Cohort Profile: The epidemiology of chronic diseases and multimorbidity. The EpiChron cohort study

Why was the cohort set up? Greater life expectancy in Europe over the past few decades has been translated into an increasing burden of chronic diseases that accumulate as the population ages, whereas acute infectious diseases have been progressively pushed into the background. The incidence of conditions such as hypertension, obesity and asthma has increased dramatically worldwide, and cancer, diabetes and respiratory and cardiovascular diseases are responsible for almost 70% of global deaths. Concurrently, the prevalence of multimorbidity (as of people affected by more than one chronic disorder) is also increasing and appears as the most common chronic condition at present. Multimorbidity affects almost 3 in 4 individuals aged 65 years and older, although it represents a problem not only for the elderly but also for adult and even young populations, at whom prevention strategies should aim. People affected by multimorbidity often experience fragmentation of care, greater and inadequate use of health services and polypharmacy, which in turn may increase the risk of low adherence and adverse drug reactions. All of this leads to individuals’ quality of life deterioration and higher risk of mortality. Besides, handling patients with multimorbidity represents a daily challenge for physicians and health systems..

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)

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

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

The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era

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

Adherence to chronic medication in older populations: Application of a common protocol among three european cohorts

Purpose: The purpose of this study was to evaluate and compare medication adherence to chronic therapies in older populations across different regions in Europe. Methods: This explorative study applied a harmonized method of data extraction and analysis from pharmacy claims databases of three European countries to compare medication adherence at a cross-country level. Data were obtained for the period between January 1, 2010, and December 31, 2011. Patients (aged ≥65 years) who newly initiated to oral antidiabetics, antihyperlipidemics, or antiosteoporotics were identified and followed for over a 12-month period. Main outcome measures were medication adherence (medication possession ratio, [MPR]; implementation) and persistence on index treatment. All country-specific data sets were prepared by employing a common data input model. Outcome measures were calculated for each country and pooled using random effect models. Results: In total, 39,186 new users were analyzed. In pooled data from the three countries, suboptimal implementation (MPR <80%) was 52.45% (95% CI: 33.43–70.79) for antihyperlipidemics, 61.35% (95% CI: 52.83–69.22) for antiosteoporotics, and 30.33% (95% CI: 25.53–35.60) for oral antidiabetics. Similarly, rates of non-persistence (discontinuation) were 55.63% (95% CI: 35.24–74.29) for antihyperlipidemics, 60.24% (95% CI: 45.35–73.46) for antiosteoporotics, and 46.80% (95% CI: 36.40–57.4) for oral antidiabetics. Conclusion: Medication adherence was suboptimal with >50% of older people non-adherent to antihyperlipidemics and antiosteoporotics in the three European cohorts. However, the degree of variability in adherence rates among the three countries was high. A harmonized method of data extraction and analysis across health-related database in Europe is useful to compare medication-taking behavior at a cross-country level

Adherence to chronic medication in older populations: application of a common protocol among three European cohorts

Enrica Menditto,1,* Caitriona Cahir,2,* Mercedes Aza-Pascual-Salcedo,3,4 Dario Bruzzese,5 Beatriz Poblador-Plou,3 Sara Malo,6 Elisio Costa,7 Francisca Gonz&aacute;lez-Rubio,3,4,6 Antonio Gimeno-Miguel,3 Valentina Orlando,1 Przemyslaw Kardas,8 Alexandra Prados-Torres3 1CIRFF, Center of Pharmacoeconomics, University of Naples Federico II, Naples, Italy; 2Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; 3Aragon Health Sciences Institute (IACS), IIS Arag&oacute;n, REDISSEC ISCIII, Madrid, Spain; 4Aragon Health Service (SALUD), Aragon, Spain; 5Department of Public Health, Federico II University, Naples, Italy; 6University of Zaragoza, Zaragoza, Spain; 7UCIBIO, REQUINTE, Faculty of Pharmacy, Porto4ageing Reference Site, University of Porto, Porto, Portugal; 8Department of Family Medicine, Medical University of Lodz, Lodz, Poland&nbsp;*These authors contributed equally to this workPurpose: The purpose of this study was to evaluate and compare medication adherence to chronic therapies in older populations across different regions in Europe.Methods: This explorative study applied a harmonized method of data extraction and analysis from pharmacy claims databases of three European countries to compare medication adherence at a cross-country level. Data were obtained for the period between January 1, 2010, and December 31, 2011. Patients (aged &ge;65 years) who newly initiated to oral antidiabetics, antihyperlipidemics, or antiosteoporotics were identified and followed for over a 12-month period. Main outcome measures were medication adherence (medication possession ratio, [MPR]; implementation) and persistence on index treatment. All country-specific data sets were prepared by employing a common data input model. Outcome measures were calculated for each country and pooled using random effect models.Results: In total, 39,186 new users were analyzed. In pooled data from the three countries, suboptimal implementation (MPR &lt;80%) was 52.45% (95% CI: 33.43&ndash;70.79) for antihyperlipidemics, 61.35% (95% CI: 52.83&ndash;69.22) for antiosteoporotics, and 30.33% (95% CI: 25.53&ndash;35.60) for oral antidiabetics. Similarly, rates of non-persistence (discontinuation) were 55.63% (95% CI: 35.24&ndash;74.29) for antihyperlipidemics, 60.24% (95% CI: 45.35&ndash;73.46) for antiosteoporotics, and 46.80% (95% CI: 36.40&ndash;57.4) for oral antidiabetics.Conclusion: Medication adherence was suboptimal with &gt;50% of older people non-adherent to antihyperlipidemics and antiosteoporotics in the three European cohorts. However, the degree of variability in adherence rates among the three countries was high. A harmonized method of data extraction and analysis across health-related database in Europe is useful to compare medication-taking behavior at a cross-country level. Keywords: drug utilization, medication adherence, medication persistence, prescribin

High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies

[EN]Objective: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification

Effectiveness of the MULTIPAP Plus intervention in youngest-old patients with multimorbidity and polypharmacy aimed at improving prescribing practices in primary care: study protocol of a cluster randomized trial

10.1186/s13063-022-06293-xTrials231479