Faculty Bibliography

OBJECTIVES/OBJECTIVE:The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. METHODS:In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. RESULTS:In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. CONCLUSIONS:Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

BACKGROUND:Although germline genetic testing can inform medical management for patients with prostate cancer (PCa), data are limited regarding patient-reported outcomes (PROs) after germline genetic testing for PCa. Recall and comprehension of germline genetic testing results, uptake of post-test clinical recommendations, and psychological impact of germline genetic testing among patients with PCa were evaluated. METHODS:This is a secondary analysis of data from the PROCLAIM trial. PROs were analyzed overall and by germline genetic testing results. Differences between groups were determined by two-tailed Fisher's exact test with significance set at p < 0.05. RESULTS:Among 494 patients with informative survey responses, 60% and 71% accurately recalled and interpreted their germline genetic testing results, respectively, with the highest rates among patients with negative results and the lowest among those with variant of uncertain significance-only (VUS) results. Among 42/55 (76%) patients with positive results for whom clinicians made germline genetic testing-informed recommendations, 39 (93%) completed or planned to complete >1 clinical recommendation. Conversely, no further recommendations were made for 160/221 (72%) and 211/218 (97%) patients with VUS and negative results, respectively. However, 57% (213/371) of these patients indicated that they or their family members intended to pursue clinical management strategies that were not recommended by their clinicians. Of the patients who responded to the survey, >90% of patients reported no post-germline genetic testing increase in their level of concern for themselves or their family members. CONCLUSION/CONCLUSIONS:germline genetic testing for patients with PCa did not cause appreciable psychological harm to the tested patients. Furthermore, patients with positive results had a high uptake of clinician-recommended management strategies. Of note, there were inconsistencies in the understanding of VUS results, with some clinicians making recommendations not warranted by personal/family history; conversely, some patients pursued management strategies not recommended by their clinicians. This suggests that educational efforts are needed in the communication of germline genetic testing results and clinical recommendations to patients.

BACKGROUND AND AIMS/OBJECTIVE:There are currently no brief quantitative assessments that capture the drug patterns of people who engage in use of more than one drug on the same day or simultaneously. The current study examined the retest reliability, acceptability and feasibility of a new quantitative assessment to measure polysubstance use. DESIGN/METHODS:A tool for assessing simultaneous and same-day polysubstance behaviors, the polysubstance assessment tool (PAT) was developed in interviewer-administered and electronic self-administered formats. Participants were allocated 1:1 to receive either version of the PAT and returned one to three days later to repeat the assessment. SETTING/METHODS:New York City, New York, USA. PARTICIPANTS/METHODS:Adults (18 + years, n = 115) who reported use of more than one drug per day in the last 30 days. MEASUREMENTS/METHODS:Test-retest reliability estimates for dichotomous items were assessed using Cohen's kappa, Gwet's Agreement Coefficient 1 (AC1) and percent agreement. Continuous items were assessed with two-way mixed effects intraclass correlations. Bivariate analyses examined acceptability using nine Likert-type survey questions. Feasibility was examined via time to completion. FINDINGS/RESULTS:Overall reliability was moderate to excellent [Gwet's AC1 range 0.70-0.96; intraclass correlation (ICC) range 0.62-0.88]. Reliability was higher for simultaneous polysubstance use (Gwet's AC1 = 0.90) as compared with same-day (Gwet's AC1 = 0.70). Acceptability was high, with no statistically significant difference between the self- and interviewer-administered versions of the tool. Median time to completion was 7 minutes, and was statistically significantly lower for the self-administered tool (median = 5 minutes) compared with the interviewer-administered version (median = 8 minutes) (P < 0.001). CONCLUSIONS:A new polysubstance assessment tool appears to have good reliability and can be considered by researchers seeking a quantitative measure of polysubstance use behaviors given its simplicity, high acceptability and quick completion time.

PURPOSE/OBJECTIVE:Pancreatic cystic lesions (PCL) commonly undergo surveillance using MRI with MR cholangiopancreatography (MRCP). Our objective is to compare the performance of a single-shot fat-saturated T2-weighted technique with deep-learning reconstruction (DL HASTE-FS) to a conventional T2-weighted Half fourier Single-shot Turbo spin-Echo (HASTE) sequence and to MRCP for the purpose of PCL detection, characterization, and surveillance. METHODS:In this retrospective study, 91 consecutive patients underwent 3T abdominal MRI with MRCP protocol including DL HASTE-FS and conventional HASTE between 8/2/2023 and 10/3/2023. Three abdominal radiologists rated overall and lesion-specific image quality on a 5-point Likert scale, including pancreatic margin and duct sharpness, and PCL conspicuity. A subset of 70 preselected index PCLs were evaluated for cyst features, confidence of diagnosing side-branch IPMN, and suitability of DL HASTE-FS in replacing MRCP for PCL surveillance. RESULTS:DL HASTE-FS received higher scores for pancreatic duct border sharpness (4.1 vs. 3.9; p = .004), pancreatic duct visibility compared to MRCP (2.0 vs. 1.9; p = .04), cyst conspicuity (4.4 vs. 3.9; p < .001), and sharpness of cyst wall and internal septations (4.3 vs. 3.7; p < .001) compared to conventional HASTE. In contrast, conventional HASTE received higher scores for pancreatic margin sharpness (4.2 vs. 3.8; p < .001) and peripancreatic vessel clarity (4.2 vs. 3.4; p < .001). For the 70 preselected index PCLs, readers visualized more PCLs and had higher confidence in diagnosing SB-IPMN on DL HASTE-FS than on conventional HASTE (3.6 vs. 3.4; p < .001). Finally, DL HASTE-FS was deemed a suitable replacement to MRCP for more cases than conventional HASTE (83% vs. 48%; p < .001). CONCLUSION/CONCLUSIONS:DL HASTE-FS outperforms conventional HASTE for PCL detection and characterization, and is a suitable alternative to 3D MRCP in the context of PCL surveillance, potentially reducing exam time and cost.

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.

RAS proteins control signals required for cell growth and survival and, when constitutively activated by mutation, can drive oncogenesis. RAS proteins are primarily regulated by their GTP or GDP binding state, which is controlled by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). RAS proteins are also substrates for dozens of posttranslational modifications (PTMs) that target them to membranes and serve as a secondary means of regulation. Because the newly developed direct RAS inhibitors do not produce durable responses in RAS-dependent cancer, there is renewed interest in targeting the PTMs of RAS. These modifications are the subject of this review.

Adolescents and young adults (AYA) in Nigeria with increased HIV risk, such as those who engage in multiple sexual partnerships (i.e., more than one sexual partner within a specified period), transactional sex (i.e., exchange of money or gifts for sex), or needle-sharing (i.e., needles or other injection equipment are shared by multiple people), are eligible for pre-exposure prophylaxis (PrEP). One strategy that has the potential to reach PrEP-eligible AYA is HIV self-testing, which can expand existing HIV testing services and support differentiated PrEP programs. However, little is known about HIV self-testing in these AYA populations. We examined associations between these three high-risk behaviors and HIV self-testing. We analyzed data from Innovative Tools to Expand Youth-friendly HIV Self-Testing (I-TEST), a stepped-wedge trial examining the impact of a combination intervention package on HIV self-testing among AYA aged 14-24 years in Nigeria. We fit generalized linear models, with an identity link and a binomial error distribution, using generalized estimating equations. We generalized trial estimates to all AYA in Nigeria using a two-stage weighted approach. Of 1,429 participants, the median age was 20 years (IQR: 18-22), 50.3% were female, and 69.4% reported secondary school as their highest education level completed. AYA who engaged in transactional sex had higher HIV self-testing uptake (8.1% [4.8, 11.5]) than AYA with no history of transactional sex. There were no statistically significant differences in recent HIV self-testing uptake among AYA by sexual partnerships or needle-sharing history. The trial estimates were similar in the adjusted models. The estimates for the trial and generalized samples were in the same direction, except for AYA with two recent sexual partners. There was a high level of HIV self-testing uptake across all categories of sexual partnerships, transactional sex, and needle-sharing, with significantly higher uptake among those who engaged in transactional sex, indicating that HIV self-testing strategies are reaching these various AYA populations and the need to sustain access for these groups.

BACKGROUND:Despite a high incidence of tracheostomy-related airway complications with potentially life-threatening implications, nonsurgical tracheostomy first-responders receive limited formal education on the management of tracheostomy emergencies. While the U.K. has developed multidisciplinary guidelines and education for tracheostomy emergencies, such programs have not been widely implemented in the United States. OBJECTIVE:We evaluated the feasibility and effectiveness of an immersive virtual reality (VR) simulation training as a potential generalizable and scalable approach to tracheostomy-related emergency training. METHODS:Over the academic year 2023-2024, critical care fellows were randomized to participate in tracheostomy emergency training either via immersive VR simulation or via small group discussion sessions facilitated by expert faculty. After each case-based educational intervention, participants were asked to manage four simulated tracheostomy-related emergencies involving common tracheostomy complications. Fellow performance was evaluated using a purpose-built task trainer. Three independent and blinded graders completed fellow scoring using a checklist assessment for which validation evidence was also collected. Fellows received pre- and post-intervention surveys to measure attitudes towards VR training. RESULTS:Nineteen out of 27 eligible fellows participated in the study, managing a total of 76 simulated tracheostomy emergencies. There were 10 fellows in the VR arm and 9 fellows in the Small Group arm. Out of a total possible 26 points on the checklist assessment, fellows in the VR group scored an average of 18.03 ± 3.39 compared to the Small Group score of 16.96 ± 4.41 (P = .558). Surveys indicated improvements in fellow confidence after the training and high levels of acceptance of the VR curriculum. CONCLUSIONS:An immersive VR educational intervention for the management of tracheostomy-related emergencies was feasible and well-received by learners. There was no significant difference in post-training checklist assessment scores between the VR and Small Group participants, suggesting non-inferiority of the VR intervention, and contributing validation evidence to our task trainer simulation assessment. FUNDING/BACKGROUND:This study was funded via the APCCMPD, CHEST, and ATS Education Research Award.