Faculty Bibliography

BACKGROUND/UNASSIGNED:Moderate kidney dysfunction is independently associated with increased cardiovascular mortality. Sudden cardiac arrest (SCA) accounts for at least 25% of chronic kidney disease (CKD) mortality. METHODS/UNASSIGNED:(2021 CKD-EPI formula). A population-based SCA study in Southern California was used for validation. RESULTS/UNASSIGNED:eGFR drop below 90 increased SCA risk (OR: 1.24, 95% CI: 1.18-1.31). Similar findings were observed in the validation cohort (817 SCA and 3,249 controls), where moderate CKD was associated with SCA (OR: 1.51, 95% CI: 1.16-1.97). CONCLUSION/UNASSIGNED:Moderate CKD is associated with an increased risk of SCA in the general population. Further research into the potential integration of moderate renal dysfunction into SCA risk stratification are warranted.

BACKGROUND:Changing from standing to sitting positions requires rotation of the femur from an almost vertical plane to the horizontal plane. Osteoarthritis of the hip limits hip extension, resulting in less ability to recruit spinopelvic tilt (SPT) while standing and requiring increased SPT while sitting to compensate for the loss of hip range of motion. To date, the effect of total hip arthroplasty (THA) on spinopelvic sitting and standing mechanics has not been reported, particularly in the setting of patients with coexistent sagittal plane spinal deformity. METHODS:A retrospective review was performed of patients ≥18 years of age undergoing unilateral THA for hip osteoarthritis with sitting and standing radiographs made before and after THA. Alignment was analyzed at baseline and follow-up after THA in both standing and sitting positions in a relaxed posture with the fingers resting on top of the clavicles. Patients were grouped according to the presence or absence of sagittal plane deformity preoperatively into 3 groups: no sagittal plane deformity (normal), thoracolumbar (TL) deformity (pelvic incidence-lumbar lordosis [PI-LL] mismatch > 10° and/or T1-pelvic angle [TPA] > 20°), or apparent deformity (PI-LL ≤ 10° and TPA ≤ 20°, but sagittal vertical axis [SVA] > 50 mm). RESULTS:In this study, 192 patients were assessed: 64 had TL deformity, 39 had apparent deformity, and 89 had normal alignment. Overall, patients demonstrated a reduction in standing SVA (45 to 34.1 mm; p < 0.001) and an increase in SPT (14.6° to 15.7°; p = 0.03) after THA. There was a greater change in standing SVA (p < 0.001) among patients with apparent deformity (-29.0 mm) compared with patients with normal alignment (0.9 mm) and patients with TL deformity (-16.3 mm). Those with apparent deformity also experienced the greatest difference (p = 0.03) in postural SPT change (moving from standing to sitting) (-10.1°) from before to after THA when compared with those with normal alignment (-3.6°) and TL deformity (-1.2°). The difference in postural SVA change from before to after THA was also greatest (p < 0.001) in those with apparent deformity (32.1 mm) compared with those with normal alignment (6.5 mm) and TL deformity (17.3 mm). CONCLUSIONS:Postural changes in spinopelvic alignment vary after THA depending on the presence of TL deformity or apparent deformity due to hip flexion contracture. Patients with apparent deformity had larger changes in standing and sitting alignment than patients with TL deformity or patients with normal alignment. The assessment of global sagittal alignment findings can be used to predict the likelihood of improvement in sagittal alignment after THA. LEVEL OF EVIDENCE/METHODS:Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND:Eyebrow and eyelash (EB/EL) involvement is an important consideration in the assessment of alopecia areata (AA) severity. OBJECTIVES/OBJECTIVE:We report integrated results from BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) characterising EB/EL involvement at baseline in patients with AA and response to baricitinib treatment. METHODS:BRAVE-AA1 and BRAVE-AA2 were randomised, double-blind, placebo-controlled trials conducted at 169 centres in 10 countries. Patients were randomised to placebo, baricitinib 2 mg, or baricitinib 4 mg. Pooled data from patients continually treated with baricitinib through Week 52 were included. Outcomes were assessed using the Clinician-Reported Outcome (ClinRO) measure for EB/EL and Severity of Alopecia Tool (SALT) score for scalp. RESULTS:At baseline, patients with more severe EB/EL involvement had more severe scalp hair loss, with mean SALT scores ranging from 70.6 to 96.0 for patients with no gaps to complete absence of hair, respectively, at EB/EL sites. EB/EL response rates [ClinRO (0,1) with ≥1-point improvement] at Week 36 were significantly higher in patients treated with both baricitinib 2 mg (28.2%, odds ratio [OR]=3.27, 25.1% OR=2.95) and baricitinib 4 mg (44.3% OR=6.84, 46.4% OR=8.21) as compared with placebo (12.6%, 12.4%). There was high concordance between EB response and EL response, with approximately 80% of patients who achieved hair regrowth at one site, achieving regrowth at the other with baricitinib 4 mg. Among scalp responders (SALT score <20 at Week 52), 78.5% and 82.6% achieved an EB and EL response, respectively, and 71.1% of patients achieved a response in both EB and EL with baricitinib 4 mg. Among scalp nonresponders (SALT score >20 at Week 52), 46.7% and 48.7% achieved EB and EL responses, respectively, and 35.4% achieved responses in both EB and EL. Similar trends but lower response rates were observed with baricitinib 2 mg. CONCLUSIONS:Baseline severity of EB/EL involvement parallels that of the scalp. Baricitinib was efficacious in achieving holistic response across all three hair-bearing sites in a majority of Week 52 scalp responders. These data detail the benefits of baricitinib across important hair-bearing sites involved in AA and highlight that individual patient treatment success should account for the totality of the clinical presentation. TRIAL REGISTRATION NUMBER/BACKGROUND:BRAVE-AA1, ClinicalTrials.gov number, NCT03570749, start date, September 24, 2018; BRAVE-AA2, ClinicalTrials.gov number, NCT03899259, start date, July 8, 2019.

INTRODUCTION/UNASSIGNED:Fibromyalgia (FM) is the prototypical nociplastic pain condition, characterized by widespread pain and issues with cognition, mood, and sleep. Currently, there are limited treatment options available that effectively treat FM symptoms. Psilocybin-assisted therapy (PAT) is an emerging combined drug-therapy intervention, but no studies to-date have investigated PAT for FM. METHODS/UNASSIGNED: = 5). In conjunction with psychotherapy (two preparatory, four integration sessions), participants received two doses of oral psilocybin (15 mg and 25 mg) delivered two weeks apart. RESULTS/UNASSIGNED: = -2.5, 95% CI (-4.21 to -0.75)]. Using the Patient Global Impression of Change, one participant reported their symptoms "very much improved," two reported "much improved," and two reported "minimally improved." We stopped recruitment early because of concerns about generalizability and changes in FDA guidance for psychedelic clinical trials that occurred data collection. DISCUSSION/UNASSIGNED:This small open-label trial preliminarily supports that PAT is well-tolerated by people with FM, establishing a basis for larger randomized controlled trials. CLINICAL TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov, identifier, (NCT05128162).

Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, fibroblast growth factor (FGF) receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.

OBJECTIVES/OBJECTIVE:To evaluate the predictive performance of different data sources to forecast fatal overdose in Rhode Island neighborhoods, with the goal of providing a template for other jurisdictions interested in predictive analytics to direct overdose prevention resources. METHODS:We evaluated seven combinations of data from six administrative data sources (American Community Survey (ACS) five-year estimates, built environment, emergency medical services non-fatal overdose response, prescription drug monitoring program, carceral release, and historical fatal overdose data). Fatal overdoses in Rhode Island census block groups (CBGs) were predicted using two machine learning approaches: linear regressions and random forests embedded in a nested cross-validation design. We evaluated performance using mean squared error and the percentage of statewide overdoses captured by CBGs forecast to be in top percentiles from 2019 to 2021. RESULTS:Linear models trained on ACS data combined with one other data source performed well, and comparably to models trained on all available data. Those including emergency medical service, prescription drug monitoring program, or carceral release data with ACS data achieved a priori goals for percentage of statewide overdoses captured by CBGs prioritized by models on average. CONCLUSIONS:Prioritizing neighborhoods for overdose prevention with forecasting is feasible using a simple-to-implement model trained on publicly available ACS data combined with only one other administrative data source in Rhode Island, offering a starting point for other jurisdictions.

Access to allogeneic and autologous hematopoietic stem cell transplantation (SCT) remains inadequate despite its curative potential across hematologic malignancies. In 2015, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) established the Shared Care Model (SCM) with a primary aim of enhancing SCT access for HHC patients. The SCM comprises several components: an SCT-dedicated nurse-navigator, a health-information exchange for record sharing, telemedicine, and ongoing training of HHC clinicians in transplant patient selection and management. We evaluated the SCM's impact on SCT access across 126 patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma from 2016-2020. The SCM facilitated 34 referrals. Socio-economic status of HHC referrals by Area Deprivation Index was significantly inferior (38 vs. 14, p < 0.001) when compared to 3,108 non-SCM referrals to MSK during the same period. Allogeneic recipients spent 68-247 days away from home, and autologous recipients 15-48, both requiring few subsequent visits to MSK.

Diabetes is a major risk factor for cardiovascular diseases. Patients with diabetes are at greater risk for morbidity and mortality post myocardial infarction. As the epidemic of diabetes continues at an alarming pace, identification of specific therapeutic interventions to protect diabetic patients from the devastating consequences of myocardial infarction is an urgent need. Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the diabetic circulation and heart. The interaction of AGEs with its key receptor, receptor for AGE or RAGE, contributes to cardiac injury and dysfunction. The discovery that intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, unveiled the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of pathological RAGE signaling during myocardial infarction. This review delves into intrinsic mechanisms by which AGE-RAGE axis via RAGE-DIAPH1 driven DIAPH1-Mitofusin2 (MFN2) interaction modulates pathogenic inter-organelle communications and opens opportunities for intensive studies to uncover the comprehensive mechanisms that drive injury-provoking actions from the intracellular space. This review illustrates the potential therapeutic cardioprotective benefits of antagonism of RAGE-DIAPH1interactions in the diabetic heart.