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Abstract Background Cardiometabolic risk factors among youth are rising. Epigenetic age acceleration, a biomarker for aging and disease-risk, has been associated with adiposity in children, but its association with other cardiometabolic risk markers remains understudied. We employed data from the Health Outcomes and Measures of the Environment (HOME) study, a prospective pregnancy and birth cohort in the greater Cincinnati metropolitan area, to examine whether accelerated epigenetic age at birth as well as accelerated epigenetic age and faster pace of biological aging at age 12 years were associated with higher cardiometabolic risk in adolescents. Results After adjusting for potential confounders, including estimated cell type proportions, epigenetic gestational age acceleration at birth, derived from the Bohlin, Knight, and Haftorn clocks using cord blood DNA methylation data, was not associated with cardiometabolic risk z-scores or individual cardiometabolic risk score components (visceral fat, leptin to adiponectin ratio, HOMA-IR, triglycerides to HDL-C ratio, HbA1c, or systolic blood pressure) at age 12 years. We also did not observe any associations of epigenetic age acceleration, calculated with Horvath’s skin and blood, Hannum’s, and Wu’s epigenetic clocks using peripheral blood at age 12 years, with these same cardiometabolic risk markers. In contrast, faster pace of biological aging was associated with higher cardiometabolic risk [βs (95% CIs)] cardiometabolic risk score 0.25 (0.07, 0.42); visceral fat 0.21 (0.05, 0.38); and hemoglobin A1c 0.23 (0.05, 0.41) per standard deviation increase in pace of biological aging. Faster pace of biological aging was also positively associated with systolic blood pressure, triglycerides to HDL-C ratio, HOMA-IR, and leptin to adiponectin ratio, although these associations were not statistically significant. Conclusions Our findings provide evidence that faster pace of biological aging was associated with higher cardiometabolic risk score, visceral fat, and HbA1c at age 12 years. Further research is needed to determine whether these associations persist from adolescence through adulthood.

Abstract Due to their position on glomerular capillaries, podocytes are continuously counteracting biomechanical filtration forces. Most therapeutic interventions known to generally slow or prevent the progression of chronic kidney disease appear to lower these biomechanical forces on podocytes, highlighting the critical need to better understand podocyte mechano-signalling pathways. Here we investigated whether the mechanotransducer Piezo is involved in a mechanosensation pathway in Drosophila nephrocytes, the podocyte homologue in the fly. Loss of function analysis in Piezo depleted nephrocytes reveal a severe morphological and functional phenotype. Further, pharmacological activation of endogenous Piezo with Yoda1 causes a significant increase of intracellular Ca++ upon exposure to a mechanical stimulus in nephrocytes, as well as filtration disturbances. Elevated Piezo expression levels also result in a severe nephrocyte phenotype. Interestingly, expression of Piezo which lacks mechanosensitive channel activity, does not result in a severe nephrocyte phenotype, suggesting the observed changes in Piezo wildtype overexpressing cells are caused by the mechanosensitive channel activity. Moreover, blocking Piezo activity using the tarantula toxin GsMTx4 reverses the phenotypes observed in nephrocytes overexpressing Piezo. Taken together, here we provide evidence that Piezo activity levels need to be tightly regulated to maintain normal pericardial nephrocyte morphology and function.

Abstract Vision and magnetoreception in navigating songbirds are strongly connected as recent findings link a light dependent radical-pair mechanism in cryptochrome proteins to signalling pathways in cone photoreceptor cells. A previous yeast-two-hybrid screening approach identified six putative candidate proteins showing binding to cryptochrome type 4a. So far, only the interaction of the cone specific G-protein transducin α-subunit was investigated in more detail. In the present study, we compare the binding features of the G-protein α-subunit with those of another candidate from the yeast-two-hybrid screen, cellular retinol binding protein. Purified recombinant European robin retinol binding protein bound retinol with high affinity, displaying an EC50 of less than 5 nM, thereby demonstrating its functional state. We applied surface plasmon resonance and a Förster resonance transfer analysis to test for interactions between retinol binding protein and cryptochrome 4a. In the absence of retinol, we observed no robust binding events, which contrasts the strong interaction we observed between cryptochrome 4a and the G-protein α-subunit. We conclude that retinol binding protein is unlikely to be involved in the primary magnetosensory signalling cascade.

Abstract The Tri-Service Microbiome Consortium (TSMC) was founded to enhance collaboration, coordination, and communication of microbiome research among DoD organizations and to facilitate resource, material and information sharing among consortium members, which includes collaborators in academia and industry. The 2023 annual symposium was a hybrid meeting held in Washington DC on 26–27 September 2023 concurrent with the virtual attendance, with oral and poster presentations and discussions centered on microbiome-related topics within five broad thematic areas: 1) Environmental Microbiome Characterization; 2) Microbiome Analysis; 3) Human Microbiome Characterization; 4) Microbiome Engineering; and 5) In Vitro and In Vivo Microbiome Models. Collectively, the symposium provided an update on the scope of current DoD and DoD-affiliated microbiome research efforts and fostered collaborative opportunities. This report summarizes the presentations and outcomes of the 7th annual TSMC symposium.

Abstract Carbapenem resistant (CRE) and carbapenemase producing Enterobacterales (CPE) in particular, represent a major threat for healthcare systems worldwide. Rapid, reliable, and easy to perform assays are required to enable targeted and effective therapy. MALDI-TOF MS based carbapenemase diagnostics has potential advantages over molecular and phenotypic sensitivity tests, especially in terms of time to result. So far, only one mass spectrometry (MS)-based carbapenemase test system is commercially available for routine use. The aim of this study was to compare the performance of the established system to a novel MS-based test to identify CPE isolates. Forty consecutive CRE isolates (70% CPEs) were pre-screened for carbapenemase activity by routine laboratory methods. Isolates then were tested using the to date only IVD CE certified MALDI-TOF MS carbapenemase detection assay (MBT STAR-Carba IVD Kit; Bruker Daltonics) and a novel test designed for the recently launched EXS2600 MALDI-TOF MS system (Carbapenemase Activity Kit; Zybio). Valid results were obtained for 93% and 85% isolates by the Bruker and the Zybio assay, respectively. Sensitivities, specificities, positive and negative predictive values were 92%, 91%, 96%, and 83% for the Bruker assay and 96%, 64%, 85%, and 88% for the Zybio assay. There are notable differences concerning the handling of the assays. In summary, both systems featured high sensitivities for the detection of carbapenemases, but the Bruker assay yielded less false-positive results. There are advantages and disadvantages concerning the handling for each system, but both proved to be suitable for the use in a routine laboratory.

Abstract Introduction/Background Peer-led teaching sessions (PLTS) supplement conventional medical education, allowing students to share knowledge effectively. PLTS have shown significant academic benefits for student instructors. However, the impact on attendees, especially concerning NBME-style examinations, remains underexplored. Methods This study analyzed de-identified data from 67 first-year medical students at Kirk Kerkorian School of Medicine, divided into PLTS attendees (study group) and non-attendees (control group) based on session participation. Data were collected before two NBME examinations, with attendees defined as those attending at least five Peer-led teaching sessions. Academic performance was measured using NBME Customized Assessment Services (CAS) exam scores. Statistical analyses, including p-tests, chi-square, and t-tests, assessed differences in performance and potential biases based on MCAT scores, first-generation status, and socioeconomic background. Results The study group initially had 26 students, and the control group had 31 students. Post-first examination, the study group adjusted to 22 students, and the control group to 35 students. MCAT scores and demographics showed no significant differences between groups. The first examination revealed a significant higher score in PLTS attendees’ scores (4.28% increase, p = 0.036), indicating a positive impact of PLTS on basic science knowledge. The second examination on organ systems physiology showed no significant difference (p = 0.722). Discussion PLTS effectively enhance foundational science understanding but may be less impactful for advanced topics. The diminishing effect may result from increased use of diverse study resources and adaptation to medical school. Future research should explore long-term benefits, optimal implementation strategies, and the impact of instructor quality and engagement. Therefore, the overall conclusion is that PLTS positively influence NBME-style exam performance in early medical education, but benefits decrease over time.

Abstract Background The effect of milk on the risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) is unclear. We aimed to examine the association between non-fermented and fermented milk consumption on these endpoints and investigate the relationship between milk intake and cardiometabolic-related proteins in plasma. Methods Our study is based on two Swedish prospective cohort studies that included 59,998 women and 40,777 men without IHD or cancer at baseline who provided repeated measures of diet and lifestyle factors and plasma proteomics data in two subcohorts. Through registry linkage, 17,896 cases with IHD were documented during up to 33 years of follow-up, including 10,714 with MI. We used time-updated multivariable Cox regression analysis to examine non-fermented or fermented milk intake with time to IHD or MI. Using high-throughput multiplex immunoassays, 276 cardiometabolic plasma proteins were measured in two subcohorts. We applied multivariable-adjusted regression models using a discovery-replication design to examine protein associations with increasing consumption of non-fermented or fermented milk. Results The results for non-fermented milk differed by sex (p-value for interaction = 0.01). In women, we found a pattern of successively greater risk of IHD and MI at non-fermented milk intake levels higher than 1.5 glasses/day. Compared with an intake of 0.5 glass/day (100 mL/day), non-fermented milk intake of 2 glasses/day in women conferred a multivariable-adjusted hazard ratio (HR) of 1.05 (95% CI 1.01–1.08) for IHD, an intake of 3 glasses/day an HR of 1.12 (95% CI 1.06–1.19), and an intake of 4 glasses/day an HR of 1.21 (95% CI 1.10–1.32). Findings were similar for whole, medium-fat, and low-fat milk. We did not detect higher risks of IHD with increasing milk intakes in men. Fermented milk intake was unrelated to the risk of IHD or MI in either sex. Increasing non-fermented milk intake in women was robustly associated with a higher concentration of plasma ACE2 and a lower concentration of FGF21. Conclusions We show a positive association between high amounts of non-fermented milk intake and IHD in women but not men. We suggest metabolic pathways related to ACE2 and FGF21 potentially underlie the association. Graphical abstract Our analysis of two large cohort studies involving 100,775 participants and 17,896 clinically confirmed IHD events supports a dose–response positive association between non-fermented milk intake higher than 300 mL/day with higher rates of IHD (and acute MI specifically) in women, but not in men. The higher risk of IHD with high milk intake in women was evident, irrespective of the fat content of the milk. Fermented milk intake was unrelated to the risk of IHD in both women and men. Non-fermented milk intake was associated in different directions with circulating levels of ACE2 and FGF21 in women—two essential cardiometabolic proteins, also related to IHD in women in our study.

Abstract Vestibular evoked myogenic potentials (VEMPs) are a tool to assess otolith function and a component of sensor specific vestibular diagnostics. The aim of the present study was to measure VEMP trough bone conducted (BC) stimulation using the B250 prototype and to report amplitudes, latencies and threshold levels for patients before resection of a sporadic unilateral vestibular schwannoma (VS) in order to assess function regarding to the reported nerve of origin. Twenty-seven participants (9 male/18 female) with a mean age of 55.9 years (SD: 10.8) were included for the analysis. In the side contralateral to the tumor, in 24 (89%) of the patients cVEMP could be measured, while oVEMP were recordable in 20 patients (74%). For patients with inferior vestibular nerve of origin (n = 11), cVEMP amplitudes of the affected side were significantly lower as compared to the non-affected side, while the force threshold level was increased. No statistically significant differences were observed for neither, oVEMP amplitudes nor threshold levels in the group with superior vestibular nerve of origin (n = 7). Across groups, p13 latency was significantly increased in the affected ear while all other VEMP latencies were not different between the ears. The B250 transducer was applicable to all participants of the clinical cohort. The sample size, however, was too low for a reliable statistical analysis and only allowed for exploratory analysis.

In early 2024, explosive outbreaks of Oropouche virus (OROV) linked to a novel lineage were documented in the Amazon Region of Brazil. We report the introduction of this lineage into Colombia and its co-circulation with another OROV lineage. Continued surveillance is needed to prevent further spread of OROV in the Americas.

Abstract Background Brace therapy’s influence on adolescent idiopathic scoliosis’s (AIS) natural course is inconclusive. Methods Brace-treated AIS patients from 2016 to 2020 were examined regarding four endpoints at brace weaning: surgery need, curve progress ≥ 6° and > 45°, and curve improvement ≥ 6°. Prediction variables’ influence was computed for the all-patients group and three subgroups (Subgroup 1: fulfilling the Scoliosis Research Society’s [SRS] criteria, Subgroup 2: initial Cobb angle 40°). According to the data characteristics, parametric and non-parametric tests and binary logistic regression were performed. Results The research included 69 patients. Overall, after brace weaning surgery was recommended for 20.3% of them, curve progression was ≥ 6° in 23.2%, the Cobb angle was beyond 45° in 11.6%, and the Cobb angle improved by ≥ 6° in 20.3%. Patients needing surgery had a significantly higher initial Cobb angle (38.8° ± 9.8° vs 27.8° ± 7.6°, p 40°. Real brace wear (RBW) in all groups had no significant effect on outcome. Two significant subgroup differences were found: Surgery recommendation and curve progression beyond 45° were significantly more frequent in the initial Cobb angle > 40° subgroup. Conclusions Brace effectiveness can be assumed because curve improvement was achieved in nearly one-fifth with sufficient in-brace correction. However, no significant influence of RBW on the outcome endpoints was demonstrated. To clarify conflicting results, big data management, including untreated patients, must be employed to further research AIS’s multifactorial influenced aetiology and course. Meanwhile, it is worth starting bracing in AIS in practice also beyond the SRS’s criteria.

Abstract Investigating blood-brain barrier (BBB) dysfunction has become a pre-clinical and clinical research focus as it accompanies many neurological disorders. Nevertheless, knowledge of how diagnostic BBB tracers cross the endothelium from blood-to-brain or vice versa often remains incomplete. In particular, brain-to-blood transport (efflux) may reduce tracer extravasation of intravascularly (i.v.) applied tracers. Conversely, impaired efflux could mimic phenotypic extravasation. Both processes would affect conclusions on BBB properties primarily attributed to blood-to-brain leakage. Here, we specifically investigated efflux of fluorescent BBB tracers, focusing on the most common non-toxic marker, sodium fluorescein, which is applicable in patients. We used acute neocortical slices from mice and applied fluorescein, sulforhodamine-B, rhodamine-123, FITC dextran to the artificial cerebrospinal fluid. Anionic low molecular weight (MW) fluorescein and sulforhodamine-B, but not ~ 10-fold larger FITC-dextran and cationic low MW rhodamine-123, showed efflux into the lumen of blood vessels. Our data suggest that fluorescein efflux depends on organic anion transporter polypeptides (Oatp) rather than P-glycoprotein. Furthermore, sodium-potassium ATPase inhibition and incomplete oxygen-glucose deprivation (OGD, 20% O2) reduced fluorescein efflux, while complete OGD (0% O2) abolished efflux. We provide evidence for active efflux of fluorescein in vitro. Impaired efflux of fluorescein could thus contribute to the frequently observed BBB dysfunction in neuropathologies in addition to blood-to-brain leakage.

Abstract Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age.

Abstract Brain ischemia results in the activation of a cascade of inflammatory responses, contributing to the pathogenesis of stroke. This study aimed to assess the patterns of possible changes in the expression of specific inflammation-associated protein-encoding genes and miRNAs in the peripheral blood between the acute and chronic phase of young-onset cryptogenic (Cryp) and large-artery atherosclerotic (LAA) stroke. Blood and serum were collected from patients with cryptogenic and large-artery atherosclerotic stroke at the stroke onset and 1-year follow-up. The relative expression of inflammation-related genes was analysed at the mRNA and miRNA levels using real-time quantitative PCR. Moreover, the relationship between the relative gene expression levels and clinical data was assessed using several different statistical approaches. Seventy-three patients were included in this study, with a median age of 47 (IQR, 9) years. Approximately 72% were men. In patients with cryptogenic stroke, at the mRNA level, ICAM1, CXCL8, TNF, NFKBIA, PYCARD, IL1B, and IL18 were observed to be upregulated at the stroke onset compared to the 1-year follow-up. In patients with LAA stroke, only the expression of NFKBIA was significantly higher during acute stroke. Further, the miRNA serum levels of miR-21, miR-122, and miR-155 were higher at the onset of stroke in patients with cryptogenic stroke but not in those with LAA stroke. The differences between the relative gene expression levels during acute stroke and at the 1-year follow-up were more pronounced in patients with cryptogenic stroke with no cardiovascular risk factors. The expression changes of inflammatory genes in whole blood and miRNAs in the serum differ in patients with cryptogenic and LAA stroke.

Abstract Background Acute hepatic porphyria is a group of multisystem disorders of which acute intermittent porphyria is the most common subtype. Givosiran, a subcutaneously administered RNA interference therapeutic targeting liver ALAS mRNA, is approved for treating these disorders. This Phase 1/2 open-label extension study (NCT02949830) evaluated the long-term safety and efficacy of givosiran in adults with acute intermittent porphyria, with follow-up of up to 48 months, which is the longest follow-up of givosiran treatment to date. Participants were adults aged 18–65 years who completed part C of the Phase 1 givosiran study (NCT2452372). Methods Enrollees received givosiran for up to 48 months. Primary and secondary endpoints included the incidence of adverse events, changes in urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, annualized rate of porphyria attacks, and annualized hemin use. Quality of life was assessed using the EQ-5D-5L instrument as an exploratory endpoint. Results Sixteen patients (median age: 39.5 years) participated. Common adverse events included abdominal pain, nasopharyngitis, and nausea (50% each), with injection-site erythema (38%) and injection-site pruritus (25%) noted as frequent treatment-related reactions. Givosiran therapy reduced annualized rates of porphyria attacks and hemin use by 97% and 96%, respectively. From months > 33 to 48, all patients were free from attacks requiring significant medical intervention and did not use hemin. There were substantial reductions in median urinary ALA and PBG of 95% and 98%, respectively. Additionally, a clinically meaningful improvement in quality of life was observed. Conclusions In the longest follow-up of givosiran-treated patients reported to date, the therapy maintained an acceptable safety profile and demonstrated sustained improvements in clinical outcomes over 4 years in patients with acute intermittent porphyria.

Abstract A cardiopulmonary exercise test (CPET) is a test assessing an individual’s physiological response during exercise. Results may be affected by body composition, which is best evaluated through imaging techniques like magnetic resonance imaging (MRI). The aim of this study was to assess relationships between body composition and indices obtained from CPET. A total of 234 participants (112 female), all aged 50 years, underwent CPETs and whole-body MRI scans (> 1 million voxels). Voxel-wise statistical analysis of tissue volume and fat content was carried out with a method called Imiomics and related to the CPET indices peak oxygen consumption (V̇O2peak), V̇O2peak scaled by body weight (V̇O2kg) and by total lean mass (V̇O2lean), ventilatory efficiency (V̇E/V̇CO2-slope), work efficiency (ΔV̇O2/ΔWR) and peak exercise respiratory exchange ratio (RERpeak). V̇O2peak showed the highest positive correlation with volume of skeletal muscle. V̇O2kg negatively correlated with tissue volume in subcutaneous fat, particularly gluteal fat. RERpeak negatively correlated with tissue volume in skeletal muscle, subcutaneous fat, visceral fat and liver. Some associations differed between sexes: in females ΔV̇O2/ΔWR correlated positively with tissue volume of subcutaneous fat and V̇E/V̇CO2-slope with tissue volume of visceral fat, and, in males, V̇O2peak correlated positively to lung volume. In conclusion, voxel-based Imiomics provided detailed insights into how CPET indices were related to the tissue volume and fat content of different body structures.

Abstract In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high E-cadherin expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression. KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive catecholamine neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was also detected in the KS spheroid, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies.

Abstract Background Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins are expressed on the surface of infected erythrocytes, mediating parasite sequestration in the vasculature. PfEMP1 is a major target of protective antibodies, but the features of the antibody response are poorly defined. Methods In Malawian children with cerebral or uncomplicated malaria, we characterized the antibody response to 39 recombinant PfEMP1 Duffy binding like (DBL) domains or cysteine-rich interdomain regions (CIDRs) in detail, including measures of antibody classes, subclasses, and engagement with Fcγ receptors and complement. Using elastic net regularized logistic regression, we identified a combination of seven antibody targets and Fc features that best distinguished between children with cerebral and uncomplicated malaria. To confirm the role of the selected targets and Fc features, we measured antibody-dependent neutrophil and THP-1 cell phagocytosis of intercellular adhesion molecule-1 (ICAM-1) and endothelial protein C (EPCR) co-binding infected erythrocytes. Results The selected features distinguished between children with cerebral and uncomplicated malaria with 87% accuracy (median, 80–96% interquartile range) and included antibody to well-characterized DBLβ3 domains and a less well-characterized CIDRγ12 domain. The abilities of antibodies to engage C1q and FcγRIIIb, rather than levels of IgG, correlated with protection. In line with a role of FcγRIIIb binding antibodies to DBLβ3 domains, antibody-dependent neutrophil phagocytosis of ICAM-1 and EPCR co-binding IE was higher in uncomplicated malaria (15% median, 8–38% interquartile range) compared to cerebral malaria (7%, 30–15%, p

Abstract Background Wilson disease (WD) is a rare disorder of copper metabolism, causing copper accumulation mainly in the liver and the brain. The prevalence of WD was previously estimated around 20 to 33.3 patients per million for the United States, Europe, and Asia, but data on the prevalence of WD in Germany are limited. Objectives To describe patient characteristics and to assess prevalence of WD in Germany using a representative claims database. Methods WD patients were identified in the WIG2 (Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung; Scientific Institute for Health Economics and Health Systems Research) benchmark database of 4.5 million insured Germans by combining ICD-10-coding with WD-specific lab tests and treatments. The study period ranged from 2013 to 2016 for assessing patient characteristics, and to 2018 for prevalence, respectively. Results Seventy unique patients were identified. Most patients (86%) were between 18 and 64 years of age and more often male (60%) than female. Two patients (3%) younger than 18 years were included, as well as 8 patients (11%) older than 64 years. Most common WD subtypes were hepatic (57%), psychiatric (49%), and neurologic (44%). Average prevalence was 20.3 patients per million (range: 17.8–24.4), with similar results for two-year prevalence. Generally, prevalence increased steadily over the study period. Observed mortality was low, with only one death during the study period. Conclusions This study adds valuable real-world data on the prevalence and patient characteristics of WD in Germany. Generally, our findings align with other reports and contribute to the global understanding of WD epidemiology. Still, regional and temporal trends remain to be investigated more thoroughly to further the understanding of the natural history and epidemiology of this rare disease.

Abstract In esophageal adenocarcinoma, the presence of lymph node metastases predicts patients' survival even after curative resection. Currently, there is no highly accurate marker for detecting the presence of lymph node metastasis. The SEMA3F/NRP2 axis was initially characterized in axon guidance and recent evidence has revealed its significant involvement in lymphangiogenesis, angiogenesis, and carcinogenesis. Hence, the objective of this study was to elucidate the roles of SEMA3F and its receptor NRP2 in esophageal adenocarcinoma. We conducted an immunohistochemical evaluation of SEMA3F and NRP2 protein expression in 776 patients with esophageal adenocarcinoma who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. Total and positive cancer cell counts were digitally analyzed using QuPath and verified by experienced pathologists to ensure accuracy. Positive expression was determined as a cell percentage exceeding the 50th percentile threshold. In our cohort, patients exhibiting SEMA3F positive expression experience significantly lower pT- and pN-stages. In contrast, positive NRP2 expression is associated with the presence of lymph node metastases. Survival analyses showed that the expression status of NRP2 had no impact on patient survival. However, SEMA3F positivity was associated with a favorable patient survival outcome (median OS: 38.9 vs. 26.5 months). Furthermore, SEMA3F could be confirmed as an independent factor for better patient survival in patients with early tumor stage (pT1N0-3: HR = 0.505, p = 0.014, pT1-4N0: HR = 0.664, p = 0.024, pT1N0: HR = 0.483, p = 0.040). In summary, SEMA3F emerges as an independent predictor for a favorable prognosis in patients with early-stage esophageal adenocarcinoma. Additionally, NRP2 expression is linked to a higher risk of lymph node metastases occurrence. We hypothesize that low SEMA3F expression could identify patients with early-stage tumors who might benefit from more aggressive treatment options or intensified follow-up. Furthermore, SEMA3F and its associated pathways should be explored as potential tumor-suppressing agents.

Abstract Background The ability to find, understand, appraise and utilise health information is crucial among individuals living with rare disorders. The aim of this study was to give a comprehensive overview of the literature on health literacy in adult persons with rare disorders. Methods We applied a scoping review methodology and performed a systematic search in 2021 in bibliographic databases. Searches were conducted in Medline (Ovid), Embase (Ovid), PsycInfo (Ovid), CINAHL (ebsco), and ERIC (Ovid). References were sorted and evaluated for inclusion using EndNote and Covidence. This review was guided by the question “What are the characteristics of research on health literacy in rare disorders?” Results The database searches yielded 75 eligible reports. A total of 6223 individuals with rare disorders were represented alongside 1707 caregivers. The reports in this review have included study participants representing a total of 80 different rare disorders with unique ORPHA and ICD-10 codes. The results revealed that persons with rare disorders often exhibit gaps in health literacy through a lack of knowledge and access to information related to self-management, their own diagnosis and health, as well as daily coping and social rights. In addition, the importance of aid and information from healthcare personnel and the significance of getting social support from others in the same situation were accentuated. Conclusion This review emphasizes the importance of reinforcing health literacy among persons with rare disorders through peer support and education. This is the first review to give a comprehensive and state-of-the-art overview of literature investigating health literacy among persons with rare disorders and offers a basis for further research.

Abstract Computed tomography (CT) is used as a valuable tool for device selection for interventional therapy in tricuspid regurgitation (TR). We aimed to evaluate predictors of TR reduction using CT and automated deep learning algorithms. Patients with severe to torrential TR and CTs prior to either percutaneous annuloplasty (PA) or tricuspid transcatheter edge-to-edge repair (T-TEER) were enrolled. CTs were analyzed using automated deep learning algorithms to assess tricuspid valve anatomy, right heart morphology, and function. Outcome parameters comprised post-interventional TR ≤ 1 and all-cause mortality. 84 patients with T-TEER (n = 32) or PA treatment (n = 52) were enrolled. Patients with a post-interventional TR ≤ 1 presented lower tenting heights and smaller tenting angles compared to patients with a TR > 1. Tenting height showed the best accuracy for post-interventional TR > 1 with an AUC of 0.756 (95% CI 0.560–0.951) in the T-TEER and 0.658 (95% CI 0.501–0.815) in the PA group, consistent with a suggested threshold of 6.8 mm and 9.2 mm, respectively. Patients with a post-interventional TR ≤ 1 exhibited a mortality of 4% and those with a TR > 1 of 12% during a follow-up of 331 ± 300 and 370 ± 265 days, respectively (p = 0.124). To conclude, tenting is associated with procedural outcomes and should be considered during screening for interventional TR therapy.

Abstract Capacitation is an essential post-testicular maturation event endowing spermatozoa with fertilizing capacity within the female reproductive tract, significant for fertility, reproductive health, and contraception. By using a human-relevant large animal model, the domestic boar, this study focuses on furthering our understanding of the involvement of the ubiquitin-proteasome system (UPS) in sperm capacitation. The UPS is a universal, evolutionarily conserved, cellular proteome-wide degradation and recycling machinery, that has been shown to play a significant role in reproduction during the past two decades. Herein, we have used a bottom-up proteomic approach to (i) monitor the capacitation-related changes in the sperm protein levels, and (ii) identify the targets of UPS regulation during sperm capacitation. Spermatozoa were capacitated under proteasomal activity-permissive and inhibiting conditions and extracted sperm proteins were subjected to high-resolution mass spectrometry. We report that 401 individual proteins differed at least two-fold in abundance (P

Abstract Standardized assessment of the gastroesophageal valve during endoscopy, attainable via the Hill classification, is important for clinical assessment and therapeutic decision making. The Hill classification is associated with the presence of hiatal hernia (HH), a common endoscopic finding connected to gastro-esophageal reflux disease. A novel efficient medical artificial intelligence (AI) training pipeline using active learning (AL) is designed. We identified 21,970 gastroscopic images as training data and used our AL to train a model for predicting the Hill classification and detecting HH. Performance of the AL and traditionally trained models were evaluated on an external expert-annotated image collection. The AL model achieved accuracy of 76%. A traditionally trained model with 125% more training data achieved 77% accuracy. Furthermore, the AL model achieved higher precision than the traditional one for rare classes, with 0.54 versus 0.39 (p

Abstract Background Well-trained public health professionals are key to addressing both global and local public health challenges of the twenty-first century. Though availability of programs has increased, the population health science (PHS) and public health (PH) higher education landscape in Germany remains scattered. To date, no comprehensive overview of programs exists. Objectives This study aimed to map PHS and PH master’s and structured doctoral programs in Germany, including selected program characteristics, curricula and target competencies. Methods We conducted a systematic mapping of PHS and PH programs in Germany following a prospectively registered protocol ( https://doi.org/10.17605/OSF.IO/KTCBA ). Relevant master’s and doctoral programs were identified by two study authors independently searching a comprehensive higher education database, which was, for doctoral programs, supplemented with a google search. For PHS programs, general characteristics were mapped and for the subset of PH programs, in-depth characteristics were extracted. Results Overall, 75 master’s and 18 structured doctoral PHS programs were included. Of these, 23 master’s and 8 doctoral programs focused specifically on PH. The majority of PHS master’s programs awarded a Master of Science degree (55 out of 75 programs). The PH master’s program curricula offered various courses, allowing for different specializations. Courses on topics like public health, epidemiology, health systems (research) and research methods were common for the majority of the master’s programs, while courses on physical activity, behavioral science, nutrition, and mental health were offered less frequently. Structured PH doctoral programs were mainly offered by medical faculties (6 out of 8 programs) and awarded a doctorate of philosophy (Ph.D.) (6 out of 8 programs). PH doctoral programs were very heterogeneous regarding curricula, entry, and publication requirements. There was a broad geographical distribution of programs across Germany, with educational clusters in Munich, Berlin, Bielefeld and Düsseldorf. Conclusion Germany offers a diverse landscape of PHS and PH master’s programs, but only few structured doctoral programs. The variety of mandatory courses and competencies in these programs reflect Germany’s higher education system’s answer to the evolving demands of the PH sector. This review may aid in advancing PH education both in Germany and globally.

Abstract Background Colorectal cancer is the third most common tumour entity in the world and up to 50% of the patients develop liver metastases (CRLM) within five years. To improve and personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical tumour properties measured by magnetic resonance elastography (MRE) could be implemented as such a diagnostic tool. We postulate that ex vivo MRE combined with histological and radiological evaluation of CRLM could provide biomechanics-based diagnostic markers for cell viability in tumours. Methods 34 CRLM specimens from patients who had undergone hepatic resection were studied using ex vivo MRE in a frequency range from 500 Hz to 5300 Hz with increments of 400 Hz. Single frequency evaluation of shear wave speed and wave penetration rate as proxies for stiffness and viscosity was performed, along with rheological model fitting based on the spring-pot model and powerlaw exponent α, ranging between 0 (complete solid behaviour) and 1 (complete fluid behaviour). For histological analysis, samples were stained with H&E and categorized according to the degree of regression. Quantitative histologic analysis was performed to analyse nucleus size, aspect ratio, and density. Radiological response was assessed according to RECIST-criteria. Results Five samples showed major response to chemotherapy, six samples partial response and 23 samples no response. For higher frequencies (> 2100 Hz), shear wave speed correlated significantly with the degree of regression (p ≤ 0.05) indicating stiffer properties with less viable tumour cells. Correspondingly, rheological analysis of α revealed more elastic-solid tissue properties at low cell viability and major response (α = 0.43 IQR 0.36, 0.47) than at higher cell viability and no response (α = 0.51 IQR 0.48, 0.55; p = 0.03). Quantitative histological analysis showed a decreased nuclear area and density as well as a higher nuclear aspect ratio in patients with major response to treatment compared to patients with no response (all p

Abstract Production of hard X-ray via inverse Compton scattering at photon energies below 100 keV range aimed at potential applications in medicine and material research is reported. Experiments have been performed at the Brookhaven National Laboratory, Accelerator Test Facility, employing the counter collision of a 70 MeV, 0.3 nC electron beam with a near infra-red Nd: YAG laser (1064 nm wavelength) pulse containing ~ 100 mJ in a single shot basis. The radiation distribution of the scattered photon beam is assessed to be sufficiently quasi monochromatic to produce clear contrast from the Au K- edge at 80.7 keV.

Abstract Background Patient and public involvement (PPI) in research is widely acknowledged as essential to achieving successful and impactful research. Despite this acknowledgement, there are limited reports on how to approach and apply meaningful PPI throughout the research cycle and how to address challenges for researchers such as doctoral students, particularly when undertaking research on sensitive topics. This paper provides insights and examples for researchers new to PPI, on the impact of active PPI and recommendations for building and developing a PPI group in a paediatric focused doctoral research study with bereaved parents and carers. Methods PPI was informed by the research cycle. The GRIPP2 short-form checklist was used to report PPI. The research was funded by the National Institute for Health and Care Research. Results PPI enhanced the research through input into the study design, recruitment, co-design of the study website and branding; and ethics amendments to increase participation in response to the COVID-19 pandemic. The literature review was extended to incorporate a PPI consultation phase and members contributed to data analysis. A flexible approach enabled involvement to develop iteratively throughout the research study, resulting in changes being made to enhance the study design and outcomes. Conclusion This paper contributes to the limited knowledge base on embedding PPI into a doctoral research study and within the paediatric setting specifically working in partnership with bereaved parents and carers. Employing an adaptive approach to meet individual PPI needs, building a trusting and respectful partnership, creating shared ownership and investment in the research, are essential components to successful PPI.

Abstract Williams syndrome (WS) is associated with atypical social communication and cognition reminiscent of the behaviours observed in autism. Nonetheless, WS also differs significantly from autism, such as regarding social motivation, which is typically enhanced in WS and reduced in autism. This study sought to examine the conditions’ transdiagnostic similarities and differences for autistic symptoms and social functioning, and their developmental trajectories, by comparing individuals with WS (n = 24) and those diagnosed with idiopathic autism (n = 24) and attention deficit hyperactivity disorder (ADHD; n = 24), aged 9 to 53 years, on measures of autism, social functioning, IQ and cooccurring psychiatric conditions. Although only 12.5% in the WS group met the criteria for an autism diagnosis, a majority exhibited distinct difficulties within social communication, social cognition, repetitive behaviours, and atypical sensory reactivity resembling autism. Conversely, elevated social motivation and a high number of social initiatives accompany these characteristics. No group differences in the developmental trajectories of autism symptoms were found. Our results demonstrate that autistic behaviours are more frequent in individuals with WS, than in individuals with idiopathic ADHD, and emphasize the need for clinical management of these behaviours.

Abstract This study sought to determine whether there was any correlation between the dietary diversity score and symptoms of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in Nepali women who were of reproductive age. In a national cross-sectional population-based survey of women (15–49 years) (N = 7442) in Nepal, MDD was assessed with the PHQ-9 and GAD with the GAD-7, and dietary diversity with a 24 h food consumption recall of 10 food groups. Multinominal and logistic regression were used to estimate predictors of MDD and GAD symptoms. The prevalence of mild and moderate-to-severe MDD symptoms was 15.7% and 5.4%, respectively, and the prevalence of mild and moderate-to-severe GAD symptoms was 20.8% and 7.5%, respectively. The overall dietary diversity mean score was 4.66 (SD = 1.67). In the final multivariable model, adjusted for relevant confounders, dietary diversity was inversely associated with moderate-to-severe MDD symptoms (Adjusted Incidence Risk Ratios-AIRR: 0.90, 95% CI 0.84–0.97), and with moderate-to-severe GAD symptoms (AIRR: 0.86, 95% CI 0.80–0.92). Furthermore, in the fully adjusted regression model, pulses (Adjusted Odds Ratio-AOR: 0.77, 95% CI 0.60–0.98) and Vitamin A rich fruits and vegetables (AOR: 0.69, 95% CI 0.51–0.94) were inversely associated with MDD symptoms. In addition, Vitamin A rich fruits and vegetables (AOR: 0.57, 95% CI 0.43–0.75), dairy (AOR: 0.80, 95% CI 0.67–0.97), and pulses (AOR: 0.69, 95% CI 0.56–0.85) were inversely associated with GAD symptoms. Dietary diversity was inversely associated MDD and GAD symptoms.

Abstract Chronic Otitis Media (COM) is defined as long term inflammation and colonization with pathogenic bacteria due to a defect or retraction of the tympanic membrane. Surgical interventions are often augmented by antibiotic resistance development and therefore, off-label treatment using the natural drug 1,8-Cineol was carried out. All COM patients underwent antibiotic therapy and middle ear surgery and developed antibiotic resistances. Microbiological investigations from the auditory canal and stool samples were performed in correlation with the clinical course. Therapy of COM patients with 1,8-Cineol revealed a clear reduction of inflammatory microbes P. aeruginosa and Proteus mirabilis in ear samples as well as intestinal Prevotella copri, which was associated with an improved clinical outcome in certain individuals. The present off-label study revealed manifold anti-inflammatory effects of the natural monoterpene 1,8-Cineol in Otitis media patients. A better understanding of the underlying mechanisms will improve the current treatment options and possible forms of application of this natural drug.

Abstract Background Liver grafts are frequently declined due to high donor age or age mismatch with the recipient. To improve the outcome of marginal grafts, we aimed to characterize the performance of elderly vs. young liver grafts in a standardized rat model of normothermic ex vivo liver machine perfusion (NMP). Methods Livers from Sprague–Dawley rats aged 3 or 12 months were procured and perfused for 6 h using a rat NMP system or collected as a reference group (n = 6/group). Tissue, bile, and perfusate samples were used for biochemical, and proteomic analyses. Results All livers cleared lactate during perfusion and continued to produce bile after 6 h of perfusion (614 mg/h). Peak urea levels in 12-month-old animals were higher than in younger animals. Arterial and portal venous pressure, bile production and pH did not differ between groups. Proteomic analysis identified a total of 1477 proteins with oxidoreductase and catalytic activity dominating the gene ontology analysis. Proteins such as aldehyde dehydrogenase 1A1 and 2-Hydroxyacid oxidase 2 were significantly more present in livers of older age. Conclusions Young and elderly liver grafts exhibited similar viability during NMP, though proteomic analyses indicated that older grafts are less resilient to oxidative stress. Our study is limited by the elderly animal age, which corresponds to mature but not elderly human age typically seen in marginal human livers. Nevertheless, reducing oxidative stress could be a promising therapeutic target in the future.

Abstract Neurological soft signs (NSS), discrete deficits in motor coordination and sensory integration, have shown promise as markers in autism diagnosis. While motor impairments, partly associated with core behavioral features, are frequently found in children with autism, there is limited evidence in adults. In this study, NSS were assessed in adults undergoing initial diagnosis of high-functioning autism (HFA), a subgroup difficult to diagnose due to social adaptation and psychiatric comorbidity. Adults with HFA (n = 34) and 1:1 sex-, age-, and intelligence-matched neurotypical controls were administered a structured NSS examination including motor, sensory, and visuospatial tasks. We showed that adults with HFA have significantly increased motor coordination deficits compared with controls. Using hierarchical cluster analysis within the HFA group, we also identified a subgroup that was particularly highly affected by NSS. This subgroup differed from the less affected by intelligence level, but not severity of autism behavioral features nor global psychological distress. It remains questionable whether motor impairment represents a genuinely autistic trait or is more a consequence of factors such as intelligence. Nevertheless, we conclude that examining NSS in terms of motor coordination may help diagnose adults with HFA and identify HFA individuals who might benefit from motor skills interventions.

Abstract Climate change reduces snowpack, advances snowmelt phenology, drives summer warming, alters growing season precipitation regimes, and consequently modifies vegetation phenology in mountain systems. Elevational migrants track spatial variation in seasonal plant growth by moving between ranges at different elevations during spring, so climate-driven vegetation change may disrupt historic benefits of migration. Elevational migrants can furthermore cope with short-term environmental variability by undertaking brief vertical movements to refugia when sudden adverse conditions arise. We uncover drivers of fine-scale vertical movement variation during upland migration in an endangered alpine specialist, Sierra Nevada bighorn sheep (Ovis canadensis sierrae) using a 20-year study of GPS collar data collected from 311 unique individuals. We used integrated step-selection analysis to determine factors that promote vertical movements and drive selection of destinations following vertical movements. Our results reveal that relatively high temperatures consistently drive uphill movements, while precipitation likely drives downhill movements. Furthermore, bighorn select destinations at their peak annual biomass and maximal time since snowmelt. These results indicate that although Sierra Nevada bighorn sheep seek out foraging opportunities related to landscape phenology, they compensate for short-term environmental stressors by undertaking brief up- and downslope vertical movements. Migrants may therefore be impacted by future warming and increased storm frequency or intensity, with shifts in annual migration timing, and fine-scale vertical movement responses to environmental variability.

Abstract Transmission electron microscopy (TEM) is an imaging technique used to visualize and analyze nano-sized structures and objects such as virus particles. Light microscopy can be used to diagnose diseases or characterize e.g. blood cells. Since samples under microscopes exhibit certain symmetries, such as global rotation invariance, equivariant neural networks are presumed to be useful. In this study, a baseline convolutional neural network is constructed in the form of the commonly used VGG16 classifier. Thereafter, it is modified to be equivariant to the p4 symmetry group of rotations of multiples of 90° using group convolutions. This yields a number of benefits on a TEM virus dataset, including higher top validation set accuracy by on average 7.6% and faster convergence during training by on average 23.1% of that of the baseline. Similarly, when training and testing on images of blood cells, the convergence time for the equivariant neural network is 7.9% of that of the baseline. From this it is concluded that augmentation strategies for rotation can be skipped. Furthermore, when modelling the accuracy versus amount of TEM virus training data with a power law, the equivariant network has a slope of − 0.43 compared to − 0.26 of the baseline. Thus the equivariant network learns faster than the baseline when more training data is added. This study extends previous research on equivariant neural networks applied to images which exhibit symmetries to isometric transformations.

Mechanical and thermal trauma during implant surgery may be reasons for initial peri-implant bone loss. Temperature development during drilling and implant insertion were quantified in this series of in vitro and animal experiments. Polyurethane foam material mimicking different classes of alveolar bone was used as a model material for simulating implant surgery. Using thermocouples, temperature development was determined in the model material at depths of 3 mm and 10 mm during site preparation and implant insertion. Additionally, an infrared camera allowed for measuring drill temperatures both in vitro and as part of an animal trial using an intraoral minipig model. Drill diameter and repeated usage of drills did not have a major effect on temperature generation. The addition of a diamond-like carbon coating, bone density, predrilling, and irrigation heavily affected intraosseous temperatures. In vivo, applying regular drill protocols, an intraosseous temperature rise of approximately 3 °K was determined. Implant geometry as well as the amount of undersizing of an osteotomy governed heat generation during implant insertion. Drill protocols and the amount of undersizing of an implant osteotomy constitute parameters by which clinicians can limit trauma during implant surgery.

BackgroundThe COVID-19 pandemic caused a drastic shift in the practice of research and clinical services. It has been noted that cognition measured via in-person versus remote methods differ substantially, and it is possible that subjective and experiential differences exist between modalities. ObjectiveThe aim of the study is to explore the perceptions of both researchers and older adult participants on the experience of remotely conducted research using a cognitive screener. MethodsWe conducted a thematic analysis of the experience of engaging in remote research from both the participant (n=10) and researcher (n=4) perspectives. The research interaction was framed through teleadministration of the Montreal Cognitive Assessment-Blind (suitable for telephone administration) and administration of a subsequent semistructured debriefing interview. Participant perspectives were garnered during debriefing interviews, while researcher insights were collected via self-reported qualitative field notes completed following each research session. ResultsData aggregated into themes of barriers and facilitators from the lenses of both participants and researchers. Participants noted facilitators including short instrument length, convenience, and presession contact; barriers included the length of the interaction, some tasks being more challenging on the phone, and the potential for participant dishonesty. Research assistants noted several facilitators: instrument length, rapport building, ability to prepare for and record sessions, and comfort with the protocol; barriers were items with too many response options, telephone issues (eg, response delays), and concerns about participant comprehension. ConclusionsThese results suggest remote telephone-delivered cognitive screening tools as a feasible and acceptable method of research inquiry. The findings provide a starting point for the inclusion of diverse populations in research to capture underrepresented groups whose input would immensely benefit our understanding of remotely delivered cognitive screening measures. Further, we offer materials (eg, checklists), which can be used in future investigations to promote future inclusive research and increase generalizability.

Background OSA is highly prevalent and characterised by abnormal respiration during sleep. This large, population-based study aimed to investigate the associations between OSA and lung function in subjects aged 50–64 years.Method The population-based Swedish CArdioPulmonary bioimage Study includes information on anthropometry, comorbidities and spirometry. The current analysis included data from three centres (Gothenburg, Umeå and Uppsala) on whole-night respiratory polygraphy as a meta-analysis examining the overall effect size of lung function on sleep apnoea severity, expressed as ß-coefficient after stratifying for sex and adjusting for age, waist circumference and smoking status.Results Data from 9016 participants (54% women, age 58±4 years, body mass index 27±4 kg/m2) with sleep recordings of good quality were included in the final analysis. Forced expiratory volume during 1 s (FEV1) (ß=−0.10 (95% CI −0.16 to −0.03)), forced vital capacity (FVC) (−0.15 (−0.21 to −0.10)) and diffusion capacity for carbon monoxide (DLCO) (−0.08 (−0.10 to −0.05)) were all negatively associated with the oxygen desaturation index (ODI) and also with per cent of registration with nocturnal oxygen saturation

Objectives The study aimed to describe the experiences of physicians, nurses and psychologists employed in primary care in using digital video consultations. The second objective was to study the association between the predictors of behaviour and behavioural intentions to use digital consultations and to relate underlying behavioural beliefs to experiences of digital consultations in primary care. Overall, the research questions focused on the association between previous training, profession or theory-based behavioural predictors and behavioural intentions to use digital video consultations.Design A web survey based on the theory of planned behaviour was sent to primary care professionals in western Sweden who had implemented digital video consultations. The questionnaire contained both closed and open-ended questions focusing on theory-based predictors of behavioural intentions, such as as attitudes, subjective norms and perceived behavioural control. Data were analysed with a mixed-methods approach using quantitative and qualitative analyses.Participants The questionnaire was distributed between June and October 2022 to 140 primary healthcare centres in western Sweden, of which 47 agreed to participate. Overall, the questionnaire was sent out to 969 clinicians, representing physicians, nurses and psychologists.Results Physicians and nurses had lower experience and less positive attitudes towards digital video consultations compared with psychologists. No statistically significant differences were seen among the groups in behavioural intentions to use digital video consultations. The regression analysis showed that attitude was the strongest predictor of behavioural intentions among primary care physicians, while attitude and perceived behavioural control were associated with behavioural intentions among nurses. No associations between predictors and intentions were found among psychologists.Conclusions The medical professionals reported high behavioural intentions to use digital video consultation despite different levels of experience. Attitude and perceived behavioural control were predictors of behavioural intentions among physicians and nurses, indicating that future implementation should consider the professions’ participation in the process.

Summary: Background: We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. Methods: 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. Findings: The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019). Interpretation: The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Funding: Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

Summary: Background: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer’s disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive. Methods: Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum’s de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood–brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan–Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses. Findings: From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P

Institutes for pathology act as operators, users and in-house manufacturers of in vitro diagnostic medical devices and are subject to national and European regulations depending on their function. The entry into force of the EU regulation on medical devices (Regulation (EU) 2017/745, MDR) and the EU regulation on in vitro diast medical devices (Regulation (EU) 2017/746, IVDR) resulted in a need for regulatory adjustments to German medical device law. This has created a new legal framework in which institutes for pathology operate, depending on their function as users, operators or in-house manufacturers of in vitro diagnostic medical devices. This overview of the current legal situation represents a snapshot and provides an up-to-date overview of the landscape of European and German medical device law.

BackgroundArtificial intelligence (AI) has become a pivotal element in health care, leading to significant advancements across various medical domains, including palliative care and hospice services. These services focus on improving the quality of life for patients with life-limiting illnesses, and AI’s ability to process complex datasets can enhance decision-making and personalize care in these sensitive settings. However, incorporating AI into palliative and hospice care requires careful examination to ensure it reflects the multifaceted nature of these settings. ObjectiveThis scoping review aims to systematically map the landscape of AI in palliative care and hospice settings, focusing on the data diversity and model robustness. The goal is to understand AI’s role, its clinical integration, and the transparency of its development, ultimately providing a foundation for developing AI applications that adhere to established ethical guidelines and principles. MethodsOur scoping review involves six stages: (1) identifying the research question; (2) identifying relevant studies; (3) study selection; (4) charting the data; (5) collating, summarizing, and reporting the results; and (6) consulting with stakeholders. Searches were conducted across databases including MEDLINE through PubMed, Embase.com, IEEE Xplore, ClinicalTrials.gov, and Web of Science Core Collection, covering studies from the inception of each database up to November 1, 2023. We used a comprehensive set of search terms to capture relevant studies, and non-English records were excluded if their abstracts were not in English. Data extraction will follow a systematic approach, and stakeholder consultations will refine the findings. ResultsThe electronic database searches conducted in November 2023 resulted in 4614 studies. After removing duplicates, 330 studies were selected for full-text review to determine their eligibility based on predefined criteria. The extracted data will be organized into a table to aid in crafting a narrative summary. The review is expected to be completed by May 2025. ConclusionsThis scoping review will advance the understanding of AI in palliative care and hospice, focusing on data diversity and model robustness. It will identify gaps and guide future research, contributing to the development of ethically responsible and effective AI applications in these settings. International Registered Report Identifier (IRRID)DERR1-10.2196/56353

Abstract Metabolic and bariatric surgery (MBS) is widely considered the most effective option for treating obesity, a chronic, relapsing, and progressive disease. Recently, the American Society of Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) issued new guidelines on the indications for MBS, which have superseded the previous 1991 National Institutes of Health guidelines. The aim of this study is to establish the first set of consensus guidelines for selecting procedures in Class I and II obesity, using an Expert Modified Delphi Method. In this study, 78 experienced bariatric surgeons from 32 countries participated in a two-round Modified Delphi consensus voting process. The threshold for consensus was set at an agreement or disagreement of ≥ 70.0% among the experts. The experts reached a consensus on 54 statements. The committee of experts reached a consensus that MBS is a cost-effective treatment option for Class II obesity and for patients with Class I obesity who have not achieved significant weight loss through non-surgical methods. MBS was also considered suitable for patients with Type 2 diabetes mellitus (T2DM) and a body mass index (BMI) of 30 kg/m2 or higher. The committee identified intra-gastric balloon (IGB) as a treatment option for patients with class I obesity and endoscopic sleeve gastroplasty (ESG) as an option for patients with class I and II obesity, as well as for patients with T2DM and a BMI of ≥ 30 kg/m2. Sleeve gastrectomy (1) and Roux-en-Y gastric bypass (RYGB) were also recognized as viable treatment options for these patient groups. The committee also agreed that one anastomosis gastric bypass (OAGB) is a suitable option for patients with Class II obesity and T2DM, regardless of the presence or severity of obesity-related medical problems. The recommendations for selecting procedures in Class I and II obesity, developed through an Expert Modified Delphi Consensus, suggest that the use of standard primary bariatric endoscopic (IGB, ESG) and surgical procedures (SG, RYGB, OAGB) are acceptable in these patient groups, as consensus was reached regarding these procedures. However, randomized controlled trials are still needed in Class I and II Obesity to identify the best treatment approach for these patients in the future.

Surgical aortic valve replacement (SAVR) was the only symptom relieving and life-prolonging treatment until transcatheter aortic valve implantation (TAVI) became available. This option was introduced to treat old and high-risk patients. In a series of 2500 consecutive patients referred for SAVR with a biologic heart valve (BHV) prosthesis, their age, comorbid conditions, the complexity of the procedure, postoperative outcome, need for resources, and long-term survival were compared in patients before versus after the introduction of TAVI. Although the Carpentier-Edwards valve was used in most patients, the outcomes with respect to several other BHV types were studied. Patients undergoing isolated SAVR (i-SAVR) were studied separately from those who underwent SAVR with a concomitant procedure (c-SAVR). The number of referrals increased over time until 2016, whereafter the reimbursement for TAVI broadened. Age, prior percutaneous coronary interventions, diabetes, and chronic renal disease increased over time in both groups, while atrial fibrillation, the need for emergent SAVR, and other comorbid conditions increased significantly only in the c-SAVR group. Postoperative acute renal injury, conduction defects, and bleeding increased over time in both groups. The need for renal replacement therapy increased in both surgical groups, but this was more pronounced in c-SAVR; the need for a pacemaker implant (p < 0.001), blood products, and reintervention increased only in the c-SAVR group. There was a moderate but non-significant increase in the 30-day mortality for both groups over time. Furthermore, the long-term survival of both groups did not change after the introduction of TAVI. The Carpentier-Edwards Perimount valve showed good long-term results for durability. The Perceval device was used in older patients and showed good hemodynamic results, but the need for a postoperative permanent pacemaker implant was high. The results seem to indicate that a broader reimbursement for TAVI was warranted after its introduction in 2008. Nevertheless, with the development of newer devices for SAVR, surgery will remain one of the major treatment options for aortic valve disease.

Abstract Wastewater based epidemiology has become a widely used tool for monitoring trends of concentrations of different pathogens, most notably and widespread of SARS-CoV-2. Therefore, in 2022, also in Rhineland–Palatinate, the Ministry of Science and Health has included 16 wastewater treatment sites in a surveillance program providing biweekly samples. However, the mere viral load data is subject to strong fluctuations and has limited value for political deciders on its own. Therefore, the state of Rhineland–Palatinate has commissioned the University Medical Center at Johannes Gutenberg University Mainz to conduct a representative cohort study called SentiSurv, in which an increasing number of up to 12,000 participants have been using sensitive antigen self-tests once or twice a week to test themselves for SARS-CoV-2 and report their status. This puts the state of Rhineland–Palatinate in the fortunate position of having time series of both, the viral load in wastewater and the prevalence of SARS-CoV-2 in the population. Our main contribution is a calibration study based on the data from 2023-01-08 until 2023-10-01 where we identified a scaling factor ( $$0.208 \pm 0.031$$ 0.208 ± 0.031 ) and a delay ( $$5.07 \pm 2.30$$ 5.07 ± 2.30 days) between the virus load in wastewater, normalized by the pepper mild mottle virus (PMMoV), and the prevalence recorded in the SentiSurv study. The relation is established by fitting an epidemiological model to both time series. We show how that can be used to estimate the prevalence when the cohort data is no longer available and how to use it as a forecasting instrument several weeks ahead of time. We show that the calibration and forecasting quality and the resulting factors depend strongly on how wastewater samples are normalized.

Abstract Hemozoin is a natural biomarker formed during the hemoglobin metabolism of Plasmodium parasites, the causative agents of malaria. The rotating-crystal magneto-optical detection (RMOD) has been developed for its rapid and sensitive detection both in cell cultures and patient samples. In the current article we demonstrate that, besides quantifying the overall concentration of hemozoin produced by the parasites, RMOD can also track the size distribution of the hemozoin crystals. We establish the relations between the magneto-optical signal, the mean parasite age and the median crystal size throughout one erythrocytic cycle of Plasmodium falciparum parasites, where the latter two are determined by optical and scanning electron microscopy, respectively. The significant correlation between the magneto-optical signal and the stage distribution of the parasites indicates that the RMOD method can be utilized for species-specific malaria diagnosis and for the quick assessment of drug efficacy.

Abstract Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) suppress production of pro-inflammatory cytokines and chemokines in human smooth muscle cells (SMCs) through sequestration of RelA in the NF-κB complex, but additional mechanisms are likely involved. The cGAS-STING pathway is activated by double-stranded DNA in the cytosolic compartment and acts through TANK-binding kinase 1 (TBK1) to spark inflammation. The present study tested if MRTFs suppress inflammation also by targeting cGAS-STING signaling. Interrogation of a transcriptomic dataset where myocardin was overexpressed using a panel of 56 cGAS-STING cytokines showed the panel to be repressed. Moreover, MYOCD, MRTFA, and SRF associated negatively with the panel in human arteries. RT-qPCR in human bronchial SMCs showed that all MRTFs reduced pro-inflammatory cytokines on the panel. MRTFs diminished phosphorylation of TBK1, while STING phosphorylation was marginally affected. The TBK1 inhibitor amlexanox, but not the STING inhibitor H-151, reduced the anti-inflammatory effect of MRTF-A. Co-immunoprecipitation and proximity ligation assays supported binding between MRTF-A and TBK1 in SMCs. MRTFs thus appear to suppress cellular inflammation in part by acting on the kinase TBK1. This may defend SMCs against pro-inflammatory insults in disease.

Abstract Timber plantations across the world are suffering from the effects of increasingly frequent wildfires, which potentially degrade the wood of affected trees, depending on the exposure temperature and time. However, it is rather complicated to determine the exact temperature of the fire, or the temperature to which the wood was exposed. This study aimed to determine the exposure temperature of wood retrospectively through solid-state NMR analysis. Models were developed from softwood and hardwood samples exposed to defined temperatures, which successfully linked the NMR signal to the exposure temperature. Various fit equations were developed to link the half-width or peak area of the NMR signal to the exposure temperatures. Hard- and softwoods displayed noticeable differences: a linear function best described the half-width in the higher temperature region for Pine and Eucalyptus, whereas a parabolic function for the peak area of Eucalyptus yielded the best correlation to the entire temperature range. This non-destructive and direct method offers a valuable evaluation method to determine, if wood in burnt trees is degraded and can be processed. An informed choice can be made on the decision to use, or discard burnt wood.

Abstract All quantum random number generators based on measuring value indefinite observables are at least three-dimensional because the Kochen–Specker Theorem and the Located Kochen–Specker Theorem are false in dimension two. In this article, we construct quantum random number generators based on measuring a three-dimensional value indefinite observable that generates binary quantum random outputs with the same randomness qualities as the ternary ones: the outputs are maximally unpredictable.

Recent evidence suggests that an ever-growing number of pediatric patients require invasive treatments such as root canal therapy (RCT) in their permanent dentition, albeit with little information about risk factors such as prior invasive treatments of pulpotomy or pulpectomy in their primary dentition. Therefore, the primary objectives of this study were to determine the number of pediatric patients who have had any type of invasive treatment in their primary teeth, to assess their association with any subsequent invasive treatment (root canal therapy, extractions) in their permanent dentition, and to assess these trends over time. This retrospective study utilized summary data from a clinical pediatric patient pool (ages 0–17) over the period of 2013–2022. This analysis revealed that pediatric patients requiring pulpotomies and pulpectomies in primary dentition declined between 2013 (n = 417, n = 156) and 2022 (n = 250, n = 12), while root canal therapy (RCT) in permanent dentition increased six-fold from n = 54 to n = 330. In addition, few (7.8%) patients with RCT had a previous history of pulpotomy or pulpectomy, which suggests that invasive treatments performed in primary dentition have no direct association with the subsequent need for invasive treatments in permanent dentition, although more research is needed to determine the explanations for these observations.