THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p\u3c0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion

APP processing is regulated by cytoplasmic phosphorylation

Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Carotid Intima-Media Thickness and Plaque in Cardiovascular Risk Assessment

AbstractCarotid intima-media thickness (CIMT) has been shown to predict cardiovascular (CV) risk in multiple large studies. Careful evaluation of CIMT studies reveals discrepancies in the comprehensiveness with which CIMT is assessed—the number of carotid segments evaluated (common carotid artery [CCA], internal carotid artery [ICA], or the carotid bulb), the type of measurements made (mean or maximum of single measurements, mean of the mean, or mean of the maximum for multiple measurements), the number of imaging angles used, whether plaques were included in the intima-media thickness (IMT) measurement, the report of adjusted or unadjusted models, risk association versus risk prediction, and the arbitrary cutoff points for CIMT and for plaque to predict risk. Measuring the far wall of the CCA was shown to be the least variable method for assessing IMT. However, meta-analyses suggest that CCA-IMT alone only minimally improves predictive power beyond traditional risk factors, whereas inclusion of the carotid bulb and ICA-IMT improves prediction of both cardiac risk and stroke risk. Carotid plaque appears to be a more powerful predictor of CV risk compared with CIMT alone. Quantitative measures of plaques such as plaque number, plaque thickness, plaque area, and 3-dimensional assessment of plaque volume appear to be progressively more sensitive in predicting CV risk than mere assessment of plaque presence. Limited data show that plaque characteristics including plaque vascularity may improve CV disease risk stratification further. IMT measurement at the CCA, carotid bulb, and ICA that allows inclusion of plaque in the IMT measurement or CCA-IMT measurement along with plaque assessment in all carotid segments is emerging as the focus of carotid artery ultrasound imaging for CV risk prediction

Opioid and naloxone prescribing following insertion of prompts in the electronic health record to encourage compliance with California state opioid law.

IMPORTANCE: Opioid addiction or dependency is a serious crisis in the US that affects public health as well as social and economic welfare. The State of California passed Assembly Bill (AB) 2760 in 2018 that mandates the coprescription of naloxone and opioids for patients with a high overdose risk. OBJECTIVE: To assess whether the AB 2760–based electronic prompts were associated with increased naloxone orders for opioid users and reduced opioid prescribing when integrated into the practitioner workflow. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used interrupted time series mixed models to evaluate data obtained from the regional integrated health care system Kaiser Permanente Southern California (KPSC) from January 1, 2018, to December 31, 2019. Clinician participants were continuously employed at KPSC during the study period and ordered an opioid analgesic for eligible patients in 2018. Patient participants were KPSC members aged 18 years or older who received an opioid analgesic prescription during the study period. A series of AB 2760–based electronic prompts were integrated into the KPSC electronic health record system on December 27, 2018. The prompts are triggered or activated when 1 or more opioid prescribing conditions, defined in the AB 2760, are met at outpatient visits. Data were analyzed from January 8, 2021, to September 15, 2021. EXPOSURES: Assembly Bill 2760–based electronic prompts for outpatient opioid prescriptions in the electronic health record system. MAIN OUTCOMES AND MEASURES: Primary outcomes were changes in outpatient naloxone order rates among patients who were prescribed opioids and changes in outpatient opioid prescribing rates. Secondary outcomes were total morphine milligram equivalents (MMEs) ordered per prescriber-month, prompts-targeted objectives, and unintended consequences. Risk for opioid abuse among 3 types of patients was also assessed. RESULTS: The 6515 eligible clinicians (mean [SD] age, 45.9 [9.43] years; 3604 men [55.3%]) included in the study served 500 711 unique patients in 1 903 289 outpatient encounters (mean [SD] age, 60.4 [15.67] years; 1 121 004 women [58.9%]) in which an opioid analgesic was prescribed. Naloxone order rate increased from 2.0% in December 2018 to 13.2% in January 2019 and then continued to increase to 27.1% in December 2019. Outpatient opioid prescribing rates decreased by 15.1% (rate ratio [RR], 0.85; 95% CI, 0.83-0.87) per prescriber-month when the electronic prompts were implemented. The postimplementation trend increased by 0.7% per prescriber-month (RR, 1.01; 95% CI, 1.01-1.01); the overall trend was still decreasing. The total MMEs per prescriber-month decreased by 7.8% (RR, 0.92; 95% CI, 0.89-0.96) after implementation of the prompts. The postimplementation trend tapered off. Other safe opioid prescribing measures also improved after implementation (decreases in concomitant muscle relaxants orders [RR, 0.94; 95% CI, 0.89-1.00], initial [RR, 0.86; 0.83-0.89] and renewal [RR, 0.65; 95% CI, 0.62-0.69] opioid orders, and long-term high-dose orders [RR, 0.96; 95% CI, 0.94-0.98]). CONCLUSIONS AND RELEVANCE: This study found an association between implementation of AB 2760–based prompts and increased naloxone order rate; improved opioid prescribing measures (ie, decreased concomitant muscle relaxants orders, initial and renewal opioid orders, and long-term high-dose orders), except monthly median MMEs; and reduced opioid prescribing. The findings suggest that opioid overdose risks can be mitigated by encouraging safe prescribing habits