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Summary: Background: The hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel diseases (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. Methods: This study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture-informed analyses and selection scans of rs11209026-A and its haplotypes. Findings: rs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%). AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe. Interpretation: Given the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralisation therapies for chronic inflammatory diseases. Funding: German Research Foundation (EXC 2167 390884018 and EXC 2150 390870439).

Background: Vulnerability to infectious diseases in refugees is dependent on country of origin, flight routes, and conditions. Information on specific medical needs of different groups of refugees is lacking. We assessed the prevalence of infectious diseases, immunity to vaccine-preventable diseases, and chronic medical conditions in children, adolescents, and adult refugees from Ukraine who arrived in Germany in 2022. Methods: Using different media, we recruited Ukrainian refugees at 13 sites between 9–12/2022. An antigen test for acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, serologies for a range of vaccine-preventable diseases, as well as interferon gamma release assays (IGRAs) for tuberculosis (TB), and SARS-CoV-2 were performed. We assessed personal and family history of chronic medical conditions, infectious diseases, vaccination status, and conditions during migration. Results: Overall, 1793 refugees (1401 adults and 392 children/adolescents) were included. Most participants were females (n = 1307; 72·3%) and from Eastern or Southern Ukraine. TB IGRA was positive in 13% (n = 184) of the adults and in 2% (n = 7) of the children.Serology-based immunological response was insufficient in approximately 21% (360/1793) of the participants for measles, 32% (572/1793) for diphtheria, and 74% (1289/1793) for hepatitis B. Conclusions: We show evidence of low serological response to vaccine-preventable infections and increased LTBI prevalence in Ukrainian refugees. These findings should be integrated into guidelines for screening and treatment of infectious diseases in migrants and refugees in Germany and Europe. Furthermore, low immunity for vaccine-preventable diseases in Ukrainians independent of their refugee status, calls for tailor-made communication efforts.

Abstract Background Systemic Lutetium-177 prostate-specific membrane antigen-617 radioligand therapy (Lu-177-PSMA-617-RLT) is a novel treatment approach in patients suffering from metastasized castration-resistant prostate cancer. Nonetheless, a therapeutic response may fail to appear in a proportion of patients. This study aims to identify routinely obtainable pre- and intratherapeutic parameters to allow a prediction of overall survival in patients receiving Lu-177-PSMA-617 radioligand therapy. Methods Between January 2015 and December 2020 52 patients treated with a total of 146 cycles Lu-177-PSMA-617-RLT were retrospectively analysed in a single-center trial. The median overall survival time (OS) was compared to pre-therapeutic serological parameters, the extend of metastatic spread and previously performed therapies using Kaplan–Meier estimators and multivariate Cox-regression. Bonferroni-Holm correction was performed on all statistical tests. Results The median OS of all patients was 55.6 weeks. Multivariate Cox-regression revealed significant lower survival for decreased pretherapeutic hemoglobin levels (HR 0.698 per g/dl; 95%-CI 0.560–0.872; p = 0.001), increased lactate dehydrogenase (LDH) levels (HR 1.073 per 25 U/l; 95%-CI 1.024–1.125; p = 0.003) and the presence of hepatic metastasis (HR 6.981; 95%-CI 2.583–18.863; p

The article in the Journal of Magnetic Resonance Imaging presents a study that aimed to provide MRI Z-scores for two ventricular contouring methods in children and adolescents. The study included 184 participants and created Z-score curves and tables based on body height for different measurements. The results are available on an online calculator webpage and may improve the accuracy of reporting MRI examinations in pediatric patients with various diseases. [Extracted from the article]

Purpose The role of positive endexpiratory pressure (PEEP) for successful cannulation of the subclavian vein (SCV) remains inconclusive. The aim of our study was to assess the effect of different levels of PEEP on distance from SCV to parietal pleura (DVP) and on the cross-sectional area (CSA) of the SCV. Methods Invasive mechanically ventilated adult patients with a clinical indication for a stepwise PEEP-trial (0, 5, 10, and 15 cm H2O) were included in this prospective observational single-center study. Ultrasound examinations of SCV were performed with a linear ultrasound probe using the infraclavicular view. DVP and CSA were measured on the right and left bodyside. Examinations were repeated at each PEEP step. Results 27 patients were enrolled (12 female; 60±21 years; BMI 24.6±4.9 kg/m2; 20 patients on controlled, 7 on assisted ventilation). A statistically significant increase of DVP in the in-plane view was found on the left side which was not clinically relevant. No significant differences of DVP were observed in all other views. PEEP induced changes in CSAs were statistically significant but clinically not relevant on both sides. The largest change in CSA (2mm2) was observed when comparing PEEP 10 with PEEP 0 cm H2O. Conclusion A stepwise PEEP increase was not associated with clinically relevant changes of the DVP and CSA. Thus, a PEEP-optimization for the cannulation of the subclavian vein is not indicated.

Abstract Background Although the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now. Results We enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue. Conclusions We have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.

Abstract Background Pediatric patients are becoming increasingly referred for cardiovascular magnetic resonance (CMR). Measurement of ventricular wall thickness is typically part of the assessment and can be of diagnostic importance, e.g. in arterial hypertension. However, normal values for left ventricular (LV) and right ventricular (RV) wall thickness in pediatric patients are lacking. The aim of this study was to establish pediatric centile charts for segmental LV and RV myocardial thickness in a retrospective multicenter CMR study. Methods CMR was performed in 161 healthy children and adolescents with an age range between 6 and 18 years from two centers in the UK and Germany as well as from a previously published CMR project of the German Competence Network for Congenital Heart Defects. LV myocardial thickness of 16 segments was measured on the short axis stack using the American Heart Association segmentation model. In addition, the thickness of the RV inferior and anterior free wall as well as biventricular mass was measured. Results The mean age (standard deviation) of the subjects was 13.6 (2.9) years, 64 (39.7%) were female. Myocardial thickness of the basal septum (basal antero- and inferoseptal wall) was 5.2 (1.1) mm, and the basal lateral wall (basal antero- and inferolateral) measured 5.1 (1.2) mm. Mid-ventricular septum (antero- and inferoseptal wall) measured 5.5 (1.2) mm, and mid-ventricular lateral wall (antero- and inferolateral wall) was 4.7 (1.2) mm. Separate centile charts for boys and girls for all myocardial segments and myocardial mass were created because gender was significantly correlated with LV myocardial thickness (p

Abstract Background Ultrasound education is propagated already during medical school due to its diagnostic importance. Courses are usually supervised by experienced faculty staff (FS) with patient bedside examinations or students among each other but often overbooked due to limited FS availability. To overcome this barrier, use of teaching videos may be advantageous. Likewise, peer teaching concepts solely with trained student tutors have shown to be feasible and effective. The aim was to evaluate 1) objective learning outcomes of a combined video-based, student-tutor (ViST) as compared to a FS-led course without media support, 2) acceptance and subjective learning success of the videos. Methods Two ultrasound teaching videos for basic and advanced abdominal ultrasound (AU) and transthoracic echocardiography (TTE) were produced and six students trained as tutors. Fourth-year medical students (N = 96) were randomized to either the ViST- or FS course (6 students per tutor). Learning objectives were defined equally for both courses. Acquired practical basic and advanced ultrasound skills were tested in an objective structured clinical examination (OSCE) using modified validated scoring sheets with a maximum total score of 40 points. Acceptance and subjective learning success of both videos were evaluated by questionnaires based on Kirkpatrick’s evaluation model with scale-rated closed and open questions. Results 79 of 96 medical students completed the OSCE and 77 could be finally analyzed. There was no significant difference in the mean total point score of 31.3 in the ViST (N = 42) and 32.7 in the FS course (N = 35, P = 0.31) or in any of the examined basic or advanced ultrasound skill subtasks. Of the 42 ViST participants, 29 completed the AU and 27 the TTE video questionnaire. Acceptance and subjective learning success of both videos was rated positively in 14–52% and 48–88% of the rated responses to each category, respectively. Attendance of either the student or faculty tutor was deemed necessary in addition to the videos. Conclusions A ViST versus FS teaching concept was able to effectively teach undergraduate students in AU and TTE, albeit acceptance of the teaching videos alone was limited. However, the ViST concept has the potential to increase course availability and FS resource allocation.

The molecular mechanisms for uveal ring melanoma are still unclear until today. In this case report, we describe a patient with a malignant uveal melanoma with exudative retinal detachment that had been treated with plaque brachytherapy, resulting in successful tumor regression. After 1 year, a ring-shaped recurrence with extraocular extension appeared, and the eye required enucleation. Histological and molecular genetic analyses revealed an epithelioid-cell-type melanoma with complete circumferential involvement of the ciliary body and, so far, unreported GNAQ and SF3B1 mutations in ring melanoma. Therefore, this report gives new genetic background information on this ocular tumor usually leading to enucleation.

The cyanobacterium Synechocystis sp.PCC 6803 possesses a bidirectional NiFe-hydrogenase, HoxEFUYH. It functions to produce hydrogen under dark, fermentative conditions and photoproduces hydrogen when dark-adapted cells are illuminated. Unexpectedly, we found that the deletion of the large subunit of the hydrogenase (HoxH) in Synechocystis leads to an inability to grow on arginine and glucose under continuous light in the presence of oxygen. This is surprising, as the hydrogenase is an oxygen-sensitive enzyme. In wild-type (WT) cells, thylakoid membranes largely disappeared, cyanophycin accumulated, and the plastoquinone (PQ) pool was highly reduced, whereas ΔhoxH cells entered a dormant-like state and neither consumed glucose nor arginine at comparable rates to the WT. Hydrogen production was not traceable in the WT under these conditions. We tested and could show that the hydrogenase does not work as an oxidase on arginine and glucose but has an impact on the redox states of photosynthetic complexes in the presence of oxygen. It acts as an electron valve as an immediate response to the supply of arginine and glucose but supports the input of electrons from arginine and glucose oxidation into the photosynthetic electron chain in the long run, possibly via the NDH-1 complex. Despite the data presented in this study, the latter scenario requires further proof. The exact role of the hydrogenase in the presence of arginine and glucose remains unresolved. In addition, a unique feature of the hydrogenase is its ability to shift electrons between NAD(H), NADP(H), ferredoxin, and flavodoxin, which was recently shown in vitro and might be required for fine-tuning. Taken together, our data show that Synechocystis depends on the hydrogenase to metabolize organic carbon and nitrogen in the presence of oxygen, which might be an explanation for its prevalence in aerobic cyanobacteria.

Abstract Background Use of big data is becoming increasingly popular in medical research. Since big data-based projects differ notably from classical research studies, both in terms of scope and quality, a debate is apt as to whether big data require new approaches to scientific reasoning different from those established in statistics and philosophy of science. Main text The progressing digitalization of our societies generates vast amounts of data that also become available for medical research. Here, the big promise of big data is to facilitate major improvements in the treatment, diagnosis and prevention of diseases. An ongoing examination of the idiosyncrasies of big data is therefore essential to ensure that the field stays congruent with the principles of evidence-based medicine. We discuss the inherent challenges and opportunities of big data in medicine from a methodological point of view, particularly highlighting the relative importance of causality and correlation in commercial and medical research settings. We make a strong case for upholding the distinction between exploratory data analysis facilitating hypothesis generation and confirmatory approaches involving hypothesis validation. An independent verification of research results will be ever more important in the context of big data, where data quality is often hampered by a lack of standardization and structuring. Conclusions We argue that it would be both unnecessary and dangerous to discard long-established principles of data generation, analysis and interpretation in the age of big data. While many medical research areas may reasonably benefit from big data analyses, they should nevertheless be complemented by carefully designed (prospective) studies.

[This corrects the article DOI: 10.1371/journal.pgen.1009679.].

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

Leprosy, caused by infection with Mycobacterium leprae, was common in Europe in the Middle Ages. Here, Krause-Kyora et al. analyze ancient DNA from a medieval Danish leprosarium to assemble 10 complete bacterial genomes and perform association analysis of the DRB1*15:01 allele with risk of leprosy infection.