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The vibration level is the key index to measure the performance of marine gear transmission device. The compound gear transmission system, which is composed of a helical gear pair and a spur star gear train, is widely used in marine gear transmission device. This paper presents a multi-node dynamic model for a marine compound gear transmission system, investigating the modal properties and dynamic responses of the system. The mesh stiffness and transmission error for each gear pair are determined using the loaded tooth contact analysis (LTCA) model. The theoretical and experimental vibration acceleration responses of the gearbox housing are contrastively analysed. The results show that some vibration modes are very similar to those of a single planetary gear train, but other modes are multi-node and multi-degree of freedom coupling modes. The vibration coupling and transferring phenomenon between two stages can be observed remarkably, but those show obvious differences under different working conditions. The torsional stiffness of the elastic connecting shaft has significant influence on the vibration coupling and transferring phenomenon. The results can provide useful guidance for the low vibration and noise design of the marine compound gear transmission system.

Aims The minute ventilation–carbon dioxide production relationship (VE/VCO2 slope) is widely used for prognostication in heart failure (HF) with reduced left ventricular ejection fraction (LVEF). This study explored the prognostic value of VE/VCO2 slope across the spectrum of HF defined by ranges of LVEF. Methods and results In this single‐centre retrospective observational study of 1347 patients with HF referred for cardiopulmonary exercise testing, patients with HF were categorized into HF with reduced (HFrEF, LVEF

BACKGROUND: Immune checkpoint inhibitors (ICI) are widely used cancer treatments. There are limited data the risk for developing venous thromboembolism (VTE) among patients on an ICI. METHODS: This was a retrospective study of 2854 patients who received ICIs at a single academic center. VTE events, defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were identified by individual chart review and were blindly adjudicated using standard imaging criteria. A self-controlled risk-interval design was applied with an “at-risk period” defined as the two-year period after, and the “control period”, defined as the two-year prior to treatment. The hazard ratio (HR) was calculated using a fixed-effect proportional hazards model. RESULTS: Of the 2854 patients, 1640 (57.5%) were men; mean age was 64±13 years. The risk for VTE was 7.4% at 6 months and 13.8% at 1 year after starting an ICI. The rate of VTE was >4-fold higher after starting an ICI (HR 4.98, 95% CI 3.65 – 8.59, p

Aims The prognostic importance of post-diagnosis assessment of cardiorespiratory fitness (CRF) in cancer patients is not well established. We sought to examine the association between CRF and mortality in cancer patients. Methods and results This was a single-centre cohort analysis of 1632 patients (58% male; 64 ± 12 years) with adult-onset cancer who were clinically referred for exercise treadmill testing a median of 7 [interquartile range (IQR): 3–12] years after primary diagnosis. Cardiorespiratory fitness was defined as peak metabolic equivalents (METs) achieved during standard Bruce protocol and categorized by tertiles. The association between CRF and all-cause and cause-specific mortality was assessed using multivariable Cox proportional hazard models adjusting for important covariates. Median follow-up was 4.6 (IQR: 2.6–7.0) years; a total of 411 deaths (229, 50, and 132 all-cause, cardiovascular (CV), and cancer related, respectively) occurred during this period. Compared with low CRF (range: 1.9–7.6 METs), the adjusted hazard ratio (HR) for all-cause mortality was 0.38 [95% confidence interval (CI): 0.28–0.52] for intermediate CRF (range: 7.7–10.6 METs) and 0.17 (95% CI: 0.11–0.27) for high CRF (range: 10.7–22.0 METs). The corresponding HRs were 0.40 (95% CI: 0.19–0.86) and 0.41 (95% CI: 0.16–1.05) for CV mortality and 0.40 (95% CI: 0.26–0.60) and 0.16 (95% CI: 0.09–0.28) for cancer mortality, respectively. The adjusted risk of all-cause, CV, and cancer mortality decreased by 26%, 14%, and 25%, respectively with each one MET increment in CRF. Conclusion Cardiorespiratory fitness is a strong, independent predictor of all-cause, CV, and cancer mortality, even after adjustment for important clinical covariates in patients with certain cancers.

Over the past decade, researchers have identified intervention methods and program models that reduce juvenile delinquency and encourage prosocial development. Preventing juvenile delinquency not only saves young lives from being wasted but also prevents the onset of adult criminal careers and thus reduces the burden of crime on its victims and society. Aiming at this social problem, this study combines Internet of Things and grid models to study the attribution and prevention mechanisms of minor campus violence crimes. It realizes the modern network system mode of information management, collaborative operation, and grid integration in the target area through Internet of Things and grid models. In addition, based on consulting-related literature and practical research, the causes of campus violence crimes are analyzed through a self-organizing competitive neural network. Finally, this article combines the judicial practice of the management of campus violence and presents the prevention and control countermeasures of juvenile campus violence crimes to effectively prevent and control the occurrence of juvenile campus violence crimes.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with established heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [10% decline in ejection fraction to 53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013).SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

Background: Recent guidelines have outlined echo markers of diastolic dysfunction (DD); evidence is limited for their prognostic value for hospitalization for heart failure (HHF) in overweight and obese pts. Methods: CAMELLIA-TIMI 61 was a randomized placebo-controlled trial of the weight loss agent lorcaserin in 12,000 pts with BMI ≥27 with or at risk for CV disease (median follow-up, 3.3 yrs). Echo with core lab interpretation was performed on a subset of pts. Established DD parameters were measured, including the ratio of the peak early transmitral diastolic flow velocity over the early diastolic mitral annulus velocity (average E/e’), left atrium volume index (LAVi), and tricuspid regurgitation jet velocity (TRV). These were analyzed continuously, using the standard cutpoints of >14, >34 mL/m 2 , and >2.8 m/s, respectively, and separately to determine the optimal cutpoints. The primary outcome for this analysis was HHF. Results: In 3,972 pts with baseline ejection fraction ≥50%, all 3 variables on a continuous scale predicted increased risk of HHF; using standard cutpoints, only E/e’>14 remained independently associated with HHF after adjustment for the other 2 echo parameters and clinical variables ( Panel A ). In an analysis of optimal cutpoints in these overweight and obese pts, >13 was optimal for E/e’, >2.5 m/s for TRV, and >58 mL/m 2 for LAVi. In a model with all 3 echo parameters, all remained significant predictors of HHF. After incorporation of clinical variables, E/e’ (HR 2.15, 95%CI 1.24-3.72) and LAVi (HR 2.41, 1.33-4.36) remained independent predictors of HHF ( Panel A ). Rates of HHF were 0.6, 3.3, and 10.1% (p-trendPanel B ). Conclusions: Several echocardiographic markers of diastolic dysfunction used in current guidelines predict increased risk of HHF events in the understudied obese and overweight population. A higher LAVi (> 58 ml/m 2 ) cutpoint should be considered in these pts to prognosticate risk of HHF.

Background There are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis after treatment with immune checkpoint inhibitors (ICIs). Purpose To evaluate incidence of pericardial disease in patients treated with an ICI. Methods This was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI (design 1). A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, in a second analysis, we also compared patients who developed an event on an ICI to patients treated with an ICI who did not develop a pericardial event (design 2). Cox proportional hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias. Results There were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (interquartile range 64 to 411) with an incidence rate of 1.57 events per 100 person-years. There was a 4-fold increase in the risk for pericarditis or a pericardial effusion among patients on an ICI compared to controls not treated with ICI after adjusting for potential confounders (hazard ratio [HR] 4.37, 95% confidence interval [CI] 2.09–9.14, p0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00–6.57, p=0.049). Conclusions ICI use was associated with an increased risk for development of pericardial disease among cancer patients and a pericardial event on an ICI was associated with a trend towards increased mortality. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health/National Heart, Lung, and Blood Institute; a gift from A. Curt Greer and Pamela Kohlberg

Recent studies indicated obvious impacts of nano-carriers on cytochrome P450 enzymes (CYP450s) in vitro , but the effects in vivo are still unknown. In the present research, mPEG 2k -PCL x micelles with different length of hydrophobic block (2000–10,000 Da) were intravenously administrated into rats for 14 days to evaluate the sub-chronic influences in the metabolic function of hepatic CYP450s. Although CYP1A1/B2 was susceptible to mPEG 2k -PCL x micelles compared with other CYP isoenzymes, induction was mainly observed and varied with micelle type, administration dose, and CYP isoform. Interestingly, mPEG 2k -PCL 3.5k micelles at 5 mg/kg increased the activity of CYP1A2, CYP2B1, CYP2C6, CYP2C11, and CYP3A1/2 while mPEG 2k -PCL 5k micelles only induced the latter three enzymes at 75 mg/kg. The mRNA expression of corresponding CYPs was mostly up-regulated by mPEG 2k -PCL 3.5k micelles whilst less effect in protein level except for CYP3A1/2. Moreover, mPEG 2k -PCL 3.5k micelles could affect the pharmacokinetic properties of phenacetin (CYP1A2), tolbutamide (CYP2C6), omeprazole (CYP2C11), and midazolam (CYP3A1/2) with a decrease of 19.6% in C max , 20.5% in AUC 0-t , 31.6% in AUC 0-t , and 40.1% in C max at 5 mg/kg, respectively ( P P

Trogocytosis, in which cells nibble away parts of neighboring cells, is an intercellular cannibalism process conserved from protozoa to mammals. Its underlying molecular mechanisms are not well understood and are likely distinct from phagocytosis, a process that clears entire cells. Bi-directional contact repulsion induced by Eph/ephrin signaling involves transfer of membrane patches and full-length Eph/ephrin protein complexes between opposing cells, resembling trogocytosis. Here, we show that the phagocytic adaptor protein Gulp1 regulates EphB/ephrinB trogocytosis to achieve efficient cell rearrangements of cultured cells and during embryonic development. Gulp1 mediates trogocytosis bi-directionally by dynamic engagement with EphB/ephrinB protein clusters in cooperation with the Rac-specific guanine nucleotide exchange factor Tiam2. Ultimately, Gulp1’s presence at the Eph/ephrin cluster is a prerequisite for recruiting the endocytic GTPase dynamin. These results suggest that EphB/ephrinB trogocytosis, unlike other trogocytosis events, uses a phagocytosis-like mechanism to achieve efficient membrane scission and engulfment.

PURPOSE: Little is known about how a breast cancer diagnosis and treatment affects job-related outcomes in young women with breast cancer, who are an integral part of the workforce. We sought to describe employment trends among young breast cancer survivors. METHODS: 911 women with non-metastatic breast cancer were surveyed about employment-related outcomes 1-year post-diagnosis. Participants were enrolled in the Young Women’s Breast Cancer Study an ongoing, multi-center cohort of women diagnosed with breast cancer at age ≤40. RESULTS: Among 911 women, median age at diagnosis was 37 years (range: 17–40). Most women (80%, n=729) were employed 1-year post-diagnosis. Among the 7% (n=62) employed before diagnosis but who reported unemployment at 1-year, approximately half reported they were unemployed for health reasons. Among employed women, 7% said treatment affected their ability to perform their job. Women with stage 3 disease (vs. stage 1 disease, odds ratio (OR): 3.73, 95% CI, 1.39–9.97) and those who reported having money to pay bills after cutting back or difficulty paying bills at baseline (vs. having enough money for special things, OR: 2.70, 95% CI, 1.32–5.52) at baseline were more likely to have transitioned out of the workforce. CONCLUSIONS: Our results suggest an impact of disease burden and socioeconomic status on employment in young breast cancer survivors. There is a need to ensure young survivors who leave the workforce following diagnosis are sufficiently supported given the potential adverse psychosocial and financial impacts unemployment on survivors, their families, communities, and society.

BackgroundThere are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs).MethodsThis was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias.ResultsThere were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64–411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049).ConclusionsICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality.

There is increasing use of sodium glucose co-transporter 2 (SGLT2) inhibitors to treat diabetes. Since trials apply specific entry and exclusion criteria to ensure internal validity, comparisons of trial populations with nationally representative samples can inform the applicability of study findings to practice.To compare individuals with diabetes from a nationally representative sample to patients who underwent randomization in the EMPA-REG trial. A secondary aim was to characterize what proportion of individuals prescribed an SGLT2 inhibitor in a nationally representative sample would have been included in the EMPA-REG trial.Retrospective cross-sectional study.Adults with diabetes who took part in the National Health and Nutrition Examination Survey (NHANES) between 2011-2014 (primary analysis corresponding to EMPA-REG enrollment) and 2015-2018 (secondary analysis corresponding to contemporary sample).The primary outcome was a comparison of demographic (age, sex, ethnicity, and pregnancy status), clinical (comorbidities and medication use), examination (weight, body mass index, and systolic and diastolic blood pressure), and laboratory (hgba1c, low- and high-density lipoprotein cholesterol, triglycerides, and estimated glomerular filtration rate) characteristics of NHANES respondents versus EMPA-REG trial participants. The secondary outcome was the proportion of NHANES respondents who had been prescribed an SGLT2 inhibitor that would have met inclusion criteria for the EMPA-REG trial.There were 655 and 48 respondents, representing a weighted sample of 21,849,775 and 1,062,573 individuals, included in the primary and secondary analyses, respectively. Overall, 7.6% (95% CI 4.8-10.6%) of 2011-2014 NHANES respondents would have met all EMPA-REG trial inclusion criteria. NHANES respondents and EMPA-REG participants differed across demographic, clinical, examination, and laboratory domains. Of NHANES respondents from 2015 to 2018 who were prescribed an SGLT2 inhibitor, 10.6% (95% CI1-24.7%) would have met all inclusion criteria for the EMPA-REG trial.The EMPA-REG population differed from a nationally representative sample, which could affect generalizability.

Summary Objectives Skeletal myopathies are highly morbid, and in rare cases even fatal, immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI). Skeletal myopathies are also a recognized statin-associated side effect. It is unknown whether concurrent use of statins and ICIs increases the risk of skeletal myopathies. Methods This was a retrospective cohort study of all patients who were treated with an ICI at a single academic institution (Massachusetts General Hospital, Boston, MA, USA). The primary outcome of interest was the development of a skeletal myopathy. The secondary outcome of interest was an elevated creatine kinase level (above the upper limit of normal). Results Among 2757 patients, 861 (31.2%) were treated with a statin at the time of ICI start. Statin users were older, more likely to be male and had a higher prevalence of cardiovascular and non-cardiovascular co-morbidities. During a median follow-up of 194 days (inter quartile range 65–410), a skeletal myopathy occurred in 33 patients (1.2%) and was more common among statin users (2.7 vs. 0.9%, P < 0.001). Creatine kinase (CK) elevation was present in 16.3% (114/699) and was higher among statin users (20.0 vs. 14.3%, P = 0.067). In a multivariable Cox model, statin therapy was associated with a >2-fold higher risk for skeletal myopathy (HR, 2.19; 95% confidence interval, 1.07–4.50; P = 0.033). Conclusion In this large cohort of ICI-treated patients, a higher risk was observed for skeletal myopathies and elevation in CK levels in patients undergoing concurrent statin therapy. Prospective observational studies are warranted to further elucidate the potential association between statin use and ICI-associated myopathies., Graphical Abstract Graphical Abstract

Introduction: Immune checkpoint inhibitors (ICI) lead to immune activation, increased inflammation and cancer cell death. Both immune activation and inflammation are critical pathobiological drivers for venous thromboembolism (VTE). There are no robust data testing the effect of ICIs on the risk of developing VTE. Methods: This is a retrospective study of 2854 patients who received ICIs at Massachusetts General Hospital, Boston, MA. VTE events, defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were identified by individual chart review and were blindly adjudicated using standard criteria. A case-crossover design was applied with an “at-risk period” defined as the two-year period after and the “control period” as the two years prior to treatment. Incidence rate ratio (IRR) was calculated using Poisson’s regression. Results: Immune checkpoint inhibitor use increased VTE risk by 1.84-fold from 4.85 per 100-person years to 8.91 per 100 person-years (IRR 1.84, 95% confidence interval: 1.54 - 2.19, p Conclusions: Patients with cancer treated with ICIs are at increased risk of developing VTE. Whether prophylaxis for VTE among patients starting an ICI reduces this risk is unclear.

Background Prolonged androgen deprivation therapy (ADT) is favored over short-term use in patients with localized high-risk prostate cancer (PC). Objectives This study sought to compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure and to explore how duration of ADT exposure influences CRF and CV mortality. Methods Retrospective cohort study of patients referred for exercise treadmill testing (ETT) after a PC diagnosis. PC risk classification was based on Gleason score (GS): high risk if GS ≥8; intermediate risk if GS = 7; and low risk if GS 8 defined as good CRF and METs ≤8 as reduced CRF. ADT exposure was categorized as short term (≤6 months) versus prolonged (>6 months). Results A total of 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0, 7.9 years) after PC diagnosis. Of those, 150 patients (24.3%) received ADT prior to the ETT; 99 with short-term and 51 with prolonged exposure. 504 patients (81.8%) had ≥2 CV risk factors. Prolonged ADT was associated with reduced CRF (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.31 to 5.61; p = 0.007) and increased CV mortality (hazard ratio [HR]: 3.87; 95% CI: 1.16 to 12.96; p = 0.028) in adjusted analyses. Although the association between short-term ADT exposure and reduced CRF was of borderline significance (OR: 1.71; 95% CI: 1.00 to 2.94; p = 0.052), there was no association with CV mortality (HR: 1.60; 95% CI: 0.51 to 5.01; p = 0.420) in adjusted Cox regression models. Conclusions Among patients with PC and high baseline CV risk, prolonged ADT exposure was associated with reduced CRF and increased CV mortality., Central Illustration

Metabolic homeostasis is maintained by an interplay among tissues, organs, intracellular organelles, and molecules. Cidea and Cidec are lipid droplet (LD)–associated proteins that promote lipid storage in brown adipose tissue (BAT) and white adipose tissue (WAT). Using ob/ob/Cidea−/−, ob/ob/Cidec−/−, and ob/ob/Cidea−/−/Cidec−/− mouse models and CIDE-deficient cells, we studied metabolic regulation during severe obesity to identify ways to maintain metabolic homeostasis and promote antiobesity effects. The phenotype of ob/ob/Cidea−/− mice was similar to that of ob/ob mice in terms of serum parameters, adipose tissues, lipid storage, and gene expression. Typical lipodystrophy accompanied by insulin resistance occurred in ob/ob/Cidec−/− mice, with ectopic storage of lipids in the BAT and liver. Interestingly, double deficiency of Cidea and Cidec activated both WAT and BAT to consume more energy and to increase insulin sensitivity compared with their behavior in the other three mouse models. Increased lipolysis, which occurred on the LD surfaces and released fatty acids, led to activated β-oxidation and oxidative phosphorylation in peroxisomes and mitochondria in CIDE-deficient adipocytes. The coordination among LDs, peroxisomes, and mitochondria was regulated by adipocyte triglyceride lipase (ATGL)-peroxisome proliferator–activated receptor α (PPARα). Double deficiency of Cidea and Cidec activated energy consumption in both WAT and BAT, which provided new insights into therapeutic approaches for obesity and diabetes.

A 37-year-old woman with a history of inflammatory bowel disease on mercaptopurine presented with a week of recurrent fever, headache, myalgias and mildly elevated serum transaminases and leucopenia. Her workup revealed primary cytomegalovirus (CMV) infection with atypical lymphocytosis, elevated viral load, positive IgM and negative IgG. Two weeks after her initial presentation, she developed odynophagia and diarrhoea prompting endoscopic evaluation with biopsies, which demonstrated CMV disease of the gastrointestinal tract. Her fever and systemic symptoms improved rapidly with initiation of intravenous ganciclovir. She was transitioned to and maintained on oral valganciclovir until two and half months after discharge when her symptoms and lab abnormalities had fully subsided.

Recent studies indicated obvious impacts of nano-carriers on cytochrome P450 enzymes (CYP450s) in vitro, but the effects in vivo are still unknown. In the present research, mPEG

Ephs interact with ESCRT complex components and are released via extracellular vesicles or exosomes. EphB2 released via exosomes mediates a novel cell contact–independent mode of ephrin-Eph signaling that contributes to axon guidance in cell–cell repulsion processes., The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that ephrin-Eph signaling requires direct cell contact. Although the biological functions of ephrin-Eph signaling are well understood, our mechanistic understanding remains modest. Here we report the release of EVs containing Ephs and ephrins by different cell types, a process requiring endosomal sorting complex required for transport (ESCRT) activity and regulated by neuronal activity. Treatment of cells with purified EphB2+ EVs induces ephrinB1 reverse signaling and causes neuronal axon repulsion. These results indicate a novel mechanism of ephrin-Eph signaling independent of direct cell contact and proteolytic cleavage and suggest the participation of EphB2+ EVs in neural development and synapse physiology.

Background Minute ventilation-carbon dioxide production relationship (VE/VCO2 slope), as assessed by cardiopulmonary exercise testing (CPET), strongly predicts outcomes in heart failure (HF). High VE/VCO2 slope can indicate ventilatory inefficiency. A single VE/VCO2 slope threshold defining abnormal of ≥ 34 to 36 is used clinically across HF categories; however, this threshold has been validated largely in patients with reduced left ventricular ejection fraction (LVEF). Objectives To examine the associations between VE/VCO2 slope categories and a composite outcome of all-cause mortality and HF hospitalization across the spectrum of HF patients defined by LVEF. Methods Single-center retrospective cohort study of 1347 patients with heart failure (60.5% male, age 58.0±14.6 years, LVEF 42 ± 17%) clinically referred for CPET between 2010 and 2016. LVEF was obtained from echocardiogram (n=1309) or cardiac MRI (n=38). All-cause mortality was determined using Partners Research Patient Data Registry, which is linked to National Death Index. HF hospitalization data were adjudicated by review of electronic medical record. Patients with HF were categorized based on LVEF into heart failure with reduced (HFrEF, LVEF Results At two-year follow-up post CPET, there were 197 composite events (64 deaths and 133 HF hospitalizations). Across the entire cohort, increases in VC category were associated with increasing risk of two-year composite outcome in unadjusted and adjusted models. Compared to patients in VC-I, patients in VC-II were at increased risk of having two-year composite outcome in both HFrEF and HFpEF cohorts. Patients in VC III and IV had incremental increases in the likelihood of two-year composite outcome across all three HF cohorts (Table). Conclusions Higher VE/VCO2 slope categories are associated with increased risk of the two-year composite outcome of all-cause mortality and HF hospitalization across the spectrum of HF defined by LVEF. A VE/VCO2 slope between 29 and 36, often considered borderline in clinical practice, is associated with increased risk of this composite outcome in patients with HFrEF and HFpEF. Identifying a wider VE/VCO2 slope associated with increased risk in HF may have important implications on risk stratification clinically.

Targeted and inducible regulation of mammalian gene expression is a broadly important research capability that may also enable development of novel therapeutics for treating human diseases. Here we demonstrate that a catalytically inactive RNA-guided CRISPR-Cpf1 nuclease fused to transcriptional activation domains can up-regulate endogenous human gene expression. We engineered drug-inducible Cpf1-based activators and show how this system can be used to tune the regulation of endogenous gene transcription in human cells. Leveraging the simpler multiplex capability of the Cpf1 platform, we show that we can induce both synergistic and combinatorial gene expression in human cells. Our work should enable the creation of other Cpf1-based gene regulatory fusion proteins and the development of multiplex gene perturbation library screens for understanding complex cellular phenotypes.

Targeted and inducible regulation of mammalian gene expression is a broadly important capability. We engineered drug-inducible catalytically inactive Cpf1 nuclease fused to transcriptional activation domains to tune the expression of endogenous genes in human cells. Leveraging the multiplex capability of the Cpf1 platform, we demonstrate both synergistic and combinatorial gene expression in human cells. Our work should enable the development of multiplex gene perturbation library screens for understanding complex cellular phenotypes.

11576 Background: Androgen deprivation therapy (ADT) plays a pivotal role in management of prostate cancer (PC), with prolonged ADT favored over short-term use in the definitive treatment of high risk PC with radiation. Objectives: To compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure, and to explore how duration of ADT exposure influences CRF and CV mortality risk. Methods: This is a retrospective study of patients referred for exercise treadmill testing (ETT) after a diagnosis of PC. PC risk classification was based on Gleason score (GS) at diagnosis: high risk GS ≥ 8, intermediate risk GS= 7, and low risk GS ≤ 6. CRF was categorized according to metabolic equivalents (METs): METs ≥ 8 defined as good CRF and METs < 8 as reduced CRF. ADT exposure was grouped as short-term (≤ 6 months) versus prolonged (> 6 months). Results: 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0-7.9) after diagnosis of PC. 150 patients (24.3%) received ADT prior to ETT; 51 with short-term versus 99 with prolonged exposure. 524 (85.1%) patients had ≥ 2 CV risk factors, and 28 CV deaths occurred over 4.2 (interquartile range: 2.3-7.1) years following the ETT. Reduced CRF was more frequent among ADT-exposed versus ADT-naive patients (48.7 versus 32.6%, p< 0.001). Prolonged ADT was associated with reduced CRF (odds ratio (OR): 2.71; 95% confidence interval (CI): 1.31-5.61; p=0.007) and increased CV mortality (hazard ratio (HR): 3.87; 95% CI: 1.16-12.96; p=0.03) in adjusted analyses. In contrast, short-term ADT exposure was not independently associated with either reduced CRF (OR 1.71; 95% CI: 1.00-2.94); p=0.05) or CV mortality (HR: 1.60; 95% CI: 0.51-5.01; p=0.42). Conclusions: Among patients with PC and high baseline CV risk, > 6 months ADT exposure but not less was associated with reduced CRF and increased CV mortality. Reduced CRF may in part mediate increased CV mortality risk. Exercise interventions concurrent with prolonged ADT warrants investigation to potentially offset risk.

The lipid droplet–associated protein Fsp27 mediates lipid droplet growth by promoting directional lipid transfer from smaller to larger lipid droplets., Lipid droplets (LDs) are dynamic cellular organelles that control many biological processes. However, molecular components determining LD growth are poorly understood. Genetic analysis has indicated that Fsp27, an LD-associated protein, is important in controlling LD size and lipid storage in adipocytes. In this paper, we demonstrate that Fsp27 is focally enriched at the LD–LD contacting site (LDCS). Photobleaching revealed the occurrence of lipid exchange between contacted LDs in wild-type adipocytes and Fsp27-overexpressing cells but not Fsp27-deficient adipocytes. Furthermore, live-cell imaging revealed a unique Fsp27-mediated LD growth process involving a directional net lipid transfer from the smaller to larger LDs at LDCSs, which is in accordance with the biophysical analysis of the internal pressure difference between the contacting LD pair. Thus, we have uncovered a novel molecular mechanism of LD growth mediated by Fsp27.