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Abstract Archaea are vital components of the human microbiome, yet their study within the gastrointestinal tract (GIT) is limited by the scarcity of cultured representatives. Our study presents a method for the targeted enrichment and isolation of methanogenic archaea from human fecal samples. The procedure combines methane breath testing, in silico metabolic modeling, media optimization, FACS, dilution series, and genomic sequencing through Nanopore technology. Additional analyzes include the co-cultured bacteriome, comparative genomics of archaeal genomes, functional comparisons, and structure-based protein function prediction of unknown differential traits. Successful establishment of stable archaeal cultures from 14 out of 16 fecal samples yielded nine previously uncultivated strains, eight of which are absent from a recent archaeome genome catalog. Comparative genomic and functional assessments of Methanobrevibacter smithii and Candidatus Methanobrevibacter intestini strains from individual donors revealed features potentially associated with gastrointestinal diseases. Our work broadens available archaeal representatives for GIT studies, and offers insights into Candidatus Methanobrevibacter intestini genomes’ adaptability in critical microbiome contexts.

Abstract Immunoglobulin G4 (IgG4) related hypertrophic pachymeningitis of the spinal cord is a rare condition, characterized by infiltration of the spinal meninges with IgG4-producing plasma cells and subsequent hypertrophic fibrosis. Here, we report on a 65-year-old woman with IgG4 associated hypertrophic spinal pachymeningitis, in whom cerebrospinal fluid (CSF) analysis was a decisive diagnostic tool. Not only could we demonstrate an intrathecal IgG4 production, but also IgG4 positive plasma cells in CSF. Following decompressive surgery, diagnosis of IgG4 associated hypertrophic pachymeningitis was confirmed histologically. Surgery and immunosuppressive therapy with rituximab were associated with clinical improvement. This case highlights CSF analyses as diagnostic tool for detection of IgG4 related hypertrophic pachymeningitis.

Abstract Understanding the impact of induction and maintenance therapy on patients’ quality of life (QoL) is important for treatment selection. This study aims to compare patient‐reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL‐C 30 and QOL‐MY20 questionnaires in the AGMT‐02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health‐related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross‐sectional comparisons indicated a “slight” superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross‐sectional comparisons revealed a “slight” improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with “slight” or “moderate” impairments in several QoL scales compared with the observation group.

Abstract Transcatheter aortic valve replacement (TAVR) is a widely used intervention for patients with severe aortic stenosis. Identifying high-risk patients is crucial due to potential postprocedural complications. Currently, this involves manual clinical assessment and time-consuming radiological assessment of preprocedural computed tomography (CT) images by an expert radiologist. In this study, we introduce a probabilistic model that predicts post-TAVR mortality automatically using unprocessed, preprocedural CT and 25 baseline patient characteristics. The model utilizes CT volumes by automatically localizing and extracting a region of interest around the aortic root and ascending aorta. It then extracts task-specific features with a 3D deep neural network and integrates them with patient characteristics to perform outcome prediction. As missing measurements or even missing CT images are common in TAVR planning, the proposed model is designed with a probabilistic structure to allow for marginalization over such missing information. Our model demonstrates an AUROC of 0.725 for predicting all-cause mortality during postprocedure follow-up on a cohort of 1449 TAVR patients. This performance is on par with what can be achieved with lengthy radiological assessments performed by experts. Thus, these findings underscore the potential of the proposed model in automatically analyzing CT volumes and integrating them with patient characteristics for predicting mortality after TAVR.

Abstract Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.

Abstract InsectSound1000 is a dataset comprising more than 169000 labelled sound samples of 12 insects. The insect sound level spans from very loud (Bombus terrestris) to inaudible to human ears (Aphidoletes aphidimyza). The samples were extracted from more than 1000 h of recordings made in an anechoic box with a four-channel low-noise measurement microphone array. Each sample is a four-channel wave-file of 2500 kHz length, at 16 kHz sample rate and 32 bit resolution. Acoustic insect recognition holds great potential to form the basis of a digital insect sensor. Such sensors are desperately needed to automate pest monitoring and ecological monitoring. With its significant size and high-quality recordings, InsectSound1000 can be used to train data-hungry deep learning models. Used to pretrain models, it can also be leveraged to enable the development of acoustic insect recognition systems on different hardware or for different insects. Further, the methodology employed to create the dataset is presented in detail to allow for the extension of the published dataset.

Neutron irradiation causes embrittlement of reactor pressure vessel (RPV) steels. Post-irradiation annealing is capable of partly or fully restoring the unembrittled condition. While annealing at high temperatures (e.g., 475°C) was successfully applied to extend the lifetime of operating VVER-440 reactors, the benefit of annealing at lower temperatures (e.g., 343°C–the maximum to which the primary cooling water can be heated) is a matter of debate. In this study, neutron-irradiated VVER-440 RPV base metal and weld were exposed to isothermal annealing at 343°C up to 2,000 h. Given the limited amount of material, the degree of recovery was estimated in terms of Vickers hardness, the ductile-brittle transition temperature derived from small punch tests, and the master curve reference temperature derived from fracture mechanics tests of mini samples. For the base metal, small-angle neutron scattering was applied to underpin the findings at the nm-scale. We have found significant partial recovery in both materials after annealing for 300 h or longer. The variations of the degree of recovery are critically discussed and put into the context of wet annealing.

Summary: Background: DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months–12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders. Methods: In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023. Findings: We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5–∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12–∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved. Interpretation: dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders. Funding: This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.

Background & Aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p

Abstract Background Escape rooms are increasingly used in medical education as a complementary learning technique or even alternative to traditional educational approaches. Few studies focus on debriefing following medical escape rooms and how escape rooms can be used to achieve pre-defined learning objectives. Evaluating the use of narrow learning objectives may increase the depth of reflections and transform an engaging team event into an effective learning opportunity. This study aimed to explore participants’ experiences and perceived learning outcomes of narrow learning objectives in a medical escape room with debriefing. Methods In this explorative, qualitative study, participants saw a video lecture, participated in an escape room experience, and in a following debriefing. Throughout this learning session, the learning objectives concerned “exchange of information” and are therefore relatively narrow. Participants then participated in a semi-structured focus group interview and completed a demographic questionnaire. Participants were volunteer final-year medical students. Focus group interview recordings were transcribed and analysed using systematic text condensation. Results Thirty-two students in eight groups completed the study. Five themes were described in the analysis of the focus group interviews: Experience with the narrow learning objectives, topics discussed in the debriefing, learning mechanisms, learning outcomes concerning exchange of information and influences of the learning approach. Conclusions Narrow learning objectives and structured debriefing seem to increase perceived learning depth of medical escape room sessions. Using semi-structured debriefing still allows for discussions of other elements relevant to the students. Clinical trials Clinical.trials ID NCT04783259.

Abstract The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5–6, 2024 ( http://www.cvot.org ).

Introduction: Skin cancer is often fatal, which motivates new therapy avenues. Recent advances in cancer treatment are indicative of the importance of combination treatments in oncology. Previous studies have identified small molecule-based therapies and redox-based technologies, including photodynamic therapy or medical gas plasma, as promising candidates to target skin cancer. Objective: We aimed to identify effective combinations of experimental small molecules with cold gas plasma for therapy in dermato-oncology. Methods: Promising drug candidates were identified after screening an in-house 155-compound library using 3D skin cancer spheroids and high content imaging. Combination effects of selected drugs and cold gas plasma were investigated with respect to oxidative stress, invasion, and viability. Drugs that had combined well with cold gas plasma were further investigated in vascularized tumor organoids in ovo and a xenograft mouse melanoma model in vivo. Results: The two chromone derivatives Sm837 and IS112 enhanced cold gas plasma-induced oxidative stress, including histone 2A.X phosphorylation, and further reduced proliferation and skin cancer cell viability. Combination treatments of tumor organoids grown in ovo confirmed the principal anti-cancer effect of the selected drugs. While one of the two compounds exerted severe toxicity in vivo, the other (Sm837) resulted in a significant synergistic anti-tumor toxicity at good tolerability. Principal component analysis of protein phosphorylation profiles confirmed profound combination treatment effects in contrast to the monotherapies. Conclusion: We identified a novel compound that, combined with topical cold gas plasma-induced oxidative stress, represents a novel and promising treatment approach to target skin cancer.

Abstract As other mental illnesses, agoraphobia is associated with a significant risk for relapse after the end of treatment. Personalized and adaptive approaches appear promising to improve maintenance treatment and aftercare as they acknowledge patients’ varying individual needs with respect to intensity of care over time. Currently, there is a deficit of knowledge about the detailed symptom course after discharge from acute treatment, which is a prerequisite for the empirical development of rules to decide if and when aftercare should be intensified. Therefore, this study aimed firstly at the investigation of the naturalistic symptom course of agoraphobia after discharge from initial treatment and secondly at the development and evaluation of a data-driven algorithm for a digital adaptive aftercare intervention. A total of 56 agoraphobia patients were recruited in 3 hospitals. Following discharge, participants completed a weekly online monitoring assessment for three months. While symptom severity remained stable at the group level, individual courses were highly heterogeneous. Approximately two-thirds of the patients (70%) reported considerable symptoms at some time, indicating a need for medium or high-intense therapeutic support. Simulating the application of the algorithm to the data set resulted in an early (86% before week six) and relatively even allocation of patients to three groups (need for no, medium, and high-intense support respectively). Overall, findings confirm the need for adaptive aftercare strategies in agoraphobia. Digital, adaptive approaches may provide immediate support to patients who experience symptom deterioration and thus promise to contribute to an optimized allocation of therapeutic resources and overall improvement of care.

Abstract Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.

The programme of the German Congress for Laboratory Medicine 2022 was essentially designed by the divisions of the German Society for Clinical Chemistry and Laboratory Medicine (DGKL). Almost all chairpersons of the divisions organised a 90-min symposium on current topics, i.e. conceptualised the symposia and invited speakers. For this article all chairpersons summarised the lectures that were given within the symposia. The DGKL’s work is structured into 5 areas of expertise: Molecular Diagnostics, Learning & Teaching, Quality & Management, Laboratory & Diagnostics and Biobanks & Informatics. The areas of expertise are in turn subdivided into divisions. About the history of the establishment of this new structure within the DGKL you can find information in the editorial of this issue.

Abstract Introduction Studies of cognitive functioning in patients with attention‐deficit/hyperactivity disorder (ADHD) have often used healthy comparison groups. The present study examines cognitive profiles, including general intellectual and executive functions, in a young adult psychiatric outpatient clientele with ADHD and evaluates whether their cognitive profiles can help differentiate them from patients with non‐ADHD‐associated psychiatric disorders. Methods The study group comprised 141 young adult psychiatric patients (age range 18–25 years) of whom 78 had ADHD. Comprehensive neuropsychological assessment included the Wechsler Adult Intelligence Scale, 4th version and subtests from Delis–Kaplan Executive Function System. Clinical psychiatric assessments and diagnostic evaluation were performed. Results The ADHD group (including all subtypes) had significantly lower verbal comprehension and full‐scale intelligence quotient than the non‐ADHD group. Tests measuring working memory or executive function did not separate those with and without ADHD. Conclusion The results of our study suggest that, except for the need to establish overall cognitive performance level, the clinical implication of testing is small if the purpose is to “rule out” an ADHD diagnosis.

ObjectiveGlobally, many societies are experiencing an increase in the number of older adults (>65 years). However, there has been a widening gap between the chronological and biological age of older adults which trend to a more active and social participating part of the society. Concurrently, the incidence of traumatic brain injury (TBI) is increasing globally. The aim of this study was to investigate the outcome after TBI and decompressive craniectomy (DC) in older adults compared with younger patients.MethodsA retrospective, multi-centre, descriptive, observational study was conducted, including severe TBI patients who were treated with DC between 2005 and 2022. Outcome after discharge and 12 months was evaluated according to the Glasgow Outcome Scale (Sliding dichotomy based on three prognostic bands). Significance was established as p ≤ 0.05.ResultsA total of 223 patients were included. The majority (N = 158, 70.9%) survived TBI and DC at discharge. However, unfavourable outcome was predominant at discharge (88%) and after 12 months (67%). There was a difference in favour of younger patients (≤65 years) between the age groups at discharge (p = 0.006) and at 12 months (p 65 years old had a good or very good outcome. 25% were depending on support in everyday activities. After 12 months, the age (OR 0.937, p = 0.007, CI 95%: 0.894–0.981; univariate) and performed cranioplasty (univariate and multivariate results) were influential factors for the dichotomized GOS. For unfavourable outcome after 12 months, the thresholds were calculated for age = 55.5 years (p 65 years of age following severe TBI and DC died or were dependent and usually required extensive support. This aspect should also be taken into account during decision making and counselling (inter-, intradisciplinary or with relatives) for a very mobile and active older section of society, together with the patient’s will.