Faculty Bibliography

BACKGROUND/UNASSIGNED:Effective management of alcohol withdrawal syndrome during hospitalization is paramount to patient safety and quality care. NYC Health + Hospitals initiated a quality improvement project to pilot an electronic health record (EHR) integrated, nurse-driven CIWA-Ar symptom-triggered protocol, including recommendations for medications for alcohol use disorder (MAUD), in medical and surgical units at 3 public hospitals. OBJECTIVE/UNASSIGNED:To describe implementation processes and to report related implementation outcomes (appropriateness, feasibility, and adoption) of the updated CIWA-Ar protocol in a safety net hospital setting. METHODS/UNASSIGNED:NYC Health + Hospitals implemented a standardized CIWA-Ar symptom-triggered, nurse-driven EHR protocol on March 15, 2022. The protocol included order sets, practice advisories, task lists, and reminders for assessments and orders. We measured nursing perspectives on feasibility and appropriateness at 6 months via a survey. We measured provider adoption as the proportion of admissions with a CIWA-Ar protocol ordered among admissions that triggered a recommendation, and MAUD use as the proportion of admissions with a MAUD order during hospitalization among all patients with a protocol ordered. RESULTS/UNASSIGNED:= .249). CONCLUSIONS/UNASSIGNED:The CIWA-Ar protocol was appropriate, feasible, and adopted at NYC public hospitals. Quality improvements to ensure protocol fidelity with benzodiazepine dosing and MAUD prescribing are needed.

BACKGROUND:Coronary microvascular dysfunction (CMD) is present in approximately 40% of patients with ischemia with no obstructive coronary arteries (INOCA) and has been associated with inflammation. We investigated associations between measures of inflammation of the coronary perivascular adipose tissue assessed by coronary computed tomography angiography (CCTA) and results of invasive coronary function testing (CFT) to diagnose CMD. METHODS:Adults referred for clinically indicated invasive coronary angiography who had less than 50% stenosis in all epicardial arteries were prospectively enrolled. CMD was defined as a coronary flow reserve (CFR) less than 2.5 or index of microvascular resistance (IMR) greater than or equal to 25 using bolus thermodilution in the left anterior descending (LAD) coronary artery. Coronary perivascular fat attenuation index was assessed by CCTA in the right coronary artery (RCA) and LAD. T tests were used to evaluate differences in perivascular FAI by CMD status. RESULTS:A total of 31 participants underwent CFT and CCTA. The mean age was 58 ± 11.7 years, 77% were female, and 61% were white. CMD was present in 15 participants (48%). No differences in perivascular FAI were observed in patients with and without CMD, either in the RCA [-74.2 ± 9.8 vs. -69.9 ± 10.3 Hounsfield units (HU), P = 0.24] or LAD (-76.4 ± 10.2 vs. -74.8 ± 12.7 HU, P = 0.69). Perivascular FAI was not correlated with CFR or IMR measurements in the RCA or LAD. CONCLUSION/CONCLUSIONS:There were no associations between CMD diagnosed by invasive CFT and perivascular FAI by CCTA in patients with INOCA. Further research is needed to understand the relationship between vascular inflammation and CMD in INOCA.

BACKGROUND AND AIMS/OBJECTIVE:OCE-205 is a mixed agonist-antagonist selective for the vasopressin 1a (V1a) receptor with no vasopressin 2 (V2) receptor activity. Safety and efficacy of OCE-205 were evaluated in patients with hepatorenal syndrome-acute kidney injury (HRS-AKI). METHODS:A randomized, double-blind, placebo-controlled, dose-ranging study was conducted at 23 North American centers. Patients received a continuous infusion of OCE-205 at 8, 15, 30 or 50 µg/hr or placebo. Primary endpoint was time to confirmed clinical improvement, defined as serum creatinine (sCr) <1.5 mg/dL, with at least an absolute reduction of ≥0.3 mg/dL, for 2 days. Following terlipressin's approval, this study was stopped early due to lack of equipoise in conducting a placebo-controlled trial. RESULTS:Baseline characteristics between OCE-205 (n=37) vs. placebo (n=10) groups were: sCr 2.6 vs 2.3 mg/dL, MELD 27.9 vs 25.8, alcohol-related cirrhosis 51.4% vs 60.0%. The primary endpoint was met in 48.6% vs. 30.0% (p=0.48 by Log-rank test and NS by Bayesian analysis). Bradycardia was the most common adverse event (21.6% vs 0%). Most events were asymptomatic, requiring no intervention. No new/unexpected safety findings, no events of ischemia, and no related events of respiratory failure occurred. CONCLUSIONS:OCE-205 was well tolerated, with no evidence of excessive vasoconstriction or related events of ischemia or respiratory failure at any dose level. OCE-205 had a predictable, capped maximal efficacy that improved HRS-AKI in numerically more patients than placebo, though was underpowered for statistical significance. OCE-205 warrants additional investigation as a novel HRS therapy with a favorable benefit/risk profile.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Trimodality therapy (TMT) is an accepted bladder-preserving option for selected patients with muscle-invasive bladder cancer (MIBC). Pembrolizumab has demonstrated activity in MIBC and may enhance the effects of chemotherapy and radiation. We evaluated the safety and efficacy of adding pembrolizumab to TMT. METHODS:In this multicenter phase 2 trial, patients with MIBC received one dose of pembrolizumab followed by maximal transurethral resection, then definitive bladder radiation with concurrent low-dose gemcitabine and pembrolizumab every 3 wk for three doses. The primary end point was 2-yr bladder-intact disease-free survival (BIDFS). Secondary end points included safety, metastasis-free survival (MFS), and overall survival (OS). KEY FINDINGS AND LIMITATIONS/UNASSIGNED:Fifty-four patients were enrolled, including 48 in the efficacy cohort; 67% had clinical stage T2 disease. The 2-yr BIDFS was 60% (95% confidence interval [CI], 45-73). Two-yr MFS and OS were 81% (95% CI, 66-92) and 83% (95% CI, 69-91), respectively. Grade ≥3 treatment-related adverse events occurred in 25% of patients. Limitations include the single-arm design and modest sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:Pembrolizumab combined with gemcitabine-based chemoradiation was feasible and showed efficacy comparable to standard TMT. Ongoing phase 3 trials will further define its role in bladder preservation.

BACKGROUND:Pulmonary vein isolation (PVI) and posterior wall isolation (PWI) are frequently used in the treatment of persistent atrial fibrillation (AF). Minimal data support adjunct PWI, possibly due to lack of durability via epicardial reconnections. OBJECTIVE:To determine the impact of very high output PW pace-capture testing in patients with persistent AF on AF/AT recurrence. METHODS:We performed a retrospective study of consecutive patients who underwent radiofrequency ablation for persistent AF and received PVI and PWI, as well as a cavotricuspid isthmus line (CTI). After the creation of three linear PW lesions (roof, carina-to-carina, and inferior PV levels), pace-capture testing was performed on the PW. The first cohort confirmed PWI using 10 mA at 2 ms (10 × 2) to pace capture. Sequentially, the second cohort utilized 20 mA at 10 ms (20 × 10). If the PW was captured, additional lesions were performed. Patients were excluded if additional lesion sets beyond PVI, PWI, and CTI were performed. RESULTS:A total of 232 patients were included. Of these, 129 (56%) patients were in the 20 × 10 group, and 103 (44%) patients were in the 10 × 2 group. The two groups did not differ in age, sex, proportion of comorbidities, presenting rhythm, left ventricular ejection fraction, or left atrial size. Despite the increase in procedure time and lesion number, in the time-to-event analysis, patients in the 20 × 10 group experienced recurrent AF/AT more frequently than those in the 10 × 2 group (log rank p = 0.01). CONCLUSION/CONCLUSIONS:Testing PWI in persistent AF with pace capture at 20 mA at 10 ms did not improve freedom from arrhythmia and may paradoxically be associated with harm. Our findings question whether PWI, regardless of durability, is effective in treating persistent AF.

BACKGROUND AND AIM/UNASSIGNED:Extended-release injectable naltrexone (XR-Naltrexone) is an effective treatment for opioid use disorder (OUD); however, initiation can be challenging as it requires an opioid-free period. This exploratory analysis examines patient characteristics associated with successful initiation of XR-Naltrexone in the National Drug Abuse Treatment Clinical Trials Network (CTN-0051) Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (X:BOT) trial. METHODS/UNASSIGNED:Patient demographics and clinical variables associated with successful XR-Naltrexone initiation were examined among 283 participants with OUD randomized to XR-Naltrexone in the X:BOT trial. Variables included severity of opioid use, characteristics of opioid and other substance use, treatment history, psychiatric history, baseline depression, and pain. Logistic regression models were used to estimate the effect of variables on the odds of induction success. RESULTS/UNASSIGNED:204 (72%) of 283 participants randomized to receive XR-Naltrexone completed successful induction. Housing status and pain were significantly associated with XR-Naltrexone induction status. Reported homelessness was significantly associated with higher odds of successful XR-Naltrexone induction (OR: 2.31; 95% CI: 1.12, 4.76). Individuals that reported moderate or extreme pain on the EuroQoL had half the odds of successful induction compared to those without pain (OR: 0.49; 95% CI: 0.27, 0.89). CONCLUSIONS/UNASSIGNED:Among patients with OUD initiating treatment on inpatient units, homelessness was associated with greater likelihood of successfully initiating XR-Naltrexone, while chronic pain was associated with lower likelihood of XR-Naltrexone initiation. Future research on XR-Naltrexone initiation should consider tailoring treatment based on housing status and other social determinants, and evaluation and management of pain.

BACKGROUND:Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a transient prothrombotic process, although recent data suggests that VITT anti-platelet factor 4 (PF4) antibodies are more persistent than those in heparin-induced thrombocytopenia. OBJECTIVES/OBJECTIVE:We sought to interrogate whether anti-PF4 antibody persistence in VITT is related to the continued persistence of antibody clones from the acute phase or to the development of novel anti-PF4 antibodies due to epitope spreading. PATIENTS/METHODS/METHODS:Samples from six Ad26.COV2.S-associated VITT patients with a median time to follow-up of 244 days from acute presentation (Range, 114-664 days) were studied in antigenic/functional assays and by mass spectrometry. One ChAdOx1 nCoV-19-associated VITT patient was tested >4 years after acute presentation. RESULTS:Upon affinity-enrichment of anti-PF4 antibodies, mono/oligoclonal anti-PF4 antibodies were observed despite negative results in serum protein electrophoresis/"Mass-Fix" testing of native sera. Anti-PF4 antibody abundance decreased over time, with no evidence of novel anti-PF4 antibody production after acute presentation. Although previous studies indicate a stereotypical pairing of VITT antibodies with lambda light chains, one VITT patient produced antibodies with a kappa light chain. Long-term thrombocytopenia/thrombosis was not seen in any of these six patients, however, platelet-activating anti-PF4 antibodies were seen four years after the acute event in an additional ChAdOx1 nCoV-19-associated VITT patient with chronic low-grade thrombocytopenia. CONCLUSIONS:VITT, unlike monoclonal gammopathy of thrombotic significance, appears to be an MGUS-negative state, but needs confirmation in larger studies. VITT antibodies can be comprised of lambda or kappa light chains, and some VITT patients exhibit persistent thrombocytopenia many years after the acute event.

High-grade serous ovarian carcinoma (HGSC) remains an incompletely understood, highly lethal disease. Historically, a lack of fidelitous in vitro and in vivo models representing HGSC biology and therapy response has been a major barrier to progress. As we discuss below, multiple (if not most) early studies used-and some investigators continue to use-human "ovarian cancer cell lines" that lack key genomic/genetic features of HGSC, rendering their conclusions questionable. The frequently deployed ID8 syngeneic mouse model is similarly suspect, as it derives from ovarian surface epithelium (OSE) and is Trp53 wild-type. In contrast, most, if not all, HGSC arises in fallopian tube epithelium (FTE), and bona fide HGSC is universally TP53 mutant or silenced. Over the past 10 years, attempts have been made to rectify these historical deficiencies, including careful assessment of the genetic composition of standard ovarian cancer cell lines and the development of mouse and human organoids, genetically engineered mouse models (GEMMs), and patient-derived xenografts (PDXs). In this review, we discuss these advances, exploring their differences, strengths, and weaknesses. We also describe "next-generation" approaches to more faithfully model HGSC cells in the context of a more realistic tumor microenvironment.