Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance.

Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p < 5 × 10-8) and showed consistent results among all three populations. In 10 genomic regions, strong promoter, enhancer and regulatory element-related histone marks and their connections to target genes as well as genome segmentation data supported the importance of these regions in MGUS susceptibility. Several associated haplotypes affected pathways important for MM cell survival such as ubiquitin-proteasome system (RNF186, OTUD3), PI3K/AKT/mTOR (HINT3), innate immunity (SEC14L1, ZBP1), cell death regulation (BID) and NOTCH signaling (RBPJ). These pathways are important current therapeutic targets for MM, which may highlight the advantage of the haplotype approach homing to functional units.

Association between caseload volume and outcomes in left ventricular assist device implantations - a EUROMACS analysis.

AIMS: This EUROMACS study was conducted with the primary aim of investigating the association between a centre's annual caseload and postoperative outcomes among patients undergoing left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: A total of 4802 patients identified between 2011 and 2020 from 35 participating centres were dichotomized based on the annual caseload of the treating centre at the time of device implant (≤30 vs. >30 LVAD implantations/year). The primary endpoint was 1-year survival. Secondary outcomes included overall survival analysis, device-related adverse events and readmissions. Cumulative follow-up was 10 003 patient-years, with a median follow-up of 1.54 years (interquartile range 0.52-3.15). Patients from higher volume centres more frequently presented in INTERMACS levels 1 and 2, suffered from right heart dysfunction and needed inotropic support. No difference was observed in adjusted 1-year survival. Adjusted overall survival probability was lower in higher volume centres (p = 0.002). In the subgroup analysis of HeartMate 3 devices only, higher volume centres were associated with decreased odds of 1-year survival (adjusted odds ratio 0.43, 95% confidence interval 0.20-0.97, p = 0.041). Similar findings were observed in the cumulative (i.e. learning curve) caseload analyses. CONCLUSION: In patients undergoing LVAD implantation, centre volume was not associated with 1-year survival, but was related to device-related adverse events. Patient profiles differed with respect to centre size. These findings underscore the necessity for ongoing quality improvement initiatives in all centres, regardless of their annual caseload. Efforts are needed to standardize patient selection and preconditioning to further improve patient outcome.

Polygenic risk scores for nicotine use and family history of smoking are associated with smoking behaviour.

INTRODUCTION: Formal genetics studies show that smoking is influenced by genetic factors; exploring this on the molecular level can offer deeper insight into the etiology of smoking behaviours. METHODS: Summary statistics from the latest wave of the GWAS and Sequencing Consortium of Alcohol and Nicotine (GSCAN) were used to calculate polygenic risk scores (PRS) in a sample of ~2200 individuals who smoke/individuals who never smoked. The associations of smoking status with PRS for Smoking Initiation (i.e., Lifetime Smoking; SI-PRS), and Fagerström Test for Nicotine Dependence (FTND) score with PRS for Cigarettes per Day (CpD-PRS) were examined, as were distinct/additive effects of parental smoking on smoking status. RESULTS: SI-PRS explained 10.56% of variance (Nagelkerke-R2) in smoking status (p=6.45x10-30). In individuals who smoke, CpD-PRS was associated with FTND score (R2=5.03%, p=1.88x10-12). Parental smoking alone explained R2=3.06% (p=2.43×10-12) of smoking status, and 0.96% when added to the most informative SI-PRS model (total R²=11.52%). CONCLUSION: These results show the potential utility of molecular genetic data for research investigating smoking prevention. The fact that PRS explains more variance than family history highlights progress from formal to molecular genetics; the partial overlap and increased predictive value when using both suggests the importance of combining these approaches.

Amino acid metabolism in kidney health and disease.

Amino acids form peptides and proteins and are therefore considered the main building blocks of life. The kidney has an important but under-appreciated role in the synthesis, degradation, filtration, reabsorption and excretion of amino acids, acting to retain useful metabolites while excreting potentially harmful and waste products from amino acid metabolism. A complex network of kidney transporters and enzymes guides these processes and moderates the competing concentrations of various metabolites and amino acid products. Kidney amino acid metabolism contributes to gluconeogenesis, nitrogen clearance, acid-base metabolism and provision of fuel for tricarboxylic acid cycle and urea cycle intermediates, and is thus a central hub for homeostasis. Conversely, kidney disease affects the levels and metabolism of a variety of amino acids. Here, we review the metabolic role of the kidney in amino acid metabolism and describe how different diseases of the kidney lead to aberrations in amino acid metabolism. Improved understanding of the metabolic and communication routes that are affected by disease could provide new mechanistic insights into the pathogenesis of kidney diseases and potentially enable targeted dietary or pharmacological interventions.

Densities, Viscosities, and Self-Diffusion Coefficients of Octan-1-ol and Related Ether-Alcohols.

Density, viscosity, and self-diffusion coefficients are reported for octan-1-ol and the related ether-alcohols 2-pentoxy-ethan-1-ol, 3-butoxypropan-1-ol, 4-propoxybutan-1-ol, 5-ethoxypentan-1-ol, and 6-methoxyhexan-1-ol covering temperature ranges from 298.15 to 359.15 K. These new data reveal structure-property relationships affected by the presence and the position of the ether moiety in the molecular structure of the ether-alcohols. Compared to octan-1-ol, the presence of the ether moiety causes an increase in intermolecular hydrogen bonding interactions, resulting in higher densities. The increase in density is less pronounced for those ether-octanols that engage in intramolecular hydrogen bonding. As for the effects of the ether moiety on the dynamics, these are generally faster for the ether-alcohols compared to octan-1-ol, suggesting that hydrogen bonding between ether oxygen and hydroxy hydrogen is weaker compared to hydrogen bonding between two hydroxy groups. The activation energies obtained from an Arrhenius analysis are higher for translational motion than for momentum transfer for all alcohols. There are additional finer details across the ether alcohols for these activation barriers. These differences cancel out for the mathematical product of self-diffusion coefficient and viscosity (Dη). The effect of water impurities on the studied properties was also investigated and found to lead to small increases in densities for all alcohols. Viscosities decrease for octan-1-ol and 2-pentoxyethan-1-ol but increase for the other ether-alcohols that can engage in intramolecular hydrogen bonding.

Association of Preoperative Copeptin Levels with Risk of All-Cause Mortality in a Prospective Cohort of Adult Cardiac Surgery Patients.

We aimed to investigate the association of preoperative copeptin, a new cardiovascular biomarker, with short- and long-term mortality in a cohort of adult patients undergoing cardiac surgery, including its potential as a prognostic marker for clinical outcome. Preoperative blood samples of the Bern Perioperative Biobank, a prospective cohort of adults undergoing cardiac surgery during 2019, were analyzed. The primary and secondary outcome measures were 30-day and 1-year all-cause mortality. Optimal copeptin thresholds were calculated with the Youden Index. Associations of copeptin levels with the two outcomes were examined with multivariable logistic regression models; their discriminatory capacity was assessed with the area under the receiver operating characteristic (AUROC). A total of 519 patients (78.4% male, median age 67 y (IQR: 60-73 y)) were included, with a median preoperative copeptin level of 7.6 pmol/L (IQR: 4.7-13.2 pmol/L). We identified an optimal threshold of 15.9 pmol/l (95%-CI: 7.7 to 46.5 pmol/L) for 30-day mortality and 15.9 pmol/L (95%-CI: 9.0 to 21.3 pmol/L) for 1-year all-cause mortality. Regression models featured an AUROC of 0.79 (95%-CI: 0.56 to 0.95) for adjusted log-transformed preoperative copeptin for 30-day mortality and an AUROC of 0.76 (95%-CI: 0.64 to 0.88) for 1-year mortality. In patients undergoing cardiac surgery, the baseline levels of copeptin emerged as a strong marker for 1-year all-cause death. Preoperative copeptin levels might possibly identify patients at risk for a complicated, long-term postoperative course, and therefore requiring a more rigorous postoperative observation and follow-up.

Treatment of anastomotic leak in colorectal surgery by endoluminal vacuum therapy with the VACStent avoiding a stoma - a pilot study.

PURPOSE: Anastomotic leak (AL) represents the most relevant and devastating complication in colorectal surgery. Endoscopic vacuum therapy (EVT) using the VACStent is regarded as a significant improvement in the treatment of upper gastrointestinal wall defects. The innovative concept of the VACStent was transferred to the lower GI tract, gaining initial experience by investigating safety and efficacy in 12 patients undergoing colorectal resections. METHODS: The pilot study, as part of a German registry, began with 2 patients suffering from AL, who were treated with the VACStent after stoma placement. Subsequently, 6 patients with AL were treated with the VACStent omitting a stoma placement, with a focus on fecal passage and wound healing. Finally, the preemptive anastomotic coverage was investigated in 4 patients with high-risk anastomoses to avoid prophylactic stoma placement. RESULTS: In total 26 VACStents were placed without problems. The conditioning and drainage function were maintained, and no clogging problems of the sponge cylinder were observed. No relevant clinical VACStent-associated complications were observed; however, in 2 patients, a dislodgement of a VACStent occurred. The 6 patients with AL but without stoma had a median treatment with 3 VACStents per case with a laytime of 17 days, leading to complete wound healing in all cases. The 4 prophylactic VACStent applications were without complications. CONCLUSION: The clinical application of the VACStent in the lower GI tract shows that successful treatment of anastomotic colonic leaks and avoidance of creation of an anus praeter is possible. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT04884334, date of registration 2021-05-04, retrospectively registered.

Characteristics and outcomes of men with erectile dysfunction as the presenting symptom due to a lactotroph adenoma.

PURPOSE: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. METHODS: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. RESULTS: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0-1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. CONCLUSIONS: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships.

VacStent as an Innovative Approach in the Treatment of Anastomotic Insufficiencies and Leakages in the Gastrointestinal Tract-Review and Outlook.

Anastomotic insufficiencies are severe complications of abdominal surgery, often leading to prolonged hospitalization, serious tissue inflammation, and even sepsis, along with the need for recurrent surgery. Current non-surgical treatments such as self-expanding metal stents (SEMSs) and endoscopic vacuum therapy (EVT) have limitations, including stent migration or perforation. This review evaluates the effectiveness of the VacStent GITM (Möller Medical GmbH, Fulda, Germany), a novel medical device combining SEMS and negative-pressure wound therapy in treating gastrointestinal leaks. Data were gathered from four prospective studies and compared with existing treatments. Studies on the VacStent GITM application demonstrate technical success and competitive closure rates in upper gastrointestinal leaks, with minimal complications reported. Comparative analyses with SEMS and EVT reveal promising and most importantly equally good outcomes while maintaining the possibility for sustained enteral nutrition and reducing the risk of stent migration. The VacStent GITM presents a promising alternative to current non-surgical treatments. Ongoing research aims to validate its efficacy in lower gastrointestinal leaks and comprehensively establish its role in leak management. Further investigation is necessary to confirm these findings and optimize treatment protocols. Future usages of the VacStent GITM in colonic anastomotic insufficiencies promise an effective approach and might be able to lower the rates of necessary implementations of a stoma.

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.

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.

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.

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.

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.

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.

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.

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.