Faculty Bibliography

Widespread screening for hepatitis C virus (HCV) is necessary for Canada to meet its HCV elimination goals by 2030. People who currently or previously injected drugs are at high risk for HCV. Opioid agonist therapy (OAT, such as methadone and buprenorphine) has been shown to help stabilize the lives of people who are opioid-dependent. The distribution of OAT in North America typically requires daily, weekly, or monthly clinic visits and presents an opportunity for engagement, screening and treatment for those at high-risk of HCV. In this study, HCV screening was conducted by staff at OAT clinics in Ontario from 2016 to 2020 and those with chronic infections were treated on-site with direct-acting antivirals. Point-of-care or dried blood spot (DBS) testing was used for antibodies, DBS or serum for HCV RNA and serum for HCV RNA at SVR12 (sustained virological response). Clinics screened 1954 people (mean age 40 years ±12, 63% male). Forty-five percent were antibody positive, of whom 64% were HCV RNA+. Eighty percent of those RNA+ set an appointment in which 99% attended. Ninety-six percent started treatment with 87% completing treatment. Sixty-eight percent of people who completed treatment submitted a sample for SVR12 testing of which 97% achieved a virological cure. Results suggest that HCV screening and treatment at OAT clinics is feasible, effective and warrants expansion. Data suggest strong treatment adherence due to high rates of SVR12 comparable with other OAT-based HCV treatment programs. The lack of SVR12 sampling could be addressed by either on-site phlebotomy or incentivizing SVR12 sampling.

BACKGROUND:Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS/METHODS:TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS:Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS:With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.

This review summarizes the implementation characteristics of parenting interventions to promote early child development (ECD) outcomes from birth to 3 years. We included 134 articles representing 123 parenting trials (PROSPERO record CRD42022285998). Studies were conducted across high-income (62%) and low-and-middle-income (38%) countries. The most frequently used interventions were Reach Up and Learn, Nurse Family Partnership, and Head Start. Half of the interventions were delivered as home visits. The other half used mixed settings and modalities (27%), clinic visits (12%), and community-based group sessions (11%). Due to the lack of data, we were only able to test the moderating role of a few implementation characteristics in intervention impacts on parenting and cognitive outcomes (by country income level) in the meta-analysis. None of the implementation characteristics moderated intervention impacts on cognitive or parenting outcomes in low- and middle-income or high-income countries. There is a significant need in the field of parenting interventions for ECD to consistently collect and report data on key implementation characteristics. These data are needed to advance our understanding of how parenting interventions are implemented and how implementation factors impact outcomes to help inform the scale-up of effective interventions to improve child development.

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.

The field of patient engagement in radiology is evolving and offers ample opportunities for neuroradiologists to become involved. The patient journey can serve as a model that inspires patient engagement initiatives. The patient journey in radiology may be viewed in 5 stages: 1) awareness that an imaging test is needed, 2) considering having a specific imaging test, 3) access to imaging, 4) imaging service delivery, and 5) ongoing care. Here, we describe patient engagement opportunities based on literature review and paired with case studies by practicing neuroradiologists.

OBJECTIVE:The infrageniculate popliteal artery is a potential source for inflow in lower extremity bypass surgery in patients with isolated tibial artery disease. The objective of our study was to assess the short- and long-term outcomes of popliteal-distal bypasses using data from the Vascular Quality Initiative (VQI). METHODS:The VQI registry was queried between 2003 and 2021 for patients undergoing surgical revascularizations with the below-knee popliteal artery serving as inflow. Demographics, comorbidities, intraoperative characteristics, and postoperative complications were analyzed. Kaplan-Meier models were used to estimate amputation-free survival, survival, and freedom from amputation. Cox regression analysis was conducted to determine factors associated with major amputation or death. RESULTS:A total of 1884 procedures were analyzed. The mean age of the included patients was 67.7 years. The most frequently observed preoperative comorbidities included insulin-dependent diabetes (52.3%), coronary disease (32.4%), and end-stage renal disease (14.4%). Of all the patients, 670 (35.6%) had a history of ipsilateral endovascular intervention. The procedures were performed for a variety of indications, including tissue loss (84.3%), rest pain (10.9%), and claudication (4.8%). Intraoperatively, the outflow targets were the dorsalis pedis (31.4%), the posterior tibial (24.4%), and the anterior tibial arteries (15.6%). Vein conduit was used in 92.1% of cases. The rate of perioperative myocardial infarction (MI) was 2.4%, and the 30-day mortality was 1.9%. The median length of follow up was 371 days. Amputation-free survival was found to be 85.6% (95% confidence interval [CI], 84.0%-87.2%) at 6 months and 78.6% (95% CI, 76.6%-80.4%) at 12 months. Survival was found to be 93.4% (95% CI, 92.2%-94.5%) at 6 months and 88.6% (95% CI, 87.1%-90.0%) at 12 months. Freedom from amputation was found to be 92.0% (95% CI, 90.7%-93.3%) at 6 months and 89.0% (95% CI, 87.3%-90.4%) at 12 months. Cox regression analysis demonstrated that age greater than 65 years, congestive heart failure, coronary artery disease, and end-stage renal disease were associated with a higher risk of major amputation or death (P < .05). CONCLUSIONS:Below-knee popliteal-distal bypass is a safe and effective approach to treat severe tibial vessel occlusive disease in this challenging patient cohort. Patients exhibited low perioperative complication rates and good amputation-free survival at 1 year.

INTRODUCTION/BACKGROUND:We evaluate the rate of developing ciprofloxacin resistance in patients undergoing repeat prostate biopsies (PBx), associated risk factors, and impact on complications. MATERIALS AND METHODS/METHODS:We retrospectively evaluated pre-procedural rectal culture (RCx) data in men undergoing PBx from 1/1/2016 to 1/15/2021. Univariate and multivariate logistic regression were utilized to identify risk factors associated with development of antibiotic resistance. Complication rates were compared between ciprofloxacin-sensitive and ciprofloxacin-resistant patients. RESULTS:A total of 743 men underwent initial RCx. Initial RCx detected ciprofloxacin resistance in 22% of patients. A history of diabetes (p = 0.01), > 2 prior prostate biopsies (p = 0.01), and ciprofloxacin use (p = 0.002) were significant risk factors for ciprofloxacin resistance on initial RCx. The rate of new ciprofloxacin resistance following biopsy with standard ciprofloxacin prophylaxis on 1st and 2nd exposure was 17.2% and 9.1% respectively. The number of biopsy cores, interval antibiotic exposure and interval procedures performed between first and second RCx were not significant predictors of developing ciprofloxacin resistance. Patients who received a non-ciprofloxacin antibiotic between first and second RCx did not develop ciprofloxacin resistance. Antibiotic resistance profile did not significantly affect the rate or type of complications after various prostate procedures. CONCLUSIONS:Serial exposure to standard antibiotic prophylaxis for PBx and associated procedures can lead to development of ciprofloxacin resistance after each subsequent exposure. This carries important implications for serial biopsy and highlights the role for RCx prior to repeat biopsy.

OBJECTIVE/UNASSIGNED:The authors examined participants' experiences with peer specialists in Parachute NYC, a community mental health program of support teams trained in Open Dialogue and intentional peer support. METHODS/UNASSIGNED:Qualitative interviews were conducted with eight enrollees and 10 network members (enrollees' family members). All excerpts coded as pertaining to peers were thematically analyzed. RESULTS/UNASSIGNED:Experiences with peer specialists were mostly positive. Participants especially valued peers' relatability and tendency to instill hope and engender empathy among enrollees and network members; peers' ability to foster community connections was also highly regarded. Generally, enrollees benefited from having peers and other health care professionals on a Parachute team because of their different forms of expertise. Concerns about peer specialists in dialogic care were reported by some network members, who questioned peers' degree of shared experiences, professionalism, and contributions to team unity. CONCLUSIONS/UNASSIGNED:Despite generally positive findings, the optimal role for peers within the Open Dialogue model needs further exploration.

INTRODUCTION:To report outcomes of a 3-year quality improvement pilot study to improve advance directive (AD) completion. METHODS:The pilot consisted of champions, education, electronic health record templates, and workflow changes. We assessed changes, predictors, and effects of AD completion. RESULTS:The pilot led to greater (8.3%-36%) and earlier AD completion, particularly among those divorced, with alcohol-associated liver disease, and with higher Model of End-Stage Liver Disease-Sodium score. Decedents whose AD specified nonaggressive goals experienced lower hospital lengths of stay. DISCUSSION:Advance care planning initiatives are feasible and may reduce health care utilization among decedents requesting less aggressive care.