University of Lübeck

Background Biological age reflects inter-individual differences in biological function and capacity beyond chronological age. DNA methylation age (DNAmA) and its deviation from chronological age, DNAmA acceleration (DNAmAA), which was calculated as residuals of leukocyte cell count adjusted linear regression of DNAmA on chronological age, were used to estimate biological age in this study. Low levels of serum selenium, selenoprotein P (SELENOP), and the selenocysteine-containing glutathione peroxidase 3 (GPx3) are associated with adverse health outcomes and selenium supplementation is discussed as an anti-aging intervention. Methods In this study, we cross-sectionally analyzed 1568 older participants from the observational Berlin Aging Study II (mean age ± SD: 68.8 ± 3.7 years, 51% women). Serum selenium was measured by total reflection X-ray fluorescence (TXRF) spectroscopy and SELENOP was determined by sandwich ELISA. GPx3 was assessed as part of a proteomics dataset using liquid chromatography–mass spectrometry (LC–MS). The relationship between selenium biomarkers and epigenetic clock measures was analyzed using linear regression analyses. P values and 95% confidence intervals (not adjusted for multiple testing) are stated for each analysis. Results Participants with deficient serum selenium levels (< 90 μg/L) had a higher rate of biological aging (DunedinPACE, β = − 0.02, SE = 0.01, 95% CI − 0.033 to − 0.004, p = 0.010, n = 865). This association remained statistically significant after adjustment for age, sex, BMI, smoking, and first four genetic principal components (β = − 0.02, SE = 0.01, 95% CI − 0.034 to − 0.004, p = 0.012, n = 757). Compared to the highest quartile, participants in the lowest quartile of SELENOP levels showed an accelerated biological aging rate (DunedinPACE, β = − 0.03, SE = 0.01, 95% CI − 0.051 to − 0.008, p = 0.007, n = 740, fully adjusted model). Similarly, after adjustment for confounders, accelerated biological age was found in participants within the lowest GPx3 quartile compared to participants in the fourth quartile (DunedinPACE, β = − 0.04, SE = 0.01, 95% CI − 0.06 to − 0.02, p = 0.001, n = 674 and GrimAge, β = − 0.98, SE = 0.32, 95% CI − 1.6 to − 0.4, p = 0.002, n = 608). Only the association with GPx3 remained statistically significant after multiple testing correction. Conclusion Our study suggests that low levels of selenium biomarkers are associated with accelerated biological aging measured through epigenetic clocks. This effect was not substantially changed after adjustment for known confounders.

GP2015 is an etanercept biosimilar. Equivalent efficacy and comparable safety of GP2015 to reference etanercept (ref-ETN) was demonstrated in two phase III studies, one in patients with moderate-to-severe chronic plaque-type psoriasis (PsO; EGALITY study) and the other in patients with rheumatoid arthritis (RA; EQUIRA study). EGALITY also included patients with reported psoriatic arthritis (PsA). Here, patient-reported outcome (PRO) data from both studies are presented. EGALITY included 531 patients with PsO and EQUIRA included 376 patients with RA. In EGALITY, patients who had achieved ≥ 50% improvement in Psoriasis Area and Severity Index (PASI) at week 12 either continued the initial treatment or underwent three treatment switches between GP2015 and ref-ETN starting at week 12. In EQUIRA, patients with at least moderate European League Against Rheumatism response at week 24 received GP2015 up to week 48. Assessed PROs included Dermatology Life Quality Index (DLQI) and EuroQol five-dimension health status questionnaire (EQ-5D-5L) in EGALITY, Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score in EQUIRA, and Health Assessment Questionnaire–Disability Index (HAQ-DI) in both studies. In EGALITY, mean DLQI decreased from baseline in the GP2015 and ref-ETN groups, and the mean (standard deviation [SD]) percent reductions from baseline in DLQI were comparable between groups at week 12 (GP2015, – 67.7 [40.7]; ref-ETN, – 67.3 [30.6]), and were sustained after the switch at week 52 (‘continued GP2015,’ – 77.3 [36.5]; ‘continued ref-ETN,’ – 72.8 [33.7]; ‘switched GP2015,’ − 73.9 [37.0]; ‘switched ref-ETN,’ − 78.1 [30.9]). The proportion of patients with EQ-5D-5L scores of 1 (‘no problems’) improved from baseline to week 52 for all five dimensions and was comparable between treatment groups. In EGALITY, in patients with reported PsA at baseline, mean (SD) HAQ-DI scores decreased from baseline, and scores were comparable between treatment groups at week 12 (GP2015, 0.6 [0.7]; ref-ETN, 0.6 [0.6]) and after switching at week 52 (‘continued GP2015,’ – 0.4 [0.6]; ‘continued ref-ETN,’ – 0.4 [0.6]; ‘switched GP2015,’ – 0.4 [0.6]; ‘switched ref-ETN,’ – 0.1 [0.4]). In EQUIRA, the proportion of patients achieving HAQ-DI in normal range (≤ 0.5) was comparable between treatment groups up to week 48 (‘continued GP2015,’ 36.7%; ‘switched to GP2015,’ 39.9%). The mean FACIT-Fatigue scores increased from baseline and the mean (SD) percent change from baseline in FACIT-Fatigue score at week 24 was 9.6 (9.5) in the ‘continued GP2015’ and 11.4 (9.7) in the ‘switched to GP2015’ groups; the scores were sustained after switching until week 48. Treatment with GP2015 and ref-ETN resulted in similar improvements in PROs and quality-of-life scores across the three diseases, namely RA, PsA, and PsO. These improvements were sustained after switching, with consistent benefit on PROs during the treatment period. ClinicalTrials.gov identifiers: NCT01891864, NCT02638259.

Myelofibrosis (MF) in 50% of cases is driven by an activating JAK2 mutation, mostly V617F. Ruxolinitib is approved for the treatment of MF. Responses to ruxolitinib in MF are of limited duration. Unexpectedly, treatment of JAK2-V617F expressing cells with ruxolitinib causes paradoxical hyperphosphorylation of JAK2 at activation loop Tyr1007/Tyr1008. The significance of ruxolitinib-induced JAK2 hyperphosphorylation is not well understood. We found that a ruxolitinib-resistant JAK2 variant (V617F + L983F) and a kinase dead mutant (JAK2-V617F + K882R) did not show paradoxical hyperphosphorylation after ruxolitinib treatment indicating that it is an intrinsic mechanism. Antibodies against pTyr1007/1008 failed to immunoprecipitate native JAK2-V617F in the presence of ruxolitinib, although JAK2-V617F was hyperphosphorylated at these sites, suggesting that in the presence of ruxolitinib the JAK2 activation loop is buried within the kinase domain. This stabilization of the activation loop conformation resulted in the protection of pTyr1007/1008 sites from phosphatases. Mutation of Arg975 and Lys999 to Ala reduced the phosphorylation at both Tyr1007/Tyr1008 residues, and notably, ruxolitinib treatment did not lead to JAK2 hyperphosphorylation. Importantly, hyperphosphorylated JAK2 after ruxolitinib dissociation displayed excess rebound activation of STAT5 target gene PIM kinase. Our results suggest a novel mode of kinase regulation by modulating kinase activity through conformational changes induced by ruxolitinib. Subject categories: JAK2-V617F, Ruxolitinib, JAK2 hyperphosphorylation, Phosphatases action, PIM kinases

Atherosclerosis is the leading cause of death in Western industrial nations. To study the etiology of plaque progression, atherosclerotic mouse models are widely used. Traditionally, analyzing the obtained histological whole slide images of Oil Red O-stained aortic roots required manual segmentation. To accelerate this process, an artificial intelligence-driven solution is proposed that comprises three stages: (1) defining the region of interest (ROI) of the aortic root using a YOLOv8l object detector, (2) applying supervised machine learning with ensembles of U-Net++ networks for artery segmentation using ROI masks, and (3) performing plaque segmentation within arterial walls with the unsupervised W-Net method. To establish a robust segmentation pipeline, we benchmark our methods using manually created masks ($\text {n}=6085$ for artery segmentation, $\text {n}=1089$ for plaque segmentation). A key finding is that an ensemble of U-Net++ networks applied on ROI masks outperformed single network architectures. Through a novel combination strategy, the ensemble output can be easily modified, paving the way for a quick and robust application in the lab. Finally, a case study utilizing published mouse data ($\text {n}=373$ slices) underscored the ability of our optimized pipeline to replicate human-made plaque predictions with a high correlation (Pearson’s $\text {r}=0.91$) and reproduce biological insights derived from manual analysis.

Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of MS, did not benefit from DMF treatment when fed a lauric acid-rich (LA) diet. Mice on normal chow (NC) diet, in contrast, and even more so mice on high-fiber (HFb) diet showed the expected protective DMF effect. DMF lacked efficacy in the LA diet-fed group despite similar resorption and preserved effects on plasma lipids. When mice were fed the permissive HFb diet, the protective effect of DMF treatment depended on hydroxycarboxylic receptor 2 (HCAR2) which is highly expressed in neutrophil granulocytes. Indeed, deletion of Hcar2 in neutrophils abrogated DMF protective effects in EAE. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCAR2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.

Xerosis cutis (dry skin) is a common and burdensome symptom of atopic dermatitis (AD). Topical emollients restore skin hydration and barrier function through the physicochemical properties of their nonactive constituents (e.g., glycerol, urea, lactic acid, liquid paraffin, petrolatum) and represent the mainstay of basic therapy for xerosis cutis associated with AD. Newer “emollients plus” containing active ingredients may expand the treatment options available to patients with AD; however, we believe that basic emollients remain an important strategy for the long‐term management of xerosis cutis. To that end, this article aims to review the clinical value of basic emollients for treating xerosis cutis in AD. We performed a series of literature searches to identify clinical studies of basic emollients containing one or more of the following ingredients: almond and coconut oils, amino acids, chondroitin, dexpanthenol, glucose, glycerol, glycosaminoglycans, hyaluronic acid, lactic acid, lanolin, olive oil, paraffin, petrolatum, phospholipids, polyunsaturated fatty acids, pyroglutamic acid, squalene, triglycerides, urea, vegetable oils, and vitamin E. From these searches, the authors identified articles of interest that described the efficacy of basic emollients for the treatment of xerosis cutis associated with AD. Studies included in our review varied widely in terms of sample size, study design, interventions, and endpoints but collectively showed that most basic emollient formulations are safe and effective at improving objective and subjective measures of xerosis cutis. These studies also demonstrated the importance of ongoing emollient therapy to avoid xerosis relapse and the additive benefits of emollients that combine ingredients with complementary biophysical properties (e.g., glycerol with its humectant effect plus petrolatum with its occludent effect). Overall, the current body of literature reinforces the role of basic emollients as effective and accessible treatment options for the long‐term management of xerosis cutis in patients with AD.

The VA ECMO Registry of Germany (VERGE, http://va-ecmo-register.de/) is a prospective, multicenter, investigator-driven registry of Venoarterial Extracorporeal Membrane Oxygenation (VA ECMO) all-comers, free from industrial support. VERGE is Germany’s first multicenter registry to systematically gather and analyze data from various centers on the clinical use of VA ECMO. This first report compromises data from 581 VA ECMO patients from 2022. Median age was 60 years, hospital survival was 42% and 25% were female. The leading indication for VA ECMO was extracorporeal cardiopulmonary resuscitation (ECPR) followed by VA ECMO in shock (48.9 and 34.9%, respectively). Hospital survival of ECPR was significantly worse compared to shock (28 and 55%, respectively, p < 0.001). Age, pH, and lactate before cannulation all significantly correlated independently with hospital survival (p < 0.001). In VERGE, no patients with pH below 6.7 or lactate above 25 mmol/l survived.

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control1, 2–3. This form of distant communication mirrors that of metabolic hormones (for example, leptin, ghrelin), which convey information about the organism’s energy status by exerting effects on diverse brain regions, including the master homeostatic centre, the hypothalamus⁴. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here we present a study designed to unravel this challenging question. To this aim, we used chemogenetics⁵ (to selectively activate or inhibit hypothalamic pro-opiomelanocortin or agouti-related peptide neurons) or centrally administered leptin or ghrelin to male mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2–4 h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated the brain-mediated changes triggered by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a previously unanticipated brain–gut axis that acutely attunes microbiota composition on fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.

Type 2 diabetes (T2D) presents a global health concern, with evidence highlighting the role of the human gut microbiome in metabolic diseases. This study employs metabolic modelling to elucidate changes in host–microbiome interactions in T2D. Glucose levels, diet, 16S sequences and metadata were collected for 1866 individuals. In addition, microbial community models, and ecological interactions were simulated for the gut microbiomes. Our findings revealed a significant decrease in metabolic fluxes provided by the host’s diet to the microbiome in T2D patients, accompanied by increased within-community exchanges. Moreover, the diabetic microbiomes shift towards increased exploitative ecological interactions at the expense of collaborative interactions. The reduced microbiome-to-host butyrate flux, along with decreased fluxes of amino acids (including tryptophan), nucleotides, and B vitamins from the host’s diet, further highlight the dysregulation in microbial-host interactions in diabetes. In addition, microbiomes of T2D patients exhibit enrichment in energy metabolism, indicative of increased metabolic activity and antagonism. This study sheds light on the increased microbiome autonomy and antagonism accompanying diabetes, and provides candidate metabolic targets for intervention studies and experimental validation.

Zusammenfassung Das Gesundheitssystem befindet sich im demografischen Wandel, und gleichzeitig lässt der medizinische Fortschritt der letzten Jahrzehnte die Nachfrage nach Gesundheitsdienstleistungen anwachsen. Angesichts knapper werdender Ressourcen müssen innovative Lösungen und Technologien weiterentwickelt werden, um die Verfügbarkeit von Gesundheitsdienstleistungen zu gewährleisten. Die vorgestellten Technologien können wertvolle Ansätze liefern, um Krankheitsverläufe und Therapiefortschritte engmaschig und mithilfe selbstlernender Methoden der KI zu dokumentieren.

The Internet of Things (IoT) paradigm is redefining our lives, allowing us to make “smart” decisions. This boom has also gained popularity in academic research, one of the core goals being to make IoT research more accessible to students and early researchers, while making sure that experienced researchers keep up with the changes happening in the research area. A large number of review papers are available covering surveys related to IoT vision enabling technologies, applications, key features, and future directions. Nevertheless, there is a lack of analysis of these reviews. This study provides a scientometric analysis of already available reviews in the field of IoT to identify upcoming research needs and bring simplicity to literature research. In total, 964 review articles in the field of IoT written in English and published in peer-reviewed journals and conferences from 2010 to April 2023 have been finalized from the Google Scholar database. Three broad categories of analysis have been performed on the 964 relevant collected literature, namely (a) statistical; (b) machine learning-based; and (c) evaluative analysis. An important differentiating feature of the current study is the use of machine learning for data exploration, thereby providing better interpretation. We find that the trend to review the field of IoT has increased in the last five years with only one article in 2010. This article identifies and quantifies the knowledge gaps to inform the community, industry, and government authorities about research directions for IoT. Furthermore, this scientometric analysis serves as a foundational resource for IoT researchers in identifying relevant and important survey papers that target their research fields in IoT.

Blockchain technology is increasingly being adopted across critical domains, such as healthcare and finance, yet it remains susceptible to anomalies and malicious attacks. Hence, robust anomaly detection is essential in these decentralized systems to maintain integrity, trust, and reliability. However, anomaly detection is still challenging due to data imbalances, adversarial resilience, and the lack of explanation in existing approaches. This work presents ARCADE, a novel approach for adversarially resilient anomaly detection in blockchain networks that leverages an optimized cost-sensitive stacking ensemble learning combined with explainable artificial intelligence (XAI) techniques. Firstly, the proposed approach uses cost-sensitive learning to address the data imbalance problem by optimizing class weights that are integrated with stacking ensemble learning to enhance detection accuracy. Secondly, along with this, newly engineered features are employed to strengthen the resilience of the model against malicious perturbations. Lastly, XAI techniques are applied to provide comprehensive insights and explanations for model prediction. To evaluate ARCADE, the Ethereum network transactions dataset is utilized to ensure a realistic case study. The experimental results show the superiority of the ARCADE in several aspects, achieving a high accuracy of 99.65%; strong resilience against adversarial perturbations, achieving an accuracy of 99.38% for low-intensity attacks, 91.04% for moderate attacks, and over 78% for extreme attacks; and surpassing existing techniques while also providing explainability for domain users.

Bispecific T‐cell engagers (BTCEs) represent a paradigm shift in the treatment of relapsed/refractory multiple myeloma (RRMM). Talquetamab, a GPRC5DxCD3 BTCE, has shown promising results in the MonumenTAL‐1 trial and was recently approved by the Food and Drug Administration and the European Medicines Agency. However, treatment under real‐world conditions may not represent patient characteristics in clinical trials with restricted enrollment criteria. We performed a retrospective real‐world analysis including 138 RRMM patients treated with talquetamab at 21 German centers. Of evaluable patients, 43% had ISS stage III, 37% had extraosseous disease, and 48% had high‐risk cytogenetics. After a median of six prior therapy lines, 58% of patients would not have been eligible for MonumenTAL‐1. With a median follow‐up of 8.2 months, we observed an overall response rate of 65% and a median progression‐free survival of 6.4 months (95% confidence interval 5.1–9.0). Prior BTCE exposure, ISS stage III, extraosseous disease, and penta‐drug refractory disease were associated with unfavorable outcomes. Grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 5.1% and 1.5% of patients, respectively. In summary, our real‐world study confirms the efficacy and safety of talquetamab, despite a high proportion of patient‐ and disease‐related risk factors. These results support its use as bridging or long‐term treatment, even in advanced stages.

As evidenced by the clinical symptoms in hyper- or hypothyroidism, thyroid hormones have strong effects on cardiovascular and metabolic functions. While these actions had been initially attributed to direct molecular mechanisms in the respective peripheral tissues such as heart, muscle or adipose tissue, a recent paradigm shift has occurred with accumulating observations that demonstrated important indirect effects via the brain on these systems. However, the individual contributions of the peripheral versus central thyroid hormone actions for the well-known phenotypical symptoms are still not entirely understood. Similarly, the neuroanatomical substrates for these central actions have remained largely enigmatic, although many studies point to the hypothalamus as a major target of thyroid hormone action. This review critically discusses the role of the central actions of thyroid hormone for the regulation of heart rate, body temperature, energy expenditure and food intake, and integrates some novel findings to summarize the current state of the field.

Partial phenotypic overlap has been suggested between multiple system atrophy (MSA) and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. This study investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1,003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing. We identified 19 multiple system atrophy cases carrying an FGF14 GAA≥250 expansion (2.89%, n=19/657), a significantly higher frequency than in controls (1.40%, n=12/1,003) (p=0.04). Long-read Oxford Nanopore Technologies sequencing confirmed repeat sizes and polymorphisms detected by PCR, with high concordance (Pearson’s r=0.99, p<0.0001). Seven multiple system atrophy patients had a pathogenic FGF14 GAA≥300 expansion (five pathologically confirmed and two clinically diagnosed) and 12 had intermediate GAA250-299 expansion (six pathologically confirmed and six clinically diagnosed). A similar proportion of cerebellar-predominant and parkinsonism-predominant multiple system atrophy cases had FGF14 expansions. multiple system atrophy patients carrying an FGF14 GAA≥250 expansion exhibited severe gait ataxia, autonomic dysfunction and parkinsonism in keeping with a MSA phenotype, with a faster progression to falls (p=0.03) and regular wheelchair use (p=0.02) compared to the multiple system atrophy cases without FGF14 GAA expansion. The length of the GAA•TTC repeat expansion lengths inversely correlated with survival in multiple system atrophy patients (r = −0.67; p=0.02), but not with age of onset. Therefore, screening for FGF14 GAA•TTC repeat expansion should be considered for multiple system atrophy patients with rapid loss of mobility and for complete diagnostic accuracy at inclusion in disease-modifying multiple system atrophy drug trials.