Citations

Background. Acral melanoma (AM) is a rare subtype of melanoma, which is one of the least common in Caucasian patients but is a common subtype of melanoma in Chinese patients. It is unclear if prognosis differs between Chinese and Caucasian patients diagnosed with AM. The aim of our study is to investigate patient characteristics and survival differences between Chinese and Caucasian AM patients. Methods. Two large institutional melanoma databases from Fudan University Shanghai Cancer Center (FUSCC) and Mayo Clinic enterprise were retrospectively reviewed from 2009 to 2015. Clinicopathologic and survival data were collected and analyzed between the two groups. The primary outcome was disease-specific survival (DSS) and was calculated using the Kaplan Meier (KM) method. Results. The Chinese group presented with more advanced disease compared with Caucasians: thicker Breslow depth (median 3.0 mm vs. 1.2 mm, p = 0.003 ), more ulcerated disease (66.1% vs. 29%; p < 0.001 ), and advanced stages (stage II/III 84.3% vs. 37.1%; p < 0.001 ). No significant difference was identified in terms of age at diagnosis, location, histologic subtypes, or node positive rate. The 5-year DSS rate was 68.4% and 73% ( p = 0.56 ) in Chinese and Caucasians AM patients, respectively. Male gender, Breslow thickness, ulceration, and positive sentinel lymph nodes were independent poor prognostic factors on multivariate analysis. Conclusions. There appears to be no difference in stage-stratified survival between Chinese and Caucasians, supporting the implementation of clinical trials for AM that could include both Chinese and Caucasian patients.

Background: A patient with ischemic cardiomyopathy and left bundle branch block (LBBB) who did not respond to standard bi-ventricular pacing underwent attempted left bundle area (LBA) pacing to achieve better cardiac resynchronization (CRT). Methods: LBA pacing failed to correct the LBBB or narrow the QRS. However, simultaneous pacing through the coronary sinus (CS) and LBA pacing leads resulted in marked shortening of the QRS Results: The patient’s EF improved from 30% to 45% two months post procedure and heart failure symptoms improved by one functional class. Conclusions: Simultaneous LBA and CS pacing may improve clinical outcomes compared to either alone.

AbstractIntroductionThe need for transparency in financial relationships in the healthcare system, has culminated in Open Payments database, managed by the Center for Medicare and Medicaid Services (CMS). Since its inception in 2013, the trend in such payments to physicians practicing cardiac electrophysiology was not examined.Methods and ResultsPayment information reported to CMS from January 2013 to December 2018 was obtained from the publicly available Open Payments data set using the online query tool. The data were analyzed by an individual provider and by state. An in‐depth analysis of payments in the year 2018 payments was performed. From 2014 to 2018, there was an 18% increase in the total number of payments reported from 88 877 payments in 2014 to 105 000 in 2018. Despite the increase in the total number of payments reported, the average payment steadily decreased over time, resulting in an overall reduction in the total amount of payments from 2014 to 2018 ($34.9 million to $28.2 million). Payments to the top 5% of individual recipients have also decreased over this time. In 2018, 2888 unique providers received reportable payments, a total of 105 000 payments, with a median payment amount of $1378 (interquartile range: $165–$5781). The majority of these payments were for food and beverage (82%) and travel/lodging (10%). The top five payers include Boston Scientific, Medtronic Vascular, Abbott Laboratories, Janssen Pharmaceuticals, and Biotronik.ConclusionAmong cardiac electrophysiologists, there is increased reporting of payments in the Open Payments program over time, with a notable decrease in the payment amount.

Abstract Background Individual carrying germline mutations within BRCA1 or BRCA2 gene confers well-established increased risk of developing breast and ovarian cancers in the life-time than the general population. Recent advancement in clinical oncology and pharmacology discovered that poly ADP ribose polymerase (PARP) inhibitors are particularly effective in treating cancer that is homologous recombination deficient (HRD) through synthetic lethality, irrespective of the primary tumor site or the type of the BRCA1/2 inactivation variant. Methods A dedicated next-generation sequencing (NGS) panel was designed to interrogate the mutational status of BRCA1/2 and 18 other HRD-associated genes. Using a cohort of 522 clinical samples and artificially engineered cell line samples, we evaluated the mutation detection proficiency for single nucleotide variant (SNV) and small insertion or deletion (Indel) variants. BRCA1/2 inactivation is often the consequence of large genomic rearrangement (LGR) within the gene and phenotypically shown as exon-level copy number variant (CNV). Given the technical challenge of accurate exon-level CNV detection within a small panel, we developed a noise-reduction model based on a pool of normal (PON) samples for CNV result analysis. We further designed droplet digital polymerase chain reaction (ddPCR) for each exon of BRCA1/2 to verify the exonic CNV findings. Results Using a comparator assay as the gold standard, the BRCA1/2 panel achieved an accuracy of 96.7%, a precision of 98.9%, and a lower limit of detection of 3% variant allelic frequency (VAF) for SNV and Indel. The CNV pipeline achieved 97.8% sensitivity and 99.7% specificity for exonic CNV events that were supported by at least one piece of secondary evidence, out-performing publicly available software. The ddPCR verification further enhances assay accuracy and provides a significantly improved statistically confidence for the final CNV calls unparalleled by any other experimental methodologies. Conclusions Using a large cohort of clinical samples, the authors demonstrated the proficiency of a targeted NGS approach for variant and LGR detection of BRCA1/2 and the other genes of the DNA damage repair pathway. An effective method was developed to suppress the noise within the NGS-derived CNV profile, which is exaggerated by the small panel size and short targeted regions. The authors would also like to call the researcher's attention to a critical caveat within the CNV testing results generated from NGS-based methods. Citation Format: Xiangyuan Ma, Hua Bao, Zhili Chang, Yong Wu, Changwan Du, Rong Gao, Yu Song, Ryan S. Robetyore, Xue Wu, Yang W. Shao. Technical validation of a NGS-based analysis pipeline for BRCA1/2 variants and large genomic rearrangements detection [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4268.

G 4 C 2 repeat–derived poly(GR) plays a key role in mediating TDP-43 mislocalization and aggregation in vitro and in vivo.

Kidney diseases secondary to several pathogeneses affect millions of people worldwide and have become increasingly recognized as a global public health problem. Recent evidence suggests that cellular senescence plays an important role in the pathogenesis of different forms of renal damage, including acute and chronic kidney disease, and renal transplantation. Renal senescence involves cell cycle arrest and affects several cellular pathways, manifesting in downregulation of klotho, elevated expression of cyclin-dependent kinase inhibitors, cellular telomere shortening, and oxidative stress. Furthermore, senescent cells might induce kidney injury by paracrine release of inflammatory factors. Yet, cellular senescence may be renoprotective during development and in some models of renal diseases, reflecting the yin/yang duality of cellular senescence. This review provides an overview of the role of this emerging player in renal injury, with emphasis on new findings of cellular senescence.

Background Nationwide studies documenting temporal trends in permanent pacemaker implantation (PPMI) following transcatheter aortic valve replacement (TAVR) are limited. Methods and Results We selected patients who underwent TAVR between 2012 and 2017 in the National Readmission Database. The primary end point was the 6‐year trend in post‐TAVR PPMI at index hospitalization and at 30, 90, and 180 days after discharge. The secondary end point was the association between PPMI and in‐hospital mortality, stroke, cost, length of stay, and disposition. Among the 89 202 patients who underwent TAVR, 77 405 (86.8%) with no prior pacemaker or defibrillator were included. Patients who required PPMI had a higher prevalence of atrial fibrillation (43.6% versus 38.7%, P <0.001) and conduction abnormalities (28.4% versus 15.3%, P <0.001). The incidence of PPMI during index admission increased from 8.7% in 2012 to 13.2% in 2015, and then decreased to 9.6% in 2017. The incidence of inpatient PPMI within 30 days after discharge increased from 0.5% in 2012 to 1.25% in 2017 ( P trend <0.001). Inpatient PPMI beyond 30 days remained rare (<0.5%) during the study period. After risk adjustment, PPMI was not associated with in‐hospital mortality or stroke but was associated with increased nonhome discharge, longer hospitalization, and higher cost. The incremental expenditure associated with post‐TAVR PPMI during index admission increased from $9.6 million to $72.2 million between 2012 and 2017. Conclusions After an upward trend, rates of PPMI after TAVR in the United States stabilized at ~10% in 2016 to 2017, but there was a notable increase in PPMI within 30 days after the index admission. PPMI was not associated with increased in‐hospital morbidity or mortality but led to longer hospitalization, higher cost, and more nonhome discharges.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear.Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01-1.5; P=0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13-1.84; P=0.004). Conclusions CRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid -stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01-1.5; P=0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13-1.84; P=0.004). Conclusions CRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.