Cause Of Death In Individuals Research Articles

Mini Review: the non-neuronal cardiac cholinergic system in type-2 diabetes mellitus.

Diabetic heart disease remains the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Both insulin resistance and metabolic derangement, hallmark features of T2DM, develop early and progressively impair cardiovascular function. These factors result in altered cardiac metabolism and energetics, as well as coronary vascular dysfunction, among other consequences. Therefore, gaining a deeper understanding of the mechanisms underlying the pathophysiology of diabetic heart disease is crucial for developing novel therapies for T2DM-associated cardiovascular disease. Cardiomyocytes are equipped with the cholinergic machinery, known as the non-neuronal cardiac cholinergic system (NNCCS), for synthesizing and secreting acetylcholine (ACh) as well as possessing muscarinic ACh receptor for ACh binding and initiating signaling cascade. ACh from cardiomyocytes regulates glucose metabolism and energetics, endothelial function, and among others, in an auto/paracrine manner. Presently, there is only one preclinical animal model - diabetic db/db mice with cardiac-specific overexpression of choline transferase (Chat) gene - to study the effect of activated NNCCS in the diabetic heart. In this mini-review, we discuss the physiological role of NNCCS, the connection between NNCCS activation and cardiovascular function in T2DM and summarize the current knowledge of S-Nitroso-NPivaloyl-D-Penicillamine (SNPiP), a novel inducer of NNCCS, as a potential therapeutic strategy to modulate NNCCS activity for diabetic heart disease.

Systematic review and meta-analysis of observational studies evaluating glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCHL1) as blood biomarkers of mildacute traumatic brain injury (mTBI) or sport-related concussion (SRC) in adult subjects.

Neurotrauma is the leading cause of death in individuals <45 years old. Many of the published articles on UCHL1 and GFAP lack rigorous methods and reporting. Due to the high heterogeneity between studies, we evaluated blood GFAP and UCHL1 levels in the same subjects. We determined the biomarker congruence among areas under the ROC curves (AUCs), sensitivities, specificities, and laboratory values in ng/L to avoid spurious results. The definitive meta-analysis included 1,880 subjects in eight studies. The items with the highest risk of bias were as follows: cut-off not prespecified and case-control design not avoided. The AUC of GFAP was greater than the AUC of UCHL1, with a lower prediction interval (PI) limit of 50.1 % for GFAP and 37.3 % for UCHL1, and a significantly greater percentage of GFAP Sp. The PI of laboratory results for GFAP and UCHL1 were 0.517-7,518 ng/L (diseased), 1.2-255 ng/L (nondiseased), and 3-4,180 vs. 3.2-1,297 ng/L, respectively. Only the GFAP positive cut-off (255 ng/L) appears to be reliable. The negative COs appear unreliable. GFAP needs better standardization. However, the AUCs of the phospho-Tau and phospho-Tau/Tau proteins resulted not significantly lower than AUC of GFAP, but this result needs further verifications.

Chronic Kidney Disease, Mortality in the Elderly in Cuba

Introduction: Population aging is a global reality. Age is the most important prognostic factor for kidney disease. Objective: To characterize the mortality of the elderly with chronic kidney disease (CKD) in Cuba, in the period 2011-2019. Methods: Cross-sectional descriptive research. The universe corresponded to the 24 181 deceased over 60 years with CKD in Cuba in the period. The information was taken from the mortality database of the Ministry of Public Health. Absolute and relative frequencies, crude rates of mortality, specific and years of life potentially lost were calculated. Mortality was stratified by province of residence. Results: Among the deceased older than 60, males (52,%) and white-skinned subjects (64,%) predominated. The average mortality rate during the period was 12,5 per 10,000 inhabitants (h). The risk of death was higher in those older than 85 years (34,5 x 10,000 h). The highest rates corresponded to the provinces: Artemisa (18,2), Cienfuegos (15.7), Matanzas (14,5) and Havana (14,5). The main cause of death in the subjects studied was hypertensive kidney disease (42,3 per 100,000 h). Conclusions: There is a slight tendency to increase mortality in the group studied in the country. The risk of death from CKD at the provincial level presents differences; it is higher in the provinces of Artemisa, Cienfuegos, Matanzas and Havana. The main causes of death in individuals with the characteristics studied are hypertensive kidney disease and diabetes mellitus.

Causes of death in individuals with lifetime major depression: a comprehensive machine learning analysis from a community-based autopsy center

BackgroundDepression can be associated with increased mortality and morbidity, but no studies have investigated the specific causes of death based on autopsy reports. Autopsy studies can yield valuable and detailed information on pathological ailments or underreported conditions. This study aimed to compare autopsy-confirmed causes of death (CoD) between individuals diagnosed with major depressive disorder (MDD) and matched controls. We also analyzed subgroups within our MDD sample, including late-life depression and recurrent depression. We further investigated whether machine learning (ML) algorithms could distinguish MDD and each subgroup from controls based on their CoD.MethodsWe conducted a comprehensive analysis of CoD in individuals who died from nontraumatic causes. The diagnosis of lifetime MDD was ascertained based on the DSM-5 criteria using information from a structured interview with a knowledgeable informant. Eleven established ML algorithms were used to differentiate MDD individuals from controls by simultaneously analyzing different disease category groups to account for multiple tests. The McNemar test was further used to compare paired nominal data.ResultsThe initial dataset included records of 1,102 individuals, among whom 232 (21.1%) had a lifetime diagnosis of MDD. Each MDD individual was strictly paired with a control non-psychiatric counterpart. In the MDD group, the most common CoD were circulatory (67.2%), respiratory (13.4%), digestive (6.0%), and cancer (5.6%). Despite employing a range of ML models, we could not find distinctive CoD patterns that could reliably distinguish individuals with MDD from individuals in the control group (average accuracy: 50.6%; accuracy range: 39-59%). These findings were consistent even when considering factors within the MDD group, such as late-life or recurrent MDD. When comparing groups with paired nominal tests, no differences were found for circulatory (p=0.450), respiratory (p=0.790), digestive (p=1.000), or cancer (p=0.855) CoD.ConclusionsOur analysis revealed that autopsy-confirmed CoD exhibited remarkable similarity between individuals with depression and their matched controls, underscoring the existing heterogeneity in the literature. Future research should prioritize more severe manifestations of depression and larger sample sizes, particularly in the context of CoD related to cancer.

Incretin-mediated control of cardiac energy metabolism.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.

Trauma patients have reduced ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model of vessel injury.

Trauma is the leading cause of death in individuals up to 45 years of age. Alterations in platelet function are a critical component of trauma-induced coagulopathy (TIC), yet these changes and the potential resulting dysfunction is incompletely understood. The lack of clinical assays available to explore platelet function in this patient population has hindered detailed understanding of the role of platelets in TIC. The objective of this study was to assess trauma patient ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model. We hypothesized that trauma patients would have flow-regime dependent alterations in platelet function. Blood was collected from trauma patients with level I activations (N = 34) within 60 min of hospital arrival, as well as healthy volunteer controls (N = 10). Samples were perfused through a microfluidic model of injury at venous and arterial shear rates, and a subset of experiments were performed after incubation with fluorescent anti-CD41 to quantify platelets. Complete blood counts were performed as well as plasma-based assays to quantify coagulation times, fibrinogen, and von Willebrand factor (VWF). Exploratory correlation analyses were employed to identify relationships with microfluidic hemostatic parameters. Trauma patients had increased microfluidic bleeding times compared to healthy controls. While trauma patient samples were able to deposit a substantial amount of clot in the model injury site, the platelet contribution to microfluidic hemostasis was attenuated. Trauma patients had largely normal hematology and plasma-based coagulation times, yet had elevated D-Dimer and VWF. Venous microfluidic bleeding time negatively correlated with VWF, D-Dimer, and mean platelet volume (MPV), while arterial microfluidic bleeding time positively correlated with oxygenation. Arterial clot growth rate negatively correlated with red cell count, and positively with mean corpuscular volume (MCV). We observed changes in clot composition in trauma patient samples reflected by significantly diminished platelet contribution, which resulted in reduced hemostatic function in a microfluidic model of vessel injury. We observed a reduction in platelet clot contribution under both venous and arterial flow ex vivo in trauma patient samples. While our population was heterogenous and had relatively mild injury severity, microfluidic hemostatic parameters correlated with different patient-specific data depending on the flow setting, indicating potentially differential mechanistic pathways contributing to platelet hemostatic capacity in the context of TIC. These data were generated with the goal of identifying key features of platelet dysfunction in bleeding trauma patients under conditions of flow and to determine if these features correlate with clinically available metrics, thus providing preliminary surrogate markers of physiological platelet dysfunction to be further studied across larger cohorts. Future studies will continue to explore those relationships and further define mechanisms of TIC and their relationship with patient outcomes.

Strategies for protecting lung health after spinal cord injury and gastric reflux

Spinal cord injuries have a significant and far-reaching impact, affecting more than 300,000 people in the United States alone. Among these injuries, cervical-level injuries are the most common, accounting for approximately 60% of all spinal cord injuries. Pulmonary complications, specifically aspiration-related pneumonia, rank as the primary cause of death in individuals with these injuries. Notably, those with cervical spinal cord injuries have an elevated risk of experiencing acute lung injury and acute respiratory distress syndrome. Moreover, spinal cord injuries, regardless of their location, often lead to gastric dysmotility, a condition frequently linked with gastroesophageal reflux disease. This research aims to untangle the intricate relationship between these interconnected health issues and their collective impact on pulmonary function. Here we tested the hypotheses 1) that cervical spinal cord injury increases the susceptibility for developing acute lung injury associated with gastric juice aspiration and 2) that TRPV4 inhibitors will mitigate gastric fluid/SCI-induced lung injury. These studies employed a rat model of spinal cord injury, C2 hemisection (C2Hx). This model mimics the reduced inspiratory tidal volume observed in individuals with cervical spinal cord injuries and has more recently been shown to recapitulate certain aspects of lung injury associated with spinal cord injuries. Additionally, to produce the effects of gastric reflux, gastric juices were introduced into the trachea in a subset of animals following spinal cord injury. Furthermore, TRPV4 inhibitors were administered to assess their potential to mitigate lung damage after spinal injury, gastric juice instillation or at both times. Preliminary data suggest that C2Hx and low levels of gastric juice increase inflammatory markers in the lung and circulation above even high levels of gastric instillation. Further, preliminary data supports the hypothesis that TRVP4 inhibition may protect the lung. The outcomes of these investigations will provide valuable insights into how spinal cord injuries might predispose individuals to lung injury. Additionally, they will evaluate the effcacy of a promising therapeutic approach using TRPV4 inhibitors to restore lung barrier function, potentially reversing this susceptibility. R21NS121966-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Trends in cause-specific mortality among people with type 2 and type 1 diabetes from 2002 to 2019: a Danish population-based study

BackgroundDespite advances in primary and secondary prevention of cardiovascular disease, excess mortality persists within the diabetes population. This study explores the components of this excess mortality and their interaction with sex. MethodsUsing Danish registries (2002-2019), we identified residents aged 18-99 years, their diabetes status, and recorded causes of death. Applying Lexis-based methods, we computed age-standardized mortality rates (asMRs), mortality relative risks (asMRRs), and log-linear trends for cause-specific mortality. FindingsFrom 2002-2019, 958,278 individuals died in Denmark (T2D: 148,620; T1D: 7,830) during 84.4M person-years. During the study period, overall asMRs declined, driven by reducing cardiovascular mortality, notably in men with T2D. Conversely, cancer mortality remained high, making cancer the leading cause of death in individuals with T2D. Individuals with T2D faced an elevated mortality risk from nearly all cancer types, ranging from 9% to 257% compared to their non-diabetic counterparts. Notably, obesity-related cancers exhibited the highest relative risks: liver cancer (Men: asMRR 3·58(3·28;3·91); Women: asMRR 2·49(2·14;2·89)), pancreatic cancer (Men: asMRR 3·50(3·25;3·77); Women: asMRR 3·57(3·31;3·85)), and kidney cancer (Men: asMRR 2·10(1·84;2·40); Women: asMRR 2·31(1·92;2·79)). In men with type 2 diabetes, excess mortality remained stable, except for dementia. In women, diabetes-related excess mortality increased by 6-17% per decade across all causes of death, except cardiovascular disease. InterpretationIn the last decade, cancer has emerged as the leading cause of death among individuals with T2D in Denmark, emphasizing the need for diabetes management strategies incorporating cancer prevention. A sex-specific approach is crucial to address persistently higher relative mortality in women with diabetes. FundingSupported by Steno Diabetes Center Aarhus, which is partially funded by an unrestricted donation from the Novo Nordisk Foundation, and by The Danish Diabetes Academy.

Comorbidities, mortality and metabolic profile in individuals with primary biliary cholangitis-A Phenome-Wide-Association-Study.

Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease that can lead to fibrosis and cirrhosis. In this cohort study, we aimed to investigate morbidity and mortality in conjunction with metabolomic changes of PBC in a UK population-based cohort. 454 participants with PBC and 908 propensity score (age, sex, BMI, ethnicity) matched controls without liver disease were included in the study. A subset of participants with PBC and controls were analysed for their metabolomic profile. Further, PBC-associated comorbidities were investigated by PheWAS analysis. Lastly, we assessed causes of death in individuals with PBC using a Fine and Grey competing-risks regression model. Compared to the control group, various pathways associated with the metabolism of amino acids, lipids, and liver biochemistry were significantly enriched in individuals with PBC. We found reduced levels of S-HDL-cholesterol and Glycoprotein Acetyls in individuals with PBC as well as an association with diseases of the circulatory system. Notably, PBC individuals had a higher prevalence of digestive diseases, autoimmune diseases, cardiovascular diseases, anaemias, mental disorders, and urinary tract infections compared to the control group. Strikingly, the overall mortality was almost three times higher in the PBC group compared to the control group, with diseases of the digestive system accounting for a significant elevation of the death rate. A subsequent analysis, enhanced by propensity score matching that included the APRI score, demonstrated that the observed morbidity could not be exclusively attributed to advanced hepatic disease. Our study provides a detailed perspective on the morbidity of individuals with PBC. The exploration of potential effects of disease state on morbidity suggest that early detection and early treatment of PBC could enhance patient prognosis and prevent the onset of comorbid diseases. Finally, the metabolomic alterations could represent a link between the pathophysiological processes underlying PBC development, progression, and associated morbidity.

Abstract 2767: Exploring ADAR1 dependencies in breast cancer brain-metastases

Abstract Background: Adenosine deaminase acting on double-stranded RNA (ADAR1) is a recognized driver of epitranscriptomic (post-transcriptional) remodeling and tumor progression. Changes in amino acid sequence, mRNA splicing, and/or polyadenylation sites are only some of the adenosine-to-inosine (A-to-I) RNA editing effects. Under physiological conditions, ADAR1 activity prevents autoinflammation by inhibiting the accumulation of endogenous immunostimulatory double-stranded RNA and by suppressing the Z-RNA sensor ZBP1. Such mechanisms are exploited by cancer cells to desensitize tumor response to therapies, therefore augmenting aggressiveness. Approximately 10 to 20% of patients diagnosed with breast cancer (BC) will develop metastatic disease, which remains the leading cause of death in individuals with BC. We have hypothesized that ADAR1 and its interferon-inducible p150 isoform, play a pivotal role in promoting BC metastases since high levels of ADAR1 are associated with a worse prognosis in patients with high grade BC, especially in the triple-negative BC subgroup (TNBC), which is the most likely to develop brain metastases. Methods: We established a humanized mouse model of breast cancer brain metastases (BC-BrM) using neonatal intracerebroventricular inoculation of MDA-MD-231 TNBC cells and primary patient derived metastatic cells in Rag2−/−γc−/− mice. Before implantation, MDA-MD-231 cells were transduced with a nanoluc-GFP reporter for tracing ADAR1 enzymatic activity in the brain metastatic niche. Lentiviral shRNA knockdown vectors targeting ADAR1, combined with over-expression vectors of full-length ADAR1 or the p150 deleted isoform were adopted to detect editing changes in the metastatic model through RNA-sequencing of BC-BrM. Results: BrM derived from MDA-MD-231 implants display upregulation of ADAR1 p150 and activation of the WNT/β-catenin pathway compared to the non-implanted cell lines. Upon shRNA knockdown of ADAR1, decreased expression of BC stem cell markers was detected via FACS in MDA-MD-231 ADAR1 knocked-down versus control BC-BrM isolated cells. We are now exploring molecular pathways affected by ADAR1 loss/overexpression in establishing BrM. Future Directions: We have developed a biorepository of primary patient-derived metastatic breast cancer samples and have begun the process of tracking metastatic kinetics and ADAR1 activation with the ADAR1 reporter in an orthotopic mouse model. Overall, this study will provide new insights into the molecular role of ADAR1 deaminase activity in establishing and maintaining metastatic niches. Citation Format: Teresa Sposito, Emma E. Klacking, Antonio W. Ruiz, Jessica Pham, Catriona Jamieson. Exploring ADAR1 dependencies in breast cancer brain-metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2767.

U.S. dementia care spending by state: 2010-2019.

Dementia is the fourth largest cause of death for individuals 70 years of age and older in the United States, and it is tremendously costly. Existing estimates of the indirect costs of dementia are dated and do not report on differences across the United States. We used data from multiple surveys to create cost estimates and projections for informal dementia caregiving at the U.S. state level from 2010 through 2050. In 2019, the annual replacement cost of informal caregiving was $42,422 per prevalent case, and the forgone wage cost was $10,677 per prevalent case. In 2019, it would have cost $230 billion to hire home health aides to provide all this care. If past trends persist, this cost is expected to grow to $404 billion per year in 2050. The cost of informal care varied substantially by state and is expected to grow through at least 2050. In the United States in 2019, foregone wages due to informal dementia care was $58 billion. Replacing informal dementia care with health aides would have cost $230 billion. These costs vary dramatically by state, even when assessed per prevalent case. These costs are expected to nearly double by 2050.

A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.

Identifying factors, such as low sleep quality, that predict suicidal thoughts using machine learning

Every year, around 800,000 people die by suicide worldwide, and it is the second leading cause of death for individuals aged 15-24 years. The National Survey on Drug Use and Health (NSDUH) is conducted annually to ask the general United States population aged 12 years and older questions about mental health, substance use, and suicidal thoughts. Some of the factors the survey considers are substance use, including need for treatment and disorders, and mental health topics, including major depressive episodes, suicidal ideation and attempts, and mental illness. In our research, we sought to identify associations between suicidal ideation and relevant variables, such as sleep quality, hopelessness, and anxious behavior, by analyzing survey responses from the 2020 NSDUH. Due to the density of the survey and no obvious direct relationship between any variables with suicidal ideation, through our research we aimed to clearly find and display any association. We hypothesized that frequent anxious thoughts and behavior (such as fidgeting and restlessness), feelings of sadness, and/or low sleep quality would be the factors most predictive of having suicidal thoughts. Using a random forest classifier, we found that sleep problems were highly predictive of suicidal ideation. Professionals and clinicians should keep these findings in mind when developing suicide prevention efforts, such as identifying and supporting people potentially at risk, intervening to improve sleep quality, and teaching coping skills.

Bronchial obstruction in osteogenesis imperfecta can be detected by forced oscillation technique.

Respiratory insufficiency is a leading cause of death in individuals with osteogenesis imperfecta (OI). However, evaluating pulmonary function in OI presents challenges. Commonly used pulmonary function tests such as spirometry and body plethysmography are sometimes difficult to perform for OI patients, and reference intervals are not always applicable. The forced oscillation technique (FOT) is a patient-friendly method for detecting respiratory abnormalities that requires no effort from the patient. This study investigates the feasibility of FOT in the evaluation of respiratory function in the clinical management of OI patients. Twelve OI patients, comprising eight with Sillence OI I, two with OI IV, and two with OI III, underwent spirometry, body plethysmography, and FOT, both pre-and post-administration of salbutamol. FOT measurements exhibited consistent trends that aligned with spirometry and body plethysmography findings. The resistance at 8 Hz decreased after the administration of salbutamol, indicating that FOT is able to detect bronchial obstruction and its alleviation by medication (p < 0.05). The resonant frequency during expiration was higher than during inspiration in nearly all patients, suggesting obstructive disease. The technique gives insight into both inspiratory and expiratory impairment of pulmonary ventilation. The main FOT parameters showed a relatively high repeatability in duplicate measurements. Bronchial obstruction can be detected by FOT in patients with OI during quiet breathing, making it an easily executable alternative to other lung function measurements. The technique can detect the bronchodilator effect of sympathomimetic medication. It has the potential to provide information on expiratory flow limitation, pulmonary restriction, and reduced lung compliance.

IUPHAR review: Recent progress in the development of Mu opioid receptor modulators to treat opioid use disorders

Opioid Use Disorder (OUD) can be described as intense preoccupation with using or obtaining opioids despite the negative consequences associated with their use. As the number of OUD cases in the U.S. increase, so do the number of opioid-related overdose deaths. In 2022, opioid-related overdose became the No. 1 cause of death for individuals in the U.S. between the ages of 25 and 64 years of age. Because of the introduction of highly potent synthetic opioids (e.g. fentanyl) to the illicit drug market, there is an urgent need for therapeutics that successfully reduce the number of overdoses and can help OUD patients maintain sobriety. Most abused opioids stimulate the mu-opioid receptor (MOR) and activation of this receptor can lead to positive (e.g., euphoria) consequences. However, the negative side effects of MOR stimulation can be fatal (e.g., sedation, respiratory depression). Therefore, the MOR is an attractive target for developing medications to treat OUD. Current FDA drugs include MOR agonists that aid in detoxification and relapse prevention, and MOR antagonists that also serve as maintenance therapies or reverse overdose. These medications are limited by their abuse potential, adverse effects, or pharmacological profiles which leaves ample room for research into designing new chemical entities with optimal physiological effects. These includes, orthosteric ligands that target the primary binding site of the MOR, allosteric ligands that positively, negatively, or “silently” modulate receptor function, and lastly, bitopic ligands target both the orthosteric and allosteric sites simultaneously.

Upregulation of E-cadherin by the combination of methionine restriction and HDAC2 intervention for inhibiting gastric carcinoma metastasis.

Invasion and metastasis are the leading causes of death in individuals with malignant tumors, including gastric cancer. In this study, we aim to explore the effect and related mechanisms of methionine restriction (MR) on gastric carcinoma metastasis. In the MR cell model, gastric carcinoma cells are cultured in the MR medium, and in the animal model, BALB/c nude rodents are administered with a methionine-free diet after receiving injections of MKN45 cells into the caudal vein. Transwell assay is used to detect cell invasion and migration. Chromatin immunoprecipitation is performed to investigate the levels of H3K9me2, H3K27Ac, and H3K27me3 in the E-cadherin promoter. The results show that MR inhibits gastric carcinoma cell migration, invasion, and lung metastasis. MR increases E-cadherin while reducing the H3K27me3 level in the E-cadherin promoter. E-cadherin expression in gastric carcinoma cells is adversely regulated by HDAC2. Overexpressing HDAC2 reduces the H3K27Ac level in the E-cadherin promoter, while interfering with HDAC2 increases the H3K27Ac level. HDAC2 interference under MR conditions further upregulates E-cadherin expression and inhibits gastric carcinoma cell migration, invasion, and lung metastasis. MR combined with HDAC2 interference promotes E-cadherin expression by mediating the methylation and acetylation of E-cadherin, thus inhibiting the invasion, migration, and lung metastasis of gastric carcinoma cells. Our study provides a new theoretical basis for the inhibitory effect of MR on gastric cancer.

Absolute and Relative Risks of Hematologic Disease and Cause-Specific Death in Individuals with Incidentally Discovered Thrombocytopenia: A Prospective Study of Two Independent General Population Cohorts Including 486,782 Individuals from the United Kingdom and Denmark

Background: Incidentally discovered thrombocytopenia in asymptomatic individuals often result in a referral to hematology. Clinical decisions for these individuals are mostly based on local practice, as little evidence exists on their risk of hematologic disease and death. We aim to lay ground for an evidence-based clinical approach to incidental thrombocytopenia with or without concurrent anemia by studying relative and absolute risk of being diagnosed with hematologic disease, death from hematologic disease and death from any cause. Methods: We studied 382,424 general population individuals from the United Kingdom (UK) Biobank aged 40-70 years, of whom 9,151 had thrombocytopenia with or without anemia. Individuals with leukocytosis, neutropenia or prior hematologic disease were excluded. As a validation cohort, we studied 104,358 Danish general population individuals. All individuals attended a health examination and had platelets, hemoglobin, leukocyte and differential count measured at study enrolment. Individuals were followed prospectively for up to 16 years for hematologic disease and cause-specific death using national registries, covering all deaths and almost all cancer cases in the UK and Denmark. Results: Among 382,424 individuals from the UK, 6,044 had hematologic disease during follow-up, 28,403 died from any cause and 1,213 died due to hematologic disease. For all analyses, the reference group was individuals with normal platelet count and normal hemoglobin. Individuals with isolated mild thrombocytopenia (platelets 100-149 x 10 9/L) or isolated moderate-severe thrombocytopenia (&amp;lt;100 x 10 9/L) had increased relative risk of hematologic disease (multivariable adjusted Cox regression hazard ratios [HR] 2.19; 95% CI:1.94-2.47 and HR 7.68; 6.35-9.29, respectively), death from hematologic disease (HR 1.81; 1.37-2.38 and HR 2.80; 1.45-5.39, respectively) and death from any cause (HR 1.30; 1.22-1.39 and HR 1.84; 1.58-2.16, respectively). Individuals with mild thrombocytopenia combined with mild anemia (hemoglobin 11-11.8 g/dL for women; 11.9-13.4 for men) also had increased risk of hematologic disease (HR 5.36; 3.82-7.52), death from hematologic disease (4.99; 2.49-10.04), and death from any cause (2.57; 2.14-3.10). Relative risk estimates were increased to a similar or higher extent in individuals having moderate-severe thrombocytopenia with mild anemia, mild thrombocytopenia with severe anemia (hemoglobin &amp;lt;11 g/dL for women; &amp;lt;11.9 for men) or moderate-severe thrombocytopenia with severe anemia. When studying absolute risk (Figure 1), the 10-year risk of death from any cause was especially high (23-53%) in individuals aged 60-70 years with combined thrombocytopenia and anemia. However, 10-year risk of death from hematologic disease was below 5% for all combinations of sex, age, platelet count and hemoglobin, except for women (5.0%) and men (7.9%) aged 60-70 years having moderate-severe thrombocytopenia with mild anemia. For risk of hematologic disease, absolute 10-year risk was below 5% for all age and sex-groups with isolated mild thrombocytopenia, while 10-year risk was as high as 21% in 60-70 year-old men having mild anemia combined with moderate-severe thrombocytopenia. For individuals with thrombocytopenia with or without anemia, the most common hematologic diseases were lymphoid malignancies (41% of diagnoses; HR 1.73; 1.49-2.01), ITP (34%; HR 22.85; 18.56-28.13), and myeloid malignancies (25%; HR 2.90; 2.39-3.52). Among causes of death in individuals with thrombocytopenia were non-hematologic cancer (35% of deaths; HR 1.21; 1.10-1.33), heart disease (21%; HR 1.43; 1.27-1.62), infections (4%; HR 1.84; 1.36-2.49), and bleeding (2%; HR 1.37; 0.94-1.99). In the independent Danish validation cohort, results were generally similar to those presented in Figure 1. Conclusion: Individuals with thrombocytopenia with or without anemia had increased relative risk of hematologic disease, death from hematologic disease and death from any cause. However, 10-year absolute risk of death from hematologic disease was below 5% for most combinations of sex, age, platelet count and hemoglobin. Our absolute 10-year risk estimates can help clinicians to identify low and high-risk individuals and guide decisions on which individuals with incidentally discovered thrombocytopenia that should undergo investigations for possible hematologic disease.

The Role of Socioeconomic Position in the Association Between Mental Disorders and Mortality

Studies are lacking summarizing how the association between mental disorders and mortality varies by socioeconomic position (SEP), particularly considering different aspects of SEP, specific types of mental disorders, and causes of death. To investigate the role of SEP in the association between mental disorders and mortality and the association between SEP and mortality among people with mental disorders. MEDLINE, Embase, PsycINFO, and Web of Science were searched from January 1, 1980, through April 3, 2023, and a snowball search of reference and citation lists was conducted. Inclusion criteria were observational studies estimating the associations between different types of mental disorders and mortality, stratified by SEP and between SEP and mortality in people with mental disorders. Pairs of reviewers independently extracted data using a predefined data extraction form and assessed the risk of bias using the adapted Newcastle-Ottawa scale. Graphical analyses of the dose-response associations and random-effects meta-analyses were performed. Heterogeneity was explored through meta-regressions and sensitivity analyses. All-cause and cause-specific mortality. Of 28 274 articles screened, 71 including more than 4 million people with mental disorders met the inclusion criteria (most of which were conducted in high-income countries). The relative associations between mental disorders and mortality were similar across SEP levels. Among people with mental disorders, belonging to the highest rather than the lowest SEP group was associated with lower all-cause mortality (pooled relative risk [RR], 0.79; 95% CI, 0.73-0.86) and mortality from natural causes (RR, 0.73; 95% CI, 0.62-0.85) and higher mortality from external causes (RR, 1.18; 95% CI, 0.99-1.41). Heterogeneity was high (I2 = 83% to 99%). Results from subgroup, sensitivity, and meta-regression analyses were consistent with those from the main analyses. Evidence on absolute scales, specific diagnoses, and specific causes of death was scarce. This study did not find a sufficient body of evidence that SEP moderated the relative association between mental disorders and mortality, but the underlying mortality rates may differ by SEP group, despite having scarcely been reported. This information gap, together with our findings related to SEP and a possible differential risk between natural and external causes of death in individuals with specific types of mental disorders, warrants further research.

Abstract 13004: Blockade of Endothelial to Mesenchymal Transition (EndMT) by an AP-1 Inhibitor Attenuates Atherosclerosis in Diabetes

Background: Atherosclerotic cardiovascular disease is the leading cause of death in individuals with diabetes. Endothelial to mesenchymal transition (EndMT) is characterized by endothelial transformation to a mesenchymal like cellular state. EndMT-mediated endothelial cell dysfunction is known to be involved in cardiovascular complications of diabetes including atherosclerosis. Gene expression changes occur when endothelial cells transition to mesenchymal cells. These transcriptomic changes are regulated by multiple factors including transcription factors (TFs). Although, previous studies have implicated the role of EndMT in atherosclerosis, the role of AP-1 TF complex in EndMT in diabetes induced atherosclerosis is not known. Methods: Single cell transcriptomic (SCT) analysis of diabetic aorta in atheroprone Apoe -/- mice was performed using 10X Genomics platform. In vitro model mimicking diabetes-induced EndMT was established in human aortic endothelial cells (HAECs) using high glucose (25mM) and TNF- α ± a small molecular inhibitor of AP-1, T-5224. RNA and ChIP (chromatin Immunoprecipitation) sequencing was performed. Moreover, Apoe -/- mice made diabetic with streptozotocin, were treated with T-5224 (30 mg/kg daily for 5 weeks) in a 10-week intervention study. Results: SCT analysis of aorta identified increased expression of AP-1 members cFOS and Junb in diabetic endothelial cells in Apoe -/- mice. These genes were also upregulated in the HAECs-based in vitro EndMT model. Interestingly, AP-1 inhibition by T-5224 attenuated EndMT . RNA and ChIP sequencing identified several AP-1 target genes including Col1A2, Col4A1, TGFB, THBD, INSR, PIK3R3 (FDR &lt;0.05, Log2 fold change (2x)) that were common to many enriched pathways including “leukocyte trans-endothelial migration” and “AGE-RAGE signaling pathways in diabetic complications” directly relevant to EndMT in diabetes. Importantly, T-5224 treatment blocked EndMT resulting in reduced atherosclerosis in diabetic Apoe -/- mice. Conclusion: This study identified the AP-1 inhibition with T-5224 as a novel treatment for the first time for the diabetes induced EndMT and atherosclerosis.

Socio-hygienic aspects of mortality of the working-age population of an industrial city in Eastern Siberia (on the example of Usolye-Sibirskoye, Irkutsk region)

Introduction. For more than 80 years of its operation, JSC Usolekhimprom (Usolye-Sibirskoye, Irkutsk region) has released a significant amount of pollutants into the environment, such as mercury, lead, manganese, nickel, formaldehyde, phenols, etc. Despite the measures taken to rehabilitate the territory affected by the plant's activities, environmental pollution in Usolye-Sibirskoye remains a large-scale environmental problem and poses a threat to the city's population. Earlier it was found that the mortality rate of the population in the city exceeds similar indicators in comparison with the Irkutsk region and Russia in all age groups (child population, working age, older than working age). Scientists have established the maximum excess of the mortality rate among the working-age population.&#x0D; The study aims to assess the hygienic and socio–economic situation in the territory of Usolye-Sibirskoye and determine its impact on the causes and mortality rates of the working-age population.&#x0D; Materials and methods. Based on the official yearbooks of Roshydromet and reports of the Ministry of Natural Resources and Ecology of the Irkutsk region, the authors studied the state of the environment in Usolye-Sibirsky for 2010–2019. The scientists analyzed information on the main indicators of socio-economic development according to analytical reports on the socio-economic situation in the municipality "Usolye-Sibirskoye" for 2010–2019, as well as based on information from the database of indicators of municipalities of the Irkutsk region (Irkutskstat).The authors studied the mortality rate of the working-age population according to forms C-51 "Number of deaths by sex, age and individual causes of death" and 2RN "Population by sex and age" for 2010–2019. Based on the data obtained, they calculated age-standardized mortality rates from the main classes of causes in accordance with the indicators averaged over 10 years. As a standard, the researchers adopted the age structure of the Russian population for 2010 in accordance with the census data. Standardization was carried out by the direct method.&#x0D; Results. There is a severe environmental situation in Usolye-Sibirskoye is experiencing associated with man-made pollution of all components of the biosphere, including carcinogenic substances. When comparing mortality rates in Usolye-Sibirsky with regional and average Russian values, experts revealed an excess of mortality rates from all studied classes of causes among both men and women. There is an extremely unfavorable situation in terms of mortality from infectious diseases (5 times and 7.3 times higher compared to Russia for men and women, respectively), including from HIV infection and tuberculosis, as well as causes of death related to alcohol, the prevalence of which is associated with the socio-economic instability of the city. It is possible to note high mortality rates from causes that have an etiological connection with the consequences of the production activities of the Usolekhimprom enterprise (from diseases of the nervous system, malignant neoplasms, liver diseases).&#x0D; Conclusion. Sanitary and hygienic living conditions of the population of Usolye-Sibirskoye can be characterized by an extremely high level of contamination of all components of the biosphere with substances of hazard classes 1–2 and carcinogens. The unfavorable socio-economic situation due to the closure of the largest enterprise exacerbates the existing risks of premature mortality and leads to an increase in mortality from socially significant diseases. The working-age population is most vulnerable to these factors, since it is on it that the entire demographic burden falls.