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Browsing by Author "Desai, Ankit"
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Item 25 In-hospital Change in Lung Ultrasound Congestion Score Predicts Heart Failure Rehospitalization and Death: Implications for Clinical Trials(Cambridge University Press, 2023-04-24) Harrison, Nicholas Eric; Desai, Ankit; Pang, Peter; Emergency Medicine, School of MedicineOBJECTIVES/GOALS: Lung Ultrasound Congestion Score (LUS-CS) is a proposed measure for guiding treatment in acute heart failure (AHF). An emergency department (ED) pilot trial of LUS-guided diuresis showed reduced LUS-CS at 48 hours but no difference at hospital discharge or for clinical outcomes. We hypothesized total change in LUS-CS would predict adverse outcomes. METHODS/STUDY POPULATION: This was a post-hoc secondary analysis of the BLUSHED-AHF trial. BLUSHED-AHF was a pilot trial in which AHF patients were randomized to a LUS-guided diuresis strategy vs. usual care in the ED. The intervention was stopped after the ED course (i.e. during hospitalization). BLUSHED-AHF was designed for the intervention to target absolute values of LUS-CS over time, rather than change in LUS-CS from each patient’s baseline. We fit a cox regression model for a primary outcome of death or AHF rehospitalization, with total (ED to Hospital Discharge) change in LUS-CS as the primary predictor, adjusted for the Get-With-The-Guidelines heart failure risk score (GWTG). Survival curves were plotted, and hazard ratios calculated. RESULTS/ANTICIPATED RESULTS: 128 patients in BLUSHED-AHF were analyzed. Greater reduction in LUS-CS from ED to hospital discharge predicted event-free survival (HR = 0.74 for each 20 unit reduction in LUS-CS, 95%CI 0.56-0.99). This effect did not vary by hospitalization length or ED disposition. There was a significant interaction between change in LUS-CS and GWTG score. DISCUSSION/SIGNIFICANCE: LUS-CS total change, and not absolute values, predict adverse events in LUS-guided diuresis. Post-ED cessation of the intervention in BLUSHED-AHF may have precluded opportunity for clinical benefit. Future trials should run the entire hospital course, target change from baseline, and consider patient selection by AHF severity and initial LUS-CS.Item A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subject(Elsevier, 2022) Belvitch, Patrick; Casanova, Nancy; Sun, Xiaoguang; Camp, Sara M.; Sammani, Saad; Brown, Mary E.; Mascarhenas, Joseph; Lynn, Heather; Adyshev, Djanybek; Siegler, Jessica; Desai, Ankit; Seyed-Saadat, Laleh; Rizzo, Alicia; Bime, Christian; Shekhawat, Gajendra S.; Dravid, Vinayak P.; Reilly, John P.; Jones, Tiffanie K.; Feng, Rui; Letsiou, Eleftheria; Meyer, Nuala J.; Ellis, Nathan; Garcia, Joe G. N.; Dudek, Steven M.; Medicine, School of MedicineThe cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: (i) delayed EC barrier recovery following thrombin-induced permeability; (ii) reduced levels of critical Tyr486 cortactin phosphorylation; (iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and (iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/- heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.