Aging underlies heterogeneity between comorbidity and multimorbidity frameworks.
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ABSTRACT:
SUBMITTER: Lenti MV
PROVIDER: S-EPMC8736290 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and aimsThe pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.MethodsBy performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.ResultsCooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.ConclusionsThis novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
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Project description:BackgroundThere is growing interest in identifying interventions that may increase health span by targeting biological processes underlying aging. The design of efficient and rigorous clinical trials to assess these interventions requires careful consideration of eligibility criteria, outcomes, sample size, and monitoring plans.MethodsExperienced geriatrics researchers and clinical trialists collaborated to provide advice on clinical trial design.ResultsOutcomes based on the accumulation and incidence of age-related chronic diseases are attractive for clinical trials targeting aging. Accumulation and incidence rates of multimorbidity outcomes were developed by selecting at-risk subsets of individuals from three large cohort studies of older individuals. These provide representative benchmark data for decisions on eligibility, duration, and assessment protocols. Monitoring rules should be sensitive to targeting aging-related, rather than disease-specific, outcomes.ConclusionsClinical trials targeting aging are feasible, but require careful design consideration and monitoring rules.
| S-EPMC5777384 | biostudies-literature
Project description:BackgroundThe management of comorbidity and multimorbidity poses major challenges to health services around the world. Analysis of scientific research in comorbidity and multimorbidity is limited in the biomedical literature. This study aimed to map global scientific research in comorbidity and multimorbidity to understand the maturity and growth of the area during the past decades.Methods and findingsThis was a cross-sectional analysis of the Web of Science. Searches were run from inception until November 8, 2016. We included research articles or reviews with no restrictions by language or publication date. Data abstraction was done by one researcher. A process of standardization was conducted by two researchers to unify different terms and grammatical variants and to remove typographical, transcription, and/or indexing errors. All potential discrepancies were resolved via discussion. Descriptive analyses were conducted (including the number of papers, citations, signatures, most prolific authors, countries, journals and keywords). Network analyses of collaborations between countries and co-words were presented. During the period 1970-2016, 85994 papers (64.0% in 2010-2016) were published in 3500 journals. There was wide diversity in the specialty of the journals, with psychiatry (16558 papers; 19.3%), surgery (9570 papers; 11.1%), clinical neurology (9275 papers; 10.8%), and general and internal medicine (7622 papers; 8.9%) the most common. PLOS One (1223 papers; 1.4%), the Journal of Affective Disorders (1154 papers; 1.3%), the Journal of Clinical Psychiatry (727 papers; 0.8%), the Journal of the American Geriatrics Society (634 papers; 0.7%) and Obesity Surgery (588 papers; 0.7%) published the largest number of papers. 168 countries were involved in the production of papers. The global productivity ranking was headed by the United States (37624 papers), followed by the United Kingdom (7355 papers), Germany (6899 papers) and Canada (5706 papers). Twenty authors who published 100 or more papers were identified; the most prolific authors were affiliated with Harvard Medical School, State University of New York Upstate Medical University, National Taiwan Normal University and China Medical University. The 50 most cited papers ("citation classics" with at least 1000 citations) were published in 20 journals, led by JAMA Psychiatry (11 papers) and JAMA (10 papers). The most cited papers provided contributions focusing on methodological aspects (e.g. Charlson Comorbidity Index, Elixhauser Comorbidity Index, APACHE prognostic system), but also important studies on chronic diseases (e.g. epidemiology of mental disorders and its correlates by the U.S. National Comorbidity Survey, Fried's frailty phenotype or the management of obesity).ConclusionsOurs is the first analysis of global scientific research in comorbidity and multimorbidity. Scientific production in the field is increasing worldwide with research leadership of Western countries, most notably, the United States.
| S-EPMC5751979 | biostudies-literature
Project description:ImportanceMultimorbidity is a growing health care problem in aging societies and is strongly associated with epidemiologic characteristics and sociodemographic factors. Knowledge of these associations is important for the design of effective preventive and management strategies.ObjectivesTo determine the association between multimorbidity and sociodemographic factors (age, socioeconomic status [SES], sex, and race/ethnicity) and the association between mental health diseases and physical diseases, as well as their implications for the types and costs of health care use.Design, setting, and participantsThis population-based cross-sectional study used deidentified Singapore Eastern Regional Health System data collected between January 1, 2012, and December 31, 2016. Patients who were alive as of January 1, 2016, and residing in the Regional Health System region in 2016 (N = 1 181 024) were included. Patients who had no year of birth records (n = 573), were born in 2017 (n = 93), or died before January 1, 2016 (n = 47 322), were excluded.Main outcomes and measuresMultimorbidity, age, sex, SES, mental health, race/ethnicity, and health care use.ResultsIn the study population of 1 181 024 individuals, the mean (SD) age was 39.6 (22.1) years, 51.2% were women, 70.1% were Chinese, 7.1% were Indian, 13.5% were Malayan, and 9.3% were other races/ethnicities. Multimorbidity, present in 26.2% of the population, was more prevalent in female (26.8%; 95% CI, 26.7%-26.9%) than in male (25.6%; 95% CI, 25.5%-25.7%) patients and among patients with low SES (41.6%) than those with high SES (20.1%). Mental health diseases were significantly more prevalent among individuals with low SES (5.2%; 95% CI, 5.1%-5.2%) than high SES (2.1%; 95% CI, 2.0%-2.1%; P < .001). The 3 most prevalent disease combinations were chronic kidney disease and hypertension, chronic kidney disease and lipid disorders, and hypertension and lipid disorders. Although chronic kidney disease, hypertension, lipid disorders, and type 1 and/or type 2 diabetes-related diseases had a low cost per capita, the large number of patients with these conditions caused the overall proportion of the cost incurred by health care use to be more than twice that incurred in other diseases.Conclusions and relevanceThese findings emphasize the association between multimorbidity and sociodemographic factors such as increasing age, lower SES, female sex, and increasing number of mental disorders. Health care policies need to take sociodemographic factors into account when tackling multimorbidity in a population.
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Project description:BackgroundAlmost 1% of Canadians are hepatitis C (HCV)-infected. The liver-specific complications of HCV are established but the extra-hepatic comorbidity, multimorbidity, and its relationship with HCV treatment, is less well known. We describe the morbidity burden for people with HCV and the relationship between multimorbidity and HCV treatment uptake and cure in the pre- and post-direct acting antiviral (DAA) era.MethodsWe linked adults with HCV at The Ottawa Hospital Viral Hepatitis Program as of April 1, 2017 to provincial health administrative data and matched on age and sex to 5 Ottawa-area residents for comparison. We used validated algorithms to identify the prevalence of mental and physical health comorbidities, as well as multimorbidity (2+ comorbidities). We calculated direct age- and sex-standardized rates of comorbidity and comparisons were made by interferon-based and interferon-free, DAA HCV treatments.ResultsThe mean age of the study population was 54.5 years (SD 11.4), 65% were male. Among those with HCV, 4% were HIV co-infected, 26% had liver cirrhosis, 47% received DAA treatment, and 57% were cured of HCV. After accounting for age and sex differences, the HCV group had greater multimorbidity (prevalence ratio (PR) 1.38, 95% confidence interval (CI) 1.20 to 1.58) and physical-mental health multimorbidity (PR 2.71, 95% CI 2.29-3.20) compared to the general population. Specifically, prevalence ratios for people with HCV were significantly higher for diabetes, renal failure, cancer, asthma, chronic obstructive pulmonary disease, substance use disorder, mood and anxiety disorders and liver failure. HCV treatment and cure were not associated with multimorbidity, but treatment prevalence was significantly lower among middle-aged individuals with substance use disorders despite no differences in prevalence of cure among those treated.ConclusionPeople with HCV have a higher prevalence of comorbidity and multimorbidity compared to the general population. While HCV treatment was not associated with multimorbidity, people with substance use disorder were less likely to be treated. Our results point to the need for integrated, comprehensive models of care delivery for people with HCV.
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Project description:Multimorbidity has great impact on health care. We constructed multimorbidity networks in the general population, extracted subnets focused on common chronic conditions and analysed type 2 diabetes mellitus (T2DM) comorbidity network. We used electronic records from 3,135,948 adult people in Catalonia, Spain (539,909 with T2DM), with at least 2 coexistent chronic conditions within the study period (2006-2017). We constructed networks from odds-ratio estimates adjusted by age and sex and considered connections with OR > 1.2 and p-value < 1e-5. Directed networks and trajectories were derived from temporal associations. Interactive networks are freely available in a website with the option to customize characteristics and subnets. The more connected conditions in T2DM undirected network were: complicated hypertension and atherosclerosis/peripheral vascular disease (degree: 32), cholecystitis/cholelithiasis, retinopathy and peripheral neuritis/neuropathy (degree: 31). T2DM has moderate number of connections and centrality but is associated with conditions with high scores in the multimorbidity network (neuropathy, anaemia and digestive diseases), and severe conditions with poor prognosis. The strongest associations from T2DM directed networks were to retinopathy (OR: 23.8), glomerulonephritis/nephrosis (OR: 3.4), peripheral neuritis/neuropathy (OR: 2.7) and pancreas cancer (OR: 2.4). Temporal associations showed the relevance of retinopathy in the progression to complicated hypertension, cerebrovascular disease, ischemic heart disease and organ failure.
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Project description:Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene. The expanded repeat induces repressive histone changes and DNA hypermethylation, which result in epigenetic silencing and FXN transcriptional deficiency. A class I histone deacetylase inhibitor (HDACi-109) reactivates the silenced FXN gene, although with considerable inter-individual variability, which remains etiologically unexplained. Because HDAC inhibitors work by reversing epigenetic silencing, we reasoned that epigenetic heterogeneity among patients may help to explain this inter-individual variability. As a surrogate measure for epigenetic heterogeneity, a highly quantitative measurement of DNA hypermethylation via bisulfite deep sequencing, with single molecule resolution, was used to assess the prevalence of unmethylated, partially methylated, and fully methylated somatic FXN molecules in PBMCs from a prospective cohort of 50 FRDA patients. Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.
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Project description:Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent abscesses in the groin and flexural areas. HS is associated with a wide range of comorbidities that complicate the disease course. Although these comorbidities have been well described, it remains unclear how these comorbidities coassociate and whether comorbidity profiles affect disease trajectory. In addition, it is unknown how comorbidity associations are modulated by race and sex. In this comprehensive analysis of 77 million patients in a large US population-based cohort, we examined coassociation patterns among HS comorbidities and identified clinically relevant phenotypic subtypes within HS. We demonstrated that these subtypes not only differed among races, but also influenced clinical outcomes as measured by HS-related emergency department visits and cellulitis. Taken together, our findings provide key insights that elucidate the unique disease trajectories experienced by patients with HS and equip clinicians with a framework for risk stratification and improved targeted care in HS.
| S-EPMC8663549 | biostudies-literature
Project description:OBJECTIVES:To explore the association between rate of physical health deterioration, operationalized as rising multimorbidity overtime, and longitudinal decline in cognitive function in older adults without dementia. DESIGN:Longitudinal (Baltimore Longitudinal Study of Aging (BLSA)). SETTING:Community. PARTICIPANTS:BLSA participants aged 65 and older followed for an average of 3 years and free of dementia or mild cognitive impairment (MCI) at baseline and follow-up (N = 756). MEASUREMENTS:Standardized neurocognitive tests evaluating mental status, memory, executive function, processing speed, and verbal fluency were administered. Multimorbidity was assessed at each visit as number of diagnosed chronic diseases from a predefined list. Faster accumulation of chronic diseases was defined as upper quartile of rate of change in number of diseases over time (?0.25 diseases/year). RESULTS:Faster accumulation of chronic diseases was significantly associated with greater rate of decline on the Category (P = .01) and Letter (P = .01) Fluency Tests. Similar trends were also found for the Trail-Making Test Parts A (P = .08) and B (P = .07); no association was found with rate of change in visual and verbal memory. CONCLUSION:Although further investigations are required to validate the results and fully understand the underlying mechanisms, these findings suggest that accelerated deterioration of physical health is associated with accelerated decline with aging in specific cognitive domains in older adults without dementia.
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