Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy.

The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene (Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy

Kitchen Area Air Quality Measurements in Northern Ghana: Evaluating the Performance of a Low-Cost Particulate Sensor within a Household Energy Study

Household air pollution from the combustion of solid fuels is a leading global health and human rights concern, affecting billions every day. Instrumentation to assess potential solutions to this problem faces challenges-especially related to cost. A low-cost ($159) particulate matter tool called the Household Air Pollution Exposure (HAPEx) Nano was evaluated in the field as part of the Prices, Peers, and Perceptions cookstove study in northern Ghana. Measurements of temperature, relative humidity, absolute humidity, and carbon dioxide and carbon monoxide concentrations made at 1-min temporal resolution were integrated with 1-min particulate matter less than 2.5 microns in diameter (PM2.5) measurements from the HAPEx, within 62 kitchens, across urban and rural households and four seasons totaling 71 48-h deployments. Gravimetric filter sampling was undertaken to ground-truth and evaluate the low-cost measurements. HAPEx baseline drift and relative humidity corrections were investigated and evaluated using signals from paired HAPEx, finding significant improvements. Resulting particle coefficients and integrated gravimetric PM2.5 concentrations were modeled to explore drivers of variability; urban/rural, season, kitchen characteristics, and dust (a major PM2.5 mass constituent) were significant predictors. The high correlation (R2 = 0.79) between 48-h mean HAPEx readings and gravimetric PM2.5 mass (including other covariates) indicates that the HAPEx can be a useful tool in household energy studies.</p

FLNC Gene Splice Mutations Cause Dilated\ua0Cardiomyopathy

OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM

A glimpse into real-world kitchens: Improving our understanding of cookstove usage through in-field photo-observations and improved cooking event detection (CookED) analytics

The combustion of solid fuels in residential cookstoves is a global health and climate issue, and expanded use ofimproved cookstoves could have significant benefits locally and globally. Evaluating impacts of improved cookstove programs requires more accurately measuring stove use patterns. This work builds on and improves existing stove use monitoring methods. First, we introduce and describe a novel, in-field photo-observation sampling method designed to capture near-continuous, real-world, ground-truth stove usage information. These measurements are used to validate predictions made by electronic stove use monitors (SUMs). Second, we present Cooking Event Detector (CookED), a SUM algorithm that translates stove-temperature measurements into classifications of cooking or not-cooking. The predictive performance of the new algorithm is evaluated using results from the photo-observations and compared to existing algorithms. CookED demonstrates considerable improvement over some methods for all five types of improved and traditional stoves monitored in the study. Overall minute-level predictive accuracy of CookED ranges from 95.6% to 98.4%, depending on the stove type, while Matthews correlation coefficients range from 72.8% to 88.3%. Comparisons between predicted and observed average cooking event durations show high correlation (Pearson&rsquo;s r = 0.85). These methods can be applied in a wide variety of applications, including research studies linking behavior, technology, exposure, and human and environmental health, as well as operational programs that aim to scale up improved cookstove adoption and quantify benefits.</p

A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies

8siTitin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.openopenGigli, Marta; Begay, Rene L; Morea, Gaetano; Graw, Sharon L; Sinagra, Gianfranco; Taylor, Matthew R G; Granzier, Henk; Mestroni, LuisaGigli, Marta; Begay, Rene L; Morea, Gaetano; Graw, Sharon L; Sinagra, Gianfranco; Taylor, Matthew R. G; Granzier, Henk; Mestroni, Luis

Kitchen Area Air Quality Measurements in Northern Ghana: Evaluating the Performance of a Low-Cost Particulate Sensor within a Household Energy Study

Household air pollution from the combustion of solid fuels is a leading global health and human rights concern, affecting billions every day. Instrumentation to assess potential solutions to this problem faces challenges&mdash;especially related to cost. A low-cost ($159) particulate matter tool called the Household Air Pollution Exposure (HAPEx) Nano was evaluated in the field as part of the Prices, Peers, and Perceptions cookstove study in northern Ghana. Measurements of temperature, relative humidity, absolute humidity, and carbon dioxide and carbon monoxide concentrations made at 1-min temporal resolution were integrated with 1-min particulate matter less than 2.5 microns in diameter (PM2.5) measurements from the HAPEx, within 62 kitchens, across urban and rural households and four seasons totaling 71 48-h deployments. Gravimetric filter sampling was undertaken to ground-truth and evaluate the low-cost measurements. HAPEx baseline drift and relative humidity corrections were investigated and evaluated using signals from paired HAPEx, finding significant improvements. Resulting particle coefficients and integrated gravimetric PM2.5 concentrations were modeled to explore drivers of variability; urban/rural, season, kitchen characteristics, and dust (a major PM2.5 mass constituent) were significant predictors. The high correlation (R2 = 0.79) between 48-h mean HAPEx readings and gravimetric PM2.5 mass (including other covariates) indicates that the HAPEx can be a useful tool in household energy studies

Role of Titin Missense Variants in Dilated Cardiomyopathy

BACKGROUND-\u2014The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation. METHODS AND RESULTS-\u2014A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 \u201csevere\u201d rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN \u201csevere\u201d variants). Segregation analysis allowed the classification of the \u201csevere\u201d variants into 5 \u201clikely\u201d (cosegregating), 5 \u201cunlikely\u201d (noncosegregating), and 34 \u201cpossibly\u201d (where family structure precluded segregation analysis) disease-causing variants. Patients with DCM carrying \u201clikely\u201d or \u201cpossibly\u201d pathogenic TTN \u201csevere\u201d variants did not show a different outcome compared with \u201cunlikely\u201d and noncarriers of a \u201csevere\u201d TTN variant. However, the \u201clikely\u201d and \u201cpossibly\u201d disease-causing variants were overrepresented in the C-zone of the A-band region of the sarcomere. CONCLUSIONS-\u2014TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically \u201csevere\u201d TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of \u201clikely\u201d and \u201cpossibly\u201d disease-causing variants suggests a potential biological role for some TTN missense variants

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM) patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C (FLNC), resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM