Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Prognostic Performance of the IABP-SHOCK II Risk Score Among Cardiogenic Shock Subtypes in the Critical Care Cardiology Trials Network Registry.

BACKGROUND: Risk stratification has potential to guide triage and decision-making in cardiogenic shock (CS). We assessed the prognostic performance of the IABP-SHOCK II score, derived in Europe for acute myocardial infarct-related CS (AMI-CS), in a contemporary North American cohort, including different CS phenotypes. METHODS: The Critical Care Cardiology Trials Network (CCCTN) coordinated by the TIMI Study Group is a multicenter network of cardiac intensive care units (CICU). Participating centers annually contribute ≥2 months of consecutive medical CICU admissions. The IABP-SHOCK II risk score includes age \u3e73 years, prior stroke, admission glucose \u3e191 mg/dl, creatinine \u3e1.5 mg/dl, lactate \u3e5 mmol/l, and post-PCI TIMI flow grade RESULTS: Of 17,852 medical CICU admissions 5,340 patients across 35 sites were admitted with CS. In patients with AMI-CS (n=912), the IABP-SHOCK II score predicted a \u3e3-fold gradient in in-hospital mortality (low risk = 26.5%, intermediate risk =52.2%, high risk = 77.5%, p CONCLUSIONS: In an unselected international multicenter registry of patients admitted with CS, the IABP- SHOCK II score only moderately predicted in-hospital mortality in a broad population of CS regardless of etiology or irrespective of right, left, or bi-ventricular involvement

Management and Outcomes of Cardiogenic Shock in Cardiac ICUs With Versus Without Shock Teams.

BACKGROUND: Single-center studies suggest that implementation of multidisciplinary cardiogenic shock (CS) teams is associated with improved CS survival. OBJECTIVES: The aim was to characterize practice patterns and outcomes in the management of CS across multiple centers with versus without shock teams. METHODS: The Critical Care Cardiology Trials Network is a multicenter network of cardiac intensive care units (CICUs) in North America. All consecutive medical admissions to each CICU (n = 24) were captured during annual 2-month collection periods (2017-2019; n = 6,872). Shock management and CICU mortality among centers with versus without shock teams were compared using inverse probability weighting. RESULTS: Ten of the 24 centers had shock teams. Among 1,242 CS admissions, 44% were at shock team centers. The groups were well-balanced with respect to demographics, shock etiology, Sequential Organ Failure Assessment score, biochemical markers of end organ dysfunction, and invasive hemodynamics. Centers with shock teams used more pulmonary artery catheters (60% vs 49%; adjusted odds ratio [OR]: 1.86; 95% CI: 1.47-2.35; P \u3c 0.001), less overall mechanical circulatory support (MCS) (35% vs 43%; adjusted OR: 0.74; 95% CI: 0.59-0.95; P = 0.016), and more advanced types of MCS (53% vs 43% of all MCS; adjusted OR: 1.73; 95% CI: 1.19-2.51; P = 0.005) rather than intra-aortic balloon pumps. The presence of a shock team was independently associated with lower CICU mortality (23% vs 29%; adjusted OR: 0.72; 95% CI: 0.55-0.94; P = 0.016). CONCLUSIONS: In this multicenter observational study, centers with shock teams were more likely to obtain invasive hemodynamics, use advanced types of MCS, and have lower risk-adjusted mortality. A standardized multidisciplinary shock team approach may improve outcomes in CS

Critical Care Cardiology Trials Network (CCCTN): A Cohort Profile

AIMS: The aims of the Critical Care Cardiology Trials Network (CCCTN) are to develop a registry to investigate the epidemiology of cardiac critical illness and to establish a multicentre research network to conduct randomised clinical trials (RCTs) in patients with cardiac critical illness. METHODS AND RESULTS: The CCCTN was founded in 2017 with 16 centres and has grown to a research network of over 40 academic and clinical centres in the United States and Canada. Each centre enters data for consecutive cardiac intensive care unit (CICU) admissions for at least 2 months of each calendar year. More than 20 000 unique CICU admissions are now included in the CCCTN Registry. To date, scientific observations from the CCCTN Registry include description of variations in care, the epidemiology and outcomes of all CICU patients, as well as subsets of patients with specific disease states, such as shock, heart failure, renal dysfunction, and respiratory failure. The CCCTN has also characterised utilization patterns, including use of mechanical circulatory support in response to changes in the heart transplantation allocation system, and the use and impact of multidisciplinary shock teams. Over years of multicentre collaboration, the CCCTN has established a robust research network to facilitate multicentre registry-based randomised trials in patients with cardiac critical illness. CONCLUSION: The CCCTN is a large, prospective registry dedicated to describing processes-of-care and expanding clinical knowledge in cardiac critical illness. The CCCTN will serve as an investigational platform from which to conduct randomised controlled trials in this important patient population

Pulmonary Artery Catheter Use and Mortality in the Cardiac Intensive Care Unit.

BACKGROUND: The appropriate use of pulmonary artery catheters (PACs) in critically ill cardiac patients remains debated. OBJECTIVES: The authors aimed to characterize the current use of PACs in cardiac intensive care units (CICUs) with attention to patient-level and institutional factors influencing their application and explore the association with in-hospital mortality. METHODS: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Between 2017 and 2021, participating centers contributed annual 2-month snapshots of consecutive CICU admissions. Admission diagnoses, clinical and demographic data, use of PACs, and in-hospital mortality were captured. RESULTS: Among 13,618 admissions at 34 sites, 3,827 were diagnosed with shock, with 2,583 of cardiogenic etiology. The use of mechanical circulatory support and heart failure were the patient-level factors most strongly associated with a greater likelihood of the use of a PAC (OR: 5.99 [95% CI: 5.15-6.98]; P \u3c 0.001 and OR: 3.33 [95% CI: 2.91-3.81]; P \u3c 0.001, respectively). The proportion of shock admissions with a PAC varied significantly by study center ranging from 8% to 73%. In analyses adjusted for factors associated with their placement, PAC use was associated with lower mortality in all shock patients admitted to a CICU (OR: 0.79 [95% CI: 0.66-0.96]; P = 0.017). CONCLUSIONS: There is wide variation in the use of PACs that is not fully explained by patient level-factors and appears driven in part by institutional tendency. PAC use was associated with higher survival in cardiac patients with shock presenting to CICUs. Randomized trials are needed to guide the appropriate use of PACs in cardiac critical care

Critical Care Cardiology Trials Network (CCCTN): a cohort profile.

AIMS: The aims of the Critical Care Cardiology Trials Network (CCCTN) are to develop a registry to investigate the epidemiology of cardiac critical illness and to establish a multicenter research network to conduct randomized clinical trials (RCTs) in patients with cardiac critical illness. METHODS AND RESULTS: The CCCTN was founded in 2017 with 16 centers and has grown to a research network of over 40 academic and clinical centers in the United States and Canada. Each center enters data for consecutive cardiac intensive care unit (CICU) admissions for at least two months of each calendar year. More than 20 000 unique CICU admissions are now included in the CCCTN Registry. To date, scientific observations from the CCCTN Registry include description of variations in care, the epidemiology and outcomes of all CICU patients, as well as subsets of patients with specific disease states, such as shock, heart failure, renal dysfunction, and respiratory failure. The CCCTN has also characterized utilization patterns, including use of mechanical circulatory support in response to changes in the heart transplantation allocation system, and the use and impact of multidisciplinary shock teams. Over years of multicenter collaboration, the CCCTN has established a robust research network to facilitate multicenter registry-based randomized trials in patients with cardiac critical illness. CONCLUSIONS: The CCCTN is a large, prospective registry dedicated to describing processes-of-care and expanding clinical knowledge in cardiac critical illness. The CCCTN will serve as an investigational platform from which to conduct randomized controlled trials in this important patient population

Clinical Practice Patterns in Temporary Mechanical Circulatory Support for Shock in the Critical Care Cardiology Trials Network (CCCTN) Registry.

BACKGROUND: Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices or specific etiologies of shock, limiting data regarding overall practice patterns with temporary MCS in cardiac intensive care units. METHODS: The CCCTN (Critical Care Cardiology Trials Network) is a multicenter network of tertiary CICUs in North America. Between September 2017 and September 2018, each center (n=16) contributed a 2-month snapshot of consecutive medical CICU admissions. RESULTS: Of the 270 admissions using temporary MCS, 33% had acute myocardial infarction-related cardiogenic shock (CS), 31% had CS not related to acute myocardial infarction, 11% had mixed shock, and 22% had an indication other than shock. Among all 585 admissions with CS or mixed shock, 34% used temporary MCS during the CICU stay with substantial variation between centers (range: 17%-50%). The most common temporary MCS devices were intraaortic balloon pumps (72%), Impella (17%), and veno-arterial extracorporeal membrane oxygenation (11%), although intraaortic balloon pump use also varied between centers (range: 40%-100%). Patients managed with intraaortic balloon pump versus other forms of MCS (advanced MCS) had lower Sequential Organ Failure Assessment scores and less severe metabolic derangements. Illness severity was similar at high- versus low-MCS utilizing centers and at centers with more advanced MCS use. CONCLUSIONS: There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs. While hospital-level variation in temporary MCS device selection is not explained by differences in illness severity, patient-level variation appears to be related, at least in part, to illness severity