Changes in multimorbidity and polypharmacy patterns in young and adult population over a 4-year period: A 2011–2015 comparison using real-world data

The pressing problem of multimorbidity and polypharmacy is aggravated by the lack of specific care models for this population. We aimed to investigate the evolution of multimorbidity and polypharmacy patterns in a given population over a 4-year period (2011–2015). A cross-sectional, observational study among the EpiChron Cohort, including anonymized demographic, clinical and drug dispensation information of all users of the public health system ≥65 years in Aragon (Spain), was performed. An exploratory factor analysis, stratified by age and sex, using an open cohort was carried out based on the tetra-choric correlations among chronic diseases and dispensed drugs during 2011 and compared with 2015. Seven baseline patterns were identified during 2011 named as: mental health, respiratory, allergic, mechanical pain, cardiometabolic, osteometabolic, and allergic/derma. Of the epidemiological patterns identified in 2015, six were already present in 2011 but a new allergic/derma one appeared. Patterns identified in 2011 were more complex in terms of both disease and drugs. Results confirmed the existing association between age and clinical complexity. The systematic associations between diseases and drugs remain similar regarding their clinical nature over time, helping in early identification of potential interactions in multimorbid patients with a high risk of negative health outcomes due to polypharmacy

Baseline drug treatments as indicators of increased risk of COVID-19 mortality in Spain and Italy

This study aims to identify baseline medications that, as a proxy for the diseases they are dispensed for, are associated with increased risk of mortality in COVID-19 patients from two regions in Spain and Italy using real-world data. We conducted a cross-country, retrospective, observational study including 8570 individuals from both regions with confirmed SARS-CoV-2 infection between 4 March and 17 April 2020, and followed them for a minimum of 30 days to allow sufficient time for the studied event, in this case death, to occur. Baseline demographic variables and all drugs dispensed in community pharmacies three months prior to infection were extracted from the PRECOVID Study cohort (Aragon, Spain) and the Campania Region Database (Campania, Italy) and analyzed using logistic regression models. Results show that the presence at baseline of potassium-sparing agents, antipsychotics, vasodilators, high-ceiling diuretics, antithrombotic agents, vitamin B12, folic acid, and antiepileptics were systematically associated with mortality in COVID-19 patients from both countries. Treatments for chronic cardiovascular and metabolic diseases, systemic inflammation, and processes with increased risk of thrombosis as proxies for the conditions they are intended for can serve as timely indicators of an increased likelihood of mortality after the infection, and the assessment of pharmacological profiles can be an additional approach to the identification of at-risk individuals in clinical practice

Identifying multimorbidity profiles associated with COVID-19 severity in chronic patients using network analysis in the PRECOVID Study; 35181720

A major risk factor of COVID-19 severity is the patient''s health status at the time of the infection. Numerous studies focused on specific chronic diseases and identified conditions, mainly cardiovascular ones, associated with poor prognosis. However, chronic diseases tend to cluster into patterns, each with its particular repercussions on the clinical outcome of infected patients. Network analysis in our population revealed that not all cardiovascular patterns have the same risk of COVID-19 hospitalization or mortality and that this risk depends on the pattern of multimorbidity, besides age and sex. We evidenced that negative outcomes were strongly related to patterns in which diabetes and obesity stood out in older women and men, respectively. In younger adults, anxiety was another disease that increased the risk of severity, most notably when combined with menstrual disorders in women or atopic dermatitis in men. These results have relevant implications for organizational, preventive, and clinical actions to help meet the needs of COVID-19 patients. © 2022, The Author(s)

Chronic diseases associated with increased likelihood of hospitalization and mortality in 68, 913 COVID-19 confirmed cases in Spain: A population-based cohort study

Background Clinical outcomes among COVID-19 patients vary greatly with age and underlying comorbidities. We aimed to determine the demographic and clinical factors, particularly baseline chronic conditions, associated with an increased risk of severity in COVID-19 patients from a population-based perspective and using data from electronic health records (EHR). Methods Retrospective, observational study in an open cohort analyzing all 68, 913 individuals (mean age 44.4 years, 53.2% women) with SARS-CoV-2 infection between 15 June and 19 December 2020 using exhaustive electronic health registries. Patients were followed for 30 days from inclusion or until the date of death within that period. We performed multivariate logistic regression to analyze the association between each chronic disease and severe infection, based on hospitalization and all-cause mortality. Results 5885 (8.5%) individuals showed severe infection and old age was the most influencing factor. Congestive heart failure (odds ratio -OR- men: 1.28, OR women: 1.39), diabetes (1.37, 1.24), chronic renal failure (1.31, 1.22) and obesity (1.21, 1.26) increased the likelihood of severe infection in both sexes. Chronic skin ulcers (1.32), acute cerebrovascular disease (1.34), chronic obstructive pulmonary disease (1.21), urinary incontinence (1.17) and neoplasms (1.26) in men, and infertility (1.87), obstructive sleep apnea (1.43), hepatic steatosis (1.43), rheumatoid arthritis (1.39) and menstrual disorders (1.18) in women were also associated with more severe outcomes. Conclusions Age and specific cardiovascular and metabolic diseases increased the risk of severe SARSCoV-2 infections in men and women, whereas the effects of certain comorbidities are sex specific. Future studies in different settings are encouraged to analyze which profiles of chronic patients are at higher risk of poor prognosis and should therefore be the targets of prevention and shielding strategies. © 2021 Gimeno-Miguel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: Results from the PRECOVID study in Spain

We aimed to analyze baseline socio-demographic and clinical factors associated with an increased likelihood of mortality in men and women with coronavirus disease (COVID-19). We conducted a retrospective cohort study (PRECOVID Study) on all 4412 individuals with laboratory-confirmed COVID-19 in Aragon, Spain, and followed them for at least 30 days from cohort entry. We described the socio-demographic and clinical characteristics of all patients of the cohort. Age-adjusted logistic regressions models were performed to analyze the likelihood of mortality based on demographic and clinical variables. All analyses were stratified by sex. Old age, specific diseases such as diabetes, acute myocardial infarction, or congestive heart failure, and dispensation of drugs like vasodilators, antipsychotics, and potassium-sparing agents were associated with an increased likelihood of mortality. Our findings suggest that specific comorbidities, mainly of cardiovascular nature, and medications at the time of infection could explain around one quarter of the mortality in COVID-19 disease, and that women and men probably share similar but not identical risk factors. Nonetheless, the great part of mortality seems to be explained by other patient-and/or health-system-related factors. More research is needed in this field to provide the necessary evidence for the development of early identification strategies for patients at higher risk of adverse outcomes

Decapping Protein Edc4 Regulates Dna Repair And Phenocopies Brca1

BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

OBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis

Global urban environmental change drives adaptation in white clover.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale