Faculty Bibliography

BACKGROUND:Despite increased risk of venous thromboembolism (VTE) among hospitalized patients with inflammatory bowel disease (IBD), pharmacologic prophylaxis rates remain low. We sought to understand the reasons for this by assessing factors associated with VTE prophylaxis in patients with IBD and the safety of its use. METHODS:This was a retrospective cohort study conducted among patients hospitalized between January 2013 and August 2018. The primary outcome was VTE prophylaxis, and exposures of interest included acute and chronic bleeding. Medical records were parsed electronically for covariables, and logistic regression was used to assess factors associated with VTE prophylaxis. RESULTS:There were 22,499 patients studied, including 474 (2%) with IBD. Patients with IBD were less likely to be placed on VTE prophylaxis (79% with IBD, 87% without IBD), particularly if hematochezia was present (57% with hematochezia, 86% without hematochezia). Among patients with IBD, admission to a medical service and hematochezia (adjusted odds ratio 0.27; 95% CI, 0.16-0.46) were among the strongest independent predictors of decreased VTE prophylaxis use. Neither hematochezia nor VTE prophylaxis was associated with increased blood transfusion rates or with a clinically significant decline in hemoglobin level during hospitalization. CONCLUSION:Hospitalized patients are less likely to be placed on VTE prophylaxis if they have IBD, and hematochezia may drive this. Hematochezia appeared to be minor and was unaffected by VTE prophylaxis. Education related to the safety of VTE prophylaxis in the setting of minor hematochezia may be a high-yield way to increase VTE prophylaxis rates in patients with IBD.

Combating plasmid-mediated carbapenem resistance is essential to control and prevent the dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Here we conducted a proof-of-concept study to demonstrate CRISPR/Cas9-mediated resistance gene and plasmid curing can effectively re-sensitize CRE to carbapenems. A novel CRISPR/Cas9-mediated plasmid-curing system (pCasCure) was developed and electrotransferred into various clinical CRE isolates. The results showed that pCasCure can effectively cure bla_KPC, bla_NDM and bla_OXA-48 in various Enterobacteriaceae species of Klebsiella pneumoniae, Escherichia coli, Enterobacter hormaechei, E. xiangfangensis and Serratia marcescens clinical isolates, with > 94% curing efficiency. In addition, we also demonstrated that pCasCure can efficiently eliminate several epidemic carbapenem-resistant plasmids, including the bla_KPC-harboring IncFIIK-pKpQIL and IncN pKp58_N, bla_OXA-48-harboring pOXA-48-like, bla_NDM-harboring IncX3 plasmids, by targeting their replication and partitioning (parA in pKpQIL) genes. However, curing bla_OXA-48 gene failed to eliminate its corresponding pOXA-48-like plasmid in a clinical K. pneumoniae isolate 49210, while further next generation sequencing revealed that it was due to IS1R mediated recombination outside the CRISPR/Cas9 cleavage site, resulting in bla_OXA-48 truncation and therefor escaped plasmid curing. Nevertheless, the curing of carbapenemase genes or plasmids, including the truncation of bla_OXA-48 in 49210, successfully restore their susceptibility to carbapenems, with > 8-fold reduction of minimum inhibitory concentration (MIC) values in all tested isolates. Taken together, our study confirmed the concept of using CRISPR/Cas9-mediated carbapenemase genes and plasmids curing to re-sensitize CRE to carbapenems. Further work is needed to integrate pCasCure in an optimal delivery system to make it applicable for clinical intervention.

BACKGROUND:Ileal pouch-anal anastomosis (IPAA) is the mainstay of surgical treatment for patients with ulcerative colitis (UC) but is associated with an increased risk of infertility. We developed a simulation model examining the impact of initial surgical procedure on quality-adjusted life-years (QALYs) and fertility end points. METHODS:A patient-level state transition model was used to analyze outcomes by surgical approach strategy for females of childbearing age. Initial surgical options included IPAA, rectal-sparing colectomy with end ileostomy (RCEI), and ileorectal anastomosis (IRA). The primary outcome examined was QALYs, whereas secondary outcomes included UC and fertility-associated end points. RESULTS:IPAA resulted in higher QALYs for patients aged 20-30 years, as compared with RCEI. For patients aged 35 years, RCEI resulted in higher QALYs (7.54 RCEI vs 7.53 IPAA) and was associated with a 28% higher rate of childbirth, a 14-month decrease in time to childbirth, and a 77% reduction in in vitro fertilization utilization. When accounting for the decreased infertility risk associated with laparoscopic IPAA, IPAA resulted in higher QALYs (7.57) even for patients aged 35 years. CONCLUSIONS:Despite an increased risk of infertility, our model results suggest that IPAA may be the optimal surgical strategy for female UC patients aged 20-30 years who desire children. For patients aged 35 years, RCEI should additionally be considered, as QALYs for RCEI and IPAA were similar. These quantitative data can be used by patients and providers to help develop an individualized approach to surgical management choice.

BACKGROUND:Little is known about long-term recovery from severe COVID-19 disease. Here, we characterize overall health, physical health and mental health of patients one month after discharge for severe COVID-19. METHODS:This was a prospective single health system observational cohort study of patients ≥18 years hospitalized with laboratory-confirmed COVID-19 disease who required at least 6 liters of oxygen during admission, had intact baseline cognitive and functional status and were discharged alive. Participants were enrolled between 30 and 40 days after discharge. Outcomes were elicited through validated survey instruments: the PROMIS Dyspnea Characteristics and PROMIS Global Health-10. RESULTS:A total of 161 patients (40.6% of eligible) were enrolled; 152 (38.3%) completed the survey. Median age was 62 years (interquartile range [IQR], 50-67); 57 (37%) were female. Overall, 113/152 (74%) participants reported shortness of breath within the prior week (median score 3 out of 10 [IQR 0-5]), vs. 47/152 (31%) pre-COVID-19 infection (0, IQR 0-1), p<0.001. Participants also rated their physical health and mental health as worse in their post-COVID state (43.8, standard deviation 9.3; mental health 47.3, SD 9.3) compared to their pre-COVID state, (54.3, SD 9.3; 54.3, SD 7.8, respectively), both p <0.001. A total of 52/148 (35.1%) patients without pre-COVID oxygen requirements needed home oxygen after hospital discharge; 20/148 (13.5%) reported still using oxygen at time of survey. CONCLUSIONS:Patients with severe COVID-19 disease typically experience sequelae affecting their respiratory status, physical health and mental health for at least several weeks after hospital discharge.

Neurological complications of COVID-19 are not well described. We report two patients who were diagnosed with COVID-19 after presenting with diplopia and ophthalmoparesis.

Background/UNASSIGNED:The coronavirus disease 2019 pandemic has or threatens to overwhelm health care systems. Many institutions are developing ventilator triage policies. Objective/UNASSIGNED:To characterize the development of ventilator triage policies and compare policy content. Design/UNASSIGNED:Survey and mixed-methods content analysis. Setting/UNASSIGNED:North American hospitals associated with members of the Association of Bioethics Program Directors. Participants/UNASSIGNED:Program directors. Measurements/UNASSIGNED:Characteristics of institutions and policies, including triage criteria and triage committee membership. Results/UNASSIGNED:Sixty-seven program directors responded (response rate, 91.8%); 36 (53.7%) hospitals did not yet have a policy, and 7 (10.4%) hospitals' policies could not be shared. The 29 institutions providing policies were relatively evenly distributed among the 4 U.S. geographic regions (range, 5 to 9 policies per region). Among the 26 unique policies analyzed, 3 (11.3%) were produced by state health departments. The most frequently cited triage criteria were benefit (25 policies [96.2%]), need (14 [53.8%]), age (13 [50.0%]), conservation of resources (10 [38.5%]), and lottery (9 [34.6%]). Twenty-one (80.8%) policies use scoring systems, and 20 of these (95.2%) use a version of the Sequential Organ Failure Assessment score. Among the policies that specify the triage team's composition (23 [88.5%]), all require or recommend a physician member, 20 (87.0%) a nurse, 16 (69.6%) an ethicist, 8 (34.8%) a chaplain, and 8 (34.8%) a respiratory therapist. Thirteen (50.0% of all policies) require or recommend those making triage decisions not be involved in direct patient care, but only 2 (7.7%) require that their decisions be blinded to ethically irrelevant considerations. Limitation/UNASSIGNED:The results may not be generalizable to institutions without academic bioethics programs. Conclusion/UNASSIGNED:Over one half of respondents did not have ventilator triage policies. Policies have substantial heterogeneity, and many omit guidance on fair implementation.

OBJECTIVE:We postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA. METHODS:White matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function. RESULTS:= 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function. CONCLUSIONS:Patients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT.  Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.