La influencia de la institucionalización sobre la percepción de la autonomía y la calidad de vida en ancianos

Objetivo Evaluar la influencia de la institucionalización en la autonomía y la calidad de vida percibida entre ancianos institucionalizados. Método Estudio casi-experimental (serie temporal interrumpida) y longitudinal. La muestra estuvo compuesta de 104 añosos de tres centros residenciales de Santander, España. A fin de evaluar la calidad de vida y la dependencia fueron utilizadas dos escalas: el Índice de Barthel y el Índice de Lawton. Resultados Se observó una relación significativa entre la autonomía y la independencia y su declinio en virtud de la institucionalización, como los aspectos físicos y sociales. Conclusión La dependencia de las personas mayores es un fenómeno complejo, que demanda distintos tipos de intervención, incluyéndose las acciones de apoyo común, que tienden a cubrir la ausencia de autonomía en la vida cuotidiana, sin recurrir a la institucionalización.Objective To evaluate the influence exercised by institutionalization on the autonomy and perception of quality of life among the institutionalized elderly. Method The study is quasi-experimental (interrupted time series) and longitudinal. The sample is composed for 104 elderly people who went into a three nursing home in Santander, Spain. To assess the quality of life and dependence two scales were used: the Barthel Index and Lawton Index. Results There was an important relationship between autonomy and independence and their deterioration due to their institutionalisation, such as the physical and social aspects. Conclusion It´s important to point out that the dependence of the elderly is a complex phenomenon, which admits many types of intervention, including the customary ones referring to more classic welfare actions which tend to supplant the absence of autonomy in everyday life by facilitating services and attention to make up for this need, without having to resort to institutionalization.Objetivo Avaliar a influência da institucionalização na autonomia e na qualidade de vida percebida entre idosos institucionalizados. Método Estudo quase-experimental (série temporal interrompida) e longitudinal. A amostra foi composta de 104 idosos de três centros residenciais de Santander na Espanha. Para avaliar a qualidade de vida e a dependência foram utilizadas duas escalas: o Índice de Barthel e o Índice de Lawton. Resultados Observou-se uma relação significativa entre autonomia e independência e seu declínio devido à institucionalização, como os aspectos físicos e sociais. Conclusão A dependência dos idosos é um fenômeno complexo, que demanda vários tipos de intervenção, incluindo as ações de apoio comum, que tendem a cobrir a ausência de autonomia na vida cotidiana, sem recorrer a institucionalização

Automatic Identification of Patients With Unexplained Left Ventricular Hypertrophy in Electronic Health Record Data to Improve Targeted Treatment and Family Screening

Background: Unexplained Left Ventricular Hypertrophy (ULVH) may be caused by genetic and non-genetic etiologies (e.g., sarcomere variants, cardiac amyloid, or Anderson-Fabry's disease). Identification of ULVH patients allows for early targeted treatment and family screening. Aim: To automatically identify patients with ULVH in electronic health record (EHR) data using two computer methods: text-mining and machine learning (ML). Methods: Adults with echocardiographic measurement of interventricular septum thickness (IVSt) were included. A text-mining algorithm was developed to identify patients with ULVH. An ML algorithm including a variety of clinical, ECG and echocardiographic data was trained and tested in an 80/20% split. Clinical diagnosis of ULVH was considered the gold standard. Misclassifications were reviewed by an experienced cardiologist. Sensitivity, specificity, positive, and negative likelihood ratios (LHR+ and LHR-) of both text-mining and ML were reported. Results: In total, 26,954 subjects (median age 61 years, 55% male) were included. ULVH was diagnosed in 204/26,954 (0.8%) patients, of which 56 had amyloidosis and two Anderson-Fabry Disease. Text-mining flagged 8,192 patients with possible ULVH, of whom 159 were true positives (sensitivity, specificity, LHR+, and LHR- of 0.78, 0.67, 2.36, and 0.33). Machine learning resulted in a sensitivity, specificity, LHR+, and LHR- of 0.32, 0.99, 32, and 0.68, respectively. Pivotal variables included IVSt, systolic blood pressure, and age. Conclusions: Automatic identification of patients with ULVH is possible with both Text-mining and ML. Text-mining may be a comprehensive scaffold but can be less specific than machine learning. Deployment of either method depends on existing infrastructures and clinical applications

STRAD Pseudokinases Regulate Axogenesis and LKB1 Stability

BACKGROUND: Neuronal polarization is an essential step of morphogenesis and connectivity in the developing brain. The serine/threonine kinase LKB1 is a key regulator of cell polarity, metabolism, tumorigenesis, and is required for axon formation. It is allosterically regulated by two related and evolutionarily conserved pseudokinases, STe20-Related ADapters (STRADs) α and β. The roles of STRADα and STRADβ in the developing nervous system are not fully defined, nor is it known whether they serve distinct functions. RESULTS: We find that STRADα is highly spliced and appears to be the primal STRAD paralog. We report that each STRAD is sufficient for axogenesis and promoting cell survival in the developing cortex. We also reveal a reciprocal protein-stabilizing relationship in vivo between LKB1 and STRADα, whereby STRADα specifically maintains LKB1 protein levels via cytoplasmic compartmentalization. CONCLUSIONS: We demonstrate a novel role for STRADβ in axogenesis and also show for the first time in vivo that STRADα, but not STRADβ, is responsible for LKB1 protein stability

Genomic DNA Pooling Strategy for Next-Generation Sequencing-Based Rare Variant Discovery in Abdominal Aortic Aneurysm Regions of Interest—Challenges and Limitations

The costs and efforts for sample preparation of hundreds of individuals, their genomic enrichment for regions of interest, and sufficient deep sequencing bring a significant burden to next-generation sequencing-based experiments. We investigated whether pooling of samples at the level of genomic DNA would be a more versatile strategy for lowering the costs and efforts for common disease-associated rare variant detection in candidate genes or associated loci in a substantial patient cohort. We performed a pilot experiment using five pools of 20 abdominal aortic aneurysm (AAA) patients that were enriched on separate microarrays for the reported 9p21.3 associated locus and 42 additional AAA candidate genes, and sequenced on the SOLiD platform. Here, we discuss challenges and limitations connected to this approach and show that the high number of novel variants detected per pool and allele frequency deviations to the usually highly false positive cut-off region for variant detection in non-pooled samples can be limiting factors for successful variant prioritization and confirmation. We conclude that barcode indexing of individual samples before pooling followed by a multiplexed enrichment strategy should be preferred for detection of rare genetic variants in larger sample sets rather than a genomic DNA pooling strategy

Genotype-phenotype correlation in pseudoxanthoma elasticum

Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (13: 0.39, 95%CI:-0.62;-0.17) and total (13: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability

The genetic basis of apparently idiopathic ventricular fibrillation:A retrospective overview

Aims: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. Methods and results: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P &lt; 0.001). Conclusion: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.</p

Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort:The Use of Genetic Testing in Risk Stratification

BACKGROUND: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis. METHODS: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017. RESULTS: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and "other" in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0-4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3-5.8, P = 0.007), while transplant-free survival was significantly lower (P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups. CONCLUSIONS: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrim

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.</p