Blinded, randomized trial of sonographer versus AI cardiac function assessment.

Artificial intelligence (AI) has been developed for echocardiography1-3, although it has not yet been tested with blinding and randomization. Here we designed a blinded, randomized non-inferiority clinical trial (ClinicalTrials.gov ID: NCT05140642; no outside funding) of AI versus sonographer initial assessment of left ventricular ejection fraction (LVEF) to evaluate the impact of AI in the interpretation workflow. The primary end point was the change in the LVEF between initial AI or sonographer assessment and final cardiologist assessment, evaluated by the proportion of studies with substantial change (more than 5% change). From 3,769 echocardiographic studies screened, 274 studies were excluded owing to poor image quality. The proportion of studies substantially changed was 16.8% in the AI group and 27.2% in the sonographer group (difference of -10.4%, 95% confidence interval: -13.2% to -7.7%, P < 0.001 for non-inferiority, P < 0.001 for superiority). The mean absolute difference between final cardiologist assessment and independent previous cardiologist assessment was 6.29% in the AI group and 7.23% in the sonographer group (difference of -0.96%, 95% confidence interval: -1.34% to -0.54%, P < 0.001 for superiority). The AI-guided workflow saved time for both sonographers and cardiologists, and cardiologists were not able to distinguish between the initial assessments by AI versus the sonographer (blinding index of 0.088). For patients undergoing echocardiographic quantification of cardiac function, initial assessment of LVEF by AI was non-inferior to assessment by sonographers.

Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

Angiopoietin-like protein 4/8 complex-mediated plasmin generation leads to cleavage of the complex and restoration of LPL activity.

Triglyceride (TG) metabolism is highly regulated by angiopoietin-like protein (ANGPTL) family members [Y. Q. Chen et al., J. Lipid Res. 61, 1203-1220 (2020)]. During feeding, ANGPTL8 forms complexes with the fibrinogen-like domain-containing protein ANGPTL4 in adipose tissue to decrease ANGPTL3/8- and ANGPTL4-mediated lipoprotein lipase (LPL)-inhibitory activity and promote TG hydrolysis and fatty acid (FA) uptake. The ANGPTL4/8 complex, however, tightly binds LPL and partially inhibits it in vitro. To try to reconcile the in vivo and in vitro data on ANGPTL4/8, we aimed to find novel binding partners of ANGPTL4/8. To that end, we performed pulldown experiments and found that ANGPTL4/8 bound both tissue plasminogen activator (tPA) and plasminogen, the precursor of the fibrinolytic enzyme plasmin. Remarkably, ANGPTL4/8 enhanced tPA activation of plasminogen to generate plasmin in a manner like that observed with fibrin, while minimal plasmin generation was observed with ANGPTL4 alone. The addition of tPA and plasminogen to LPL-bound ANGPTL4/8 caused rapid, complete ANGPTL4/8 cleavage and increased LPL activity. Restoration of LPL activity in the presence of ANGPTL4/8 was also achieved with plasmin but was blocked when catalytically inactive plasminogen (S760A) was added to tPA or when plasminogen activator inhibitor-1 was added to tPA + plasminogen, indicating that conversion of plasminogen to plasmin was essential. Together, these results suggest that LPL-bound ANGPTL4/8 mimics fibrin to recruit tPA and plasminogen to generate plasmin, which then cleaves ANGPTL4/8, enabling LPL activity to be increased. Our observations thus reveal a unique link between the ANGPTL4/8 complex and plasmin generation.

Effects of pericardiocentesis on renal function and cardiac hemodynamics.

BACKGROUND: Previous case studies have reported reversal of acute renal failure after pericardiocentesis in pericardial effusion. This study examines the effects of pericardiocentesis on preprocedural low cardiac output and acute renal dysfunction in patients with pericardial effusion. METHODS: This is a retrospective study of 95 patients undergoing pericardiocentesis between 2015 and 2020. Pre- and post-procedure transthoracic echocardiograms (TTE) were reviewed for evidence of cardiac tamponade, resolution of pericardial effusion, and for estimation of right atrial (RA) pressure and cardiac output. Laboratory values were compared at presentation and post-procedure. Patients on active renal replacement therapy were excluded. RESULTS: Ninety-five patients were included for analysis (mean age 62.2 ± 17.8 years, 58% male). There was a significant increase in glomerular filtration rate pre- and post-procedure. Fifty-six patients (58.9%) had an improvement in glomerular filtration rate after pericardiocentesis (termed "responders"), and these patients had a lower pre-procedure glomerular filtration rate than "non-responders." There was a significant improvement in estimated cardiac output and right atrial pressure for patients in both groups. Patients who had an improvement in renal function had significantly lower pre-procedural diastolic blood pressure and mean arterial pressure. CONCLUSIONS: Pericardial drainage may improve effusion-mediated acute renal dysfunction by reducing right atrial pressure and thus systemic venous congestion, and by increasing forward stroke volume and perfusion pressure.

Comparison of prognostic value among echocardiographic surrogates of right ventricular-pulmonary arterial coupling: A three-dimensional echocardiographic study.

OBJECTIVES: Right ventricular (RV)-pulmonary arterial (PA) coupling is important in various cardiac diseases. Recently, several echocardiographic surrogates for RV-PA coupling have been proposed and reported to be useful in predicting outcomes. However, it remains unclear which surrogate is the most clinically relevant. This study aimed to comprehensively compare the prognostic value of different echocardiographic RV-PA coupling surrogates. METHODS: We retrospectively reviewed 242 patients with various cardiac conditions who underwent comprehensive transthoracic echocardiography with three-dimensional RV data. In addition to conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and PA systolic pressure (PASP), we analyzed RV free wall and global longitudinal strain (FWLS and GLS). We also obtained RV ejection fraction (RVEF), stroke volume (SV), and end-systolic volume (ESV) using three-dimensional RV analysis. RV-PA coupling surrogates were calculated as TAPSE/PASP, FAC/PASP, FWLS/PASP, GLS/PASP, RVEF/PASP, and SV/ESV. The study endpoint was a composite outcome of all-cause death or cardiovascular hospitalization within 1 year. RESULTS: In multivariable analysis, all the RV-PA coupling surrogates were independent predictors of the outcome. Among the surrogates, the model with TAPSE/PASP showed the lowest prognostic value in model fit and discrimination ability, whereas the model with RVEF/PASP exhibited the highest prognostic value. The partial likelihood ratio test indicated that the model with RVEF/PASP was significantly better than the model with TAPSE/PASP (p < .024). CONCLUSION: All the RV-PA coupling surrogates were independent predictors of the outcome. Notably, RVEF/PASP had the highest prognostic value among the surrogates.

Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity.

After feeding, adipose tissue lipoprotein lipase (LPL) activity should be maximized, therefore the potent LPL-inhibitory activity of angiopoietin-like protein 4 (ANGPTL4) must be blocked by ANGPTL8 through formation of ANGPTL4/8 complexes. ANGPTL4/8 tightly binds and protects LPL but also partially inhibits its activity. Recently, we demonstrated ANGPTL4/8 also binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity. Although fully active LPL in the fat postprandially is desirable, ANGPTL4/8 removal could subject LPL to profound inhibition by ANGPTL3/8 (the most potent circulating LPL inhibitor), inhibition by other LPL inhibitors like ANGPTL4, ANGPTL3, and ApoC3 or interfere with ApoC2-mediated LPL activation. To understand better these potential paradoxes, we examined LPL inhibition by ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 and LPL stimulation by ApoC2 in the presence of ANGPTL4/8 + tPA + plasminogen. Remarkably, ANGPTL3/8-mediated LPL inhibition was almost completely blocked, with the mechanism being cleavage of fibrinogen-like domain-containing ANGPTL3 present in the ANGPTL3/8 complex. The LPL-inhibitory effects of ANGPTL4, ANGPTL3, and ApoC3 were also largely reduced in the presence of ANGPTL4/8 + tPA + plasminogen. In contrast, the ability of ApoC2 to stimulate LPL activity was unaffected by ANGPTL4/8-mediated plasmin generation. Together, these results explain how plasmin generated by increased postprandial ANGPTL4/8 levels in adipose tissue enables maximal LPL activity by preventing ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 from inhibiting LPL, while permitting ApoC2-mediated LPL activation to occur.

Transcatheter edge-to-edge repair for chronic functional mitral regurgitation in patients with very severe left ventricular dysfunction.

BACKGROUND: There is scarce data on transcatheter edge-to-edge repair (TEER) for chronic functional mitral regurgitation (FMR) in the setting of very severe left ventricular dysfunction (LVD), defined by a left ventricular ejection fraction (LVEF) of <20%. METHODS: We retrospectively explored periprocedural characteristics and one-year clinical and echocardiographic outcomes of consecutive patients with chronic FMR and very severe LVD who underwent an isolated, first-time TEER. The composite of all-cause mortality or heart failure hospitalizations constituted the primary outcome. RESULTS: Ninety-six patients (median age 69 [IQR, 55-76] years, 64 (66.7%) males, median LVEF 15 [IQR, 12-17] %) were included. In 47 (49.0%), TEER was performed urgently or in the setting of hemodynamic instability. Almost all procedures (98.0%) were technically successful, leading to ≤moderate MR in 94.7% and 90.7% of cases by 1-month and 1-year, respectively. New York Heart Association class ≤II was maintained in 60.0% of patients. One-year survival and freedom from the primary outcome were 74.0% and 50.0%, respectively. Functional and echocardiographic improvement compared to baseline was independent of procedural urgency, hemodynamic stability, and downstream left ventricular assist device implantation / heart transplantation (n = 12). Mortality was not predicted by COAPT exclusion criteria, nor was the primary outcome discriminated by published risk models. CONCLUSION: TEER for chronic FMR is feasible, safe, and efficacious in selected patients with very severe LVD. Preprocedural risk stratification in this population may be optimized.

Histologic Severity of Nonalcoholic Fatty Liver Disease Associates with Reduced Bone Mineral Density in Children.

BACKGROUND: Lower whole body bone mineral density (BMD) has been reported in children with nonalcoholic fatty liver disease (NAFLD), but potential mediators remain uncertain. AIMS: To assess BMD at multiple skeletal sites in children with confirmed NAFLD and controls with obesity, adjusting for known determinants of BMD, and examine potential mediators. METHODS: We assessed age-, sex-, and race-specific, and height-adjusted BMD z-scores of whole body, lumbar spine, hip, femoral neck and forearm by dual-energy-x-ray absorptiometry in 79 children, 8-19 years old: 46 with biopsy-confirmed NAFLD [29 steatohepatitis (NASH)/17 fatty liver (NAFL)] and 33 controls without liver disease. We compared BMD z-scores by multivariable regression, adjusting for known BMD determinants and potential mediators (inflammatory and insulin resistance measures). RESULTS: Unadjusted mean BMD z-scores in NAFLD were similar to controls, but significantly lower in NASH vs. NAFL at all sites. After covariate adjustment, mean forearm BMD z-score was higher in NAFL (ß 0.60 ± SE 0.30, p < 0.05) and lower in NASH (ß - 0.49 ± SE 0.26, p = 0.06) vs. controls (p = 0.002 for group), with similar trends at whole body and total hip; hs-CRP negatively associated with whole body and forearm BMD z-scores (p < 0.05), while visceral fat area negatively associated with femoral neck (p < 0.05). Only three children had clinically low whole body BMD z-scores (< - 2), one per group (control, NAFL and NASH). CONCLUSIONS: NASH, but not NAFL, may be associated with increased risk of reduced BMD in children. Systemic inflammation, independent of body composition and load bearing, may mediate reduction in BMD in NASH.

Feasibility of laparoscopic resection for perforated diverticulitis: a retrospective observational study of 77 consecutive patients.

BACKGROUND: Perforated colonic diverticulitis with purulent or fecal contamination (PCD) is a surgical emergency with high morbidity and mortality. Traditionally, open surgery as a Hartmann procedure (HP) has been performed. Feasibility of the laparoscopic approach (LA) either with primary anastomosis (PA) or as an HP has been shown, but evidence and implementation into daily routine remain low. We analysed all patients with PCD and emergency surgery at our institution to compare post-operative outcomes between LA and open surgery. Our results should add more evidence about the potential benefit of LA in treating PCD. METHODS: This retrospective analysis conducted at a tertiary care centre in Germany included all patients with PCD undergoing emergency surgery between June 2007 and February 2019. Mortality and postoperative morbidity according to Clavien-Dindo-Classification are the primary endpoints. Secondary endpoints were stoma-free survival and length of hospital stay. RESULTS: Seventy-seven patients were identified (41 female/36 male; median age 67.9 years). Sixty patients underwent a LA (conversion in 9 of 60, 15%). PA has been performed in 25 of 77 patients (22 LA, 3 with open surgery). Severe complications and death (Clavien-Dindo-Classification grade IIIb-V) were lower in patients with LA (17/60, 28%) compared to open surgery (9/17, 53%; p = 0.082) as well as the length of hospital stay (LOS; LA 9 days vs. open surgery 17 days; p = 0.016). CONCLUSION: The LA is feasible in the majority of patients with PCD and may be warranted as a routine in emergency surgery. Although limited by a selection bias of this retrospective study, the LA seems to reduce morbidity and LOS.

An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif.

Triglycerides (TG) are required for fatty acid transport and storage and are essential for human health. Angiopoietin-like-protein 8 (ANGPTL8) has previously been shown to form a complex with ANGPTL3 that increases circulating TG by potently inhibiting LPL. We also recently showed that the TG-lowering apolipoprotein A5 (ApoA5) decreases TG levels by suppressing ANGPTL3/8-mediated LPL inhibition. To understand how LPL binds ANGPTL3/8 and ApoA5 blocks this interaction, we used hydrogen-deuterium exchange mass-spectrometry and molecular modeling to map binding sites of LPL and ApoA5 on ANGPTL3/8. Remarkably, we found that LPL and ApoA5 both bound a unique ANGPTL3/8 epitope consisting of N-terminal regions of ANGPTL3 and ANGPTL8 that are unmasked upon formation of the ANGPTL3/8 complex. We further used ANGPTL3/8 as an immunogen to develop an antibody targeting this same epitope. After refocusing on antibodies that bound ANGPTL3/8, as opposed to ANGPTL3 or ANGPTL8 alone, we utilized bio-layer interferometry to select an antibody exhibiting high-affinity binding to the desired epitope. We revealed an ANGPTL3/8 leucine zipper-like motif within the anti-ANGPTL3/8 epitope, the LPL-inhibitory region, and the ApoA5-interacting region, suggesting the mechanism by which ApoA5 lowers TG is via competition with LPL for the same ANGPTL3/8-binding site. Supporting this hypothesis, we demonstrate that the anti-ANGPTL3/8 antibody potently blocked ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowered TG levels in vivo. Together, these data show that an anti-ANGPTL3/8 antibody targeting the same leucine zipper-containing epitope recognized by LPL and ApoA5 markedly decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition.

Oral Chemotherapy Metric Performance in Quality Oncology Practice Initiative Practices: Updated Trends and Analysis.

BACKGROUND: Oral chemotherapy performance measures were first introduced into ASCO's Quality Oncology Practice Initiative (QOPI) in 2013. This study examined performance on these measures among QOPI-participating practices and evaluated whether it differed among practices based on meeting QOPI Certification Program standards. METHODS: A total of 192 QOPI-participating practices (certified, n=50 [26%]; not certified, n=142 [74%]) reported performance on oral chemotherapy measures in 2017 and 2018. Inclusion was limited to practices reporting on ≥3 charts for ≥1 oral chemotherapy measure. Performance was defined as the percentage of charts examined that adhered to the measure. Descriptive analyses were used to characterize performance within and across practices, and mixed-effects logistic regression models were conducted to compare performance based on certification status. RESULTS: Median performance across practices for the 9 oral chemotherapy measures examined ranged from 44% (education before the start of treatment addressing missed doses, toxicities, and clinical contact instructions [composite measure]) to 100% (documented dose, documented plan, and education about toxicities). Certified practices were more likely to provide education about clinic contact instructions than noncertified practices (odds ratio, 4.87; 95% CI, 1.00-24.0). Performance on all other measures was not significantly associated with certification status. CONCLUSIONS: There is wide variability in quality related to performance on oral chemotherapy measures across all QOPI-participating practices, and several areas were identified in which administration of oral chemotherapy could be improved. Our findings highlight the need for the development and implementation of appropriate standards that apply to oral chemotherapy and address the complexities that set it apart from parenteral treatment.

Utility of transesophageal echocardiogram surveillance after watchman device placement.

BACKGROUND: In atrial fibrillation patients undergoing left atrial appendage occlusion with a Watchman device, surveillance imaging with a transesophageal echocardiogram (TEE) is typically performed at 45 days and 1 year to evaluate for device-related thrombus (DRT) and peri-device leak (PDL) before the cessation of oral anticoagulation. The incidence of these complications is relatively low, and the ideal timing and duration of surveillance is unknown. We sought to evaluate the incidence of DRT and PDL after Watchman placement at 45 days and 1 year to determine the necessity of surveillance TEEs. METHODS: We retrospectively analyzed 361 patients who received a Watchman device between January 2016 and January 2020. Baseline clinical and echocardiographic data, post-procedure antithrombotic therapy, and surveillance echocardiographic data were collected from the NCDR LAAO Registry. Nested backward variable elimination regression was performed to derive independent predictors of the composite outcome of DRT and PDL. RESULTS: A total of 286 patients who had post-procedure TEEs were included in the analysis. At 45 days, 9 patients had DRT (3.2%) and 44 patients had PDL (15.0%). At 1 year, 5 patients had DRT (5.6%) and 8 patients had PDL (8.9%). All DRT at 45 days was treated with continued anticoagulation while no change in protocol occurred with PDL. All DRT at 1 year occurred in new patients without prior thrombus. A history of prior transient ischemic attack (TIA) and thromboembolism was significantly associated with DRT or PDL at 1 year. CONCLUSIONS: We identified several patients with device-related complications at 45 days and 1 year despite appropriate device sizing and adequate use of antithrombotic therapy. The incidence of DRT increased from 45 days to 1 year and occurred in patients without prior thrombus. These findings highlight the importance of surveillance imaging and suggest the potential need for extended surveillance in select patients.

Clinical and echocardiographic differences in three different etiologies of severe mitral stenosis.

BACKGROUND: In our institute, the causes of mitral stenosis (MS) are generally categorized into three main etiologies-rheumatic MS (RMS), degenerative MS with annular and leaflet calcification, and post-clip MS as a consequence of transcatheter mitral valve repair with clips for treating mitral regurgitation. However, clinical differences among the three etiologies are uncertain. METHODS: We retrospectively assessed 293 consecutive patients (53 with RMS, 118 with degenerative MS, and 122 with post-clip MS) who had a three-dimensional (3D) transesophageal echocardiography (TEE) derived mitral valve orifice area (MVA) of ≤1.5 cm2 , and a mean transmitral pressure gradient of ≥5 mmHg on transthoracic echocardiography. RESULTS: Although there was no difference in 3D-TEE-derived MVA among the three groups, patients with post-clip MS had a significantly lower mean transmitral pressure gradient compared to those with either of the other two types of MS (10.8 ([7.9-15.2] mmHg vs. 9.6 [7.3-12.5] mmHg vs. 6.9 [6.0-9.2] mmHg; p < .001). Patients with RMS had a higher prevalence of dyspnea. The independent determinants of dyspnea were pressure half time in RMS, 3D-TEE-derived MVA and estimated right atrial pressure in degenerative MS, and left ventricle ejection fraction in post-clip MS. CONCLUSIONS: Patients with post-clip MS had the lowest mean transmitral pressure gradient, and patients with RMS had the highest prevalence of dyspnea, despite having a similar 3D-TEE-derived MVA. The determinants of dyspnea were different among the three etiologies of MS.

Comparison of quality of life outcomes in a de-intensification treatment regimen for p16 + oropharyngeal cancer.

BACKGROUND: Platinum and taxane-based neoadjuvant chemotherapy with surgery (NAC + S) is a novel de-intensified treatment modality that is currently under investigation. METHODS: All patients treated for HPV positive OPSCC with NAC + S at a single institution between 2006 and 2020 were contacted to complete the University of Washington Quality of life questionnaire (UW-QOL) at least 2 years following the completion of treatment. RESULTS: The UW-QOL surveys were received from 25 of 48 eligible patients (52.1%). The mean follow-up time was 4.3 years (range 2.0-7.6 years). The overall mean score for the physical subscale was 92.4 (Standard deviation, SD = 10.9), and the social-emotional subscale was 91.1 (11.8). Compared to the normative cohort, the NAC + S cohort had a worse appearance (Mean scores Normative vs. NAC + S: 93 vs. 84.0, p = 0.009). CONCLUSION: NAC + S offers favorable long-term QOL, as evidenced by near-normal scores in most QOL domains.

ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition.

Triglyceride (TG) molecules represent the major storage form of fatty acids, and TG metabolism is essential to human health. However, the mechanistic details surrounding TG metabolism are complex and incompletely elucidated. Although it is known that angiopoietin-like protein 8 (ANGPTL8) increases TGs through an ANGPTL3/8 complex that inhibits LPL, the mechanism governing ApoA5, which lowers TGs, has remained elusive. Current hypotheses for how ApoA5 acts include direct stimulation of LPL, facilitation of TG-containing particle uptake, and regulation of hepatic TG secretion. Using immunoprecipitation-MS and Western blotting, biolayer interferometry, functional LPL enzymatic assays, and kinetic analyses of LPL activity, we show that ApoA5 associates with ANGPTL3/8 in human serum and most likely decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. We also demonstrate that ApoA5 has no direct effect on LPL, nor does it suppress the LPL-inhibitory activities of ANGPTL3, ANGPTL4, or ANGPTL4/8. Importantly, ApoA5 suppression of ANGPTL3/8-mediated LPL inhibition occurred at a molar ratio consistent with the circulating concentrations of ApoA5 and ANGPTL3/8. Because liver X receptor (LXR) agonists decrease ApoA5 expression and cause hypertriglyceridemia, we investigated the effect of the prototypical LXR agonist T0901317 on human primary hepatocytes. We observed that T0901317 modestly stimulated hepatocyte ApoA5 release, but markedly stimulated ANGPTL3/8 secretion. Interestingly, the addition of insulin to T0901317 attenuated ApoA5 secretion, but further increased ANGPTL3/8 secretion. Together, these results reveal a novel intersection of ApoA5 and ANGPTL3/8 in the regulation of TG metabolism and provide a possible explanation for LXR agonist-induced hypertriglyceridemia.

Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer.

LESSONS LEARNED: Entinostat at the selected dose levels in combination with a standard dose of enzalutamide showed a promising safety profile in this small phase I study BACKGROUND: Entinostat inhibits prostate cancer (PCa) growth and suppresses Treg cell function in vitro and in vivo. METHODS: This was a phase I study to explore the safety and preliminary efficacy of entinostat (3 and 5 mg orally per week) in combination with enzalutamide in castration resistant PCa (CRPC). The study was carried out in an open-label two-cohort design. Patients who had developed disease progression on or were eligible for enzalutamide were enrolled in the study. The safety profile of the combination therapy, Prostate specific antigen (PSA) levels, the pharmacokinetics of enzalutamide after entinostat administration, peripheral T-cell subtype (including Treg quantitation), and mononuclear cell (PBMC) histone H3 acetylation were analyzed. RESULTS: Six patients with metastatic CRPC were enrolled. There was no noticeable increment of fatigue related to entinostat. Toxicities possibly or probably related to entinostat or the combination therapy included grade 3 anemia 1/6 (17%), grade 2 white blood cell (WBC) decrease 1/6 (17%), and other self-limiting grade 1 adverse events (AEs). Median duration of treatment with entinostat was 18 weeks. Entinostat did not affect the steady plasma concentration of enzalutamide. Increased PBMC histone H3 acetylation was observed in blood samples. No evident T-cell subtype changes were detected, including in Treg quantitation. CONCLUSION: Entinostat 5 mg weekly in combination with enzalutamide showed an acceptable safety profile in this small phase I study. A planned phase II part of the trial was terminated because of sponsor withdrawal.

Angiopoietin-like protein 4(E40K) and ANGPTL4/8 complex have reduced, temperature-dependent LPL-inhibitory activity compared to ANGPTL4.

We previously demonstrated that angiopoietin-like 8 (ANGPTL8) forms a localized complex with ANGPTL4 to reduce its lipoprotein lipase (LPL)-inhibitory activity and enable increased postprandial uptake of fatty acids (FA) into adipose tissue. Because prolonged cold exposure may increase adipose tissue FA uptake and decrease circulating triglycerides (TG) by reducing ANGPTL4 expression and inducing ANGPTL8 expression (and thus ANGPTL4/8 expression), we investigated the effect of temperature on ANGPTL4 and ANGPTL4/8 LPL-inhibitory activities in vitro. As the ANGPTL4(E40K) mutation results in decreased TG, we also characterized ANGPTL4(E40K) and ANGPTL4(E40K)/8 complex LPL-inhibitory activities. Interestingly, while ANGPTL3, ANGPTL3/8, and ANGPTL4 showed similar LPL inhibition at 37 °C and 22 °C, the already reduced LPL-inhibitory activity of ANGPTL4/8 at 37 °C was even more decreased at 22 °C. At 37 °C, ANGPTL4(E40K) manifested decreased LPL-inhibitory activity compared to ANGPTL4/8, while ANGPTL4(E40K)/8 had even further reduced potency. Remarkably, ANGPTL4/8, ANGPTL4(E40K), and ANGPTL4(E40K)/8 were each actually capable of stimulating LPL activity at 22 °C. Together, these results indicate that ANGPTL4/8 stimulation of LPL activity at low temperatures may represent an additional mechanism for further increasing adipose tissue FA uptake during cold exposure, beyond that already occurring due to decreased ANGPTL4 expression and increased ANGPTL8 expression. In addition, because ANGPTL4(E40K) has decreased LPL-inhibitory activity compared to ANGPTL4/8, our findings also suggest why ANGPTL4(E40K) carriers have decreased circulating TG levels.

Impact of Percutaneous Edge-to-Edge Repair in Patients With Atrial Functional Mitral Regurgitation.

BACKGROUND: The aim of this study was to clarify the clinical outcomes of patients with atrial functional mitral regurgitation (FMR) who underwent the MitraClip procedure compared with those with conventional FMR and sinus rhythm (SR).Methods and Results:Of 303 patients with FMR who underwent the MitraClip procedure, 40 with "atrial-FMR" defined as FMR with permanent atrial fibrillation and normal left ventricular (LV) function/size and 115 with "sinus-FMR" defined as FMR with SR and LV dysfunction were reviewed. Transthoracic and 3D transesophageal echocardiography, and the cardiac complication rate (composite of all-cause death, heart failure admission, mitral valve (MV) surgery, and redo MitraClip procedure) during the 12-month follow-up were compared between the groups. After the MitraClip procedure, reductions in the mitral annular area and its anteroposterior dimension and in the leaflet closure area were observed in both groups. MV orifice area was smaller with greater transmitral pressure gradient (P<0.05) after the procedure in atrial-FMR patients than in those with sinus-FMR. The prevalence of residual MR was similar, but significant tricuspid regurgitation (TR) was more prevalent in the atrial-FMR group at follow-up. Cardiac complication rate was comparable between groups (20% vs. 25%, P=0.63). CONCLUSIONS: Reduction of MR occurred in atrial-FMR probably because of the increase in leaflet coaptation area. Significant TR was more common after the MitraClip procedure in patients with atrial-FMR than with sinus-FMR. However, mid-term outcomes were comparable between patients with atrial-FMR and sinus-FMR.

Studying pediatric health outcomes with electronic health records using Bayesian clustering and trajectory analysis.

Use of routinely collected data from electronic health records (EHR) can expedite longitudinal studies that investigate childhood exposures and rare pediatric health outcomes. For instance, characteristics of the body mass index (BMI) trajectory early in life may be associated with subsequent development of type 2 diabetes. Past studies investigating these relationships have used longitudinal cohort data collected over the course of many years to investigate the connection between BMI trajectory and subsequent development of diabetes. In contrast, EHR data from routine clinical care can provide longitudinal information on early-life BMI trajectories as well as subsequent health outcomes without requiring any additional data collection. In this study, we introduce a Bayesian joint phenotyping and BMI trajectory model to address data quality challenges in an EHR-based study of early-life BMI and type 2 diabetes in adolescence. We compared this joint modeling approach to traditional approaches using a computable phenotype for type 2 diabetes or separately estimated BMI trajectories and type 2 diabetes phenotypes. In a sample of 49,062 children derived from the PEDSnet consortium of pediatric healthcare systems, a median 8 (interquartile range [IQR] 5-13) BMI measurements were available to characterize the early-life BMI trajectory. The joint modeling and computable phenotype approaches found that age at adiposity rebound between 5 and 9 years was associated with higher odds of type 2 diabetes in adolescence compared to age at adiposity rebound between 2 and 5 years (joint model odds ratio [OR] = 1.77; computable phenotype OR = 1.88) and that BMI in excess of 140% of the 95th percentile for age and sex at age 9 years was associated with higher odds of type 2 diabetes in adolescence relative to children with BMI from 100 to 120% of the 95th percentile (joint model OR = 6.22; computable phenotype OR = 13.25). Estimates from the separate phenotyping and trajectory model were substantially attenuated towards the null. These results demonstrate that EHR data coupled with modern methodologic approaches can improve efficiency and timeliness of studies of childhood exposures and rare health outcomes.

Mesh fixation techniques in primary ventral or incisional hernia repair.

BACKGROUND: The use of a mesh in primary ventral or incisional hernia repair lowers the recurrence rate  and is the accepted standard of care for larger defects. In laparoscopic primary ventral or incisional hernia repair the insertion of a mesh is indispensable. Different mesh fixation techniques have been used and refined over the years. The type of fixation technique is claimed to have a major impact on recurrence rates, chronic pain, health-related quality of life (HRQOL) and complication rates. OBJECTIVES: To determine the impact of different mesh fixation techniques for primary and incisional ventral hernia repair on hernia recurrence, chronic pain, HRQOL and complications. SEARCH METHODS: On 2 October 2020 we searched CENTRAL, MEDLINE (Ovid MEDLINE(R)) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R)), Ovid Embase, and two trials registries. We also performed handsearches, and contacted experts from the European Hernia Society (EHS). SELECTION CRITERIA: We included randomised controlled trials (RCTs) including adults with primary ventral or incisional hernia that compared different types of mesh fixation techniques (absorbable/nonabsorbable sutures, absorbable/nonabsorbable tacks, fibrin glue, and combinations of these techniques). DATA COLLECTION AND ANALYSIS: We extracted data in standardised piloted tables, or if necessary, directly into Review Manager 5. We assessed risks of bias with the Cochrane 'Risk of bias' tool. Two review authors independently selected the publications, and extracted data on results. We calculated risk ratios (RRs) for binary outcomes and mean differences (MDs) for continuous outcomes. For pooling we used an inverse-variance random-effects meta-analysis or the Peto method in the case of rare events. We prepared GRADE 'Summary of findings' tables. For laparoscopic repair we considered absorbable tacks compared to nonabsorbable tacks, and nonabsorbable tacks compared to nonabsorbable sutures as key comparisons. MAIN RESULTS: We included 10 trials with a total of 787 participants. The number of randomised participants ranged from 40 to 199 per comparison. Eight studies included participants with both primary and incisional ventral hernia. One study included only participants with umbilical hernia, and another only participants with incisional hernia. Hernia size varied between studies. We judged the risk of bias as moderate to high. Absorbable tacks compared to nonabsorbable tacks Recurrence rates in the groups were similar (RR 0.74, 95% confidence interval (CI) 0.17 to 3.22; 2 studies, 101 participants). It is uncertain whether there is a difference between absorbable tacks and nonabsorbable tacks in recurrence because the certainty of evidence was very low. Evidence suggests that the difference between groups in early postoperative, late follow-up, chronic pain and HRQOL is negligible. Nonabsorbable tacks compared to nonabsorbable sutures At six months there was one recurrence in each group (RR 1.00, 95% CI 0.07 to 14.79; 1 study, 36 participants). It is uncertain whether there is a difference between nonabsorbable tacks and nonabsorbable sutures in recurrence because the certainty of evidence was very low. Evidence suggests that the difference between groups in early postoperative, late follow-up and chronic pain is negligible. We found no study that assessed HRQOL. Absorbable tacks compared to absorbable sutures No recurrence was observed at one year (very low certainty of evidence). Early postoperative pain was higher in the tacks group (VAS 0 - 10: MD -2.70, 95% CI -6.67 to 1.27; 1 study, 48 participants). It is uncertain whether there is a difference between absorbable tacks compared to absorbable sutures in early postoperative pain because the certainty of evidence was very low. The MD for late follow-up pain was -0.30 (95% CI -0.74 to 0.14; 1 study, 48 participants). We found no study that assessed HRQOL. Combination of different fixation types (tacks and sutures) or materials (absorbable and nonabsorbable) There were mostly negligible or only small differences between combinations (e.g. tacks plus sutures) compared to a single technique (e.g. sutures only), as well as combinations compared to other combinations (e.g. absorbable sutures combined with nonabsorbable sutures compared to absorbable tacks combined with nonabsorbable tacks) in all outcomes. It is uncertain whether there is an advantage for combining different fixation types or materials for recurrence, chronic pain, HRQOL and complications, because the evidence certainty was very low or low, or we found no study on important outcomes. Nonabsorbable tacks compared to fibrin sealant The two studies showed different directions of effects: one showed higher rates for nonabsorbable tacks, and the other showed higher rates for fibrin sealant. Low-certainty evidence suggests that the difference between groups in early postoperative, late follow-up, chronic pain and HRQOL is negligible. Absorbable tacks compared to fibrin sealant One recurrence in the tacks group and none in the fibrin sealant group were noted after one year (low certainty of evidence). Early postoperative pain might be slightly lower using tacks (VAS 0 - 100; MD -12.40, 95% CI -27.60 to, 2.80;1 study, 50 participants; low-certainty evidence). The pattern of pain and HRQOL course over time (up to 1 year) was similar in the groups (low certainty of evidence). AUTHORS' CONCLUSIONS: Currently none of the techniques can be considered superior to any other, because the certainty of evidence was low or very low for all outcomes.