Spinal anesthesia in ambulatory patients.

PURPOSE OF THIS REVIEW: To assess current practice in the use of spinal anesthesia in major ambulatory surgery, highlighting its advantages over general anesthesia and identifying potential areas for improvement to facilitate a transition to a sustainable healthcare system. RECENT FINDINGS: Spinal anesthesia might be preferred in selected populations when compared to general anesthesia providing the highest standards of healthcare quality.The use of local anesthetics with short half-life has proven to be efficient in achieving high anesthesia success rates. Spinal anesthesia does not increase perioperative complications; instead, it has shown a reduction in postoperative nausea and vomiting, an improvement in patient comfort, and a favorable economic impact when compared to general anesthesia. SUMMARY: Spinal anesthesia is an appropriate method for anesthesia in ambulatory patients, offering advantages over general anesthesia in selected populations.The use of spinal anesthesia is expanding to meet surgical needs. Therefore, it is crucial to plan ahead and anticipate organizational failures in the ambulatory setting to maintain safety and efficiency during outpatient procedures and surgeries.

Lower muscular strength is associated with greater liver fat content and higher serum liver enzymes-"The Sedentary's Liver" The Study of Health in Pomerania.

We investigated the associations of low handgrip strength (HGS, i.e., a marker of muscular fitness) with liver fat content (LFC) and serum liver enzymes in a population-based setting. We used data from 2700 participants (51.7% women), aged 21-90 years, from two independent cohorts of the population-based Study of Health in Pomerania (SHIP-START-2 and SHIP-TREND-0). Cross-sectional, multivariable adjusted regression models were performed to examine the associations of HGS with LFC, measured by magnetic resonance imaging and serum liver enzymes. We found significant inverse associations of HGS with both LFC and serum liver enzymes. Specifically, a 10-kg lower HGS was associated with a 0.59% (95% confidence interval [CI]: 0.24-0.94; p = 0.001) higher LFC, a 0.051 µkatal/L (95% CI: 0.005-0.097; p = 0.031) higher gamma-glutamyltransferase (GGT) concentration and a 0.010 µkatal/L (95% CI: 0.001-0.020; p = 0.023) higher aspartate aminotransferase (AST) concentration. The adjusted odds-ratio for prevalent hepatic steatosis (defined by a MRI-PDFF ≥5.1%) per 10-kg lower HGS was 1.21 (95% CI: 1.04-1.40; p = 0.014). When considering only obese individuals, those with low HGS had a 1.58% (95% CI: 0.18-2.98; p = 0.027) higher mean LFC and higher chance of prevalent hepatic steatosis (adjusted OR 1.74, 95% CI: 1.15-2.62; p = 0.009) compared to individuals with high HGS. We found similar associations in individuals with overweight, but not in those with normal weight. Lower HGS was strongly associated with both higher LFC and higher serum GGT and AST concentrations. Future studies might clarify whether these findings reflect adverse effects of a sedentary lifestyle or aging on the liver.

Association of Indoleamine 2,3-Dioxygenase (IDO) Activity with Outcome after Cardiac Surgery in Adult Patients.

Indoleamine 2,3-deoxygenase (IDO) plays an important role in the catabolism of the amino acid tryptophan. Tryptophan and its metabolites are key immune modulators. Increased IDO activity has been observed in various diseases and is associated with worse clinical outcomes. However, comprehensive research regarding its role in cardiac surgery remains limited. Therefore, we aimed to investigate perioperative changes in IDO activity and pathway metabolites, along with their impact on clinical outcomes in adult patients undergoing cardiac surgery. As an observational cohort study conducted at the Inselspital in Bern from January to December 2019, we retrospectively analyzed the data of prospectively collected biobank samples of patients undergoing cardiac surgery with the use of cardiopulmonary bypass. IDO pathway metabolite analysis was conducted by mass spectrometry. Perioperative dynamics were descriptively assessed and associated with pre-defined clinical outcome measures (30-day mortality, 1-year mortality, incidence of stroke and myocardial infarction, and length of hospital stay) through a multi-step exploratory regression analysis. A cohort of 192 adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass were included (median age 67.0, IQR 60.0-73.0, 75.5% male). A significant perioperative decrease in the kynurenine/tryptophan (Kyn/Trp) ratio (-2.298, 95% CI -4.028 to -596, p = 0.009) and significant perioperative dynamics in the associated metabolites was observed. No association of perioperative changes in IDO activity and pathway metabolites with clinical outcomes was found. A significant decrease in the Kyn/Trp ratio among adult patients undergoing cardiac surgery indicates a perioperative downregulation of IDO, which stands in contrast to other pro-inflammatory conditions. Further studies are needed to investigate IDO in the setting of perioperative immunomodulation, which is a key driver of postoperative complications in cardiac surgery patients.

TWINGEN: protocol for an observational clinical biobank recall and biomarker cohort study to identify Finnish individuals with high risk of Alzheimer's disease.

INTRODUCTION: A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among THL Biobank donors according to TWINGEN study criteria. METHODS AND ANALYSIS: A multi-centre study (n=800) to obtain blood-based biomarkers, telephone-administered and web-based memory and cognitive parameters, questionnaire information on lifestyle, health and psychological factors, and accelerometer data for measures of physical activity, sedentary behaviour and sleep. A subcohort is being asked to participate in an in-person neuropsychological assessment (n=200) and wear an Oura ring (n=50). All participants in the TWINGEN study have genome-wide genotyping data and up to 48 years of follow-up data from the population-based older Finnish Twin Cohort (FTC) study of the University of Helsinki. The data collected in TWINGEN will be returned to THL Biobank from where it can later be requested for other biobank studies such as FinnGen that supported TWINGEN. ETHICS AND DISSEMINATION: This recall study consists of FTC/THL Biobank/FinnGen participants whose data were acquired in accordance with the Finnish Biobank Act. The recruitment protocols followed the biobank protocols approved by Finnish Medicines Agency. The TWINGEN study plan was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (number 16831/2022). THL Biobank approved the research plan with the permission no: THLBB2022_83.

Adjuvant Analgesics in Acute Pain - Evaluation of Efficacy.

PURPOSE OF THE REVIEW: Acute postoperative pain impacts a significant number of patients and is associated with various complications, such as a higher occurrence of chronic postsurgical pain as well as increased morbidity and mortality. RECENT FINDINGS: Opioids are often used to manage severe pain, but they come with serious adverse effects, such as sedation, respiratory depression, postoperative nausea and vomiting, and impaired bowel function. Therefore, most enhanced recovery after surgery protocols promote multimodal analgesia, which includes adjuvant analgesics, to provide optimal pain control. In this article, we aim to offer a comprehensive review of the contemporary literature on adjuvant analgesics in the management of acute pain, especially in the perioperative setting. Adjuvant analgesics have proven efficacy in treating postoperative pain and reducing need for opioids. While ketamine is an established option for opioid-dependent patients, magnesium and α2-agonists have, in addition to their analgetic effect, the potential to attenuate hemodynamic responses, which make them especially useful in painful laparoscopic procedures. Furthermore, α2-agonists and dexamethasone can extend the analgesic effect of regional anesthesia techniques. However, findings for lidocaine remain inconclusive.

KPC-luciferase-expressing cells elicit an anti-tumor immune response in a mouse model of pancreatic cancer.

Mouse models for the study of pancreatic ductal adenocarcinoma (PDAC) are well-established and representative of many key features observed in human PDAC. To monitor tumor growth, cancer cells that are implanted in mice are often transfected with reporter genes, such as firefly luciferase (Luc), enabling in vivo optical imaging over time. Since Luc can induce an immune response, we aimed to evaluate whether the expression of Luc could affect the growth of KPC tumors in mice by inducing immunogenicity. Although both cell lines, KPC and Luc transduced KPC (KPC-Luc), had the same proliferation rate, KPC-Luc tumors had significantly smaller sizes or were absent 13 days after orthotopic cell implantation, compared to KPC tumors. This coincided with the loss of bioluminescence signal over the tumor region. Immunophenotyping of blood and spleen from KPC-Luc tumor-bearing mice showed a decreased number of macrophages and CD4+ T cells, and an increased accumulation of natural killer (NK) cells in comparison to KPC tumor mice. Higher infiltration of CD8+ T cells was found in KPC-Luc tumors than in their controls. Moreover, the immune response against Luc peptide was stronger in splenocytes from mice implanted with KPC-Luc cells compared to those isolated from KPC wild-type mice, indicating increased immunogenicity elicited by the presence of Luc in the PDAC tumor cells. These results must be considered when evaluating the efficacy of anti-cancer therapies including immunotherapies in immunocompetent PDAC or other cancer mouse models that use Luc as a reporter for bioluminescence imaging.

Intracellular "In Silico Microscopes"-Comprehensive 3D Spatio-Temporal Virus Replication Model Simulations.

Despite their small and simple structure compared with their hosts, virus particles can cause severe harm and even mortality in highly evolved species such as humans. A comprehensive quantitative biophysical understanding of intracellular virus replication mechanisms could aid in preparing for future virus pandemics. By elucidating the relationship between the form and function of intracellular structures from the host cell and viral components, it is possible to identify possible targets for direct antiviral agents and potent vaccines. Biophysical investigations into the spatio-temporal dynamics of intracellular virus replication have thus far been limited. This study introduces a framework to enable simulations of these dynamics using partial differential equation (PDE) models, which are evaluated using advanced numerical mathematical methods on leading supercomputers. In particular, this study presents a model of the replication cycle of a specific RNA virus, the hepatitis C virus. The diffusion-reaction model mimics the interplay of the major components of the viral replication cycle, including non structural viral proteins, viral genomic RNA, and a generic host factor. Technically, surface partial differential equations (sufPDEs) are coupled on the 3D embedded 2D endoplasmic reticulum manifold with partial differential equations (PDEs) in the 3D membranous web and cytosol volume. The membranous web serves as a viral replication factory and is formed on the endoplasmic reticulum after infection and in the presence of nonstructural proteins. The coupled sufPDE/PDE model was evaluated using realistic cell geometries based on experimental data. The simulations incorporate the effects of non structural viral proteins, which are restricted to the endoplasmic reticulum surface, with effects appearing in the volume, such as host factor supply from the cytosol and membranous web dynamics. Because the spatial diffusion properties of genomic viral RNA are not yet fully understood, the model allows for viral RNA movement on the endoplasmic reticulum as well as within the cytosol. Visualizing the simulated intracellular viral replication dynamics provides insights similar to those obtained by microscopy, complementing data from in vitro/in vivo viral replication experiments. The output data demonstrate quantitative consistence with the experimental findings, prompting further advanced experimental studies to validate the model and refine our quantitative biophysical understanding.

Factor analysis of lifetime psychopathology and its brain morphometric and genetic correlates in a transdiagnostic sample.

There is a lack of knowledge regarding the relationship between proneness to dimensional psychopathological syndromes and the underlying pathogenesis across major psychiatric disorders, i.e., Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizoaffective Disorder (SZA), and Schizophrenia (SZ). Lifetime psychopathology was assessed using the OPerational CRITeria (OPCRIT) system in 1,038 patients meeting DSM-IV-TR criteria for MDD, BD, SZ, or SZA. The cohort was split into two samples for exploratory and confirmatory factor analyses. All patients were scanned with 3-T MRI, and data was analyzed with the CAT-12 toolbox in SPM12. Psychopathological factor scores were correlated with gray matter volume (GMV) and cortical thickness (CT). Finally, factor scores were used for exploratory genetic analyses including genome-wide association studies (GWAS) and polygenic risk score (PRS) association analyses. Three factors (paranoid-hallucinatory syndrome, PHS; mania, MA; depression, DEP) were identified and cross-validated. PHS was negatively correlated with four GMV clusters comprising parts of the hippocampus, amygdala, angular, middle occipital, and middle frontal gyri. PHS was also negatively associated with the bilateral superior temporal, left parietal operculum, and right angular gyrus CT. No significant brain correlates were observed for the two other psychopathological factors. We identified genome-wide significant associations for MA and DEP. PRS for MDD and SZ showed a positive effect on PHS, while PRS for BD showed a positive effect on all three factors. This study investigated the relationship of lifetime psychopathological factors and brain morphometric and genetic markers. Results highlight the need for dimensional approaches, overcoming the limitations of the current psychiatric nosology.

Oral curcumin ameliorates acute murine campylobacteriosis.

Introduction: Human infections with the food-borne enteropathogen Campylobacter jejuni are responsible for increasing incidences of acute campylobacteriosis cases worldwide. Since antibiotic treatment is usually not indicated and the severity of the enteritis directly correlates with the risk of developing serious autoimmune disease later-on, novel antibiotics-independent intervention strategies with non-toxic compounds to ameliorate and even prevent campylobacteriosis are utmost wanted. Given its known pleiotropic health-promoting properties, curcumin constitutes such a promising candidate molecule. In our actual preclinical placebo-controlled intervention trial, we tested the anti-microbial and anti-inflammatory effects of oral curcumin pretreatment during acute experimental campylobacteriosis. Methods: Therefore, secondary abiotic IL-10-/- mice were challenged with synthetic curcumin via the drinking water starting a week prior oral C. jejuni infection. To assess anti-pathogenic, clinical, immune-modulatory, and functional effects of curcumin prophylaxis, gastrointestinal C. jejuni bacteria were cultured, clinical signs and colonic histopathological changes quantitated, pro-inflammatory immune cell responses determined by in situ immunohistochemistry and intestinal, extra-intestinal and systemic pro-inflammatory mediator measurements, and finally, intestinal epithelial barrier function tested by electrophysiological resistance analysis of colonic ex vivo biopsies in the Ussing chamber. Results and discussion: Whereas placebo counterparts were suffering from severe enterocolitis characterized by wasting symptoms and bloody diarrhea on day 6 post-infection, curcumin pretreated mice, however, were clinically far less compromised and displayed less severe microscopic inflammatory sequelae such as histopathological changes and epithelial cell apoptosis in the colon. In addition, curcumin pretreatment could mitigate pro-inflammatory innate and adaptive immune responses in the intestinal tract and importantly, rescue colonic epithelial barrier integrity upon C. jejuni infection. Remarkably, the disease-mitigating effects of exogenous curcumin was also observed in organs beyond the infected intestines and strikingly, even systemically given basal hepatic, renal, and serum concentrations of pro-inflammatory mediators measured in curcumin pretreated mice on day 6 post-infection. In conclusion, the anti-Campylobacter and disease-mitigating including anti-inflammatory effects upon oral curcumin application observed here highlight the polyphenolic compound as a promising antibiotics-independent option for the prevention from severe acute campylobacteriosis and its potential post-infectious complications.

Deep Learning Reconstructed New-Generation 0.55 T MRI of the Knee-A Prospective Comparison With Conventional 3 T MRI.

OBJECTIVES: The aim of this study was to compare deep learning reconstructed (DLR) 0.55 T magnetic resonance imaging (MRI) quality, identification, and grading of structural anomalies and reader confidence levels with conventional 3 T knee MRI in patients with knee pain following trauma. MATERIALS AND METHODS: This prospective study of 26 symptomatic patients (5 women) includes 52 paired DLR 0.55 T and conventional 3 T MRI examinations obtained in 1 setting. A novel, commercially available DLR algorithm was employed for 0.55 T image reconstruction. Four board-certified radiologists reviewed all images independently and graded image quality, noted structural anomalies and their respective reporting confidence levels for the presence or absence, as well as grading of bone, cartilage, meniscus, ligament, and tendon lesions. Image quality and reader confidence levels were compared (P < 0.05, significant), and MRI findings were correlated between 0.55 T and 3 T MRI using Cohen kappa (κ). RESULTS: In reader's consensus, good image quality was found for DLR 0.55 T MRI and 3 T MRI (3.8 vs 4.1/5 points, P = 0.06). There was near-perfect agreement between 0.55 T DLR and 3 T MRI regarding the identification of structural anomalies for all readers (each κ ≥ 0.80). Substantial to near-perfection agreement between 0.55 T and 3 T MRI was reported for grading of cartilage (κ = 0.65-0.86) and meniscus lesions (κ = 0.71-1.0). High confidence levels were found for all readers for DLR 0.55 T and 3 T MRI, with 3 readers showing higher confidence levels for reporting cartilage lesions on 3 T MRI. CONCLUSIONS: In conclusion, new-generation 0.55 T DLR MRI provides good image quality, comparable to conventional 3 T MRI, and allows for reliable identification of internal derangement of the knee with high reader confidence.

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Therapeutic effects of oral benzoic acid application during acute murine campylobacteriosis.

Serious risks to human health are posed by acute campylobacteriosis, an enteritis syndrome caused by oral infection with the food-borne bacterial enteropathogen Campylobacter jejuni. Since the risk for developing post-infectious autoimmune complications is intertwined with the severity of enteritis, the search of disease-mitigating compounds is highly demanded. Given that benzoic acid is an organic acid with well-studied health-promoting including anti-inflammatory effects we tested in our present study whether the compound might be a therapeutic option to alleviate acute murine campylobacteriosis. Therefore, microbiota-depleted IL-10-/- mice were perorally infected with C. jejuni and received benzoic acid through the drinking water from day 2 until day 6 post-infection. The results revealed that benzoic acid treatment did not affect C. jejuni colonization in the gastrointestinal tract, but alleviated clinical signs of acute campylobacteriosis, particularly diarrheal and wasting symptoms. In addition, benzoic acid mitigated apoptotic cell responses in the colonic epithelia and led to reduced pro-inflammatory immune reactions in intestinal, extra-intestinal, and systemic compartments tested on day 6 post-infection. Hence, our preclinical placebo-controlled intervention trial revealed that benzoic acid constitutes a promising therapeutic option for treating acute campylobacteriosis in an antibiotic-independent fashion and in consequence, also for reducing the risk of post-infectious autoimmune diseases.

Autoantibodies Targeting Nephrin in Podocytopathies.

BACKGROUND: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).

OrganoIDNet: a deep learning tool for identification of therapeutic effects in PDAC organoid-PBMC co-cultures from time-resolved imaging data.

PURPOSE: Pancreatic Ductal Adenocarcinoma (PDAC) remains a challenging disease due to its complex biology and aggressive behavior with an urgent need for efficient therapeutic strategies. To assess therapy response, pre-clinical PDAC organoid-based models in combination with accurate real-time monitoring are required. METHODS: We established stable live-imaging organoid/peripheral blood mononuclear cells (PBMCs) co-cultures and introduced OrganoIDNet, a deep-learning-based algorithm, capable of analyzing bright-field images of murine and human patient-derived PDAC organoids acquired with live-cell imaging. We investigated the response to the chemotherapy gemcitabine in PDAC organoids and the PD-L1 inhibitor Atezolizumab, cultured with or without HLA-matched PBMCs over time. Results obtained with OrganoIDNet were validated with the endpoint proliferation assay CellTiter-Glo. RESULTS: Live cell imaging in combination with OrganoIDNet accurately detected size-specific drug responses of organoids to gemcitabine over time, showing that large organoids were more prone to cytotoxic effects. This approach also allowed distinguishing between healthy and unhealthy status and measuring eccentricity as organoids' reaction to therapy. Furthermore, imaging of a new organoids/PBMCs sandwich-based co-culture enabled longitudinal analysis of organoid responses to Atezolizumab, showing an increased potency of PBMCs tumor-killing in an organoid-individual manner when Atezolizumab was added. CONCLUSION: Optimized PDAC organoid imaging analyzed by OrganoIDNet represents a platform capable of accurately detecting organoid responses to standard PDAC chemotherapy over time. Moreover, organoid/immune cell co-cultures allow monitoring of organoid responses to immunotherapy, offering dynamic insights into treatment behavior within a co-culture setting with PBMCs. This setup holds promise for real-time assessment of immunotherapeutic effects in individual patient-derived PDAC organoids.

Socioeconomic inequalities in pandemic-induced psychosocial stress in different life domains among the working-age population.

BACKGROUND: Psychosocial stress is considered a risk factor for physical and mental ill-health. Evidence on socioeconomic inequalities with regard to the psychosocial consequences of the COVID-19 pandemic in Germany is still limited. We aimed to investigate how pandemic-induced psychosocial stress (PIPS) in different life domains differed between socioeconomic groups. METHODS: Data came from the German Corona-Monitoring nationwide study - wave 2 (RKI-SOEP-2, November 2021-February 2022). PIPS was assessed using 4-point Likert scales with reference to the following life domains: family, partnership, own financial situation, psychological well-being, leisure activity, social life and work/school situation. Responses were dichotomised into "not stressed/slightly stressed/rather stressed" (0) versus "highly stressed" (1). The sample was restricted to the working-age population in Germany (age = 18-67 years, n = 8,402). Prevalence estimates of high PIPS were calculated by sex, age, education and income. Adjusted prevalence ratios (PRs) were estimated using Poisson regression to investigate the association between education/income and PIPS; high education and income were the reference groups. RESULTS: The highest stress levels were reported in the domains social life and leisure activity. Women and younger participants reported high stress levels more frequently. The highest inequalities were found regarding people's own financial situation, and PIPS was higher in low vs. high income groups (PR 5.54, 95% CI 3.61-8.52). Inequalities were also found regarding partnerships with higher PIPS in low vs. high education groups (PR 1.68, 95% CI 1.13-2.49) - and psychological well-being with higher PIPS in low vs. high income groups (PR 1.52, 95% CI 1.14-2.04). CONCLUSION: Socioeconomic inequalities in PIPS were found for different life domains. Generally, psychosocial support and preventive interventions to help people cope with stress in a pandemic context should be target-group-specific, addressing the particular needs and circumstances of certain socioeconomic groups.

The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression.

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

Initiation of acute pancreatitis in mice is independent of fusion between lysosomes and zymogen granules.

The co-localization of the lysosomal protease cathepsin B (CTSB) and the digestive zymogen trypsinogen is a prerequisite for the initiation of acute pancreatitis. However, the exact molecular mechanisms of co-localization are not fully understood. In this study, we investigated the role of lysosomes in the onset of acute pancreatitis by using two different experimental approaches. Using an acinar cell-specific genetic deletion of the ras-related protein Rab7, important for intracellular vesicle trafficking and fusion, we analyzed the subcellular distribution of lysosomal enzymes and the severity of pancreatitis in vivo and ex vivo. Lysosomal permeabilization was performed by the lysosomotropic agent Glycyl-L-phenylalanine 2-naphthylamide (GPN). Acinar cell-specific deletion of Rab7 increased endogenous CTSB activity and despite the lack of re-distribution of CTSB from lysosomes to the secretory vesicles, the activation of CTSB localized in the zymogen compartment still took place leading to trypsinogen activation and pancreatic injury. Disease severity was comparable to controls during the early phase but more severe at later time points. Similarly, GPN did not prevent CTSB activation inside the secretory compartment upon caerulein stimulation, while lysosomal CTSB shifted to the cytosol. Intracellular trypsinogen activation was maintained leading to acute pancreatitis similar to controls. Our results indicate that initiation of acute pancreatitis seems to be independent of the presence of lysosomes and that fusion of lysosomes and zymogen granules is dispensable for the disease onset. Intact lysosomes rather appear to have protective effects at later disease stages.

Modern Approaches to the Treatment of Acute Facial Pain.

PURPOSE OF REVIEW: Acute facial pain presents a complex challenge in medical practice, requiring a comprehensive and interdisciplinary approach to its management. This narrative review explores the contemporary landscape of treating acute facial pain, delving into pharmacological, non-pharmacological, and advanced interventions. The significance of tailored treatment strategies, rooted in the diverse etiologies of facial pain, such as dental infections, trigeminal neuralgia, temporomandibular joint disorders, sinusitis, or neurological conditions like migraines or cluster headaches, is underscored. We particularly emphasize recent advances in treating trigeminal neuralgia, elucidating current treatment concepts in managing this particular acute facial pain. RECENT FINDINGS: Recent research sheds light on various treatment modalities for acute facial pain. Pharmacotherapy ranges from traditional NSAIDs and analgesics to anticonvulsants and antidepressants. Non-pharmacological interventions, including physical therapy and psychological approaches, play pivotal roles. Advanced interventions, such as nerve blocks and surgical procedures, are considered in cases of treatment resistance. Moreover, we explore innovative technologies like neuromodulation techniques and personalized medicine, offering promising avenues for optimizing treatment outcomes in acute facial pain management. Modern management of acute facial pain requires a nuanced and patient-centric approach. Tailoring treatment strategies to the individual's underlying condition is paramount. While pharmacotherapy remains a cornerstone, the integration of non-pharmacological interventions is essential for comprehensive care. Advanced interventions should be reserved for cases where conservative measures prove inadequate. Furthermore, leveraging innovative technologies and personalized medicine holds promise for enhancing treatment efficacy. Ultimately, a holistic approach that considers the diverse needs of patients is crucial for effectively addressing acute facial pain.