Abstract Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been ...identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients.
Climate change is likely to change the relationships between commonly used climate indices and underlying patterns of climate variability, but this complexity is rarely considered in studies using ...climate indices. Here, we show that the physical and ecological conditions mapping onto the Pacific Decadal Oscillation (PDO) index and North Pacific Gyre Oscillation (NPGO) index have changed over multidecadal timescales. These changes apparently began around a 1988/1989 North Pacific climate shift that was marked by abrupt northeast Pacific warming, declining temporal variance in the Aleutian Low (a leading atmospheric driver of the PDO), and increasing correlation between the PDO and NPGO patterns. Sea level pressure and surface temperature patterns associated with each climate index changed after 1988/1989, indicating that identical index values reflect different states of basinscale climate over time. The PDO and NPGO also show timedependent skill as indices of regional northeast Pacific ecosystem variability. Since the late 1980s, both indices have become less relevant to physical–ecological variability in regional ecosystems from the Bering Sea to the southern California Current. Users of these climate indices should be aware of nonstationary relationships with underlying climate variability within the historical record, and the potential for further nonstationarity with ongoing climate change.
Heart failure is a complex disease process with underlying aberrations in neurohormonal systems that promote dysregulated cellular signaling and gene transcription. Over the past 10 years, the advent ...of small-molecule inhibitors that target transcriptional machinery has demonstrated the importance of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in regulating gene transcription in multiple mouse models of cardiomyopathy. BETs bind to acetylated histone tails and transcription factors to integrate disparate stress signaling networks into a defined gene expression program. Under myocardial stress, BRD4, a BET family member, is recruited to superenhancers and promoter regions of inflammatory and profibrotic genes to promote transcription elongation. Whole-transcriptome analysis of BET-dependent gene networks suggests a major role of nuclear-factor kappa b and transforming growth factor-beta in the development of cardiac fibrosis and systolic dysfunction. Recent investigations also suggest a prominent role of BRD4 in maintaining cardiomyocyte mitochondrial respiration under basal conditions. In this review, we summarize the data from preclinical heart failure studies that explore the role of BET-regulated transcriptional mechanisms and delve into landmark studies that define BET bromodomain-independent processes involved in cardiac homeostasis.
AIMThis executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in ...adult and pediatric patients as well as supporting documentation to encourage their use.
METHODSA comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases.
STRUCTUREMany recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.
To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer.
Eligible women had squamous cell carcinoma, at least ...1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed.
In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%).
Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.
Western Pressurized Water Reactors (PWRs) are considering the replacement from lithium hydroxide (LiOH) to potassium hydroxide (KOH) as a pH balancing agent in primary water due to the higher cost ...and lower availability of 7Li. This study qualified the irradiation-assisted stress corrosion cracking (IASCC) propagation compatibility of baffle plate materials in simulated PWR primary water with LiOH or KOH chemistries. Samples extracted from two pieces of Type 304 stainless steel baffle plates with different dose (9 and 15 dpa) were investigated. Water chemistries were switched between LiOH (1.3–2 ppm) and KOH (7.2 to 11.3 ppm) at constant pH during the crack growth rate (CGR) test on a sample, thus the effect of water chemistry was determined directly without other variations. Results indicate that there is no discernable effect on the CGR behavior by changing from LiOH to KOH.
B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). ...The aim of this study was to test the hypothesis that a normal BNP level (≤100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogenous disorder commonly associated with obesity. A total of 159 consecutive patients enrolled in the Northwestern University HFpEF Program were prospectively studied. All subjects had symptomatic HF with EF >50% and elevated pulmonary capillary wedge pressure. BNP was tested at baseline in all subjects. Clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes were compared among patients with HFpEF with normal (≤100 pg/ml) versus elevated (>100 pg/ml) BNP. Of the 159 patients with HFpEF, 46 (29%) had BNP ≤100 pg/ml. Subjects with normal BNP were younger, were more often women, had higher rates of obesity and higher body mass index, and less commonly had chronic kidney disease and atrial fibrillation. EFs and pulmonary capillary wedge pressures were similar in the normal and elevated BNP groups (62 ± 7% vs 61 ± 7%, p = 0.67, and 25 ± 8 vs 27 ± 9 mm Hg, p = 0.42, respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure and function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization 4.0, 95% confidence interval 1.6 to 9.7, p = 0.003). In conclusion, normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and although BNP is useful as a prognostic marker in HFpEF, normal BNP does not exclude the outpatient diagnosis of HFpEF.
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