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Prevalence, incidence, and risk of different comorbidity categories in pediatric multiple sclerosis: a systematic review and meta-analysis protocol
Full text linkBACKGROUND/OBJECTIVES: Pediatric-onset multiple sclerosis (POMS), defined as onset before age 18, is increasingly recognized as a distinct entity, often associated with a more burdensome disease course and earlier disability milestones than adult-onset MS. Although comorbidities may significantly affect disease progression and outcomes, their prevalence, incidence, risk, and characteristics in POMS remain poorly understood. To date, no systematic review has comprehensively evaluated comorbidities in POMS. The primary aim is to systematically identify and synthesize available evidence on the prevalence, incidence, risk, and characteristics of these comorbidities in POMS populations, as well as any reported effects on disease course, treatment outcomes, and overall clinical management. METHODS: We will conduct a systematic review and meta-analysis following a hierarchical and pragmatic analytical strategy tailored to the expected heterogeneity and limited evidence base in POMS. MEDLINE (via PubMed) and Embase (produced by Elsevier) will be searched without date restrictions, combining controlled vocabulary terms (MeSH/Emtree) and relevant keywords for POMS and 15 predefined comorbidity categories. Study selection, abstract and full-text screening, and data extraction will be performed independently by two reviewers using predefined criteria and standardized forms. The primary quantitative outcome will be the pooled prevalence of comorbidities. Where study design and reporting permit, incidence rates will be assessed as secondary outcomes, and risk estimates (e.g., odds ratios) will be evaluated only in studies with appropriate comparator groups. Meta-analyses will be conducted using random-effects models when pooling is feasible. Heterogeneity will be assessed using the I2 statistic and Cochran’s Q test, with sensitivity and subgroup analyses performed only when sufficient data are available. When quantitative synthesis is not appropriate due to limited data or substantial heterogeneity, findings will be summarized descriptively. Publication bias will be evaluated using funnel plots and, where applicable, Egger’s and Begg’s tests. This protocol adheres to PRISMA and PRISMA-P guidelines. DISCUSSION: A systematic quantification of comorbidity prevalence, incidence (where available), and risk, together with POMS-specific characteristics and any reported impact on clinical outcomes, is anticipated to provide a crucial evidence base for guiding screening, refining management strategies, and informing future research directions. Ultimately, these findings may improve clinical outcomes and quality of life for children and adolescents with MS
A gut microbiome-kidney-heart axis predictive of future cardiovascular diseases
Full text linkCardiovascular diseases (CVD) remain a major global health challenge. Early markers of disease initiation and progression are urgently needed. We, and others, have previously shown changes in the gut microbiome in association with metabolic and CVD. Here, we demonstrate that gut microbiome-related changes can be detected in association with subclinical variations in heart and kidney function. Markers related to gut microbial metabolism of aromatic amino acids, phenylalanine and tyrosine, associate with circulating pro-atrial natriuretic peptide and estimated glomerular filtration rate in a metabolically healthy European population. Observational and genetic evidence further identify microbiome-related metabolites as mediators of this gut microbiome-kidney axis, with their baseline levels associating with incident CVD in an external Canadian population. Altogether, our work suggests that the gut microbiome interacts with the cardiorenal axis and participates in an interorgan crosstalk affecting host physiology and risk of CVD
Depression and anxiety symptoms in internally migrated women and men after the German unification: Baseline results from the German National Cohort Study (NAKO)
Full text linkBACKGROUND: Internal migration is a special case in Germany, with its history of two formerly divided and re- unified states. In this study, we examined mental health of women and men who migrated internally after the German reunification and compared them with each other and with the non-migrated population in Eastern and Western Germany. METHODS: Baseline data of 161,795 participants (49.9 % women; internal migrants East-West =7160 [4.4 %] and West-East =3966 [2.5 %]) from the population-based German National Cohort were used. Internal migration was measured using information on previous (1988) and current residency. To assess mental health (i. e., current depression and anxiety symptoms), the Depression Module of the Patient Health Questionnaire (PHQ- 9) and the Generalised Anxiety Disorder Symptoms Scale (GAD-7) were applied. Group differences were assessed using analyses of covariance and Tukey’s Tests. Strengths of effects were tested using omega squared. RESULTS: Significant differences in levels of current depression and anxiety symptoms between the four groups were found for both women and men, but effect sizes were extremely small (ω² ≈0.000–0.002). East-West migrants reported slightly lower current depression symptoms (adj. Mwomen =4.00, adj. Mmen =3.17) than West-East migrants (adj. Mwomen =4.48, adj. Mmen =3.69). For East-West migrated men the same was found for anxiety symptoms (adj. M =2.52 versus adj. M =2.96). Mental health of internal migrants was not better compared to their non-migrated counterparts. CONCLUSION: Subgroup analyses revealed group differences to depend on sex, but show negligible effect sizes, with internal migration only explaining less than 0.2 % of the variance for depression and anxiety symptoms. Internal migration alone is thus no substantial factor in explaining mental health differences. Future studies should use longitudinal data to determine temporal associations between internal migration and mental health
Injured epithelial cell states impact kidney allograft survival after T-cell-mediated rejection
Full text linkT-cell-mediated rejection (TCMR) remains a major cause of kidney transplant failure, despite being considered treatable. Its impact reflects a limited understanding of the underlying molecular mechanisms and their clinical consequences. To address this, we induced acute TCMR in mouse kidney transplants and profiled molecular changes using single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics and immunofluorescence. Results were compared with human snRNA-seq data from TCMR and stable allografts, as well as single-cell deconvolution analysis of bulk transcriptomic data from kidney transplant biopsies. Here we show that TCMR induces injured epithelial cell states in mouse kidney allografts, particularly in proximal tubules and thick ascending limbs. Spatial transcriptomics of these injured epithelial states demonstrated heterogeneous localization, interactions with immune cells and cellular microenvironments. Cross-species analysis confirmed similar severely injured epithelial states in human samples, whose abundances correlated with transplant survival and persisted despite TCMR resolution. Collectively, our results identify epithelial injury cell states as a determinant of outcome after TCMR
Distinct roles for MNK1 and MNK2 in social and cognitive behavior through kinase-specific regulation of the synaptic proteome and phosphoproteome
Full text linkLocal mRNA translation is required for adaptive changes in the synaptic proteome. The mitogen-activated protein kinase (MAPK) interacting protein kinases 1 and 2 (MNK1 and MNK2) have emerged as key regulators of neuronal translation, primarily through phosphorylation of the eukaryotic initiation factor 4E (eIF4E). The therapeutic benefits of targeting the MNKs are being investigated for nervous system conditions that affect translation, including autism and pain. However, it is still unclear if MNK1 and MNK2 regulate distinct aspects of neuronal translation and how the activity of each kinase is associated with the synaptic and behavioral features linked to MNK signaling. To examine the individual neurobiological functions of each kinase, we used knockout mice lacking either MNK1 or MNK2. We found that knockout of MNK1 and MNK2 leads to different social and cognitive behavioral profiles and distinct alterations of the cortical synaptic proteome, transcriptome, and phosphoproteome. Loss of MNK1 was associated with increased ribosomal protein expression, whereas deletion of MNK2 decreased the expression and phosphorylation of synaptic proteins. Together, our findings provide evidence for a high degree of functional specialization of the MNKs in synaptic compartments and suggest that pharmacological inhibition of individual MNKs may provide more specific targets for neurological disorders
Effects of contrast medium injection pressure on angiographic image quality
Full text linkRATIONALE AND OBJECTIVES: To evaluate if higher contrast medium injection pressure can improve image quality of digital subtraction angiography (DSA) in liver-directed interventions.
MATERIALS AND METHODS: Prospective single-center study including twelve patients with hepatocellular carcinoma (n = 11) or liver metastases (n = 1) undergoing intra-arterial therapies to systematically compare DSA image quality (primary endpoint) and radiation exposure (secondary endpoint) using two microcatheters with maximum application pressures 750 ("C750") and 1,200 PSI ("C1200"). Patients underwent two DSAs with both microcatheters placed in the common hepatic artery. Application pressure, contrast medium flow, volume, and dose area product were recorded. Image quality was evaluated using a customized questionnaire and quantified by calculating signal- and contrast-to-noise-ratios, and vessel-to-liver signal intensity ratio. Results were compared by paired t-test and Wilcoxon Signed-Rank test.
RESULTS: Image quality using C1200 (achieved 917 ± 94 PSI) was rated more favorably than C750 (731 ± 45 PSI). C1200 reached higher scores of artery visualization in 72% cases, and significantly outperformed C750 regarding tumor blush in 100% (p < 0.001). Contrast-to-noise-ratio were significantly higher in C1200 (p < 0.001) and vessel-to-liver intensity ratios were significantly lower (p = 0.001), both reflecting improved visualization and delineation of liver vessels. Signal-to-noise ratio did not differ significantly. Mean dose area product was comparable (C1200; 371.9 vs. 374.8 μGym(2)).
CONCLUSION: The results suggest benefits of standardized CM injections for DSA using higher application pressure to enhance image contrast and tumor demarcation during IAT
PERK retains a predominantly monomeric state under ER stress conditions
No full textThe unfolded protein response (UPR) is a central adaptive mechanism that safeguards protein homeostasis in the endoplasmic reticulum (ER). In the heart, UPR signaling contributes to cellular remodeling and survival across a range of pathological contexts, including ischemia, pressure overload, and cardiometabolic stress. Among the three canonical UPR branches, the PKR-like ER kinase (PERK) pathway plays a critical role in modulating translational control and redox balance during stress adaptation. Despite its functional importance, the molecular dynamics of PERK activation and assembly remain incompletely understood. Here, we investigate the oligomerization behavior of PERK in living cells using advanced fluorescence microscopy. We identify a concentrationdependent mechanism of PERK self-association, as well as a distinct population of oligomeric PERK whose assembly state remains stable upon ER stress induction. These findings challenge the traditional view of stress-induced oligomerization as a prerequisite for PERK activation and suggest the existence of non-canonical modes of PERK assembly with potential regulatory significance
Microvascular remodeling and endothelial dysfunction across the Post-COVID-19 spectrum: a prospective observational case-control study
Full text linkBACKGROUND: Post-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular risk after acute infection highlights the need for accessible tools to quantify microvascular health. METHODS: All Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (matched from n = 303). Secondary matched analyses included never infected controls (n = 96), recovered individuals (n = 102), PCS patients, and PCS patients fulfilling ME/CFS criteria (n = 62). Laboratory variables, circulating markers of endothelial dysfunction and inflammation were compared between cohorts and their associations with RVA parameters were examined. RESULTS: Compared with healthy controls, PCS patients showed reduced venular flicker-induced dilation (3.7 ± 2.2% vs. 4.5 ± 2.7%, p = 0.005, Cohen´s d: 0.32), narrow retinal arterioles (CRAE, 178.3 ± 15.5 µm vs. 183.3 ± 15.9 µm, p = 0.009, d: 0.32), and lower arteriolar-to-venular ratio (0.83 ± 0.06 vs. 0.86 ± 0.07, p = 0.004, d: 0.35). Findings persisted after adjustment for cardiovascular risk factors and remained evident in an extended secondary matched analysis across never infected, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar flicker-induced dilation (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80). CONCLUSIONS: PCS is associated with persistent endothelial dysfunction, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. These findings support the potential use of RVA as a non-invasive tool for assessing and monitoring endothelial health in post-viral syndromes, with implications for cardiovascular risk stratification. TRIAL REGISTRATION: The All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552)
Heart failure therapy in patients with advanced cancer receiving specialized palliative care (EMPATICC trial)
Full text linkBACKGROUND AND AIMS: Advanced cancer may resemble a heart failure (HF)-like phenotype marked by cardiac wasting, dyspnoea, congestion, and/or physical dysfunction. The trial evaluated safety and efficacy of HF therapy among patients with advanced cancer receiving specialized palliative care to improve patients’ self-care ability. METHODS: Patients with stage 4 solid tumours with a life expectancy of 1–6 months receiving specialized palliative care were enrolled. Patients were required to meet at least two cardiovascular risk criteria and at least one criterion for functional limitation. Participants were randomized 1:1 to receive optimized HF therapy (up to four drugs: sacubitril/valsartan, empagliflozin, ivabradine, ferric carboxymaltose) or placebo in a double-blind setting. The primary hierarchical endpoint included: (i) days alive and able to wash oneself, (ii) ability to walk 4 m, and (iii) self-reported patient global assessment (PGA) of subjective well-being, during the 30-day placebo-controlled phase. RESULTS: In five centres, 93 patients were randomized. The primary endpoint did not differ between groups (win ratio 0.95, 95% confidence interval [CI] 0.57–1.58; P = .83). Overall, mortality was 32% at 30 days (not different between groups). In patients alive at 30 days, HF therapy reduced N-terminal pro-B-type natriuretic peptide levels by 41% (P = .040), increased left ventricular ejection fraction by 2.9% (P = .036), and improved PGA scores (odds ratio 0.22, 95% CI 0.06–0.75; P = .016). CONCLUSIONS: In a population with advanced cancer receiving specialized palliative care and high early mortality, optimized HF therapy did not improve patients’ self-care ability. Among survivors at 30 days, improvements in quality of life measures and cardiac biomarkers suggest potential benefit of individualized HF therapy, which is hypothesis generating and needs validation
Changes in sputum viscoelastic properties and airway inflammation in primary ciliary dyskinesia are comparable to cystic fibrosis on elexacaftor/tezacaftor/ivacaftor therapy
Full text linkBACKGROUND: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are muco-obstructive lung diseases that are caused by distinct genetically determined defects in mucociliary clearance; however, knowledge on the relative severity of airway mucus dysfunction and chronic inflammation remains limited. The aim of this study was therefore to compare sputum viscoelastic properties, inflammation markers and the proteome between patients with PCD and patients with CF before and under elexacaftor/tezacaftor/ivacaftor (ETI) therapy. METHODS: We compared sputum rheology, inflammation markers and the proteome in 42 clinically stable adolescent and adult patients with PCD, 40 patients with CF with at least one F508del allele before (baseline) and 3 months after initiation of ETI, and 15 age-matched healthy controls. RESULTS: The elastic modulus (G′) and viscous modulus (G″) of PCD sputum was increased compared to healthy controls (p<0.001), lower than in CF at baseline (p<0.001) and similar to CF on ETI. Inflammation markers in PCD sputum including neutrophil elastase, free DNA, myeloperoxidase, interleukin (IL)-1β and IL-8 were also increased compared to healthy controls (all p<0.001), lower than in CF at baseline (p<0.05 to p<0.001) and comparable to CF on ETI. Similarly, changes in the sputum proteome were less pronounced in PCD compared to CF at baseline, but comparable between PCD and CF on ETI. CONCLUCIONS: Clinically stable patients with PCD show changes in sputum viscoelastic properties, inflammation markers and the proteome that are less severe than in patients with CF at baseline, but comparable to CF patients on ETI therapy