated as design parameters to optimize absorption, while infill density can optimize manufacturing efficiency. While uncertainties in impedance tube measurements of porous materials have been extensively evaluated, metamaterial structures have received limited investigation. The findings of this work not only clarify the effects and sources of uncertainty in impedance tube measurements of metamaterials but also expand previous research analysis and provide a guideline to address ambiguities.
Cardiovascular diseases are a major cause of morbidity and mortality worldwide. Acute chest pain is a frequent reason for emergency department presentation and requires structured evaluation to identify life-threatening conditions. This study evaluated clinical characteristics, cardiovascular risk profile, risk stratification patterns, and hospitalization status in adults with acute chest pain. We conducted a retrospective study using registry data from Arad County Clinical Emergency Hospital between January 2021 and December 2024. Adult patients with documented acute chest pain were included according to predefined criteria. Demographics, comorbidities, clinical presentation, troponin values, hospitalization status, and HEART, and EDACS categories were extracted when available. The Marburg Heart Score was also assessed as an exploratory complementary score. Statistical analysis used descriptive statistics, contingency tables, and chi-square testing, with available-case analysis. Overall, 2070 patients were included. Most patients were aged 35-54 or 55-69 years. Hypertension and diabetes mellitus were the most common comorbidities, and pressure-like chest pain predominated. In unadjusted analyses, HEART and EDACS categories were significantly associated with hospitalization status across all study years. Score categories were significantly associated with hospitalization status across all study years. Age was consistently associated with cardiovascular comorbidity burden and higher-risk score categories. Structured risk stratification scores were associated with hospitalization status, while age was associated with cardiovascular risk burden.
The Notch signaling pathway is pivotal in regulating cell differentiation, stem cell maintenance and oncogenesis. While several Notch inhibitors have been developed, effective small molecule activators are scarce. Here, we identify a small molecule that robustly activates Notch signaling, leading to significant upregulation of Notch target genes in several human cell lines and in Danio rerio embryos. Mechanistically, this compound induces the expression of activated NOTCH3 protein via a cryptic internal promoter within the NOTCH3 locus. Notch induction is markedly diminished upon genetic depletion of NOTCH3 or the canonical Notch transcription factor RBPJ. Furthermore, we demonstrate that the compound inhibits complex I of the respiratory chain. This is accompanied by a raise of cytosolic Ca2+ concentration, which is pivotal for the induction of NOTCH3. Functionally, the Notch inducer enforces cell-cycle arrest and promotes terminal differentiation in acute myeloid leukemia (AML) cells. These findings suggest that this small molecule serves as a potent tool for modulating Notch signaling and holds therapeutic potential for Notch-responsive malignancies.