Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study.

BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C.

BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored. METHODS: We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. RESULTS: Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. CONCLUSION: Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.

Association between endocrine and neuropsychological endophenotypes and gambling disorder severity.

BACKGROUND: Neurobiological characteristics have been identified regarding the severity of gambling disorder (GD). The aims of this study were: (1) to examine, through a path analysis, whether there was a relationship between neuroendocrine features, potentially mediational GD variables, and GD severity, and (2) to associate neuroendocrine variables, with GD severity-related variables according to gambling preferences. METHODS: The sample included 297 outpatients with GD. We analyzed endocrine concentrations of different appetite-related hormones (ghrelin, liver antimicrobial peptide 2 [LEAP-2], leptin, adiponectin), and neuropsychological performance (working memory, cognitive flexibility, inhibition, decision making, premorbid intelligence). Path analysis assessed mechanisms between neuroendocrine features and GD severity, including mediational GD variables (impulsivity traits and gambling-related cognitive distortions). Partial correlations evaluated the associations between neuroendocrine variables, including impulsivity traits, and variables related to GD severity (DSM-5, South Oaks Gambling Screen, illness duration, and gambling-related cognitive distortions). RESULTS: Lower adiponectin concentrations predicted greater GD severity, while higher LEAP-2 concentrations predicted more gambling-related cognitive distortions. Likewise, better neuropsychological performance directly predicted GD severity, but worse neuropsychological performance was associated with GD severity through the mediational variables of impulsivity traits and gambling-related cognitive distortions. Also, in non-strategic individuals with GD, poor working memory was associated with gambling expectancies and predictive control. In strategic individuals with GD, poor cognitive flexibility was associated with illusion of control, predictive control, and inability to stop gambling. CONCLUSIONS: These results provide updated information about the comprehension of the interaction between neuroendocrine features, clinical variables, and severity of GD. Thus, neurobiological functions seem to be strongly related to GD severity.

Eating disorders and obesity: bridging clinical, neurobiological, and therapeutic perspectives.

Eating disorders (EDs) and obesity are complex health conditions sharing various risk and maintenance factors, intensified in cases of comorbidity. This review explores the similarities and connections between these conditions, examining different facets from a multidisciplinary perspective, among them comorbidities, metabolic and psychological factors, neurobiological aspects, and management and therapy implications. We aim to investigate the common characteristics and complexities of weight and EDs and explore their interrelationships in individuals who experience both. The rising prevalence of EDs in people with obesity necessitates integrated approaches to study this comorbidity and to identify and analyze both common and distinct features of these conditions. This review may offer new opportunities for simultaneous prevention and management approaches, as well as future lines of research.

Peritoneal carcinomatosis in mouse models.

Peritoneal carcinomatosis (PCa) represents a metastatic stage of a disease with unmet therapeutic options. Malignant cells from primary tumors (gastrointestinal or gynecologic malignancies) invade the peritoneal cavity and eventually seed onto peritoneal surfaces, with the omentum being the most common nest area. With a median survival of less than 6 months, PCa has a dismal prognosis that can be improved with treatments only available to a select few individuals with low tumor burden. Thus, the discovery of novel and effective therapies for this disease depends on reliable animal models. Here, we describe a method to generate syngeneic PCa mouse models based on intraperitoneal (i.p.) administration of tumor cells. This model allows to follow-up cancer progression in PCa models from ovarian and colorectal origins monitoring mice bodyweight changes, ascites development and overall survival. Moreover, luciferase-expressing tumor cells can also be used to assess tumor growth after i.p. injection through in vivo bioluminescence quantification. The establishment of reliable, easy-to-monitor and reproducible intraperitoneal syngeneic tumors models, as described here, is the first step to develop cutting-edge therapies against PCa.

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

The association of glucose metabolism measures and diabetes status with Alzheimer's disease biomarkers of amyloid and tau: A systematic review and meta-analysis.

Conflicting evidence exists on the relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) biomarkers. Therefore, we conducted a random-effects meta-analysis to evaluate the correlation of glucose metabolism measures (glycated hemoglobin, fasting blood glucose, insulin resistance indices) and DM status with AD biomarkers of amyloid-ß and tau measured by positron emission tomography or cerebrospinal fluid. We selected 37 studies from PubMed and Embase, including 11,694 individuals. More impaired glucose metabolism and DM status were associated with higher tau biomarkers (r=0.11[0.03-0.18], p=0.008; I2=68%), but were not associated with amyloid-ß biomarkers (r=-0.06[-0.13-0.01], p=0.08; I2=81%). Meta-regression revealed that glucose metabolism and DM were specifically associated with tau biomarkers in population settings (p=0.001). Furthermore, more impaired glucose metabolism and DM status were associated with lower amyloid-ß biomarkers in memory clinic settings (p=0.004), and in studies with a higher prevalence of dementia (p<0.001) or lower cognitive scores (p=0.04). These findings indicate that DM is associated with biomarkers of tau but not with amyloid-ß. This knowledge is valuable for improving dementia and DM diagnostics and treatment.

Microfracture-coagulation for the real robotic liver parenchymal transection.

The use of the robotic approach in liver surgery is exponentially increasing. Although technically the robot introduces several innovative features, the instruments linked with the traditional laparoscopic approach for the liver parenchymal transection are not available, which may result in multiple technical variants that may bias the comparative analysis between the different series worldwide. A real robotic approach, minimally efficient for the liver parenchymal transection, with no requirement of external tool, available for the already existing platforms, and applicable to any type of liver resection, counting on the selective use of the plugged bipolar forceps and the monopolar scissors, or "microfracture-coagulation" (MFC) transection method, is described in detail. The relevant aspects of the technique, its indications and methodological basis are discussed.

Probiotic and prebiotic interventions in eating disorders: A narrative review.

AIMS: The review aimed to summarise and discuss findings focused on therapeutic probiotic and prebiotic interventions in eating disorders (ED). METHODS: Using PubMed/MEDLINE, Cochrane Library, and Web of Science all published studies were retrieved until February 2023, following PRISMA guidelines. From the 111 initial studies, 5 met the inclusion criteria for this review. RESULTS: All studies included in this narrative review were focused on anorexia nervosa (AN). Three longitudinal, randomised, controlled trials aimed to evaluate interventions with probiotics (Lactobacillus reuteri, yoghurt with Lactobacillus, and Streptococcus) in children and adolescents. These studies primarily emphasised medical outcomes and anthropometric measures following the administration of probiotics. However, the findings yielded mixed results in terms of short-term weight gain or alterations in specific immunological parameters. With a lower level of evidence, supplementation with synbiotics (probiotic + prebiotic) has been associated with improvements in microbiota diversity and attenuation of inflammatory responses. CONCLUSIONS: Research on probiotics and prebiotics in ED is limited, primarily focussing on anorexia nervosa (AN). Their use in AN regarding medical and anthropometric outcomes needs further confirmation and future research should be warranted to assess their impact on psychological and ED symptomatology, where there is a notable gap in the existing literature.

Do risk factors differentiate DSM-5 and drive for thinness severity groups for anorexia nervosa?

BACKGROUND: The current study examined whether risk factors for anorexia nervosa (AN) were related to different levels of severity based on (a) the DSM-5/body mass index (BMI) and (b) drive for thinness (DT) severity ratings. METHODS: The sample comprised 153 pairs of individuals with a lifetime diagnosis AN per DSM-IV criteria and their non-ED sisters (N = 306, mean age = 26.53; mean current BMI = 20.42 kg/m2). The Oxford risk factor interview was used to establish AN-related risk factors. Individuals were categorised into the DSM-5 severity groups based on their lowest BMI, while the DT subscale from the eating disorder inventory-2 was used to classify individuals with AN into low and high DT groups. RESULTS: Multinominal regression models showed similar risk factors (e.g., perfectionism, having a history of being teased about weight and shape) contributed to the development of AN using the DSM-5 and DT severity ratings. Follow-up analyses across the severity groups for both indices revealed that only childhood perfectionism was found to be more common in the extreme severe DSM-5 BMI severity group compared to the severe DSM-5 group. CONCLUSION: Overall, this study found little evidence for AN risk factors being related to the DSM-5 and DT severity ratings. However, given the novelty of this study, replication of the current results is warranted.

Several risk factors, such as childhood obesity, have been found to contribute to the development of Anorexia Nervosa (AN). Yet, we are unsure if there is a set of risk factors that influence different levels of AN severity. While the DSM-5 suggests using BMI to measure severity, recent support favour the usage of drive for thinness (DT) as an alternative severity measure. Therefore, this study aimed to explore risk factors specifically associated with the development of different AN severity levels using both the DSM-5 BMI and DT severity classification systems. We recruited 153 pairs of individuals with a lifetime diagnosis AN per DSM-IV criteria and their non-ED sisters. The Oxford risk factor interview was used to establish AN-related risk factors. We found childhood perfectionism, weight/shape teasing, childhood obesity, and breast-related embarrassment to be significant risk factors for AN. Additionally, childhood perfectionism was more common in the extreme severe DSM-5 group compared to the severe DSM-5 group. This suggests that adding perfectionism-related aspects to prevention and early intervention programs for AN may be beneficial. Considering the novelty of this study, replication of the current results is needed.

Microbial Phenolic Metabolites Are Associated with Improved Cognitive Health.

SCOPE: Diets rich in polyphenols has been associated with better cognitive performance. The aim of this study is to assess the relationship between microbial phenolic metabolites (MPM) in urine and cognition in the context of an older population at high cardiovascular risk. METHODS AND RESULTS: A cross-sectional analysis is conducted in 400 individuals of the PREDIMED-Plus study. Liquid chromatography coupled to mass spectrometry is used to identify urinary MPM. Mediterranean diet (MedDiet) adherence is estimated with a 17-item questionnaire and cognitive function is evaluated with a battery of neuropsychological tests. Multivariable-adjusted linear regression models are fitted to assess the relationship of urinary MPM with the MedDiet and cognitive tests. Protocatechuic acid and enterolactone glucuronide are associated with higher adherence to the MedDiet. Regarding cognitive function, protocatechuic acid, vanillic acid glucuronide, 3-hydroxybenzoic acid, enterodiol glucuronide, and enterolactone glucuronide are directly associated with a global composite score of all the cognitive tests. Furthermore, protocatechuic acid and enterolactone glucuronide are associated with higher scores in the Mini-Mental State Examination, whereas enterodiol glucuronide is associated with improved Clock Drawing Test scores. CONCLUSIONS: These results suggest that the MedDiet is linked to MPM associated with better cognitive performance in an older population.

Spanish Validation of the Long and Short Versions of the Problematic Pornography Consumption Scale (PPCS and PPCS-6) in Adolescents.

Although 1-14% of adolescents may experience problematic pornography use (PPU), psychometrically sound instruments for assessing PPU in Spanish-speaking adolescents are scarce. Given the advantages of the different forms of the Problematic Pornography Consumption Scale (PPCS), the aim of the present study was to assess the psychometric properties of the PPCS and PPCS-6, and to examine associations between PPU and age among boys and girls. Two school-based adolescent samples were recruited in Spain (n = 650; Mage = 16.0 [SD = 1.1]; 50% girls and 50% boys) and Mexico (n1, 160; Mage = 15.8 [SD = 1.1]; 68% girls) to assess the psychometric properties of the PPCS and PPCS-6. Confirmatory factor analysis was applied and convergent and discriminant validity with other measures related to PPU was also tested. The results provided empirical support for the six-factor structure of the PPCS and the one-factor structure of the PPCS-6. Boys with older age showed higher levels of tolerance than girls on the PPCS in both countries. Both the PPCS and the PPCS-6 may be considered valid psychometric instruments for the assessment of PPU in Spanish-speaking adolescents from Spain and Mexico.

How to assess eating disorder severity in males?The DSM-5 severity index versus severity based on drive for thinness.

Using a male eating disorder (ED) sample, this study assessed the clinical utility of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) severity indices for males with anorexia nervosa (AN) and bulimia nervosa (BN) and compared it to an alternative transdiagnostic severity categorisation based on drive for thinness (DT). The participants included 143 males with an ED (60 [42.0%] AN and 83 [58.0%] BN) diagnosis, who were classified using these two severity classifications. The different severity categories were then compared based on ED symptoms, general psychopathology, and personality traits. Our results revealed that the DSM-5 "mild" and DT "low" severity categories were most prevalent in the AN and BN male patients. Clinically significant findings were strongest for the DT categorisation for both AN and BN. The current findings provide initial support for an alternative transdiagnostic DT severity classification for males that may be more clinically meaningful than the DSM-5 severity indices.

Coronavirus disease 2019 is associated with long-term depressive symptoms in Spanish older adults with overweight/obesity and metabolic syndrome.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has serious physiological and psychological consequences. The long-term (>12 weeks post-infection) impact of COVID-19 on mental health, specifically in older adults, is unclear. We longitudinally assessed the association of COVID-19 with depression symptomatology in community-dwelling older adults with metabolic syndrome within the framework of the PREDIMED-Plus cohort. METHODS: Participants (n = 5486) aged 55-75 years were included in this longitudinal cohort. COVID-19 status (positive/negative) determined by tests (e.g. polymerase chain reaction severe acute respiratory syndrome coronavirus 2, IgG) was confirmed via event adjudication (410 cases). Pre- and post-COVID-19 depressive symptomatology was ascertained from annual assessments conducted using a validated 21-item Spanish Beck Depression Inventory-II (BDI-II). Multivariable linear and logistic regression models assessed the association between COVID-19 and depression symptomatology. RESULTS: COVID-19 in older adults was associated with higher post-COVID-19 BDI-II scores measured at a median (interquartile range) of 29 (15-40) weeks post-infection [fully adjusted ß = 0.65 points, 95% confidence interval (CI) 0.15-1.15; p = 0.011]. This association was particularly prominent in women (ß = 1.38 points, 95% CI 0.44-2.33, p = 0.004). COVID-19 was associated with 62% increased odds of elevated depression risk (BDI-II ≥ 14) post-COVID-19 when adjusted for confounders (odds ratio; 95% CI 1.13-2.30, p = 0.008). CONCLUSIONS: COVID-19 was associated with long-term depression risk in older adults with overweight/obesity and metabolic syndrome, particularly in women. Thus, long-term evaluations of the impact of COVID-19 on mental health and preventive public health initiatives are warranted in older adults.

[Medical complications in anorexia and bulimia nervosa]. / Complicaciones médicas en anorexia y bulimia nerviosa.

Anorexia nervosa and bulimia nervosa are eating disorders associated with life-threatening multisystemic medical complications. This narrative review aimed to present the medical complications most related to these disorders. In anorexia nervosa, many of them are linked to malnutrition and underweight, usually reversible with renutrition and weight restoration, although refeeding can also be linked to some medical complications. Purging behaviors observed in the anorexia nervosa binge-purging subtype and bulimia nervosa have been mainly related to hydrolectrolyte and acid-base disturbances, in addition to local complications. Thus, an early identification and therapeutic intervention of these disorders is considered crucial. Integral medical monitoring should be ensured to prevent potential serious complications from the early stages, with the involvement of physicians, psychologists, nutritionists, and other specialists in a multidisciplinary approach according to the patient's needs.

Student survey after ten years of continuous blended teaching of echocardiography.

OBJECTIVE: To analyse the impact of 10 years of blended echocardiography teaching. METHODS AND RESULTS: A questionnaire was emailed to all medical doctors who graduated from the blended learning diploma in echocardiography developed by the University of Chile and taught by a team from Chile and Spain. One hundred and forty of the 210 students who graduated from the program between 2011 and 2020 completed the questionnaire: 53.57% were anaesthesiologists, and 26.42% were intensivists. More than 85% of respondents indicated that the online teaching met their expectations, and 70.2% indicated that the hands-on practice fulfilled the stated objectives. In a retrospective analysis using self-reported data, graduates reported that their use of transthoracic and transoesophageal echocardiography has increased from 24.29% to 40.71% and from 13.57% to 27.86%, repectively, after the programme compared to before the programme. They used echocardiography mainly in the perioperative period (56.7%) and during intensive care (32.3%), while only 11% of respondents used it in emergency care units. Nearly all (92.4%) respondents reported that the skills learned was very useful in their professional practice. CONCLUSIONS: Ten years after its launch, the blended learning diploma in echocardiography was well rated by graduate specialists, and is associated with a significant increase in the use of echocardiography in the perioperative period and during intensive care. The main challenges are to establish a longer period of practice and achieve greater implantation in emergency medicine.