Search

Age of stratospheric air is a well established metric for the stratospheric transport circulation. Rooted in a robust theoretical framework, this approach offers the benefit of being deducible from observations of trace gases. Given potential climate‐induced changes, observational constraints on stratospheric circulation are crucial. In the past two decades, scientific progress has been made in three main areas: (a) Enhanced process understanding and the development of process diagnostics led to better quantification of individual transport processes from observations and to a better understanding of model deficits. (b) The global age of air climatology is now well constrained by observations thanks to improved quality and quantity of data, including global satellite data, and through improved and consistent age calculation methods. (c) It is well established and understood that global models predict a decrease in age, that is, an accelerating stratospheric circulation, in response to forcing by greenhouse gases and ozone depleting substances. Observational records now confirm long‐term forced trends in mean age in the lower stratosphere. However, in the mid‐stratosphere, uncertainties in observational records are too large to confirm or disprove the model predictions. Continuous monitoring of stratospheric trace gases and further improved methods to derive age from those tracers will be crucial to better constrain variability and long‐term trends from observations. Future work on mean age as a metric for stratospheric transport will be important due to its potential to enhance the understanding of stratospheric composition changes, address climate model biases, and assess the impacts of proposed climate geoengineering methods. Plain Language Summary: Transport strongly influences the composition of the stratosphere, the layer at around 10–50 km altitude. Air masses are transported upward into the stratosphere in the tropics, and get distributed globally by a hemisphere‐wide overturning circulation. Stratospheric age of air is a measure of the transport times along this circulation. This metric is a crucial measure of the circulation strength, deducible from observations of certain stratospheric gases. Over the past two decades, scientific progress has been made in three main areas. First, we now understand better which processes influence transport times. Second, we have good knowledge on the global average distribution of age of air, thanks to more observational data and improved methods to deduce this metric. Third, a large focus has been on climate‐change related trends in age of air. While it is well established and understood that global models predict an accelerating stratospheric circulation, the related decrease in age of air can only be confirmed observationally in the lower stratosphere. Continuous monitoring of stratospheric trace gases will be crucial to constrain circulation trends throughout the stratosphere. This is essential for understanding climate change effects, improving climate models, and assessing potential climate intervention strategies. Key Points: Understanding of how individual processes impact stratospheric age of air has been improved through development of dedicated diagnosticsThe global age of air climatology is now well constrained by observations thanks to improved data records and age calculation methodsObserved age trends confirm lower stratospheric model predictions but are too uncertain to confirm or dismiss middle stratospheric trends [ABSTRACT FROM AUTHOR]

Background: Protein‐losing enteropathy (PLE) is a devastating complication of the Fontan circulation. Although orthotopic heart transplantation (HTx) typically results in resolution of PLE symptoms, isolated cases of PLE relapse have been described after HTx. Methods: Patients with Fontan‐related PLE who had undergone HTx at participating centers and experienced relapse of PLE during follow‐up were retrospectively identified. Available data related to pre‐ and post‐HTx characteristics and PLE events were collected. Results: Eight patients from four different centers were identified. Median time from Fontan procedure to the development of PLE was 8 years, and median age at HTx was 17 years (range 7.7–21). In all patients, PLE resolved at a median time of 1 month after HTx (0.3–5). PLE recurrences occurred at a median time of 7.5 months after HTx (2–132). Each occurrence was associated with one or more significant clinical events; most commonly cellular‐ or antibody‐mediated rejection; and less commonly graft dysfunction, infection, thrombosis, and posttransplant lymphoproliferative disease. PLE recurrences resolved after the successful treatment of the concomitant event, after a median time of 2 months in seven cases, while persisted and recurred in one patient in association with atypical mycobacterium infection and subsequent PTLD onset and relapses. Six patients were alive during follow‐up at a median time of 4 years (1.3–22.5) after HTx. Conclusions: This is the largest series of PLE recurrence after HTx. All cases were associated with one or more concomitant and significant clinical events. PLE typically resolved after resolution of the inciting clinical event. [ABSTRACT FROM AUTHOR]

Precision medicine genetics study design requires large, diverse cohorts and thoughtful use of electronic technologies. Involving patients in research design may increase enrollment and engagement, thereby enabling a means to relevant patient outcomes in clinical practice. Few data, however, illustrate attitudes of patients with dilated cardiomyopathy (DCM) and their family members toward genetic study design. This study assessed attitudes of 16 enrolled patients and their family members (P/FM), and 18 investigators or researchers (I/R) of the ongoing DCM Precision Medicine Study during a conjoint patient and investigator meeting using structured, self‐administered surveys examining direct‐to‐participant enrollment and web‐based consent, return of genetic results, and other aspects of genetic study design. Survey respondents were half women and largely identified as white. Web‐based consent was supported by 93% of P/FM and 88% of I/R. Most respondents believed that return of genetic results would motivate study enrollment, but also indicated a desire to opt out. Ideal study design preferences included a 1‐hour visit per year, along with the ability to complete study aspects by telephone or web and possibility of prophylactic medication. This study supports partnership of patients and clinical researchers to inform research priorities and study design to attain the promise of precision medicine for DCM. [ABSTRACT FROM AUTHOR]

Background: Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A‐band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. Methods: Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. Results: Forty‐nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3') end of the A‐band. All cardioskeletal probands had onset of proximal‐predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. Conclusion: Although heterozygous TTNtv in the A‐band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb‐girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A‐band TTNtv who may be at risk for multisystem disease. [ABSTRACT FROM AUTHOR]

Aims: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. Methods and results: We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo. Conclusions: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility. [ABSTRACT FROM AUTHOR]

Methyl ethyl ketone (MEK) is a relatively abundant but understudied oxygenated volatile organic compound that can serve as a source of both HOx and PAN when photooxidized. We use aircraft observations of MEK from the remote marine troposphere to show that the ocean serves as a source of MEK to the atmosphere during both meteorological winter and summer. There is pronounced seasonality in the MEK profiles in the extratropical troposphere, with higher MEK mixing ratios observed in summer than in winter. MEK in clean air over the remote oceans correlates with both acetone and acetaldehyde, whose primary sources in the ocean water are the photooxidation of organic material. We show that even a small (>1 nM) concentration of MEK in surface waters is sufficient to allow the ocean to be a net source of MEK to the atmosphere over ocean basins across multiple seasons. Plain language summary: Methyl ethyl ketone (MEK) is an abundant but understudied gas in Earth' atmosphere, which is emitted into the atmosphere from both human and natural sources. When MEK is broken apart by ultraviolet sunlight, the products released by those reactions play important roles in the formation and destruction of air pollution. In this paper, we show that the oceans are a source of MEK to the atmosphere. The oceanic emissions we document correlate strongly with some other gases that are known to be produced in the ocean but not those most closely associated with the growth of microscopic oceanic phytoplankton. Finding this new source helps us better understand the importance of MEK to the atmosphere and provides guidance for future oceanic and atmospheric research. Key Points: We use aircraft observations of MEK from the remote marine troposphere to suggest that the ocean is a source of MEK to the atmosphereEvidence exists for this source in both winter and summer in the tropical Pacific, south Atlantic and Pacific, and in the Southern OceanMEK in clean air over the remote oceans does not correlate with DMS, but it does correlate with acetone and acetaldehyde [ABSTRACT FROM AUTHOR]

The U.S. government has become increasingly focused on school climate, as recently evidenced by its inclusion as an accountability indicator in the Every Student Succeeds Act. Yet, there remains considerable variability in both conceptualizing and measuring school climate. To better inform the research and practice related to school climate and its measurement, we leveraged item response theory (IRT), a commonly used psychometric approach for the design of achievement assessments, to create a parsimonious measure of school climate that operates across varying individual characteristics. Students (n = 69,513) in 111 secondary schools completed a school climate assessment focused on three domains of climate (i.e., safety, engagement, and environment), as defined by the U.S. Department of Education. Item and test characteristics were estimated using the mirt package in R using unidimensional IRT. Analyses revealed measurement difficulties that resulted in a greater ability to assess less favorable perspectives on school climate. Differential item functioning analyses indicated measurement differences based on student academic success. These findings support the development of a broad measure of school climate but also highlight the importance of work to ensure precision in measuring school climate, particularly when considering use as an accountability measure. [ABSTRACT FROM AUTHOR]

Genome‐scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high‐quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants. ClinGen is organizing Variant Curation Expert Panels (VCEPs) to develop specifications to the ACMG/AMP guidelines for genes or diseases of interest, interpret variants according to these guidelines, and publish the expert interpretations through the publicly available ClinVar database. A stepwise process was iteratively developed for ClinGen VCEPs to apply to submit variant assertions to ClinVar at the Expert Panel level of review. Other groups that wish to assemble as VCEPs are encouraged, though not required, to follow these steps. [ABSTRACT FROM AUTHOR]

An effective approach for the design of spectrum estimation (SE) in cognitive radio systems using multi‐taper method (MTM) and spatiotemporal features is presented in this study, whereas the MTM balances the bias‐variance dilemma, the multiple‐input–multiple‐output (MIMO) and space–time block code (STBC) are customarily aimed to defeat the adverse channel effects and enhance the system capacity and performance. The singular value decomposition is exploited to determine the dominant eigenchannels in MIMO and STBC setups. The maximum‐ratio combining, on the other hand, is adopted to produce higher signal‐to‐noise ratios usually intended for high data rates and reliability levels. The statistical analysis and modelling of the performance metrics associated with the SE based on MTM‐STBC and MIMO are approached using the quadratic form approximation. Simulation exercises are employed to compare this different SE, which will be called multitaper spectrum estimation (MTSE), against other typical methods such as the periodogram without tapering options. The results exhibit performance gains due to the merger of MTSE and STBC technologies over MIMO and periodogram SE (PSE) algorithms. Further computational analysis shows that the MTSE–STBC has no extra burdens compared with its PSE counterpart. [ABSTRACT FROM AUTHOR]

The stratospheric circulation is an important element of climate as it determines the concentration of radiatively active species like water vapor and aerosol above the tropopause. Climate models predict that increasing greenhouse gas levels speed up the stratospheric circulation. However, these results have been challenged by observational estimates of the circulation strength, constituting an uncertainty in current climate simulations. Here, we quantify the effect of volcanic aerosol on the stratospheric circulation focusing on the Mount Pinatubo eruption and discussing further the minor extratropical volcanic eruptions after 2008. We show that the observed pattern of decadal circulation change over the past decades is substantially driven by volcanic aerosol injections. Thus, climate model simulations need to realistically take into account the effect of volcanic eruptions, including the minor eruptions after 2008, for a reliable reproduction of observed stratospheric circulation changes. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy ( DCM) is a disease of the myocardium characterized by left ventricular dilatation and diminished contractile function. Here we describe a novel DCM mutation in the myosin regulatory light chain ( RLC), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first-degree relatives who met formal criteria for idiopathic DCM. To obtain insight into the functional significance of this pathogenic MYL2 variant, we cloned and purified the human ventricular RLC wild-type ( WT) and D94A mutant proteins, and performed in vitro experiments using RLC-mutant or WT-reconstituted porcine cardiac preparations. The mutation induced a reduction in the α-helical content of the RLC, and imposed intra-molecular rearrangements. The phosphorylation of RLC by Ca2+/calmodulin-activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of RLC to the myosin heavy chain, and its incorporation into RLC-depleted porcine myosin. The actin-activated ATPase activity of mutant-reconstituted porcine cardiac myosin was significantly higher compared with ATPase of wild-type. No changes in the myofibrillar ATPase- pCa relationship were observed in wild-type- or D94A-reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross-section of muscle, with no change in the calcium sensitivity of force in D94A-reconstituted skinned porcine papillary muscle strips compared with wild-type. Our data indicate that subtle structural rearrangements in the RLC molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the DCM phenotype. [ABSTRACT FROM AUTHOR]

Background The value of family history (FH) is well established, but its sensitivity to detect familial dilated cardiomyopathy (FDC) has been infrequently examined. Methods A genetic ancillary study was created as a component of the HF-ACTION trial, a multicenter, prospective, randomized clinical trial of exercise in patients with heart failure and an ejection fraction <35%. A FH-based study using a structured questionnaire mailed to all consenting individuals was incorporated into the genetic ancillary. FH responses were analyzed for dilated cardiomyopathy (DCM) in family members. Results Of the 741 individuals with data available, 358 (48.3%) had nonischemic and 383 (51.6%) had ischemic etiology, and of these 164 (45.8%) and 201 (52.4%), respectively, returned evaluable questionnaires. Of those with nonischemic etiology, 14/164 (8.5%) reported at least one first-degree family member with DCM or an enlarged heart; another 21/164 (12.8%) reported a FH of 'cardiomyopathy,' a less specific term to indicate DCM. Conclusion At least 8.5% of patients with nonischemic etiology in the HF-ACTION genetic ancillary study provided FH indicating familial DCM, information important to inform further genetic analyses of this cohort and to plan other studies. [ABSTRACT FROM AUTHOR]

Although refugees are generally thought to be at increased risk for posttraumatic stress disorder (PTSD) and major depressive episode (MDE), few studies have compared onset of PTSD and MDE between refugees and voluntary migrants. Given differences in migration histories, onset should differ pre- and postmigration. The National Latino and Asian American Survey (NLAAS) is a national representative, complex dataset measuring psychiatric morbidity, mental health service use, and migration history among Latino and Asian immigrants to the United States. Of the 3,260 foreign-born participants, 660 were refugees (a weighted proportion of 9.52%). Refugees were more likely to report a history of war-related trauma, but reports of other traumatic events were similar. Premigration onset of PTSD was statistically higher for refugees than voluntary migrants, odds ratio ( OR) = 4.86, 95% confidence interval (CI) [2.01, 11.76], where postmigration onset for PTSD was not, OR = 0.61, 95% CI [0.29, 1.28]; a similar pattern was found for MDE, OR = 1.98, 95% CI [1.11, 3.51]; and OR = 1.02, 95% CI [0.65, 1.62], respectively. Although refugees arrive in host countries with more pressing psychiatric needs, onset is comparable over time, suggesting that postmigration refugees and voluntary migrants may be best served by similar programs. [ABSTRACT FROM AUTHOR]

Environmentally smart nitrogen (ESN) is a polymer-coated form of N that provides controlled-release, allowing higher seed-placed safe rates of urea fertilizer. The influence of coating integrity on the rate of N release in field conditions is unknown. Field studies were conducted from 2008 to 2011 near Lethbridge, AB, Canada, to determine the impact of handling methods on the polymer coating of ESN when seed-placed with canola (Brassica napus L.), wheat (Triticum aestivum L.), or triticale (X Triticosecale Wittmack). Abrasion levels were created through laboratory simulation (0-80% N release after 7d in 23°C water, calibrated in increments of 10%; Exp. 1), or from handling by collecting ESN from exit points on nine implements, which was subjected to two methods of loading and unloading at the retail point and farm (9×2×2 factorial; Exp. 2). Nitrogen release data was related to plant responses in the field by seed placing the ESN at rates of 45 kg N ha-1 with canola and 90 kg N ha-1 for cereals. At the highest N release treatment in Exp. 1, winter cereal and canola stands were reduced by ∼30% and spring cereals by 18%. Grain yield was unaffected in winter wheat but reduced in canola and spring cereals by 20 and 10%, respectively. In Exp. 2, abrasion from transferring ESN in equipment containing scaly deposits or seeders configured with header-manifold systems operating at high fan speeds corresponded to higher N release treatments, which reduced winter wheat and canola stands. Crop injury and grain yield, however, was usually mitigated through proper equipment maintenance and settings. [ABSTRACT FROM AUTHOR]

The Central Claypan region is an important agricultural production contributor in the U.S. Midwest. Because of the tendency for grain yield fluctuations caused by water stress, however, claypan soils may have potential for conversion from grain to grass production in support of biomass energy markets and conservation programs. This study examined the economic potential of transitioning from grain to perennial switchgrass (Panicum virgatum L.) production on claypan soils using comparative break- even analysis. Partial budgets for a corn (Zea mays L.)-soybean [Glycine max (L.) Merr.] rotation and a perennial switchgrass cropping system were developed. Yield data from research plots with varying topsoil depths defined by the underlying claypan layer were used to establish yield expectations as affected by topsoil depth. Switchgrass yield projections for the claypan region were simulated with the Agricultural Land Management Alternatives with Numerical Assessment Criteria (ALMANAC) model. Comparative breakeven prices for two switchgrass cultivars ranged from US$65 on marginal, eroded soils to US$124 Mg-1 on soils with >27cm of topsoil. Breakeven yields with a biomass price of US$40 Mg-1 would require yield increases of up to 450% for lower yielding cultivars. The switchgrass cultivar Kanlow holds the most promise for biomass production on claypan soils; with an average projected yield of 12.56 Mg ha-1, breakeven prices fall to around US$60-80 Mg-1 for marginal soils with <15cm of topsoil. Based on these projections, perennial switchgrass shows potential to compete with conventional grain crops at reasonable yield levels on eroded soils in the Central Claypan region. [ABSTRACT FROM AUTHOR]

Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70-year-old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time ( DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life-threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life-threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding. [ABSTRACT FROM AUTHOR]

The article focuses on the composition and combustion performance of biodiesel produced from waste cooking oil (WCO). It states that biodiesel is composed of fatty acid methyl esters and contains 75 percent of oleic acids and linoleic acids. It mentions that biodiesel produced from WCO has a higher viscosity, cetane number and density than conventional diesel. It reports that the use of biodiesel reduces exhaust emissions of particulate matter, total hydrocarbons and carbon monoxide.

Obtaining functional data with newly identified rare variants increases certainty that the variant identified is relevant for dilated cardiomyopathy (DCM) causation. Two novel SCN5A rare variants, R222Q and I1835T, segregated with DCM in two families with affected individuals homozygous or heterozygous for the common SCN5A polymorphism H558R. cDNAs with each rare variant were constructed in the common Q1077del or Q1077 splice variant backgrounds with and without the H558R polymorphism and expressed in HEK293 cells. Sodium current ( I) was studied for each using whole-cell voltage clamp. In the Q1077del background I densities of R222Q and I1835T were not different from wild type, but the combined variants of R222Q/H558R, I1835T/H558R caused approximately 35% and approximately 30% reduction, respectively, and each showed slower recovery from inactivation. In the Q1077del background R222Q and R222Q/H558R also exhibited a significant negative shift in both activation and inactivation while I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak I densities, decay, or recovery from inactivation for R222Q/H558R and I1835T/H558R. We conclude that the biophysical findings, dependent upon common SCN5A variants, provide further evidence that these novel SCN5A rare variants are relevant for DCM. Clin Trans Sci 2010; Volume 3: 287-294 [ABSTRACT FROM AUTHOR]

Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year-old woman, previously healthy with a left ventricular ejection fraction of 50%-55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring cardiac transplantation. Clinical genetic testing revealed a novel TNNT2 R139H mutation but no relevant variants in 18 other DCM genes. Her explanted heart showed partial fatty replacement in the right ventricle. Sequencing for five arrhythmogenic right ventricular dysplasia genes was negative. Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca sensitivity at pH 7, characteristic of DCM. Because fatty infiltration may acidify the myocellular environment, maximal force development examined at pH 6.5 was diminished, suggesting a possible environmental trigger. We conclude that the TNNT2 R139H mutation was likely to be disease causing. Further, later age of onset may not be relevant to exclude genetic testing for TNNT2 mutations. Clin Trans Sci 2010; Volume 3: 219-226. [ABSTRACT FROM AUTHOR]

The genetic basis of most of dilated cardiomyopathy (DCM) cases remains unknown. A recent study indicated that mutations in a highly localized five amino acid hotspot in exon 9 of RBM20, a gene encoding a ribonucleic acid-binding protein, caused aggressive DCM. We undertook this study to confi rm and extend the nature of RBM20 mutations in another DCM cohort. Clinical cardiovascular data, family histories, and blood samples were collected from patients with idiopathic DCM. DNA from 312 DCM probands was sequenced for nucleotide alterations in exons 6 through 9 of RBM20, and additional family members as possible. We found six unique RBM20 rare variants in six unrelated probands (1.9%). Four mutations, two of which were novel (R634W and R636C) and two previously identified (R634Q and R636H), were identified in a five amino acid hotspot in exon 6. Two other novel variants (V535I in exon 6 and R716Q in exon 9) were outside of this hotspot. Age of onset and severity of heart failure were variable, as were arrhythmias and conduction system defects, but many subjects suffered severe heart failure resulting in early death or cardiac transplantation. This article concludes that DCM in patients with RBM20 mutations is associated with advanced disease. Clin Trans Sci 2010; Volume 3: 90–97 [ABSTRACT FROM AUTHOR]

Rare mutations in more than 20 genes have been suggested to cause dilated cardiomyopathy (DCM), but explain only a small percentage of cases, mainly in familial forms. We hypothesised that more common variants may also play a role in increasing genetic susceptibility to DCM, similar to that observed in other common complex disorders. To test this hypothesis, we performed case-control analyses on all DNA polymorphic variation identified in a resequencing study of six candidate DCM genes ( CSRP3, LDB3, MYH7, SCN5A, TCAP, and TNNT2) conducted in 289 unrelated white probands with DCM of unknown cause and 188 unrelated white controls. In univariate analyses, we identified associated common variants at LDB3 site 10779, LDB3 site 57877, MYH7 sites 16384 and 17404, and TCAP sites 140 and 1735. Multivariate analyses to examine the joint effects of multiple gene variants confirmed univariate results for MYH7 and TCAP and identified a block of nine variants in MYH7 that was strongly associated with DCM. Common variants in genes known to be causative of DCM may play a role in genetic susceptibility to DCM. Our results suggest that examination of common genetic variants may be warranted in future studies of DCM and other Mendelian-like disorders. [ABSTRACT FROM AUTHOR]

Background and purpose: α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4- a]phthalazine) is a triazolophthalazine with subnanomolar affinity for α1-, α2-, α3- and α5-containing GABAA receptors. Here we have evaluated the relationship between plasma α5IA concentrations and benzodiazepine binding site occupancy in rodents and primates (rhesus monkey). Experimental approach: In awake rats, occupancy was measured at various times after oral dosing with α5IA (0.03–30 mg·kg−1) using an in vivo {[3H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester)} binding assay. In anaesthetized rhesus monkeys, occupancy was measured using {[123I]iomazenil (ethyl 5,6-dihydro-7-iodo-5-methyl-6-oxo-4 H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester)} γ-scintigraphy and a bolus/infusion paradigm. In both rat and rhesus monkey, the plasma drug concentration corresponding to 50% occupancy (EC50) was calculated. Key results: In rats, α5IA occupancy was dose- and time-dependent with maximum occupancy occurring within the first 2 h. However, rat plasma EC50 was time-independent, ranging from 42 to 67 ng·mL−1 over a 24 h time course with the average being 52 ng·mL−1 (i.e. occupancy decreased as plasma drug concentrations fell). In rhesus monkeys, the EC50 for α5IA displacing steady-state [123I]iomazenil binding was 57 ng·mL−1. Conclusions and implications: Rat plasma EC50 values did not vary as a function of time indicating that α5IA dissociates readily for the GABAA receptor in vivo. These data also suggest that despite the different assays used (terminal assays of [3H]flumazenil in vivo binding in rats and [123I]iomazenil γ-scintigraphy in anaesthetized rhesus monkeys), these techniques produced similar plasma α5IA EC50 values (52 and 57 ng·mL−1 respectively) and that the plasma–occupancy relationship for α5IA translates across these two species. [ABSTRACT FROM AUTHOR]

Background: More than 20 genes have been reported to cause idiopathic and familial dilated cardiomyopathy (IDC/FDC), but the frequency of genetic causation remains poorly understood. Methods and Results: Blood samples were collected and DNA prepared from 313 patients, 183 with FDC and 130 with IDC. Genomic DNA underwent bidirectional sequencing of six genes, and mutation carriers were followed up by evaluation of additional family members. We identified in 36 probands, 31 unique protein-altering variants (11.5% overall) that were not identified in 253 control subjects (506 chromosomes). These included 13 probands (4.2%) with 12 β-myosin heavy chain ( MYH7) mutations, nine probands (2.9%) with six different cardiac troponin T ( TNNT2) mutations, eight probands (2.6%) carrying seven different cardiac sodium channel ( SCN5A) mutations, three probands (1.0%) with three titin-cap or telethonin ( TCAP) mutations, three probands (1.0%) with two LIM domain binding 3 ( LDB3) mutations, and one proband (0.3%) with a muscle LIM protein ( CSRP3) mutation. Four nucleotide changes did not segregate with phentoype and/or did not alter a conserved amino acid and were therefore considered unlikely to be disease-causing. Mutations in 11 probands were assessed as likely disease-causing, and in 21 probands were considered possibly disease-causing. These 32 probands included 14 of the 130 with IDC (10.8%) and 18 of the 183 with FDC (9.8%) Conclusions: Mutations of these six genes each account for a small fraction of the genetic cause of FDC/IDC. The frequency of possible or likely disease-causing mutations in these genes is similar for IDC and FDC. [ABSTRACT FROM AUTHOR]

In this emerging era of cardiovascular genetic medicine, increasing responsibility will be placed on cardiovascular practitioners to be aware of the latest clinical genetic testing methods and the knowledge base needed to interpret genetic test results. Some cardiovascular specialists will develop the expertise within the field to order genetic testing and interpret results, while other practitioners will refer patients to centers of excellence in cardiovascular genetic medicine. A previous article in the Cardiovascular Genetic Medicine: Clinical Perspectives and Future Applications series 1 highlighted an increasing recognition of the cardiomyopathies (hypertrophic [HCM], dilated [DCM], arrhythmogenic right ventricular dysplasia [ARVD]) and channelopathies (long QT syndrome [LQTS] and others) as genetic diseases, and focused on the importance of a targeted family history as a critical part of patient evaluation. The goal of this article, second in the series, is to provide a general framework for understanding the principles of genetic testing and genetic counseling. We review the growing number of genetic tests currently available to cardiac specialists, the selection of an appropriate test, and the numerous genetic counseling issues raised by the testing process. We also provide our preliminary recommendations for genetic testing in cardiovascular genetic medicine. [ABSTRACT FROM AUTHOR]

The article considers the use of a family history in ascertaining and identifying patients at risk for idiopathic dilated cardiomyopathy (IDC). A family history is constructed using various methods such as the use of questionnaires, pedigrees and computer programs. A family history, integrated with clinical screening can also identify individuals prone to genetic susceptibility to dilated cardiomyopathy (DCM). An overview of important familial dilated cardiomyopathy (FDC) family history features is presented.

We are pleased to provide a new section devoted to topics in cardiovascular genetic medicine. An emerging field, cardiovascular genetic medicine is devoted to the identification and understanding of cardiac conditions resulting from genetic mechanisms and to the development and validation of treatment algorithms and guidelines. Cardiovascular genetic medicine is rapidly enlarging, and we anticipate a broad range of comprehensive reviews. We will first focus on the most tractable diagnoses to apply the principles of cardiovascular genetic medicine: the cardiomyopathies such as dilated, hypertrophic, arrhythmogenic right ventricular dysplasia/cardiomyopathy and the channelopathies such as long QT syndrome and related disorders. These conditions follow classical or Mendelian genetics, otherwise known as the single gene disorders. As greater numbers of disease genes and their specific mutations are identified, and as large clinical cohorts of affected probands and their at-risk family members become available for study, clinical recommendations, and then guidelines, will follow. Progress is also evident for those conditions considered to be complex or multigenic diseases, such as coronary disease and hypertension, which affect large segments of the population. Risk alleles are now being identified that may rapidly lead to genetic testing to assess risk for these conditions. Cardiovascular genetic medicine must also be responsive to public concerns regarding confidentiality, and it must also demonstrate clinical integrity and utility for genetic testing. Our first topic features the role of family history in cardiovascular genetic medicine. Assisted by my clinical and research group—genetic counselors and nursing personnel devoted to the field—we have provided a glossary with explanations of genetic terminology, as illustrated in this first article, and will continue to do so for the series. We will prepare additional topics and others will be solicited from experts in the field. I also invite any potential contributors to propose and submit topics that are both of interest to you and relevant to the field. Please also give us your feedback, especially to improve the clarity, diversity, and timeliness of the genetic concepts presented. So, away we go.—Ray E. Hershberger, MD, Section Editor [ABSTRACT FROM AUTHOR]

Accurately estimating lime requirements (LR) of acidic soils has been a concern since liming practices began. The objectives of this study were to: (i) determine if the Shoemaker-McLean-Pratt (SMP) buffer is accurately predicting the LR of Kansas soils, (ii) calibrate the SMP and Mehlich buffers to accurately estimate the LR of Kansas soils to specific target pH values, and (iii) compare the effectiveness of 60-d incubations vs. field-observed lime response in determining LR. Kansas soils were used to evaluate the current LR according to the SMP buffer and calibrate SMP and Mehlich methods. Slope values (SMP LR vs. 60-d LR) <1 andy intercepts >0 indicated that the SMP either overestimated the LR at low values or underestimated the LR at relatively high LR values compared with 60-d incubations with CaCO3. Calibration of the Mehlich buffer to a target pH of 6.8 provided a better fit than the SMP buffer but the opposite was true at target pHs of 5.5 and 6.0. Titration with 0.022 MCa(OH)2 resulted in a LR (target pH 6.8) 55% less than that measured by the 60-d incubation. Evaluation of the SMP buffer, Mehlich buffer, and Ca(OH)2 titration method on 12 soils indicated that the LR estimated by the Mehlich buffer was not significantly different than the LR from the 60-d incubation. Comparison of the LR from 60-d incubations with field-observed lime response showed that the actual LR in the field was greater than that predicted by the 60-d incubation, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Both left ventricular (LV) hypertrophy and decreased autonomic function are predictors of adverse cardiac events. Patients with diabetic nephropathy have an excess cardiovascular risk. The authors determined heart rate variability from 24-hour ambulatory electrocardiographic recordings and measures of LV mass with systolic and diastolic function from echocardiograms. Patients with diabetic nephropathy (n=16) were seen weekly for insulin and hypertension management. Glycohemoglobin decreased from 9.5 ±0.4% to 8.3 ±0.4% (p=0.01), and advanced glycated end products decreased from 12.1±2.2 to 7.4±1.2 units (p=0.03). Mean arterial pressure and body weight did not change. Serum creatinine increased (1.8±0.1 mg/dL to 2.0±0.2 mg/dL; p=0.03). The authors used a panel of markers of baseline heart rate variation to assess autonomic function. When covariance of the heart rate interval results were evaluated, the group below the median was found to have a significant decrease in LV mass, from 230 g to 184 g (p=0.013); the group above the median had an increase (182 g to 193 g; p=0.5329). Baseline covariance of the heart rate interval predicted 12-month changes in LV mass in 13 of 16 patients (predictive accuracy, 81%). Improvement in measures of heart rate variation correlated with a decrease in LV mass. Parallel improvement of LV mass and autonomic function suggests a common mechanism, allowing for prediction of LV mass improvement through analysis of baseline heart rate variation. [ABSTRACT FROM AUTHOR]

Left ventricular hypertrophy regression was postulated more likely to occur in diabetic patients when renal function was preserved. Seventeen type 1 diabetic patients followed for 12 months while receiving protocol-driven glycemic and blood pressure control had baseline and 12-month echocardiography. Despite identical treatment resulting in similar blood pressures, patients with better renal function (below the group mean, serum creatinine ≤1.7 mg/dL) demonstrated reduction in left ventricular mass and septal thickness as well as increase in left ventricular fractional fiber shortening not observed in those with worse renal function (above the group mean, serum creatinine >1.7 mg/dL). This latter group also did not experience the improvement in glycemic control observed in those with better renal function. Regression of left ventricular mass and functional improvement can be accomplished with improved glycemic control. In the presence of renal dysfunction, however, efforts to control glycemia and cardiac work are suboptimal. Aggressive glycemic and blood pressure targets to reduce cardiovascular morbidity in this high-risk population should be studied. [ABSTRACT FROM AUTHOR]

Current debates in the insurance and public policy literatures over health care financing and cost control measures continue to focus on managed care and HMOs. The lower utilization rates found in HMOs (compared to traditional fee-for-service indemnity plans) have generally been attributed to the organization's incentive to eliminate all unnecessary medical services. As a consequence HMOs are often considered to be a more efficient arrangement for delivering health care. However, it is important to make a distinction between utilization and efficiency (the ratio of outcomes to resources). Few studies have investigated the effect that HMO arrangements would have on the actual efficiency of health care delivery. Because greater control over provider autonomy appears to be a recurrent theme in the literature on reform, it is important to investigate the effects these restrictions have already had within the HMO market. In this article, the efficiencies of two major classes of HMO arrangements are compared using “game-theoretic” data envelopment analysis (DEA) models. While other studies confirm that absolute costs to insurance firms and sponsoring companies are lowered using HMOs, our empirical findings suggest that, within this framework, efficiency generally becomes worse when provider autonomy is restricted. This should give new fuel to the insurance companies providing fee-for-service (FFS) indemnification plans in their marketplace contentions. [ABSTRACT FROM AUTHOR]