A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Chasing Red Herrings: Palladium Metal Salt Impurities Feigning KRAS Activity in Biochemical Assays.

Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS "on" remains of great importance to clinical oncology and represents a significant challenge in medicinal chemistry. Here, we describe broadly applicable learnings from a KRAS hit finding campaign: While we initially identified KRAS inhibitors in a biochemical high-throughput screen, we later discovered that compound potencies were all but assay artifacts linked to metal salts interfering with KRAS AlphaScreen assay technology. The source of the apparent biochemical KRAS inhibition was ultimately traced to unavoidable palladium impurities from chemical synthesis. This discovery led to the development of a Metal Ion Interference Set (MIIS) for up-front assay development and testing. Profiling of the MIIS across 74 assays revealed a reduced interference liability of label-free biophysical assays and, as a result, provided general estimates for luminescence- and fluorescence-based assay susceptibility to metal salt interference.

Energy expenditure estimation during activities of daily living in middle-aged and older adults using an accelerometer integrated into a hearing aid.

Background: Accelerometers were traditionally worn on the hip to estimate energy expenditure (EE) during physical activity but are increasingly replaced by products worn on the wrist to enhance wear compliance, despite potential compromises in EE estimation accuracy. In the older population, where the prevalence of hearing loss is higher, a new, integrated option may arise. Thus, this study aimed to investigate the accuracy and precision of EE estimates using an accelerometer integrated into a hearing aid and compare its performance with sensors simultaneously worn on the wrist and hip. Methods: Sixty middle-aged to older adults (average age 64.0 ± 8.0 years, 48% female) participated. They performed a 20-min resting energy expenditure measurement (after overnight fast) followed by a standardized breakfast and 13 different activities of daily living, 12 of them were individually selected from a set of 35 activities, ranging from sedentary and low intensity to more dynamic and physically demanding activities. Using indirect calorimetry as a reference for the metabolic equivalent of task (MET), we compared the EE estimations made using a hearing aid integrated device (Audéo) against those of a research device worn on the hip (ZurichMove) and consumer devices positioned on the wrist (Garmin and Fitbit). Class-estimated and class-known models were used to evaluate the accuracy and precision of EE estimates via Bland-Altman analyses. Results: The findings reveal a mean bias and 95% limit of agreement for Audéo (class-estimated model) of -0.23 ± 3.33 METs, indicating a slight advantage over wrist-worn consumer devices (Garmin: -0.64 ± 3.53 METs and Fitbit: -0.67 ± 3.40 METs). Class-know models reveal a comparable performance between Audéo (-0.21 ± 2.51 METs) and ZurichMove (-0.13 ± 2.49 METs). Sub-analyses show substantial variability in accuracy for different activities and good accuracy when activities are averaged over a typical day's usage of 10 h (+61 ± 302 kcal). Discussion: This study shows the potential of hearing aid-integrated accelerometers in accurately estimating EE across a wide range of activities in the target demographic, while also highlighting the necessity for ongoing optimization efforts considering precision limitations observed across both consumer and research devices.

Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection.

BACKGROUND & AIMS: Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs). METHODS: PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide LPS, and IFN or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP. RESULTS: E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced LPS-mediated tumor necrosis factor production without toll-like receptor 4 tolerance induction. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1ß upon bacterial infection. Proteomic screen in mouse macrophages revealed progranulin as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin-D in a type-I IFN and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP. CONCLUSIONS: Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP. IMPACT AND IMPLICATIONS: Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.

Predictors of short-term anxiety outcome in subthalamic stimulation for Parkinson's disease.

The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Glenoid Concavity Affects Anterior Shoulder Stability in an Active-Assisted Biomechanical Model.

Background: The treatment of bony glenoid defects after anteroinferior shoulder dislocation currently depends on the amount of glenoid bone loss (GBL). Recent studies have described the glenoid concavity as an essential factor for glenohumeral stability. The role of glenoid concavity in the presence of soft tissue and muscle forces is still unknown. Hypothesis: Glenoid concavity would have a major impact on glenohumeral stability in an active-assisted biomechanical model including soft tissue and the rotator cuff's compression forces. Study Design: Controlled laboratory study. Methods: In 8 human shoulder specimens, individual coordinate systems were calculated based on anatomic landmarks. The glenoid concavity was measured biomechanically and based on computed tomography. Static load was applied to the rotator cuff tendons and the deltoid muscle. In a robotic test setup, anteriorly directed force was applied to the humeral head until translation of 5 mm (Nant) was achieved. Nant was used as a parameter indicating shoulder stability. This was performed in the following testing stages: (1) intact joint, (2) labral lesion, (3) 10% GBL, and (4) 20% GBL. The 8 specimens were divided equally into 2 subgroups (low concavity [LC] versus high concavity [HC]), with 4 specimens each, according to the previously measured concavity. Results: Anterior glenohumeral stability was highly correlated with the native glenoid concavity (R 2 = 0.8). In the testing stages 1 to 3, we found a significantly higher mean stability in the HC subgroup compared with the LC subgroup (P≤ .0142). The HC subgroup still showed higher absolute Nant values with 20% GBL; however, there was no significant difference from the LC subgroup. The loss of stability in 20% GBL was correlated with the initial concavity (R 2 = 0.86). Thus, a higher loss of Nant in the HC subgroup was observed (P = .0049). Conclusion: In an active-assisted model with intact soft tissue surrounding and muscular compression forces, the glenoid concavity correlates with shoulder stability. In bony defects, loss of concavity is an essential factor causing instability. Due to their significantly higher native stability, glenoids with HC can tolerate a higher amount of GBL. Clinical Relevance: Glenoid concavity should be considered in an individualized treatment of bony glenoid defects. Further studies are required to establish reference values and develop therapeutic algorithms.

Virtual reality assessment of a high-calorie food bias: Replication and food-specificity in healthy participants.

BACKGROUND: Theoretical models and behavioural studies indicate faster approach behaviour for high-calorie food (approach bias) among healthy participants. A previous study with Virtual Reality (VR) and online motion-capture quantified this approach bias towards food and non-food cues in a controlled VR environment with hand movements. The aim of this study was to test the specificity of a manual approach bias for high-calorie food in grasp movements compared to low-calorie food and neutral objects of different complexity, namely, simple balls and geometrically more complex office tools. METHODS: In a VR setting, healthy participants (N = 27) repeatedly grasped or pushed high-calorie food, low-calorie food, balls and office tools in randomized order with 30 item repetitions. All objects were rated for valence and arousal. RESULTS: High-calorie food was less attractive and more arousing in subjective ratings than low-calorie food and neutral objects. Movement onset was faster for high-calorie food in push-trials, but overall push responses were comparable. In contrast, responses to high-calorie food relative to low-calorie food and to control objects were faster in grasp trials for later stages of interaction (grasp and collect). Non-parametric tests confirmed an approach bias for high-calorie food. CONCLUSION: A behavioural bias for food was specific to high-calorie food objects. The results confirm the presence of bottom-up advantages in motor-cognitive behaviour for high-calorie food in a non-clinical population. More systematic variations of object fidelity and in clinical populations are outstanding. The utility of VR in assessing approach behaviour is confirmed in this study by exploring manual interactions in a controlled environment.

Engineering an inducible leukemia-associated fusion protein enables large-scale ex vivo production of functional human phagocytes.

Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed the capacity of an inducible fusion protein to enable sustained ex vivo proliferation of hematopoietic precursors and their capacity to differentiate into functional phagocytes. We fused the coding sequences of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) fusion gene to generate the fusion protein DD-MLL-ENL and retrovirally expressed the protein switch in human CD34+ progenitors. Using Shield1, a chemical inhibitor of DD fusion protein degradation, we established large-scale and long-term expansion of late monocytic precursors. Upon Shield1 removal, the cells lost self-renewal capacity and spontaneously differentiated, even after 2.5 y of continuous ex vivo expansion. In the absence of Shield1, stimulation with IFN-γ, LPS, and GM-CSF triggered terminal differentiation. Gene expression analysis of the obtained phagocytes revealed marked similarity with naïve monocytes. In functional assays, the novel phagocytes migrated toward CCL2, attached to VCAM-1 under shear stress, produced reactive oxygen species, and engulfed bacterial particles, cellular particles, and apoptotic cells. Finally, we demonstrated Fcγ receptor recognition and phagocytosis of opsonized lymphoma cells in an antibody-dependent manner. Overall, we have established an engineered protein that, as a single factor, is useful for large-scale ex vivo production of human phagocytes. Such adjustable proteins have the potential to be applied as molecular tools to produce functional immune cells for experimental cell-based approaches.

Microstructure predicts non-motor outcomes following deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson's disease (PD). As considerable interindividual variability of outcomes exists, neuroimaging-based biomarkers, including microstructural metrics, have been proposed to anticipate treatment response. In this prospective open-label study, we sought to detect microstructural properties of brain areas associated with short-term non-motor outcomes following STN-DBS. Thirty-seven PD patients underwent diffusion MRI and clinical assessments at preoperative baseline and 6-month follow-up. Whole brain voxel-wise analysis assessed associations between microstructural metrics and non-motor outcomes. Intact microstructure within specific areas, including the right insular cortex, right putamen, right cingulum, and bilateral corticospinal tract were associated with greater postoperative improvement of non-motor symptom burden. Furthermore, microstructural properties of distinct brain regions were associated with postoperative changes in sleep, attention/memory, urinary symptoms, and apathy. In conclusion, diffusion MRI could support preoperative patient counselling by identifying patients with above- or below-average non-motor responses.

Associations between brain morphology, inflammatory markers and symptoms of fatigue, depression or anxiety in active and remitted Crohn's disease.

BACKGROUND: Fatigue and psychosocial impairments are highly prevalent in IBD, especially during active disease. Disturbed brain-gut-interactions may contribute to these symptoms. This study examined associations between brain structure, faecal calprotectin and symptoms of fatigue, depression and anxiety in persons with Crohn's Disease (CD) in different disease states. METHODS: In this prospective observational study, n=109 participants (n=67 persons with CD, n=42 healthy controls) underwent cranial magnetic resonance imaging, provided stool samples for analysis of faecal calprotectin and completed questionnaires to assess symptoms of fatigue, depression and anxiety. We analysed differences in grey matter volume (GMV) between patients and controls and associations between regional GMV alterations, neuropsychiatric symptoms and faecal calprotectin. RESULTS: Symptoms of fatigue, depression and anxiety were increased in patients with CD compared to controls, with highest scores in active CD. Patients exhibited regionally reduced GMV in cortical and subcortical sensorimotor regions, occipitotemporal and medial frontal areas. Regional GMV differences showed a significant negative association with fatigue, but not with depression or anxiety. Subgroup analyses revealed symptom-GMV-associations for fatigue in remitted, but not in active CD, while fatigue was positively associated with faecal calprotectin in active, but not remitted disease. CONCLUSION: Our findings support disturbed brain-gut-interactions in CD which may be particularly relevant for fatigue during remitted disease. Reduced GMV in the precentral gyrus and other sensorimotor areas could reflect key contributions to fatigue pathophysiology in CD. A sensorimotor model of fatigue in CD could also pave the way for novel treatment approaches.

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists.

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1ß, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3ß, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.

Percutaneous transcatheter aspiration of pulmonary embolism leading to diagnosis of hepatocellular carcinoma tumor embolus and change in systemic chemotherapy.

The management of metastatic hepatocellular carcinoma (HCC) is complex, particularly when complicated by pulmonary embolism. In these cases, atezolizumab-bevacizumab therapy is contraindicated due to an elevated risk of thromboembolic events. Differentiating pulmonary tumor embolism from thromboembolic disease is diagnostically challenging. This report outlines the benefit of transcatheter aspiration to obtain pathological evidence of pulmonary artery tumor embolus in an HCC patient. The intervention enabled a significant shift in the management strategy, leading to an escalation of systemic HCC therapy. This case underscores the importance of precise diagnostic techniques such as transcatheter aspiration in guiding treatment decisions, particularly in cases where pulmonary embolism may signify an underlying malignancy-driven process.

Immunohistochemistry as a Reliable Tool for the Diagnosis of Cystic Echinococcosis in Patients from Sardinia, Italy-A Confirmatory Study.

Cystic Echinococcosis (CE) is a zoonotic disease caused by the larval stage of the tapeworm Echinococcus granulosus sensu lato (s.l.). This study aims to investigate the use of two monoclonal antibodies (mAbEmG3 and mAbEm2G11) by immunohistochemistry (IHC) to confirm the diagnosis of CE in human patients, in particular in those cases in which other techniques fail to provide a correct or conclusive diagnosis. For this purpose, a survey on 13 patients was performed. These subjects were referred to Sardinian hospitals (Italy) from 2017 to 2022 and were suspected to be affected by CE. Our findings from these 13 patients showed the detection of E. granulosus sensu stricto by IHC in 12 of 13 echinococcal cysts, as one sample was of a non-parasitological origin. The results confirmed that IHC, by means of the mAbEmG3 and mAbEm2G11, is a reliable diagnostic tool that showed a very high performances when tested on strain of E. granulosus s.l. from Sardinia.

Inhibition of de novo ceramide synthesis by Sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular diseases (CVD). Dysregulated pro-apoptotic ceramide synthesis reduces ß-cell insulin secretion, thereby promoting hyperglycemic states which may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor cardiovascular outcomes. Sirtuin-1 (SIRT1) is a NAD + - dependent deacetylase that protects against pancreatic ß-cell dysfunction; however, systemic levels are decreased in obese T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. METHODS AND RESULTS: Circulating SIRT1 levels were reduced in obese diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4-weeks prevented body weight gain, improved glucose tolerance, insulin sensitivity and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin-secretory function of ß-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in ß-cells thereby decreasing the rate limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among T2D patients, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored ß-cell function (HOMA2- ß) and were more likely to have T2D remission during follow-up. CONCLUSION: Acetylation of TLR4 promotes ß-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate cardiovascular complications of T2D.

Molecular subgroups of T-cell acute lymphoblastic leukemia in adults treated according to pediatric-based GMALL protocols.

In contrast to B-cell precursor acute lymphoblastic leukemia (ALL), molecular subgroups are less well defined in T-lineage ALL. Comprehensive studies on molecular T-ALL subgroups have been predominantly performed in pediatric ALL patients. Currently, molecular characteristics are rarely considered for risk stratification. Herein, we present a homogenously treated cohort of 230 adult T-ALL patients characterized on transcriptome, and partly on DNA methylation and gene mutation level in correlation with clinical outcome. We identified nine molecular subgroups based on aberrant oncogene expression correlating to four distinct DNA methylation patterns. The subgroup distribution differed from reported pediatric T-ALL cohorts with higher frequencies of prognostic unfavorable subgroups like HOXA or LYL1/LMO2. A small subset (3%) of HOXA adult T-ALL patients revealed restricted expression of posterior HOX genes with aberrant activation of lncRNA HOTTIP. With respect to outcome, TLX1 (n = 44) and NKX2-1 (n = 4) had an exceptionally favorable 3-year overall survival (3y-OS) of 94%. Within thymic T-ALL, the non TLX1 patients had an inferior but still good prognosis. To our knowledge this is the largest cohort of adult T-ALL patients characterized by transcriptome sequencing with meaningful clinical follow-up. Risk classification based on molecular subgroups might emerge and contribute to improvements in outcome.

Beyond muscles: Investigating immunoregulatory myokines in acute resistance exercise - A systematic review and meta-analysis.

Myokines, released from the muscle, enable communication between the working muscles and other tissues. Their release during physical exercise is assumed to depend on immune-hormonal-metabolic interactions concerning mode (endurance or resistance exercise), duration, and intensity. This meta-analysis aims to examine the acute changes of circulating myokines inducing immunoregulatory effects caused by a bout of resistance exercise and to consider potential moderators of the results. Based on this selection strategy, a systematic literature search was conducted for resistance exercise intervention studies measuring interleukin (IL-) 6, IL-10, IL-1ra, tumor necrosis factor (TNF-) α, IL-15, IL-7, transforming growth factor (TGF-) ß1, and fractalkines (FKN) before and immediately after resistance exercise in healthy individuals. Random-effects meta-analysis was performed for each myokine. We identified a moderate positive effect of resistance exercise for IL-6 and IL-1ra. Regarding IL-15 and TNF-α, small to moderate effects were found. For IL-10, no significant effect was observed. Due to no data, meta-analyses for IL-7, TGF-ß1, and FKN could not be performed. No moderators (training status, type of exercise, risk of bias, age, sex, time of day, exercise volume, exercise intensity, exercise dose) of the results were detected for all tested myokines. Taken together, this systematic review and meta-analysis showed immediate positive effects of an acute resistance exercise session on IL-6, IL-1ra, TNF-α, and IL-15 levels.

The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives.

Like other infections, a SARS-CoV-2 infection can also trigger Post-Acute Infection Syndromes (PAIS), which often progress into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS, characterized by post-exercise malaise (PEM), is a severe multisystemic disease for which specific diagnostic markers or therapeutic concepts have not been established. Despite numerous indications of post-infectious neurological, immunological, endocrinal, and metabolic deviations, the exact causes and pathophysiology remain unclear. To date, there is a paucity of data, that changes in the composition and function of the gastrointestinal microbiota have emerged as a potential influencing variable associated with immunological and inflammatory pathways, shifts in ME/CFS. It is postulated that this dysbiosis may lead to intestinal barrier dysfunction, translocation of microbial components with increased oxidative stress, and the development or progression of ME/CFS. In this review, we detailed discuss the findings regarding alterations in the gastrointestinal microbiota and its microbial mediators in ME/CFS. When viewed critically, there is currently no evidence indicating causality between changes in the microbiota and the development of ME/CFS. Most studies describe associations within poorly defined patient populations, often combining various clinical presentations, such as irritable bowel syndrome and fatigue associated with ME/CFS. Nevertheless, drawing on analogies with other gastrointestinal diseases, there is potential to develop strategies aimed at modulating the gut microbiota and/or its metabolites as potential treatments for ME/CFS and other PAIS. These strategies should be further investigated in clinical trials.

Soluble urokinase plasminogen activator receptor levels predict survival in patients with portal hypertension undergoing TIPS.

Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identifying ideal candidates remains a challenge. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating marker of immune activation that has previously been associated with liver inflammation, but its prognostic value in patients receiving TIPS is unknown. In the present study, we evaluated the potential clinical relevance of suPAR levels in patients undergoing TIPS insertion. Methods: suPAR concentrations were measured by ELISA in hepatic vein (HV) and portal vein (PV) blood samples from 99 patients (training cohort) as well as peripheral venous blood samples from an additional 150 patients (validation cohort) undergoing TIPS placement. The association between suPAR levels and patient outcomes was assessed using Kaplan-Meier methods and Cox-regression analyses. Results: suPAR concentrations were significantly higher in HV samples compared to PV samples and correlated with PV concentration, the presence of ascites, renal injury, and consequently with the Child-Pugh and MELD scores. Patients with lower suPAR levels had significantly better short- and long-term survival after TIPS insertion, which remained robust after adjustment for confounders in multivariate Cox-regression analyses. Sensitivity analysis showed an improvement in risk prediction in patients stratified by Child-Pugh or MELD scores. In an independent validation cohort, higher levels of suPAR predicted poor transplant-free survival after TIPS, particularly in patients with Child-Pugh A/B cirrhosis. Conclusion: suPAR is largely derived from the injured liver and its levels are predictive of outcome in patients undergoing TIPS. suPAR, as a surrogate of hepatic inflammation, may be used to stratify care in patients following TIPS insertion. Impact and implications: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identification of the ideal candidates remains challenging. We show that soluble urokinase plasminogen activator receptor (suPAR), a circulating marker of immune activation that can easily be measured in routine clinical practice, is a novel marker to identify patients who will benefit from TIPS and those who will not.

Imaging of the brain-heart axis: prognostic value in a European setting.

BACKGROUND AND AIMS: Increasing data suggest that stress-related neural activity (SNA) is associated with subsequent major adverse cardiovascular events (MACE) and may represent a therapeutic target. Current evidence is exclusively based on populations from the U.S. and Asia where limited information about cardiovascular disease risk was available. This study sought to investigate whether SNA imaging has clinical value in a well-characterized cohort of cardiovascular patients in Europe. METHODS: In this single-centre study, a total of 963 patients (mean age 58.4 ± 16.1 years, 40.7% female) with known cardiovascular status, ranging from 'at-risk' to manifest disease, and without active cancer underwent 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography between 1 January 2005 and 31 August 2019. Stress-related neural activity was assessed with validated methods and relations between SNA and MACE (non-fatal stroke, non-fatal myocardial infarction, coronary revascularization, and cardiovascular death) or all-cause mortality by time-to-event analysis. RESULTS: Over a maximum follow-up of 17 years, 118 individuals (12.3%) experienced MACE, and 270 (28.0%) died. In univariate analyses, SNA significantly correlated with an increased risk of MACE (sub-distribution hazard ratio 1.52, 95% CI 1.05-2.19; P = .026) or death (hazard ratio 2.49, 95% CI 1.96-3.17; P < .001). In multivariable analyses, the association between SNA imaging and MACE was lost when details of the cardiovascular status were added to the models. Conversely, the relationship between SNA imaging and all-cause mortality persisted after multivariable adjustments. CONCLUSIONS: In a European patient cohort where cardiovascular status is known, SNA imaging is a robust and independent predictor of all-cause mortality, but its prognostic value for MACE is less evident. Further studies should define specific patient populations that might profit from SNA imaging.

Structured feedback and operative video debriefing with critical view of safety annotation in training of laparoscopic cholecystectomy: a randomized controlled study.

BACKGROUND: The learning curve in minimally invasive surgery (MIS) is lengthened compared to open surgery. It has been reported that structured feedback and training in teams of two trainees improves MIS training and MIS performance. Annotation of surgical images and videos may prove beneficial for surgical training. This study investigated whether structured feedback and video debriefing, including annotation of critical view of safety (CVS), have beneficial learning effects in a predefined, multi-modal MIS training curriculum in teams of two trainees. METHODS: This randomized-controlled single-center study included medical students without MIS experience (n = 80). The participants first completed a standardized and structured multi-modal MIS training curriculum. They were then randomly divided into two groups (n = 40 each), and four laparoscopic cholecystectomies (LCs) were performed on ex-vivo porcine livers each. Students in the intervention group received structured feedback after each LC, consisting of LC performance evaluations through tutor-trainee joint video debriefing and CVS video annotation. Performance was evaluated using global and LC-specific Objective Structured Assessments of Technical Skills (OSATS) and Global Operative Assessment of Laparoscopic Skills (GOALS) scores. RESULTS: The participants in the intervention group had higher global and LC-specific OSATS as well as global and LC-specific GOALS scores than the participants in the control group (25.5 ± 7.3 vs. 23.4 ± 5.1, p = 0.003; 47.6 ± 12.9 vs. 36 ± 12.8, p < 0.001; 17.5 ± 4.4 vs. 16 ± 3.8, p < 0.001; 6.6 ± 2.3 vs. 5.9 ± 2.1, p = 0.005). The intervention group achieved CVS more often than the control group (1. LC: 20 vs. 10 participants, p = 0.037, 2. LC: 24 vs. 8, p = 0.001, 3. LC: 31 vs. 8, p < 0.001, 4. LC: 31 vs. 10, p < 0.001). CONCLUSIONS: Structured feedback and video debriefing with CVS annotation improves CVS achievement and ex-vivo porcine LC training performance based on OSATS and GOALS scores.