IntroductionThe Prospective Physical Activity Sitting and Sleep consortium (ProPASS) is an international collaboration platform committed to harmonise thigh-worn accelerometry data. The aim of this ...paper is to (1) outline observational thigh-worn accelerometry studies and (2) summarise key strategic directions arising from the inaugural ProPASS meeting.Methods(1) We performed a systematic scoping review for observational studies of thigh-worn triaxial accelerometers in free-living adults (n≥100, 24 hours monitoring protocols). (2)Attendees of the inaugural ProPASS meeting were sent a survey focused on areas related to developing ProPASS: important terminology (Q1); accelerometry constructs (Q2); advantages and distinct contribution of the consortium (Q3); data pooling and harmonisation (Q4); data access and sharing (Q5 and Q6).Results(1) Eighty eligible articles were identified (22 primary studies; n~17 685). The accelerometers used most often were the ActivPAL3 and ActiGraph GT3X. The most commonly collected health outcomes were cardiometabolic and musculoskeletal. (2) None of the survey questions elicited the predefined 60% agreement. Survey responses recommended that ProPASS: use the term physical behaviour or movement behaviour rather than ‘physical activity’ for the data we are collecting (Q1); make only minor changes to ProPASS’s accelerometry construct (Q2); prioritise developing standardised protocols/tools (Q4); facilitate flexible methods of data sharing and access (Q5 and Q6).ConclusionsThigh-worn accelerometry is an emerging method of capturing movement and posture across the 24 hours cycle. In 2020, the literature is limited to 22 primary studies from high-income western countries. This work identified ProPASS’s strategic directions—indicating areas where ProPASS can most benefit the field of research: use of clear terminology, refinement of the measured construct, standardised protocols/tools and flexible data sharing.
DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using ...the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.
•Structure-guided approach for κ-opioid receptor (KOR)-DREADD (KORD) design•KORD is selectively activated by salvinorin B, and not by endogenous opioids•KORD robustly silenced multiple neuronal subtypes•Inhibitory KORD combined with excitatory hM3Dq for multiplexed behavioral control
The κ-opioid receptor (KOR) was used as a template to generate a novel inhibitory DREADD (KORD), which is activated by salvinorin B and insensitive to endogenous opioid peptides. Sequential activation of the inhibitory KOR-DREADD and an excitatory M3-DREADD facilitated the bidirectional, multiplexed modulation of behavior.
Long-term outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents, as compared with coronary-artery bypass grafting (CABG), in patients with left main coronary ...artery disease are not clearly established.
We randomly assigned 1905 patients with left main coronary artery disease of low or intermediate anatomical complexity (according to assessment at the participating centers) to undergo either PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). The primary outcome was a composite of death, stroke, or myocardial infarction.
At 5 years, a primary outcome event had occurred in 22.0% of the patients in the PCI group and in 19.2% of the patients in the CABG group (difference, 2.8 percentage points; 95% confidence interval CI, -0.9 to 6.5; P = 0.13). Death from any cause occurred more frequently in the PCI group than in the CABG group (in 13.0% vs. 9.9%; difference, 3.1 percentage points; 95% CI, 0.2 to 6.1). In the PCI and CABG groups, the incidences of definite cardiovascular death (5.0% and 4.5%, respectively; difference, 0.5 percentage points; 95% CI, -1.4 to 2.5) and myocardial infarction (10.6% and 9.1%; difference, 1.4 percentage points; 95% CI, -1.3 to 4.2) were not significantly different. All cerebrovascular events were less frequent after PCI than after CABG (3.3% vs. 5.2%; difference, -1.9 percentage points; 95% CI, -3.8 to 0), although the incidence of stroke was not significantly different between the two groups (2.9% and 3.7%; difference, -0.8 percentage points; 95% CI, -2.4 to 0.9). Ischemia-driven revascularization was more frequent after PCI than after CABG (16.9% vs. 10.0%; difference, 6.9 percentage points; 95% CI, 3.7 to 10.0).
In patients with left main coronary artery disease of low or intermediate anatomical complexity, there was no significant difference between PCI and CABG with respect to the rate of the composite outcome of death, stroke, or myocardial infarction at 5 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776.).
The prognostic implications of periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) remain controversial. We examined ...the 3-year rates of mortality among patients with and without PMI undergoing left main coronary artery intervention randomized to PCI with everolimus-eluting stents vs. CABG in the large-scale, multicentre, prospective, randomized EXCEL trial.
By protocol, PMI was defined using an identical threshold for PCI and CABG creatinine kinase-MB (CK-MB) elevation >10× the upper reference limit (URL) within 72 h post-procedure, or >5× URL with new Q-waves, angiographic vessel occlusion, or loss of myocardium on imaging. Cox proportional hazards modelling was performed controlling for age, sex, hypertension, diabetes mellitus, left ventricular ejection fraction, SYNTAX score, and chronic obstructive pulmonary disease (COPD). A total of 1858 patients were treated as assigned by randomization. Periprocedural MI occurred in 34/935 (3.6%) of patients in the PCI group and 56/923 (6.1%) of patients in the CABG group odds ratio 0.61, 95% confidence interval (CI) 0.40-0.93; P = 0.02. Periprocedural MI was associated with SYNTAX score, COPD, cross-clamp duration and total procedure duration, and not using antegrade cardioplegia. By multivariable analysis, PMI was associated with cardiovascular death and all-cause death at 3 years adjusted hazard ratio (HR) 2.63, 95% CI 1.19-5.81; P = 0.02 and adjusted HR 2.28, 95% CI 1.22-4.29; P = 0.01, respectively. The effect of PMI was consistent for PCI and CABG for cardiovascular death (Pinteraction = 0.56) and all-cause death (Pinteraction = 0.59). Peak post-procedure CK-MB ≥10× URL strongly predicted mortality, whereas lesser degrees of myonecrosis were not associated with prognosis.
In the EXCEL trial, PMI was more common after CABG than PCI, and was strongly associated with increased 3-year mortality after controlling for potential confounders. Only extensive myonecrosis (CK-MB ≥10× URL) was prognostically important.
Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional ...treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell-dependent immune responses, even in β
-microglobulin (β
M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.
The randomized EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial reported a similar rate of the 3-year composite primary ...endpoint of death, myocardial infarction (MI), or stroke in patients with left main coronary artery disease (LMCAD) and site-assessed low or intermediate SYNTAX scores treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Whether these results are consistent in high-risk patients with diabetes, who have fared relatively better with CABG in most prior trials, is unknown.
In this pre-specified subgroup analysis from the EXCEL trial, the authors sought to examine the effect of diabetes in patients with LMCAD treated with PCI versus CABG.
Patients (N = 1,905) with LMCAD and site-assessed low or intermediate CAD complexity (SYNTAX scores ≤32) were randomized 1:1 to PCI with everolimus-eluting stents versus CABG, stratified by the presence of diabetes. The primary endpoint was the rate of a composite of all-cause death, stroke, or MI at 3 years. Outcomes were examined in patients with (n = 554) and without (n = 1,350) diabetes.
The 3-year composite primary endpoint was significantly higher in diabetic compared with nondiabetic patients (20.0% vs. 12.9%; p < 0.001). The rate of the 3-year primary endpoint was similar after treatment with PCI and CABG in diabetic patients (20.7% vs. 19.3%, respectively; hazard ratio: 1.03; 95% confidence interval: 0.71 to 1.50; p = 0.87) and nondiabetic patients (12.9% vs. 12.9%, respectively; hazard ratio: 0.98; 95% confidence interval: 0.73 to 1.32; p = 0.89). All-cause death at 3 years occurred in 13.6% of PCI and 9.0% of CABG patients (p = 0.046), although no significant interaction was present between diabetes status and treatment for all-cause death (p = 0.22) or other endpoints, including the 3-year primary endpoint (p = 0.82) or the major secondary endpoints of death, MI, or stroke at 30 days (p = 0.61) or death, MI, stroke, or ischemia-driven revascularization at 3 years (p = 0.65).
In the EXCEL trial, the relative 30-day and 3-year outcomes of PCI with everolimus-eluting stents versus CABG were consistent in diabetic and nondiabetic patients with LMCAD and site-assessed low or intermediate SYNTAX scores.(Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization EXCEL; NCT01205776)
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Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness
, affecting 0.9-4% of women and 0.3% of men
, with twin-based heritability estimates of 50-60%
. ...Mortality rates are higher than those in other psychiatric disorders
, and outcomes are unacceptably poor
. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)
and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
Aim
To evaluate the impact of left ventricular ejection fraction (LVEF) on 3‐year outcomes in patients with left main coronary artery disease (LMCAD) undergoing percutaneous coronary intervention ...(PCI) or coronary artery bypass grafting (CABG) in the EXCEL trial.
Methods and results
The EXCEL trial randomized patients with LMCAD to PCI with everolimus‐eluting stents (n = 948) or CABG (n = 957). Among 1804 patients with known baseline LVEF, 74 (4.1%) had LVEF <40% heart failure with reduced ejection fraction (HFrEF), 152 (8.4%) LVEF 40–49% heart failure with mid‐range ejection fraction (HFmrEF) and 1578 (87.5%) LVEF ≥50% (heart failure with preserved ejection fraction). Patients with HFrEF vs. HFmrEF vs. preserved LVEF experienced a longer postoperative hospital stay (9.0 vs. 7.0 vs. 6.0 days, P = 0.02) with greater peri‐procedural complications after CABG, while hospital stay after PCI was unaffected by LVEF (1.5 vs. 2.0 vs. 1.0 days, P = 0.20). The composite primary endpoint of death, stroke, or myocardial infarction at 3 years was 29.3% (PCI) vs. 27.6% (CABG) in patients with HFrEF, 16.2% vs. 15.0% in patients with HFmrEF, and 14.5% vs. 14.6% in those with preserved LVEF, respectively (Pinteraction = 0.90). Smoothing spline analysis demonstrated that the 3‐year risk of all‐cause death increased when LVEF decreased, both in patients undergoing CABG and PCI.
Conclusion
In the EXCEL trial, the composite rate of death, stroke or myocardial infarction at 3 years was significantly higher in patients with HFrEF compared with HFmrEF or preserved LVEF, driven by an increased rate of all‐cause death. No significant differences after PCI vs. CABG were observed among patients with HFrEF, HFmrEF and preserved LVEF. Longer‐term follow‐up could provide important insights on differences in clinical outcomes that might emerge over time.
Clinical Trial Registration:
ClinicalTrials.gov Identifier NCT01205776.
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