Faculty Bibliography

Fetal inflammation, typically measured indirectly through prenatal maternal cytokine markers, has been shown to impact early childhood executive functions (EFs), which are central to later cognitive and life outcomes. Here, we assessed the impact of prenatal inflammation on EF developmental trajectories using direct placenta histopathology measures in 131 mothers who predominantly self-identified as Black (90.8% Black; 0.8% Asian American, 1.5% biracial, 0.8% Latinx, 3.1% White, 3.1% Missing). We found that placental measures of inflammation were associated with limited gain in EF development from 3 to 5 years old. In follow up analyses, we addressed whether screening questionnaires in infancy might aid in classification of infants as higher risk for subsequent EF problems. We found that parent responses to the Ages & Stages Questionnaire and the Infant/Toddler Sensory Profile at 12 months predict the development of EF abilities in children exposed to chronic inflammation. These findings open promising opportunities for early screening of children at risk for poor executive functioning in children exposed to prenatal inflammation.

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β₄₂ ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.

BACKGROUND:The randomized, phase 2 RENEW trial (NCT01721161) evaluated efficacy/safety of opicinumab (anti-LINGO-1) versus placebo in patients with first-episode unilateral acute optic neuritis (AON). Although no significant differences in the latency recovery of visual evoked potential (VEP) were observed between opicinumab and placebo groups in the intention to treat (ITT) population, the prespecified per-protocol (PP) population showed better recovery with opicinumab than with placebo. RENEWED (NCT02657915) was a one-visit, follow-up study 2 years after the last RENEW study visit (Week 32) designed to assess the long-term electrophysiological and clinical outcomes for participants previously enrolled and having received study treatment in RENEW. METHODS:In the original study (RENEW), participants (aged 18-55 years) with a first unilateral AON episode were enrolled ≤28 days from first symptom onset and after treatment with methylprednisolone 1 g/day intravenously for 3-5 days; these participants were randomized to receive opicinumab 100 mg/kg or placebo intravenously once every 4 weeks from baseline to Week 20, assessed up to Week 32. Participants who received ≥1 dose of opicinumab 100 mg/kg or placebo in RENEW were eligible for the RENEWED follow-up study. Participants enrolled in RENEWED at 2 years (with an additional up to 12-month window) after the last RENEW study visit (Week 32) in both ITT and PP populations. The primary endpoint was change in full-field VEP (FF-VEP) latency of the affected eye at RENEWED study visit versus baseline of the fellow eye in RENEW, comparing between participants who received opicinumab and placebo in RENEW. Clinical progression and severity of multiple sclerosis (MS) were assessed. A substudy evaluated latency recovery using multifocal VEP (mfVEP) as an exploratory endpoint. RESULTS:Of 82 RENEW participants, 52 (63.4 %; opicinumab n = 28, placebo n = 24) enrolled in and completed RENEWED. The adjusted mean (95 % CI) difference in FF-VEP latency delay between opicinumab and placebo groups was -6.0 (-14.6, 2.6) msec (p = 0.165) for the PP population and -4.5 (-12.6, 3.7) msec (p = 0.274) for the ITT population at the RENEWED study visit. Nominally significant improvement on mfVEP latency in the opicinumab group versus placebo was observed in participants of the mfVEP substudy (p = 0.009). In participants from the PP population without clinically definite MS (CDMS) at RENEW baseline,12 (55 %) in the opicinumab group and 12 (67 %) in the placebo group developed CDMS from enrollment in the RENEW study up to RENEWED Day 1; the estimated proportion of participants with CDMS at 2 years after the last study visit assessment in RENEW was lower when treated with opicinumab (0.50) than when treated with placebo (0.61) (hazard ratio p-value = 0.23). No benefit on visual acuity or other neurological functions was observed in the opicinumab group vs placebo in RENEWED. CONCLUSION/CONCLUSIONS:The numerically increased VEP latency recovery with opicinumab treatment in RENEWED was consistent with those observed in the parent study RENEW. However, the VEP latency and clinical data in RENEWED should be interpreted with caution, given the nature of the follow-up study, the small sample size and the limitation in study design.

INTRODUCTION/BACKGROUND:Lupus nephritis (LN) is a frequent complication of SLE, occurring in up to 60% of adult patients and ultimately progressing from acute inflammation to chronicity with fibrosis and end-stage kidney failure in 10%-30% of patients. Racial/ethnic minority patients with lupus have worse long-term outcomes, including progression to end-stage renal disease and overall mortality. A major challenge in the management of patients with SLE is delayed identification of early kidney disease, which ultimately leads to a greater burden on both patients and the health system. METHODS AND ANALYSIS/METHODS:Using a mixed methods approach, this study will develop, adapt and evaluate a home urine sampling protocol with a text-messaging reminder and data capture system for patients at elevated risk of de novo LN or relapse. First, a feasibility pilot using a single-group trial design (n=18) will be implemented, with a feasibility assessment and qualitative, debriefing interviews with patients to further refine the intervention. The second phase is a comparative effectiveness trial of the intervention (n=160) with the primary outcome of biopsy eligibility, that is, the participant has a clinical indication for a kidney biopsy (urine protein-creatinine ratio≥0.5), whether or not the patient actually undergoes the biopsy procedure. The randomised trial includes an economic evaluation of the adapted home urinalysis protocol. DISCUSSION AND DISSEMINATION/CONCLUSIONS:It is unknown whether weekly home-based urine sampling can identify proteinuria sooner than standard care; if found sooner, kidney problems could be diagnosed earlier, hopefully leading to earlier care for less-involved disease and subsequent reduced morbidity. The data collected in this trial will inform future feasibility and effectiveness of text-messaging-based home urine sampling interventions. TRIAL REGISTRATION NUMBER/BACKGROUND:The randomised trial will be registered with ClincialTrials.gov prior to enrolment start.

Policy engagement is an essential component of implementation research for scaling up interventions targeting non-communicable diseases (NCDs). It refers to the many ways that research team members, implementers and policymakers, who represent government decision-making, connect and interact to explore common interests. Well-conducted engagement activities foster co-production, local contextualization and assist in the successful translation of research evidence into policy and practice. We aimed to identify the challenges and facilitators to policy engagement during the early implementation phase of scale-up research studies. This qualitative study was focused on the research projects that were funded through the Global Alliance for Chronic Diseases in the 2019 round. Nineteen project teams opted to participate, with these studies implemented in 20 countries. Forty-three semi-structured stakeholder interviews, representing research, implementation and government were undertaken between August 2020 and July 2021. Transcripts were open-coded using thematic analysis to extract 63 codes which generated 15 themes reflecting both challenges and facilitators to undertaking policy engagement. Knowledge of the local government structures and trusting relationships provided the foundation for successful engagement and were strengthened by the research. Four cross-cutting concepts for engagement were identified and included: (1) the importance of understanding the policy landscape; (2) facilitating a network of suitable policy champions, (3) providing an environment for policy leaders to genuinely contribute to co-creation and (4) promoting two-way learning during researcher-policymaker engagement. We recommend undertaking formative policy analysis to gain a strategic understanding of the policy landscape and develop targeted engagement plans. Through engagement, researchers must facilitate cohesive vision and build a team of policy champions to advocate NCD research within their networks and spheres of influence. Ensuring equitable partnerships is essential for enabling local ownership and leadership. Further, engagement efforts must create a synergistic policymaker-researcher lens to promote the uptake of evidence into policy.

BACKGROUND:Addressing the persistent treatment gap in substance use disorder (SUD) remains a critical challenge, with only 13 % of Americans with SUDs receiving necessary treatment. We explored the complexities of engaging in SUD treatment from patients' perspectives and aims to provide a comprehensive understanding of their treatment experiences. METHODS:We conducted semi-structured interviews with 34 patients who had been attending outpatient SUD clinics in New York State for 6 or less months. Participants were recruited from seven clinics using purposive sampling. Interviews were conducted between June and August 2022. We conducted thematic analysis of coded data to explore patients' experiences and preferences while navigating their treatment journeys. RESULTS:Critical elements for a positive treatment experience included cultural humility, confidentiality, consistency, trust, peer counselors with SUD experience, a strong sense of connection, and addressing needs beyond clinical settings. These included assistance with housing and employment, participation in external clinic events, and access to amenities like coffee and snacks. Participants favored holistic treatment approaches integrating mental health and involving peer recovery counselors. However, participants also identified ineffective aspects, including rigid and generic approaches, stigmatizing attitudes, and challenges related to communities and environmental influences. CONCLUSION/CONCLUSIONS:The study highlights the multifaceted nature of outpatient SUD treatment, emphasizing the integration of patient-centered, holistic, and culturally competent approaches. Tailoring interventions to individual circumstances and acknowledging the diverse needs of patients are imperative for effective healthcare practices.

Highly effective antiobesity and diabetes medications such as glucagon-like peptide 1 (GLP-1) agonists and glucose-dependent insulinotropic polypeptide/GLP-1 (dual) receptor agonists (RAs) have ushered in a new era of treatment of these highly prevalent, morbid conditions that have increased across the globe. However, the rapidly escalating use of GLP-1/dual RA medications is poised to overwhelm an already overburdened health care provider workforce and health care delivery system, stifling its potentially dramatic benefits. Relying on existing systems and resources to address the oncoming rise in GLP-1/dual RA use will be insufficient. Generative artificial intelligence (GenAI) has the potential to offset the clinical and administrative demands associated with the management of patients on these medication types. Early adoption of GenAI to facilitate the management of these GLP-1/dual RAs has the potential to improve health outcomes while decreasing its concomitant workload. Research and development efforts are urgently needed to develop GenAI obesity medication management tools, as well as to ensure their accessibility and use by encouraging their integration into health care delivery systems.

Exposure to pollutants and chemicals during critical developmental periods in early life can impact health and disease risk across the life course. Research in environmental epigenetics has provided increasing evidence that prenatal exposures affect epigenetic markers, particularly DNA methylation. In this article, we discuss the role of DNA methylation in early life programming and review evidence linking the intrauterine environment to epigenetic modifications, with a focus on exposure to tobacco smoke, metals, and endocrine-disrupting chemicals. We also discuss challenges and novel approaches in environmental epigenetic research and explore the potential of epigenetic biomarkers in studies of pediatric populations as indicators of exposure and disease risk. Overall, we aim to highlight how advancements in environmental epigenetics may transform our understanding of early-life exposures and inform new approaches for supporting long-term health.