Citations

AbstractThis international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

The primary purpose of this study was to examine the acute effects of a multi-ingredient (i.e., caffeine, green tea extract, Yohimbe extract, capsicum annum, coleus extract, L-carnitine, beta-alanine, tyrosine) preworkout supplement versus a dose of caffeine (6 mg·kg−1) on energy expenditure during low-intensity exercise. The effects of these treatments on substrate utilization, gas exchange, and psychological factors were also investigated. Twelve males (mean ± SD: age = 22.8 ± 2.4 years) completed three bouts of 60 min of treadmill exercise on separate days after consuming a preworkout supplement, 6 mg·kg−1 of caffeine, or placebo in a randomized fashion. The preworkout and caffeine supplements resulted in significantly greater energy expenditure (p < 0.001, p = 0.006, respectively), V˙O2 (p < 0.001, p = 0.007, respectively), V˙CO2 (p = 0.006, p = 0.049, respectively), and V˙E (p < 0.001, p = 0.007, respectively) compared to placebo (collapsed across condition). There were no differences among conditions, however, for rates of fat or carbohydrate oxidation or respiratory exchange ratio. In addition, the preworkout supplement increased feelings of alertness (p = 0.015) and focus (p = 0.005) 30-min postingestion and decreased feelings of fatigue (p = 0.014) during exercise compared to placebo. Thus, the preworkout supplement increased energy expenditure and measures of gas exchange to the same extent as 6 mg·kg−1 of caffeine with concomitant increased feelings of alertness and focus and decreased feelings of fatigue.

Background: Mitral valve-in-valve (ViV) and valve-in-ring (ViR) are alternatives to surgical reoperation in patients with recurrent mitral valve failure after previous surgical valve repair or replacement. Our aim was to perform a large-scale analysis examining midterm outcomes after mitral ViV and ViR. Methods: Patients undergoing mitral ViV and ViR were enrolled in the Valve-in-Valve International Data Registry. Cases were performed between March 2006 and March 2020. Clinical endpoints are reported according to the Mitral Valve Academic Research Consortium (MVARC) definitions. Significant residual mitral stenosis (MS) was defined as mean gradient ≥10 mm Hg and significant residual mitral regurgitation (MR) as ≥ moderate. Results: A total of 1079 patients (857 ViV, 222 ViR; mean age 73.5±12.5 years; 40.8% male) from 90 centers were included. Median STS-PROM score 8.6%; median clinical follow-up 492 days (interquartile range, 76–996); median echocardiographic follow-up for patients that survived 1 year was 772.5 days (interquartile range, 510–1211.75). Four-year Kaplan-Meier survival rate was 62.5% in ViV versus 49.5% for ViR ( P <0.001). Mean gradient across the mitral valve postprocedure was 5.7±2.8 mm Hg (≥5 mm Hg; 61.4% of patients). Significant residual MS occurred in 8.2% of the ViV and 12.0% of the ViR patients ( P =0.09). Significant residual MR was more common in ViR patients (16.6% versus 3.1%; P <0.001) and was associated with lower survival at 4 years (35.1% versus 61.6%; P =0.02). The rates of Mitral Valve Academic Research Consortium–defined device success were low for both procedures (39.4% total; 32.0% ViR versus 41.3% ViV; P =0.01), mostly related to having postprocedural mean gradient ≥5 mm Hg. Correlates for residual MS were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual MR was ViR. Significant residual MS (subhazard ratio, 4.67; 95% CI, 1.74–12.56; P =0.002) and significant residual MR (subhazard ratio, 7.88; 95% CI, 2.88–21.53; P <0.001) were both independently associated with repeat mitral valve replacement. Conclusions: Significant residual MS and/or MR were not infrequent after mitral ViV and ViR procedures and were both associated with a need for repeat valve replacement. Strategies to improve postprocedural hemodynamics in mitral ViV and ViR should be further explored.

Abstract Background and study aims The Full-Thickness Resection Device (FTRD) provides a novel treatment option for lesions not amenable to conventional endoscopic resection techniques. There are limited data on the efficacy and safety of FTRD for resection of upper gastrointestinal tract (GIT) lesions. Patients and methods This was an international multicenter retrospective study, including patients who had an endoscopic resection of an upper GIT lesion using the FTRD between January 2017 and February 2019. Results Fifty-six patients from 13 centers were included. The most common lesions were mesenchymal neoplasms (n = 23, 41 %), adenomas (n = 7, 13 %), and hamartomas (n = 6, 11 %). Eighty-four percent of lesions were located in the stomach, and 14 % in the duodenum. The average size of lesions was 14 mm (range 3 to 33 mm). Deployment of the FTRD was technically successful in 93 % of patients (n = 52) leading to complete and partial resection in 43 (77 %) and 9 (16 %) patients, respectively. Overall, the FTRD led to negative histological margins (R0 resection) in 38 (68 %) of patients. A total of 12 (21 %) mild or moderate adverse events (AEs) were reported. Follow-up endoscopy was performed in 31 patients (55 %), on average 88 days after the procedure (IQR 68–138 days). Of these, 30 patients (97 %) did not have any residual or recurrent lesion on endoscopic examination and biopsy, with residual adenoma in one patient (3 %). Conclusions Our results suggest a high technical success rate and an acceptable histologically complete resection rate, with a low risk of AEs and early recurrence for FTRD resection of upper GIT lesions.

Abstract Background: Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome. Methods: Germfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism (Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR.Results: Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity (P = 0.30) and beta-diversity (P = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, (P < 0.05), most notably deoxycholic acid (DCA) (P <0.001). Overall, analysis of transcriptomes and correlation networks indicates both bacterial species-specific responses to BBR, as well as functional commonalities among species, such as up-regulation of Na+/H+ antiporter, cell wall synthesis/repair, carbohydrate metabolism and amino acid metabolism. Bile acid concentrations in the GI tract increased significantly during BBR treatment and developed extensive correlation networks with expressed genes in the B4PC2 community. Conclusions: This work has important implications for interpreting the effects of BBR on structure and function of the complex gut microbiome, which may lead to targeted pharmaceutical interventions aimed to achieve the positive physiological effects previously observed with BBR supplementation.

Abstract Recent studies have thoroughly described genome-wide expression patterns defining molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different prognostic and predictive implications. Although the reversible nature of key regulatory transcription circuits defining the two extreme PDAC subtype lineages “classical” and “basal-like” suggests that subtype states are not permanently encoded but underlie a certain degree of plasticity, pharmacologically actionable drivers of PDAC subtype identity remain elusive. Here, we characterized the mechanistic and functional implications of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in controlling PDAC plasticity, dedifferentiation, and molecular subtype identity. Utilization of transgenic PDAC models and human PDAC samples linked EZH2 activity to PDAC dedifferentiation and tumor progression. Combined RNA- and chromatin immunoprecipitation sequencing studies identified EZH2 as a pivotal suppressor of differentiation programs in PDAC and revealed EZH2-dependent transcriptional repression of the classical subtype defining transcription factor Gata6 as a mechanistic basis for EZH2-dependent PDAC progression. Importantly, genetic or pharmacologic depletion of EZH2 sufficiently increased GATA6 expression, thus inducing a gene signature shift in favor of a less aggressive and more therapy-susceptible, classical PDAC subtype state. Consistently, abrogation of GATA6 expression in EZH2-deficient PDAC cells counteracted the acquisition of classical gene signatures and rescued their invasive capacities, suggesting that GATA6 derepression is critical to overcome PDAC progression in the context of EZH2 inhibition. Together, our findings link the EZH2-GATA6 axis to PDAC subtype identity and uncover EZH2 inhibition as an appealing strategy to induce subtype-switching in favor of a less aggressive PDAC phenotype. Significance: This study highlights the role of EZH2 in PDAC progression and molecular subtype identity and suggests EZH2 inhibition as a strategy to recalibrate GATA6 expression in favor of a less aggressive disease.

Background: Functional bracing is often used as an adjunct to nonoperative treatment of anterior shoulder instability, but no study has evaluated the effectiveness of in-season bracing. The purpose of this study was to examine successful return to play in a nonoperative cohort of adolescent athletes with in-season shoulder instability and compare those athletes treated with bracing to those who were not. Hypothesis: The use of functional bracing will improve success rates in a cohort of athletes treated nonoperatively for in-season shoulder instability. Study Design: Cohort study. Level of Evidence: Level 3. Methods: A total of 97 athletes with anterior shoulder instability were followed for a minimum of 1 year. The mean age was 15.8 ± 1.4 years (range, 12.0-18.0 years). All athletes were treated with initial nonoperative management. Twenty athletes (21%) were also treated with bracing while 77 (79%) were not. The athlete completing the current season and 1 subsequent season without surgery or time lost from shoulder injury was defined as a successful outcome. Results: There was no statistical difference in nonoperative success rates between the braced and nonbraced athletes ( P = 0.33). Braced athletes (n = 20) returned to play 80% of the time, while nonbraced athletes (n = 77) returned at a rate of 88%. Of the braced athletes, 85% were football players (n = 17). A football-only comparison demonstrated no difference between braced failures (26%) and nonbraced failures (16%) ( P = 0.47). Conclusion: This is the first study to evaluate the utility of functional bracing in returning an athlete to sport and completing a full subsequent season without surgery or time loss due to injury of the shoulder. In adolescent athletes with shoulder instability treated nonoperatively, functional bracing did not result in increased success rates when compared with no bracing. Clinical Relevance: The data from this study indicate that functional bracing may not improve success rates for athletes with shoulder instability.