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Abstract: The B-cell lymphoma 2 inhibitor venetoclax (VEN) in combination with hypomethylating agents has been approved for first-line treatment of patients with acute myeloid leukemia (AML) ineligible for intensive treatment. VEN-containing treatment strategies may also be effective in relapsed/refractory (R/R) AML; however, comparative studies with conventional therapies for fit patients as a bridge-to-transplant strategy are limited. Using propensity score matching (PSM), we compared 37 patients with R/R AML, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic stem cell transplantation (allo-HCT), with 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non–VEN-containing salvage therapy according to their treating physician’s choice (TPC). The overall response rate among VEN patients was higher than the TPC control cohort (62% vs 42%; P = .049). Overall, 73% of VEN-treated patients vs 63% of TPC patients were bridged to allo-HCT (P = .41). After a median follow-up of 34.3 months for the VEN and 21.0 months for the TPC cohort, the median overall survival (OS) were 15.8 months (95% confidence interval [CI], 10.6 to not evaluable) and 10.5 months (95% CI, 6.8-19.6; P = .15), respectively. PSM revealed a trend toward improved OS for VEN patients (hazard ratio, 0.70; 95% CI, 0.41-1.22; P = .20). Median event-free survival was significantly longer in the VEN cohort (8.0 months) than the TPC cohort (3.7 months; P = .006). Our data suggest that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.

Abstract Precision oncology offers new cancer treatment options, yet sequencing methods vary in type and scope. In this study, we compared whole-exome/whole-genome (WES/WGS) and transcriptome sequencing (TS) with broad panel sequencing by resequencing the same tumor DNA and RNA as well as normal tissue DNA for germline assessment, from 20 patients with rare or advanced tumors, who were originally sequenced by WES/WGS ± TS within the DKFZ/NCT/DKTK MASTER program from 2015 to 2020. Molecular analyses resulted in a median number of 2.5 (gene panel) to 3.5 (WES/WGS ± TS) treatment recommendations per patient. Our results showed that approximately half of the therapy recommendations (TRs) of both sequencing programs were identical, while approximately one-third of the TRs in WES/WGS ± TS relied on biomarkers not covered by the panel. Eight of 10 molecularly informed therapy implementations were supported by the panel, the remaining two were based on biomarkers absent from the panel, highlighting the potential additional clinical benefit of WGS and TS.

Abstract Purpose The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers. Methods In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10. Results Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5. Conclusion This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients.

Abstract Lung fibrosis development utilizes alveolar macrophages, with mechanisms that are incompletely understood. Here, we fate map connective tissue during mouse lung fibrosis and observe disassembly and transfer of connective tissue macromolecules from pleuro-alveolar junctions (PAJs) into deep lung tissue, to activate fibroblasts and fibrosis. Disassembly and transfer of PAJ macromolecules into deep lung tissue occurs by alveolar macrophages, activating cysteine-type proteolysis on pleural mesothelium. The PAJ niche and the disassembly cascade is active in patient lung biopsies, persists in chronic fibrosis models, and wanes down in acute fibrosis models. Pleural-specific viral therapeutic carrying the cysteine protease inhibitor Cystatin A shuts down PAJ disassembly, reverses fibrosis and regenerates chronic fibrotic lungs. Targeting PAJ disassembly by targeting the pleura may provide a unique therapeutic avenue to treat lung fibrotic diseases.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the best curative treatment modality for many malignant hematologic disorders. In the absence of a matched related donor, matched unrelated donors (MUDs) and haploidentical donors are the most important stem cell sources. In this registry-based retrospective study, we compared the outcomes of allo-HSCTs from 10/10 MUDs with antithymocyte globulin (ATG)–based regimens (n = 7050) vs haploidentical transplants (Haplo-Tx) using posttransplant cyclophosphamide (PT-CY Haplo; n = 487) in adult patients with hematologic malignancies between 2010 and 2020. Cox proportional hazard-and competing risks regression models were formed to compare the outcomes. Overall survival (OS), Disease-free survival (DFS), and graft-versus-host disease (GVHD)–free and relapse-free survival (GRFS) were superior for 10/10 MUDs (OS [hazard ratio (HR), 1.27; 95% confidence interval (CI), 1.10-1.47; P = .001]; DFS [HR, 1.17; CI, 1.02-1.34; P = .022]; GRFS [HR, 1.34; CI, 1.19-1.50; P

Abstract Background Supervisor–subordinate relationship is high relevant in dealing with work-related stress and providing a compassionate, high-quality, and safe nursing care while meeting the needs of the hospital. Our aim was to assess the predisposing risk and resilience factors of the stress of nursing staff as well as to explore the common and distinctive perceptions of these factors between nurses without a managerial position (nursing staff) and employees in a supervising position (nurse managers, ward nurses). Design Generic qualitative study using half-standardized interviews. Methods Fifty nurses and supervisors from different departments from a German hospital of maximum medical care participated in this study between August and November 2018. Nineteen face-to-face interviews and five focus groups were conducted. Transcripts were subjected to structured qualitative content analysis. Results Systematised in Lazarus’s transactional model, nurses, and supervisors mentioned similar risk and resilience factors of stress. Disagreement in suggested responsibility for nurses’ stress or health and an evaluation of implemented measures meeting the nurses’ needs are discussed. Conclusion Nursing staff and supervisors should enforce exchange to reduce disagreements in perceptions and to improve mutual understanding. Furthermore, measures to meet nurses’ needs to minimize stress and to improve collaboration and job satisfaction should be developed in close coordination with the target group. The focus should be placed on restructuring training and education programs with supplementation of self-responsibility promotion. Trail registration The study was registered with the German Register for Clinical Studies (DRKS 00013482) on 09 March 2018.

Abstract Patient-derived xenografts (PDXs) provide biologically relevant models and potential platforms for the development of treatment strategies for precision medicine in pancreatic cancer. Furthermore, circulating epithelial tumor cells (CETCs/CTCs) are released into the bloodstream by solid tumors and a rare subpopulation—circulating cancer stem cells (cCSCs) – is considered to be responsible for recurrence and plays a key role in metastasis. For the identification of cCSCs, an innovative in vitro assay to generate tumorspheres was established in this study. The number of tumorspheres and CETCs/CTCs was analyzed perioperatively in 25 pancreatic cancer patients. Additionally, an individual in vivo chorioallantoic membrane (CAM) culture system was used to generate PDXs from these tumorspheres. While overall correlations of CETCs/CTCs with clinicopathological parameters did not reach statistical significance, a significant difference in the number of tumorspheres was observed between patient subgroups with lower and higher UICC stages. This finding underscores their potential as biomarkers, providing valuable insights into clinical decision-making and tumor progression. The application of tumorspheres on the CAM successfully established PDXs within 7 days. These xenografts closely resembled the histological features of the primary tumor. Hence, this model represents a novel and fast option for individualized testing of new therapies for PDAC.

Abstract During the omicron wave of the COVID-19 pandemic and with SARS-CoV-2 vaccines becoming available, seroprevalence rates rose in children and adolescents. This study investigated the impact of both SARS-CoV-2 infections and vaccinations on the incidence of acute and prolonged symptoms in real-world conditions during the transition from the pandemic to the endemic phase. Participants from a pediatric population based seroprevalence study (CorKID study) were followed up at least two and for almost four years by survey of health status features and symptoms suggestive of post-COVID syndrome (PCS). In a subgroup (n = 259) SARS-CoV-2 antibody serology was further investigated. 789 participants of the original CorKID study cohort (n = 2.121; 37.2%) were included. 67.9% reported at least one SARS-CoV2 infection. 46.6% had received one or more SARS-CoV-2 vaccinations. In the vast majority of serologically tested participants antibodies again SARS-CoV-2 spike (98.9%) or nucleocapsid (93.3%) antigen were detected following infection and/or vaccination. At least 30% experienced one unrecognized SARS-CoV-2 infection. The overall health status was comparable between children, irrespective of SARS-CoV-2 infections and similar to pre-pandemic assessment. However, a subset of young adolescents exhibited a decline in physical performance compared to pre-pandemic conditions. After infection, PCS-like symptoms persisted in 7% of the respondents for more than three months and up to four years. SARS-CoV-2 vaccinated participants (47%) reported 12% less acute flu-like infections other than SARS-CoV-2. Nearly all participants developed SARS-CoV-2 antibodies in this longitudinal study through either vaccination or infection during the Omicron wave. About 7% of participants suffered from PCS symptoms, predominately fatigue and exhaustion. Furthermore, participants who received vaccinations against SARS-CoV-2 reported a lower frequency of acute infections during follow-up.

Abstract The impact of diabetes on incident cardiovascular disease in relation to the extent of atherosclerotic disease remains unclear. We aimed to investigate major adverse cardiovascular events (MACE) in patients with or without type 2 diabetes (T2DM) presenting with two extremes of atherosclerotic disease, those with angiographically documented minor coronary atherosclerotic lesions and those with symptomatic peripheral artery disease. We included 1238 patients from two prospective, long-term cohort studies. Patients underwent coronary angiography and/or sonography in order to assess the grade of atherosclerosis and were defined as having no signs of Atherosclerosis (n = 332; Group I), minor atherosclerosis (n = 425; Group II) and major atherosclerosis (n = 481; Group III). Cardiovascular events were recorded over a median follow-up period of 7.1 years (Q1 = 3.6 years, Q2 = 7.1 years, Q3 = 11.3 years), covering a total of 9533 patient years. We tested the hypothesis that T2DM infers the same relative risk increase irrespective of the atherosclerosis stage, considering 3-point MACE as the primary endpoint. Incident MACE was reported in 681 patients (51%). MACE occurred more frequently in patients with T2DM than in patients without T2DM (p

Abstract Diffraction-before-destruction imaging with ultrashort X-ray pulses can visualize non-equilibrium processes, such as chemical reactions, with sub-femtosecond precision in the native environment. Here, a nanospecimen diffracts a single X-ray flash before it disintegrates. The sample structure can be reconstructed from the coherent diffraction image (CDI). State-of-the-art X-ray snapshots lack high spatial resolution because of weak diffraction signal. Bleaching effects from photo-ionization significantly restrain image brightness scaling. We find that non-linear transient ion resonances can overcome this barrier if X-ray laser pulses are shorter than in most experiments. We compared snapshots from individual ≈ 100 nm Xe nanoparticles as a function of pulse duration and incoming X-ray fluence. Our experimental results and Monte Carlo simulations suggest that transient resonances can increase ionic scattering cross sections significantly beyond literature values. This provides a novel avenue towards substantial improvement of the spatial resolution in CDI in combination with sub-femtosecond temporal precision at the nanoscale.

Abstract Invasive infections with Aspergillus fumigatus in ICU patients are linked to high morbidity and mortality. Diagnosing invasive pulmonary aspergillosis (IPA) in non-immunosuppressed patients is difficult, as Aspergillus antigen (galactomannan [GM]) may have other causes. This retrospective study analyzed 160 ICU surgical patients with positive GM in broncho-alveolar lavage fluid (BALF), classifying them based on AspICU criteria for suspected IPA (pIPA) or aspiration. Patients with pIPA had higher disease severity than those with aspiration, including higher dialysis rates, organ transplantation, corticosteroid use, and Sequential Organ Failure Assessment (SOFA) score. Aspergillus culture was positive in 47.0% of pIPA cases but only 2.6% of aspiration cases (p

Abstract The development of granulomas with central necrosis harboring Mycobacterium tuberculosis (Mtb) is the hallmark of human tuberculosis (TB). New anti-TB therapies need to effectively penetrate the cellular and necrotic compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ-043 is a novel antibiotic showing good bactericidal activity in humans in a phase IIa trial. Here, we report on lesional BTZ-043 concentrations severalfold above the minimal-inhibitory-concentration and the substantial local efficacy of BTZ-043 in interleukin-13-overexpressing mice, which mimic human TB pathology of granuloma necrosis. High-resolution MALDI imaging further reveals that BTZ-043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center. This is the first study that visualizes an efficient penetration and accumulation of a clinical-stage TB drug in human-like centrally necrotizing granulomas and that also determines its lesional activity. Our results most likely predict a substantial bactericidal effect of BTZ-043 at these hard-to-reach sites in TB patients.

Abstract Background Stress responses are key the survival of parasites and, consequently, also the evolutionary success of these organisms. Despite this importance, our understanding of the evolution of molecular pathways dealing with environmental stressors in parasitic animals remains limited. Here, we tested the link between adaptive evolution of parasite stress response genes and their ecological diversity and species richness. We comparatively investigated antioxidant, heat shock, osmoregulatory, and behaviour-related genes (foraging) in two model parasitic flatworm lineages with contrasting ecological diversity, Cichlidogyrus and Kapentagyrus (Platyhelminthes: Monopisthocotyla), through whole-genome sequencing of 11 species followed by in silico exon bait capture as well as phylogenetic and codon analyses. Results We assembled the sequences of 48 stress-related genes and report the first foraging (For) gene orthologs in flatworms. We found duplications of heat shock (Hsp) and oxidative stress genes in Cichlidogyrus compared to Kapentagyrus. We also observed positive selection patterns in genes related to mitochondrial protein import (H sp) and behaviour (For) in species of Cichlidogyrus infecting East African cichlids—a host lineage under adaptive radiation. These patterns are consistent with a potential adaptation linked to a co-radiation of these parasites and their hosts. Additionally, the absence of cytochrome P450 and kappa and sigma-class glutathione S-transferases in monogenean flatworms is reported, genes considered essential for metazoan life. Conclusions This study potentially identifies the first molecular function linked to a flatworm radiation. Furthermore, the observed gene duplications and positive selection indicate the potentially important role of stress responses for the ecological adaptation of parasite species.

Abstract 4d N $$ \mathcal{N} $$ = 4 SYM admits half-BPS boundaries, defects and interfaces as well as compactifications to 3d N $$ \mathcal{N} $$ = 4 SCFTs, realized as intersections of D3, D5 and NS5 branes. We explore operators with large R-charge. We identify Penrose limits in the holographic duals with geometry AdS4 × S2 × S2 × Σ, which describe, for each theory, a spectrum of ‘seed’ operators which each give rise to a BMN-like sector described by a pp-wave. We relate the number of BMN-like sectors to the flavor symmetry of the CFT. For a sample of theories including the Janus interface, D3/D5 BCFTs and BCFTs with 3d SCFTs on the boundary, we determine the spectra of nearby operators and discuss the field theory realization of the seed operators. We further identify families of Penrose limits which give rise to more general pp-wave sectors.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) typically occurs in an older patient population. Yet, early-onset pancreatic cancer (EOPC) has one of the fastest growing incidence rates. This study investigated the influence of age and tumor location on postoperative morbidity and mortality in a large, real-world dataset. Methods Patients with confirmed PDAC undergoing pancreatic surgery between 01/01/2014 and 31/12/2019 were identified from the German StuDoQ|Pancreas registry. After categorization into early- (EOPC; 70 years), and stratification into pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), differences in morbidity and mortality as well as clinicopathologic parameters were analyzed. Results In total, 3011 patients were identified. No difference in the occurrence of postoperative pancreatic fistula (POPF), postpancreatectomy hemorrhage (PPH) or delayed gastric emptying (DGE) between different age groups and resection techniques was detected. However, in patients undergoing PD, major complications (Clavien-Dindo ≥ 3a) were observed more frequently in LOPC (30,7%) than in MOPC (26,2%) and EOPC (16,9%; p

Abstract Highly charged ions (HCIs) are less sensitive to external perturbations and are therefore attractive for the development of ultrastable clocks. However, only a few HCI candidates are known to provide optical clock transitions. In this work, we discover a large family of HCI clocks, with more than 100 suitable optical clock transitions hidden in the fine-structure terms of open-shell ions over 70 elements. Their projected instabilities and accuracies are $${\sigma }_{\tau } \sim 1{0}^{-17}/\sqrt{\tau }$$ σ τ ~ 1 0 − 17 / τ and δ ν/ν

Abstract RNA polymerase III (Pol III) transcribes short, essential RNAs, including the U6 small nuclear RNA (snRNA). At U6 snRNA genes, Pol III is recruited by the snRNA Activating Protein Complex (SNAPc) and a Brf2-containing TFIIIB complex, forming a pre-initiation complex (PIC). Uniquely, SNAPc also recruits Pol II at the remaining splicesosomal snRNA genes (U1, 2, 4 and 5). The mechanism of SNAPc cross-polymerase engagement and the role of the SNAPC2 and SNAPC5 subunits remain poorly defined. Here, we present cryo-EM structures of the full-length SNAPc-containing Pol III PIC assembled on the U6 snRNA promoter in the open and melting states at 3.2–4.2 Å resolution. The structural comparison revealed differences with the Saccharomyces cerevisiae Pol III PIC and the basis of selective SNAPc engagement within Pol III and Pol II PICs. Additionally, crosslinking mass spectrometry localizes SNAPC2 and SNAPC5 near the promoter DNA, expanding upon existing descriptions of snRNA Pol III PIC structure.

Abstract Perovskite-organic tandem solar cells (P-O-TSCs) hold substantial potential to surpass the theoretical efficiency limits of single-junction solar cells. However, their performance is hampered by non-ideal interconnection layers (ICLs). Especially in n-i-p configurations, the incorporation of metal nanoparticles negatively introduces serious parasitic absorption, which alleviates photon utilization in organic rear cell and decisively constrains the maximum photocurrent matching with front cell. Here, we demonstrate an efficient strategy to mitigate optical losses in Au-embedded ICLs by tailoring the shape and size distribution of Au nanoparticles via manipulating the underlying surface property. Achieving fewer, smaller, and more uniformly spherical Au nanoparticles significantly minimizes localized surface plasmon resonance absorption, while maintaining efficient electron-hole recombination within ICLs. Consequently, optimized P-O-TSCs combining CsPbI2Br with various organic cells benefit from a substantial current gain of >1.5 mA/cm2 in organic rear cells, achieving a champion efficiency of 25.34%. Meanwhile, optimized ICLs contribute to improved long-term device stability.

Abstract Background This study aimed to evaluate the efficacy of polydopamine (PDA) functionalization on orthodontic brackets in inhibiting biofilm formation and promoting surface bioactivity to buffer the acidity of caries-causing bacteria around orthodontic brackets and prevent demineralization. The stability of the coating in artificial saliva (AS) and distilled water was evaluated, along with its effect on pH changes in simulated body fluid (SBF) and distilled water. Methods Maxillary incisor orthodontic brackets underwent PDA functionalization using a dopamine hydrochloride solution following a specific protocol. Biofilm formation on both control (Br-0) and coated (Br-PDA) brackets was assessed immediately after coating and after two months of aging (Aged Br-PDA) in artificial saliva. The adherent biofilm bacteria on brackets were quantified with colony count assessment and optical density. Surface morphology, Bioactivity, and coating stability were analyzed using Scanning Electron Microscopy (SEM). Coated and uncoated samples were immersed in SBF and deionized water, and pH changes were monitored over 7 days using a pH meter. Results PDA-functionalized brackets, both freshly coated (1.08 OD) and aged for two months (1.6 OD), showed significantly reduced biofilm formation compared to non-functionalized control brackets (2.07 OD), with p-value

Abstract Background Chronic kidney disease (CKD) is a global health problem, affecting over 840 million individuals. CKD is linked to higher mortality and morbidity, partially mediated by higher cardiovascular risk and worsening kidney function. This study aimed to identify risk factors and develop risk prediction models for selected cardiorenal clinical outcomes in patients with non-diabetic CKD. Methods The study included adults with non-diabetic CKD (stages 3 or 4) from the Optum® Clinformatics® Data Mart US healthcare claims database. Three outcomes were investigated: composite outcome of kidney failure/need for dialysis, hospitalization for heart failure, and worsening of CKD from baseline. Multivariable time-to-first-event risk prediction models were developed for each outcome using swarm intelligence methods. Model discrimination was demonstrated by stratifying cohorts into five risk groups and presenting the separation between Kaplan–Meier curves for these groups. Results The prediction model for kidney failure/need for dialysis revealed stage 4 CKD (hazard ratio [HR] = 2.05, 95% confidence interval [CI] = 2.01–2.08), severely increased albuminuria-A3 (HR = 1.58, 95% CI = 1.45–1.72), metastatic solid tumor (HR = 1.58, 95% CI = 1.52–1.64), anemia (HR = 1.42, 95% CI = 1.41–1.44), and proteinuria (HR = 1.40, 95% CI = 1.36–1.43) as the strongest risk factors. History of heart failure (HR = 2.42, 95% CI = 2.37–2.48), use of loop diuretics (HR = 1.65, 95% CI = 1.62–1.69), severely increased albuminuria-A3 (HR = 1.55, 95% CI = 1.33–1.80), atrial fibrillation or flutter (HR = 1.53, 95% CI = 1.50–1.56), and stage 4 CKD (HR = 1.48, 95% CI = 1.44–1.52) were the greatest risk factors for hospitalization for heart failure. Stage 4 CKD (HR = 2.90, 95% CI = 2.83–2.97), severely increased albuminuria-A3 (HR = 2.30, 95% CI = 2.09–2.53), stage 3 CKD (HR = 1.74, 95% CI = 1.71–1.77), polycystic kidney disease (HR = 1.68, 95% CI = 1.60–1.76), and proteinuria (HR = 1.55, 95% CI = 1.50–1.60) were the main risk factors for worsening of CKD stage from baseline. Female gender and normal-to-mildly increased albuminuria-A1 were found to be associated with lower risk in all prediction models for patients with non-diabetic CKD stage 3 or 4. Conclusions Risk prediction models to identify individuals with non-diabetic CKD at high risk of adverse cardiorenal outcomes have been developed using routinely collected data from a US healthcare claims database. The models may have potential for broad clinical applications in patient care.

Abstract Background Predicting burn-related mortality is vital for family counseling, triage, and resource allocation. Several of the burn-specific mortality prediction scores have been developed, including the Abbreviated Burn Severity Index (ABSI) in 1982. However, these scores are not tested for accuracy to support contemporary estimates of the global burden of burn injury. This study compares burn mortality across countries with varying economic levels, as indicated by the Human Development Index (HDI), to assess if a modified ABSI (mABSI) offers enhanced predictive accuracy. Methods A retrospective study was performed, including over 90,000 patients from seven sources in five continents, including two burn registries and five referral burn centers. Data from 2015 to 2019 were collected, including age, gender, presence of inhalation injury, full-thickness burn, percentage of total body surface area, and outcome. The participating countries were classified based on the HDI and mortality was predicted using both the original and the modified ABSI. Results After removal of incomplete data, 74,460 sets remained for the analysis. Significant variations in population demographics, sample sizes, total body surface area (TBSA), and age distributions across the studied regions were noted. The modified ABSI demonstrated a smaller deviation from the 95% CI of the true survival probability than the original ABSI in countries with a very high or high HDI, indicating improved accuracy here. In these countries, the original ABSI overestimates mortality. Conversely, in countries with a middle or low HDI, the original ABSI remains more accurate, reflecting the significantly greater burn related mortality in countries with a low HDI. Conclusion In burn patients, the probability of survival remains highly dependent on the level of development of a country. Our results support the use of the modified ABSI in countries with a (very) high HDI, yet in resource constraint settings, the original ABSI seems to provide more accurate predictions. These findings underscore the need for adaptive models that take into account socioeconomic variables, potentially guiding health policy adjustments and emphasizing the necessity of resource allocation and training in lower HDI countries. Such adaptations could enhance clinical outcomes and reduce disparities in burn care effectiveness globally.

Abstract Hepatocellular cancer (HCC) therapy is in need for an ideal companion diagnostic. Preclinical experimental studies have identified the insulin receptor (IR) and its synergistic counterpart, the IGF1 receptor (IGF1R), as relevant in HCC development, and the ligands IGF1 and IGF2 have been found to be elevated in HCC. This study aimed to bridge the gap to the clinical setting and explore whether the IR or the IGF1R would be of prognostic significance and would be associated with clinicopathologic parameters in HCC patients. In our retrospective cohort study located at the University Hospital Schleswig-Holstein, Campus Kiel, Germany, HCC samples of 139 patients were examined for IR and IGF1R expression by immunohistochemistry. A HistoScore was correlated with clinicopathological characteristics and survival. IR overexpression was frequently observed and was associated with clinicopathological parameters and survival. Membranous IR expression was associated with worse tumor specific survival (p = 0.043). Intriguingly, membranous IR expression was associated with worse tumor specific survival (p = 0.017) in the subgroup of patients undergoing sorafenib therapy. IGF1R expression was not associated with survival. In conclusion, our results suggest that membranous IR expression plays a role in HCC prognosis and treatment resistance, inspiring future validation as a potential companion diagnostic in HCC.

Abstract Objective To assess the tolerability of multimodal therapy in soft tissue sarcoma patients, particularly with regard to their quality of life and level of distress. Materials and methods A retrospective cohort study enrolled individuals receiving sarcoma therapy at the sarcoma center of the University of Tuebingen between 2017 and 2022. Participants completed an online survey that included the EORTC’s questionnaire (QLQ-C30), coupled with the distress thermometer and demographic inquiries. The primary emphasis was on comparing three distinct modalities: Radiation, Chemotherapy and Surgery. The data were analysed performing one-way ANOVA. Results A total of 237 patients were included in the study. There was a significant difference (p

Abstract Background Hepatocellular Carcinoma (HCC) and cholangiocellular adenocarcinoma (CCA) are the most common primary liver tumors representing a major global health burden. In early disease stages, tumor resection may provide long-term survival in selected patients. However, morbidity and mortality rates are still relatively high after extended liver surgery with perioperative bacterial infections representing major complications. In this study, we evaluate the impact of perioperative infection on the postoperative overall survival (OS) of patients undergoing resection of HCC or CCA. Material and methods Two hundred two patients that received liver surgery for HCC (139) or CCA (63) at our tertiary referral center were included between 2008 and 2020. Infection prior or after surgery was assessed using patient documentation and correlated to patients´ survival rates and other clinical characteristics. Results Patients with perioperative infection displayed a significantly impaired OS compared to patients without a documented infection (419 (95% CI: 262–576) days vs. 959 (95% CI: 637–1281) days; log rank X2(1) = 10.28; p

Abstract Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development. Here, we demonstrate that the Y-chromosomal copy of the TGF-β family member gdf6 (gdf6Y) in Nothobranchius furzeri, an emerging model organism in aging research, gained the function of the male sex determinant through allelic diversification while retaining the skeletal developmental function shared with the X-chromosomal gdf6 allele (gdf6X). Concerning sex determination, gdf6Y is expressed by somatic supporting cells of the developing testes. There it induces the male sex in a germ cell-independent manner in contrast to sex determination in zebrafish and the medaka. Looking for downstream effectors of Gdf6Y, we identified besides TGF-β signaling modulators, especially the inhibitor of DNA binding genes id1/2/3, the mRNA decay activator zfp36l2 as a new GDF6 signaling target.

Background and objective: Patient-reported outcome measures (PROMs) are increasingly being used to capture the patients’ perspective of their functional status and quality of life (QoL). Big data can help us better understand patient-reported outcomes (PROs). Using prospectively collected data from the Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe (PIONEER) consortium, we aimed to describe the functional status and QoL in men with prostate cancer (PCa) treated with active surveillance (AS), radical prostatectomy (RP), and radiotherapy (RT), and to demonstrate the applicability of PROM data on a large scale and at a European level. Methods: We identified data sources that collected QoL data using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-PR25, or Expanded Prostate Cancer Index Composite (EPIC)-26/50 questionnaires. Aggregated summary scores for urinary, bowel, and sexual dysfunction, global health status, and QoL were shared for each data source. Key findings and limitations: We identified eight data sources originating from various settings: routine hospital data, embedded research PRO collection, survey data collected by a patient organization, multi-institutional prospective cohort study, and registry data. PRO data were available for 709 men on AS, 20 508 on RP, and 3417 on RT, with a median time between diagnosis and PROM assessment ranging from 1 to 8.7 yr. Most men were diagnosed with Gleason ≤7 disease, and T1 or T2 PCa. We observed that sexual dysfunction was the most affected PRO and found large differences between data sources. Conclusions and clinical implications: Our results support the feasibility of PRO assessment using big data in Europe. Implementation of PROMs in clinical practice and the use of standardized methods could improve value-based health care provision. Patient summary: In this study, we combined several data sources that reported urinary, bowel, and sexual dysfunction, global health status, and quality of life. We identified eight data sources and show that sexual function is the most affected domain after treatment.

Abstract Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Abstract Background: Impression materials can harbour microorganisms from saliva and blood, posing cross-contamination risks. However, post-setting disinfection might compromise the dimensional accuracy and mechanical properties of alginates. Hence, it was the aim of this research to assess the detail reproduction, tear strength, elastic recovery, and surface quality of the gypsum model of newly developed dental alginates with inherent antimicrobial properties. Methods: Three dental alginate groups with antimicrobial alterations were formulated. One group replaced water with 0.2% chlorhexidine solution (CHX group), while the other two utilized water-based extracts of Syzygium aromaticum (SA, clove) or Zingiber officinale (ZO, ginger) to reduce silver nitrate, resulting in two silver nanoparticles (AgNPs)/extract (clove or ginger) mixture solutions. These mixture solutions were employed for the preparation of dental alginate yielding the SA + AgNP and ZO + AgNPs groups. All modified groups were compared to an unmodified control group that used water for mixing. Elastic recovery, detail reproduction, and tear strength were assessed following the ISO 21563:2021 standard. The surface roughness of plaster models was analysed using the optical profilometer. Elastic recovery was assessed by applying and then releasing load on alginate specimens to measure their ability to recover from deformation. Detail reproduction was evaluated by observing the reproducibility of a 50 μm line in a metallic mold using a light microscope, while tear strength was determined by stretching the specimens until failure at a constant speed of 500 mm/min. Results: All tested groups exhibited elastic recovery values meeting ISO standards for hydrocolloid impression materials. Regarding detail reproduction, both the control and modified alginates successfully reproduced the 50-µm line without interruption in all specimens. Tear strength values for all tested groups remained within the acceptable documented ranges, surpassing the minimum requirement of 0.38 N/mm as mandated by ISO 21563:2021. The ZO + AgNPs (0.94 ± 0.17 N/mm) demonstrated significantly higher tear strength values and surface roughness values compared to the other tested groups. Conclusions: Chlorhexidine, Syzygium aromaticum, and Zingiber officinale green-synthesized silver nanoparticles are promising, cost-effective alternatives for disinfecting alginate impressions without compromising performance. Green nanoparticle synthesis is a safe, efficient, and non-toxic method, potentially synergizing metal ions with plant extract.

Abstract Previous advances have identified immune pathways associated with inflammatory skin diseases, leading to the development of targeted therapies. However, there is a lack of molecular approaches that delineate these pathways at the individual patient level for personalized diagnostic and therapeutic guidance. Here, we conduct a cross-comparison of expression profiles from multiple inflammatory skin diseases to identify gene modules defining relevant immune pathways. Seven modules are identified, representing key immune pathways: Th17, Th2, Th1, Type I IFNs, neutrophilic, macrophagic, and eosinophilic. These modules allow the development of a molecular map with high diagnostic efficacy for inflammatory skin diseases and clinico-pathologically undetermined cases. Aligning dominant modules with treatment targets offers a rational framework for treatment selection, improving response rates in both treatment-naïve patients and non-responders to targeted therapies. Overall, our approach offers precision medicine for inflammatory skin diseases, utilizing transcriptional modules to support diagnosis and guide personalized treatment selection.

Abstract Mn-doped UO2 is considered a potential advanced nuclear fuel due to ameliorated microstructural grain growth compared to non-doped variants. However, recent experimental investigations have highlighted limitations in grain growth apparently arising from misunderstandings of its redox-structural chemistry. To resolve this, we use synchrotron X-ray diffraction and spectroscopy measurements supported by ab initio calculations to cross-examine the redox and structural chemistry of Mn-doped UO2 single crystal grains and ceramic specimens. Measurements reveal Mn enters the UO2 matrix divalently as $$({{{Mn}}}_{x}^{+2}{{U}}_{1-x}^{+4}){{O}_{2-x}}$$ ( M n x + 2 U 1 − x + 4 ) O 2 − x with the additional formation of fluorite Mn+2O in the bulk material. Extended X-ray absorption near edge structure measurements unveil that during sintering, the isostructural relationship between fluorite UO2 and Mn+2O results in inadvertent interaction and subsequent incorporation of diffusing U species within MnO, rather than neighbouring UO2 grains, inhibiting grain growth. The investigation consequently highlights the significance of considering total redox-structural chemistry of main and minor phases in advanced ceramic material design.

Abstract Background Tobacco smoking is a relevant determinant of multiple sclerosis (MS) onset, and smokers have increased risk for faster progression of MS compared to non-smokers. While the smoking prevalence is high in Germany, no smoking cessation programs have been developed specifically in MS populations to date, and only little is known about the motivators and barriers influencing smoking cessation in people with MS (pwMS) in Germany. This study aims to identify these factors to inform the design of a tailored smoking cessation intervention. Methods As part of a larger program of work, we conducted semi-structured interviews in people with MS (pwMS) to explore their needs, motivators and barriers regarding smoking cessation. We recruited via MS-websites and the email-newsletter of our institution at the University Medical Centre Hamburg-Eppendorf. Participants were eligible if they had a self-reported MS-diagnosis and currently smoked or quit smoking within the last two years but after their MS-diagnosis. Interviews were conducted online and via telephone during May and June 2023. Data were analysed using thematic analysis based on a realistic approach. Results Eight women and seven men participated in our interviews. Eleven were current, four were former smokers. Median time since diagnosis was 4 years (range: 1–26). Interviews identified MS-diagnosis, concerns about general health, and social factors as relevant motivators to stop smoking. Furthermore, worries about negative consequences when quitting (e.g. fear of missing out on social interactions or weight gain) were identified as a great barrier to smoking cessation. Knowledge about the connection between MS and smoking, and satisfaction with communication with MS clinicians were low. PwMS expressed a need for better conversations with neurologists and expert-led smoking cessation interventions. Additionally, we found that the wish for peer-exchange and the willingness to participate in smoking cessation programs was high. Conclusion Our results confirm findings of previous studies from other countries, identifying lack of knowledge, unsatisfactory communication with MS clinicians, and worries about negative consequences when quitting as barriers, and the MS-diagnosis as a motivator for smoking cessation. In a next step, we will use our findings for the development of an MS-specific online smoking cessation program.

Machine learning (ML) is increasingly used to support or automate decision processes in critical decision systems such as self driving cars or systems for medical diagnosis. These systems require decisions in which human lives are at stake and the decisions should therefore be well founded and very reliable. This need for reliability contrasts with the black-box nature of many ML models, making it difficult to ensure that they always behave as intended. In face of the high stakes involved, the resulting uncertainty is a significant challenge. Explainable artificial intelligence (XAI) addresses the issue by making black-box models more interpretable, often to increase user trust. However, many current XAI applications focus more on transparency and usability than on enhancing safety of ML applications. In this work, we therefore conduct a systematic literature review to examine how XAI can be leveraged to increase safety of ML applications in critical decision systems. We strive to find out for what purposes XAI is currently used in critical decision systems, what are the most common XAI techniques in critical decision systems and how XAI can be harnessed to increase safety of ML applications in critical decision systems. Using the SPAR-4-SLR protocol, we are able to answer these questions and provide a foundational resource for researchers and practitioners seeking to mitigate risks of ML applications. Essentially, we identify promising approaches of XAI which go beyond increasing trust to actively ensure correctness of decisions. Our findings propose a three-layered framework to enhance safety of ML in critical decision systems by means of XAI. The approach consists of Reliability, Validation and Verification. Furthermore, we point out gaps in research and propose future directions of XAI research for enhancing safety of ML applications in critical decision systems.

Abstract Background Tuberculosis (TB) remains a global health challenge, with 1.3 million deaths in 2022. Ten countries in the European Union (EU) and European Economic Area (EEA) accounted for 88.3% of TB cases, of which 23.8% were from Romania. Evidence shows that mental health issues, decreased quality of life and negative socio-economic impact are common among TB patients; however, there is limited evidence available in Romania. The main aim of this study is to longitudinally assess the quality of life, mental health, and socio-economic status of patients with drug-resistant TB (DR TB) in Romania. Methods A prospective cohort study was conducted at the Marius Nasta Institute of Pneumology in Bucharest, Romania, enrolling 50 participants with DR TB. Demographic data, clinical examinations, laboratory test and medical history were recorded at study start. At baseline (week two), month 10, and month 20 we also administered the Short-Form-36 and Kessler Psychological Distress Scale to assess health-related quality of life and mental health status, and socio-economic questionnaires to 46 participants. Results Of the 46 participants with median age of 48.9 years, 71.7% were males. Majority of the participants were employed at the baseline but due to the rigorous treatment and hospitalization had to take sick leave, thereby affecting the individual and household income. 26.1% and 39.3% of participants reported psychological distress at baseline and at the end of month 20, respectively. The quality-of-life scores improved during treatment: PCS with a mean of 67.0 (SD-33.9) at baseline, 63.3 (SD-31.9) at month 10 and 70.3 (SD-30.3) at month 20, and MCS with 62.8 (SD-30.6), 67.8 (SD-29) and 70.8 (SD-27.3), accordingly, but differences were not significant. Conclusions We examined the socio-economic impact, quality of life, and psychological distress among patients affected by DR TB in Romania. The results of this study suggest that social and psychological support will ensure a better standard of living during and following TB treatment.

Abstract Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.

Abstract Background Healthcare professionals play an important role in successfully implementing digital interventions in routine mental healthcare settings. While a larger body of research has focused on the experiences of mental healthcare professionals with the combination of digital interventions and face-to-face outpatient treatment, comparatively little is known about their experiences with digital interventions combined with inpatient treatment. This is especially true for acute psychiatric inpatient care, where studies on the implementation of digital interventions are more rare. The current study aimed to investigate healthcare professionals’ experiences with an internet-based emotion regulation intervention added to acute psychiatric inpatient treatment. Methods Physicians, nurses, psychologists, social workers, and occupational therapists from three acute inpatient wards (n = 20) were interviewed regarding their experiences. A thematic analysis approach was used to analyze the interview data. Results The following themes and corresponding subthemes were identified: lack of experience (few or no previous experiences, no expectations, few points of contact), the intervention as a contemporary complement (positive expectations, necessary and contemporary, positive effects on therapeutic work and patients, characteristics of the internet-based program), concerns about fit for acute psychiatric inpatient care (fit for acute psychiatric inpatients, doubts about implementation), the human factor as essential for implementation (the team makes or breaks it, guidance is key, patient characteristics), and requirements for implementation beyond the human factor (integration into existing treatment structure, resources, changes to the internet-based program, timing). Conclusions While healthcare professionals reported few points of contact with the intervention, they saw it as a contemporary complement to acute psychiatric inpatient care with benefits for therapeutic work and patients. The findings further suggest that specific concerns regarding the fit for acute psychiatric inpatient care remain and that human factors such as support from the ward team, human guidance during the intervention and being mindful of specific patient characteristics are considered important for implementation. Moreover, factors such as integration of the intervention into the ward program, resource availability and the timing of the intervention during a patient’s individual stay should be considered for successful implementation. Trial registration Clinicaltrials.gov, NCT04990674, 04/08/2021.

Abstract Naming chemical compounds systematically is a complex task governed by a set of rules established by the International Union of Pure and Applied Chemistry (IUPAC). These rules are universal and widely accepted by chemists worldwide, but their complexity makes it challenging for individuals to consistently apply them accurately. A translation method can be employed to address this challenge. Accurate translation of chemical compounds from SMILES notation into their corresponding IUPAC names is crucial, as it can significantly streamline the laborious process of naming chemical structures. Here, we present STOUT (SMILES-TO-IUPAC-name translator) V2, which addresses this challenge by introducing a transformer-based model that translates string representations of chemical structures into IUPAC names. Trained on a dataset of nearly 1 billion SMILES strings and their corresponding IUPAC names, STOUT V2 demonstrates exceptional accuracy in generating IUPAC names, even for complex chemical structures. The model's ability to capture intricate patterns and relationships within chemical structures enables it to generate precise and standardised IUPAC names. While established deterministic algorithms remain the gold standard for systematic chemical naming, our work, enabled by access to OpenEye’s Lexichem software through an academic license, demonstrates the potential of neural approaches to complement existing tools in chemical nomenclature. Scientific contribution STOUT V2, built upon transformer-based models, is a significant advancement from our previous work. The web application enhances its accessibility and utility. By making the model and source code fully open and well-documented, we aim to promote unrestricted use and encourage further development. Graphical Abstract

Abstract We consider a class of singlet scalar extensions of the Standard Model of particle physics in which the scalar couples only to off-shell states. As a result, low-order tree-level processes involving the singlet scalar vanish, providing a unique phenomenology that may allow to evade existing constraints on new singlet scalar fields. We describe search strategies for such states at the Large Hadron Collider and identify the parameter space that can be explored in the future.

Abstract Many observables in 4d N $$ \mathcal{N} $$ = 4 SYM with Gaiotto-Witten boundary conditions can be described exactly by matrix models via supersymmetric localization. The boundaries typically introduce new degrees of freedom, through a reduction of the gauge symmetry on the boundary or as explicit boundary degrees of freedom, leading to non-trivial matrix models. We derive the saddle points dominating these matrix models at large N, expressed in terms of generalized Lambert W-functions. In string theory the BCFTs are realized by D3-branes ending on D5 and NS5 branes. We independently derive the saddle points from the holographic duals with AdS4×S2×S2×Σ geometry and provide precision tests of the dualities.

Abstract The circle of Willis (CoW) is a circular arrangement of arteries in the human brain, exhibiting significant anatomical variability. The CoW is extensively studied in relation to neurovascular pathologies, with certain anatomical variants previously linked to ischemic stroke and intracranial aneurysms. In an individual CoW, arteries might be absent (aplasia) or underdeveloped (hypoplasia, diameter < 1 mm). As the assessment of such variations is time-consuming and susceptible to subjectivity, robust automatic extraction of personalized CoW topology from time-of-flight magnetic resonance angiography (TOF-MRA) images would highly benefit large-scale clinical investigations. Previous work has sought to extract CoW topology from voxel-based semantic segmentation masks. However, hypoplastic arteries are challenging to recover in voxel-based segmentation. Instead, we propose using a complete CoW as an anatomical prior for extracting all possible CoW arteries as shortest paths between automatically identified anatomical landmarks, guided by automatically determined artery orientation vector fields. These fields are obtained using a scale-invariant and rotation-equivariant mesh-CNN-based model (SIRE). For a 3D TOF-MRA volume, a potentially overcomplete graph of the CoW is thus extracted in which each edge represents an artery. Subsequently, a binary Random Forest classifier labels each artery as normal or hypo-/aplastic. The model was optimized and validated using a data set of 351 3D TOF-MRA scans in a cross-validation setup. We showed that using a shortest path algorithm with a cost function based on local artery orientations results in continuous artery paths, even in hypoplastic cases. We tracked the correct path in the posterior communicating arteries in 70–74% of the cases, an artery that is known to pose challenges in voxel-based segmentation models. Our downstream artery path classifier obtained an average F1 score of 0.91, demonstrating the potential of our proposed framework to extract personalized CoW topology automatically.

Abstract Sponges harbour complex microbiomes and as ancient metazoans and important ecosystem players are emerging as powerful models to understand the evolution and ecology of symbiotic interactions. Metagenomic studies have previously described the functional features of sponge symbionts, however, little is known about the metabolic interactions and processes that occur under different environmental conditions. To address this issue, we construct here constraint-based, genome-scale metabolic networks for the microbiome of the sponge Stylissa sp. Our models define the importance of sponge-derived nutrients for microbiome stability and discover how different organic inputs can result in net heterotrophy or autotrophy of the symbiont community. The analysis further reveals the key role that a newly discovered bacterial taxon has in cross-feeding activities and how it dynamically adjusts with nutrient inputs. Our study reveals insights into the functioning of a sponge microbiome and provides a framework to further explore and define metabolic interactions in holobionts.

Abstract Background Post malaria neurologic syndrome (PMNS) is a rare complication of malaria, usually caused by Plasmodium falciparum. The clinical picture is highly variable and ranges from qualitative disturbances of consciousness and psychosis to damage to the peripheral nerves, usually occurring three to eight weeks after treated malaria. Case presentation We report the case of a 54-year-old male who presented with recurrent clinical symptoms three and a half weeks after severe falciparum malaria. After ruling out recurrent malaria, autoimmune encephalitis was suspected. Corticosteroid therapy led to a rapid improvement of the clinical symptoms. The extended examinations (including cranial MRI and FDG-PET/CT) revealed no pathological findings. Routine serologic autoimmune diagnostics remained negative. However, anti-septin complex antibodies were detected in the serum in a cell-based and a tissue-based immunofluorescence assay. Twelve months after discontinuation of corticosteroid therapy, the patient was free of immunosuppressants and completely asymptomatic. Conclusion To our knowledge, this is the first case of septin complex autoimmunity with encephalitis associated with PMNS. All physicians treating malaria patients should therefore be aware of this rare condition and consider extended autoimmune diagnostics if routine panels remain unremarkable.

Abstract Background Yellow nail syndrome is characterized by a yellow discoloration of the nails, respiratory symptoms, and lymphedema. It was first described in 1964 and has an estimated prevalence of less than 1:1.000.000. Despite its diverse manifestations affecting different organ systems and a wide range of associated diseases, yellow nail syndrome is most commonly related to impaired lymphatic drainage. The treatment depends on whether the underlying pathology can be identified and includes dietary, pharmacological, interventional, and surgical approaches. Case presentation We report the case of a 73-year-old Caucasian male patient presenting with exertional shortness of breath and orthopnea, nonpitting edema of his distal extremities, and yellow discoloration of both his finger and toe nails. The diagnostic workup, which included the drainage of a large chylous pleural effusion, computed tomography of the chest, and lymphangiography, led to the diagnosis of yellow nail syndrome, presumably caused by a mediastinal lipoma compressing the thoracic duct. Treatment-wise, a percutaneous lymphatic embolization was performed after conservative treatment did not lead to a significant improvement of symptoms. Conclusion While demonstrating the specific diagnostic findings of this case, we try to point out common pathogenetic aspects of the disorder and present the currently available treatment options.

Abstract Background Claudin-3 (CLDN3) participates in the formation of the tight-junctions (TJs) that regulate intercellular permeability. Altered CLDN3 expression has been linked to tumor progression in multiple tumor types. Despite its widespread expression in normal epithelial cells, CLDN3 is considered an attractive drug target candidate, since it may be more accessible in cancer cells than in normal cells due to their less orchestrated cell growth. Methods To comprehensively determine the prevalence of CLDN3 expression in cancer, a tissue microarray containing 14,966 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results CLDN3 immunostaining was observed in 8,479 (68.9%) of 12,314 analyzable tumors, including 11.6% with weak, 6.2% with moderate, and 51.1% with strong positivity. CLDN3 staining was found in 96 of 133 tumor categories, 80 of which contained at least one strongly positive case. CLDN3 positivity was most seen in neuroendocrine neoplasms (92–100%) and in adenocarcinomas (67–100%), tumors of the female genital tract, including various subtypes of ovarian and endometrial carcinoma (up to 100%), as well as different subtypes of breast cancer (95.3–100%). CLDN3 positivity was less common in squamous cell carcinomas (0–43.2%) and mainly absent in melanoma, mesenchymal, and hematolymphatic neoplasms. In clear cell renal cell carcinoma (ccRCC), low CLDN3 was strongly linked to poor ISUP (p

Abstract Background Quantification of Amyloid beta (Aβ) oligomers in plasma enables early diagnosis of Alzheimer’s Disease (AD) and improves our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology because of very low Aβ oligomer concentrations and possible interference from matrix components. Methods In this report, we developed and validated a surface-based fluorescence distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. Results The blood-based sFIDA assay delivers a sensitivity of 1.8 fM, an inter- and intra-assay variation below 20% for oligomer calibration standards and no interference with matrix components. Quantification of Aβ oligomers in 359 plasma samples from the DELCODE cohort reveals lower oligomer concentrations in subjective cognitive decline and AD patients than healthy Control participants. Conclusions Correlation analysis between CSF and plasma oligomer concentrations indicates an impaired clearance of Aβ oligomers that is dependent on the ApoE ε4 status.

Abstract Aims Concentrations of high‐sensitivity cardiac troponin T (hs‐cTnT) are frequently elevated in stable patients with confirmed muscle dystrophies. However, sparse information is available on the interpretation of serial concentration changes. Methods Hs‐cTnT was collected in 35 stable outpatients with confirmed skeletal muscle dystrophies at 0 and 1 h and after 6–12 months during scheduled outpatient visits. We simulated the effectiveness of the European Society of Cardiology (ESC) 0/1 h algorithm and assessed biological variation at 6–12 months using two established methods: reference change value (RCV) and minimal important difference (MID). Results Median baseline hs‐cTnT concentrations were 34.4 ng/L [inter‐quartile range (IQR): 17.5–46.2], and values > 99th percentile upper limit of normal were present in 34 of 35 patients. All patients were stable without cardiovascular adverse events during a follow‐up of 6.6 months (IQR: 6–7). Median concentration change was 1.9 ng/L (IQR: 0.7–3.2) and 0.8 ng/L (IQR: 0–7.0) at 60 min and 6–9 months, respectively. Applying the criteria of the ESC 0/1 h algorithm for triage of suspected acute coronary syndrome (ACS) showed poor overall effectiveness of baseline hs‐cTnT values. No patient would qualify for rule‐out based on hs‐cTnT less than the limit of detection, whereas five cases would qualify for rule‐in based on hs‐cTnT ≥ 52 ng/L. Biological variabilities at 6–12 months per MID and RCV were 1.2 ng/L [95% confidence interval (CI): 0.7–2.1] and 28.6% (95% CI: 27.9–29.6), respectively. A total of 8 (22.9%) and 25 (71.4%) cases exceeded the biological variation range, suggesting some additional myocardial damage. Conclusions The high prevalence of elevated hs‐cTnT could negatively impact the effectiveness of rule‐out and rule‐in strategies based on a single hs‐cTnT value. Knowledge of the physiological and biological variation of hs‐cTnT after 6–12 months is helpful to detect the progression of cardiac involvement or to search for cardiac complications including but not limited to arrhythmias that may trigger acute or chronic myocardial damage.

Abstract Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM. Study Design The activeDCM trial is a prospective, randomized, interventional trial with a 12 month follow‐up. Three hundred patients, aged 18–75 years with DCM, left ventricular ejection fraction (LVEF) ≤ 50% and New York Heart Association (NYHA) classes I–III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO2max, mL/kg/min) from baseline to 12 months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6 min walk distance, muscular strength, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high‐density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices. Discussion The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices.

Abstract Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) exhibit an elevated risk for cardiac arrhythmias, such as bradycardia, which may potentially lead to sudden cardiac death (SCD). While hypoglycemia, defined as a critical drop in glucose levels below the normal range, has long been associated with adverse cardiovascular events, recent studies have highlighted the need for a comprehensive reevaluation of its direct impact on cardiovascular outcomes, particularly in high-risk populations such as those with DM and CKD. In this study, we investigated the association between glucose levels and bradycardia by simultaneously monitoring interstitial glucose (IG) and ECG for 7 days in insulin-treated patients with DM and CKD. We identified bradycardia episodes in 19 of 85 patients (22%) and associated these episodes with personalized low, medium, and high relative glucose levels. Our analysis revealed a significant increase in bradycardia frequency during periods of lowest relative glucose, particularly between 06:00-09:00 and 12:00-15:00. Furthermore, leveraging a Random Forests classifier, we achieved a promising area under the curve (AUC) of 0.94 for predicting bradyarrhythmias using glucose levels and heart rate variability features. Contrary to previous findings, only 4% of bradycardia episodes in our study population occurred at glucose levels of 70 mg/dL or lower, with 28% observed at levels exceeding 180 mg/dL. Our findings not only highlight the strong correlation between relative glucose levels, heart rate parameters, and bradycardia onset but also emphasize the need for a more personalized definition of hypoglycemia to understand its relationship with bradyarrhythmias in high-risk DM and CKD patient populations.

Abstract Epigenetic heterogeneity is a fundamental property of biological systems and is recognized as a potential driver of tumor plasticity and therapy resistance. Single-cell epigenomics technologies have been widely employed to study epigenetic variation between—but not within—cellular clusters. We introduce epiCHAOS: a quantitative metric of cell-to-cell heterogeneity, applicable to any single-cell epigenomics data type. After validation in synthetic datasets, we apply epiCHAOS to investigate global and region-specific patterns of epigenetic heterogeneity across diverse biological systems. EpiCHAOS provides an excellent approximation of stemness and plasticity in development and malignancy, making it a valuable addition to single-cell cancer epigenomics analyses.

Abstract Tissue-resident immune cells, such as innate lymphoid cells, mediate protective or detrimental immune responses at barrier surfaces. Upon activation by stromal or epithelial cell-derived alarmins, group 2 innate lymphoid cells (ILC2s) are a rapid source of type 2 cytokines, such as IL-5. However, due to the overlap in effector functions, it remains unresolved whether ILC2s are an essential component of the type 2 response or whether their function can be compensated by other cells, such as T cells. Here we show a non-redundant role of ILC2s in supporting the development and function of B1 cells. We demonstrate that B1 cells fail to develop properly in the absence of ILC2s and identify the IL-33 receptor on ILC2s as an essential cell-intrinsic regulator of IL-5 production. Further, conditional deletion of Il5 in ILC2s results in defective B1 cell development and immunoglobulin production. Consequently, B1 cells with phosphatidylcholine specific B cell receptor rearrangements are diminished in ILC2-deficient mice. Thus, our data establish an essential function of ILC2s in supporting B1 cells and antibody production at barrier surfaces.

Abstract Background Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. While PD-1 based immunotherapies overall have led to improved treatment outcomes for this disease, a diverse response to frontline chemotherapy and immunotherapy still exist in TNBC, highlighting the need for more robust prognostic markers. Methods Tumor-intrinsic immunotranscriptomics, serum cytokine profiling, and tumor burden studies were conducted in two syngeneic mouse models to assess differential effects in both the early-stage and metastatic setting. Bioinformatic analyses of both early and metastatic TNBC patient data were performed to assess if identified NF-κB-associated factors are associated with improved patient clinical outcomes. Results NF-κB signaling driven by lymphotoxin beta expression is associated with tumor regression in TNBC mouse models. Furthermore, lymphotoxin beta expression in patient TNBC cohorts is prognostic of improved survival outcomes. Conclusions This study highlights the potential role for NF-κB-associated factors, specifically lymphotoxin beta to be used as prognostic markers in TNBC, which could ultimately provide insight for improved targeted treatment approaches in the clinic.