AMPK-mTORC1 pathway mediates hepatic IGFBP-1 phosphorylation in glucose deprivation: a potential molecular mechanism of hypoglycemia-induced impaired fetal growth.

Mechanisms underlying limitations in glucose supply that restrict fetal growth are not well established. IGF-1 is an important regulator of fetal growth and IGF-1 bioavailability is markedly inhibited by IGFBP-1 especially when the binding protein is hyperphosphorylated. We hypothesized that the AMPK-mTORC1 pathway increases IGFBP-1 phosphorylation in response to glucose deprivation. Glucose deprivation in HepG2 cells activated AMPK and TSC2, inhibited mTORC1 and increased IGFBP-1 secretion and site-specific phosphorylation. Glucose deprivation also decreased IGF-1 bioavailability and IGF-dependent activation of IGF-1R. AICAR (an AMPK activator) activated TSC2, inhibited mTORC1, and increased IGFBP-1 secretion/phosphorylation. Further, siRNA silencing of either AMPK or TSC2 prevented mTORC1 inhibition and IGFBP-1 secretion and phosphorylation in glucose deprivation. Our data suggest that the increase in IGFBP-1 phosphorylation in response to glucose deprivation is mediated by the activation of AMPK/TSC2 and inhibition of mTORC1, providing a possible mechanistic link between glucose deprivation and restricted fetal growth.

Racial and ethnic disparities in inferior vena cava filter placement for deep vein thrombosis in the United States.

OBJECTIVE: We sought to determine whether racial and ethnic disparities existed in inferior vena cava (IVC) filter (IVCF) placement rates among Black and Latino patients for the treatment of acute proximal lower extremity (LE) deep vein thrombosis (DVT) in the United States from 2016 to 2019. METHODS: We performed a retrospective review of National Inpatient Sample data to identify adult patients with a primary discharge diagnosis of acute proximal LE DVT from January 2016 to December 2019, including self-reported patient race and ethnicity. IVCF placement rates were identified using International Classification of Diseases, 10th revision, codes. Weighted multivariable logistic regression was used to compare IVCF use by race and ethnicity. The regression model was adjusted for patient demographics (ie, sex, primary payer, quartile classification of household income), hospital information (ie, region, location, teaching status, bed size), weekend admission, and clinical characteristics (ie, modified Charlson comorbidity index, hypertension, atrial fibrillation, diabetes mellitus type 2, congestive heart failure, dyslipidemia, coronary artery disease, smoking, obesity, alcohol abuse, chronic kidney disease, pulmonary embolism, malignancy, contraindications to anticoagulation, including other major bleeding). RESULTS: Of 134,499 acute proximal LE DVT patients, 18,909 (14.1%) received an IVCF. Of the patients who received an IVCF, 12,733 were White (67.3%), 3563 were Black (18.8%), and 1679 were Latino (8.9%). IVCF placement decreased for all patient groups between 2016 and 2019. After adjusting for the U.S. population distribution, the IVCF placement rates were 11 to 12/100,000 persons for Black patients, 7 to 8/100,000 persons for White patients, and 4 to 5/100,000 persons for Latino patients. The difference in IVCF placement rates was statistically significant between patient groups (Black patients vs White patients, P < .05; Black patients vs Latino patients, P < .05; Latino patients vs White patients, P < .05). CONCLUSIONS: This nationwide study showed that Black patients have higher IVCF placement rates compared with White and Latino patients. Given the known long-term complications and uncertain benefits of IVCFs, coupled with the 2010 U.S. Food and Drug Administration safety warning regarding adverse patient events for these devices, proactive measures should be taken to address this disparity among the Black patient population to promote health equity. Future work should assess whether clinician bias might be perpetuating this disparity.

Baseline thrombocytopenia in acute coronary syndrome: The lower, the worse.

BACKGROUND: Patients with baseline thrombocytopenia can have increased mortality and morbidity, but are typically excluded from randomized clinical trials studying acute coronary syndromes (ACS). We sought to better define the effect thrombocytopenia on clinical outcomes in ACS patients. METHODS: Patients identified from the NCDR Chest Pain registry at Mayo Clinic Arizona from Oct 2015 to Sep 2018 were retrospectively classified into two groups: TP (platelet <150 × 103 µL) and control (platelet ≥150 × 103 µL). The groups were analyzed for the clinical outcome (all-cause mortality, major adverse cardiac events (MACE), and bleeding events). The TP group was divided into moderate-severe thrombocytopenia (TPmod; platelet 50-100 × 103 µL) and mild thrombocytopenia (TPmild; platelet 100-150 × 103 µL) for further analysis. P-value <0.05 is considered significant. RESULTS: Five hundred and thirty-six patients were identified, and 72 patients (13%) had thrombocytopenia. The median follow-up time was 1.1 years. The TP group was older (TP vs. control: mean age 73 ± 13 years vs. 70 ± 13 years; P = 0.026). In patients discharged on dual-antiplatelet therapy, the TP group had higher all-cause mortality (23% vs. 7.3%; P = 0.007) but not major bleeding events (11% vs. 5.0%; P = 0.123). Only all-cause mortality increased with the severity of thrombocytopenia (TPmod vs. TPmild vs. control: 33% vs. 24% vs. 7.3%; P = 0.007). CONCLUSIONS: In patients with ACS, baseline thrombocytopenia is associated with increased all-cause mortality and all bleeding events without net MACE benefit. Further study is needed to identify the optimal antiplatelet strategy in this higher risk population.