Faculty Bibliography

BACKGROUND:Given established relationships between social class and mortality, the growing concentration of income, wealth, and power among business owners in the U.S. may have increased mortality inequities across classes. To investigate this hypothesis, we analyzed temporal changes in mortality inequities between owners and non-owners. METHODS:Our sample included respondents ages 25-64 in the 1984, 1989, 1994, and 1999-2013 Panel Study of Income Dynamics with mortality follow-up through 2022 (respondents: 22,103; observations: 103,965). Business owners were individuals with personal or family ownership of, or direct financial interest in, a business in the prior year. Using g-computation, we estimated how inequities between owners and non-owners in 10-year age-adjusted mortality risks changed from 1984-2013. Next, we analyzed whether any changes were attributable to shifting social stratification. Finally, we analyzed whether growing income and wealth disparities between owners and non-owners exacerbated inequities. RESULTS:In 1984, non-owners had 1.4 times (95% CI: 1.1, 1.8) greater 10-year age-adjusted mortality risks than owners. In 2013, the figure was 2.3 (95% CI: 1.8, 3.0), yielding a ratio of risk ratios (RRR) of 1.7 (95% CI: 1.1, 2.5). After social-stratification-adjustment, within-year inequities lessened; however, increases across years attenuated only somewhat (2013 vs 1984 RRR: 1.5 [95% CI: 0.99, 2.2]). Finally, we did not find that increases in inequities across years would have lessened if income and wealth distributions had remained at 1984 levels. CONCLUSIONS:Mortality inequities between owners and non-owners have increased and cannot be fully explained by social stratification and individual-level income and wealth distributions.

AIMS/UNASSIGNED:Femoral nerve palsy is a potential complication of brace treatment for children with developmental dysplasia of the hip (DDH). Little is known about its causes, and previous studies have been limited by their small sample size, retrospective design, and/or being single-centre series. The aim of this study was to examine the risk factors for femoral nerve palsy in the largest prospective cohort of children to date with DDH treated using an orthosis. METHODS/UNASSIGNED:A global multicentre prospective database of children with DDH was analyzed. Those treated primarily using an orthosis were included. Mixed-effects logistic regression was used to identify risk factors for the development of femoral nerve palsy, including sex, age at the time of diagnosis and application of an orthosis, the type of orthosis, the location of the femoral head, femoral head cover, and α angle. Both univariate and multivariate analyses were conducted. RESULTS/UNASSIGNED:The study included 3,008 children (5,012 affected hips) who were enrolled from 21 centres in seven countries; 99 hips (2.0%) in 94 children (3.1%) developed a femoral nerve palsy, which occurred at a median of seven days (IQR 6 to 21) after the application of a brace. A significantly increased proportion of children who developed a femoral nerve palsy were treated in a Pavlik harness compared with those who did not develop a femoral nerve palsy (84.0% (n = 79) vs 61.9% (n = 1,804); p < 0.001). Univariate analyses identified a lower percent cover of the femoral head (odds ratio (OR) 0.87 (95% CI 0.84 to 0.91); p < 0.001) and lower α angle (OR 0.82 (95% CI 0.76 to 0.89); p < 0.001) to be significantly associated with the development of femoral nerve palsy. These risk factors remained significant in the multivariate model. CONCLUSION/UNASSIGNED:This is the largest multinational study to date evaluating the incidence and risk factors for the development of a femoral nerve palsy in these children. The incidence of femoral nerve palsy was 3.1%. The severity of DDH was identified as a significant risk factor for its development. The use of a Pavlik harness was significantly associated with the development of a femoral nerve palsy. Understanding the factors which influence its development will be important to optimize outcomes of treatment in children with DDH.

OBJECTIVE:Infants with myelomeningocele (MMC) are at risk of brainstem dysfunction secondary to symptomatic Chiari II malformation with hindbrain herniation (HH), which can manifest as feeding difficulties including aspiration and dysphagia. This study aims to investigate whether prenatal repair of MMC is associated with improved feeding outcomes compared to postnatal repair. STUDY DESIGN/METHODS:Retrospective observational study of 208 infants with MMC, 105 repaired prenatally and 103 repaired postnatally, from January 2011 to July 2022. Primary outcome was feeding tube at discharge and longitudinally through 12 months corrected gestational age (CGA). RESULTS:9.5% of infants repaired prenatally and 13.6% repaired postnatally required feeding tube at discharge (p = 0.3585). By 53 weeks CGA, the prenatal repair group had decreased odds of requiring feeding tube (0.325 [95% CI 0.121, 0.872]). CONCLUSION/CONCLUSIONS:Prenatal MMC repair was associated with decreased need for long-term feeding support, suggesting a potential functional benefit of prenatal repair related to reversal of HH.

BACKGROUND:in participants with relapsed or refractory follicular lymphoma after at least one previous line of chemoimmunotherapy. METHODS:for up to 12 cycles. Epcoritamab was administered weekly in cycles 1-3 and every 4 weeks in cycles 4-12, lenalidomide once daily during cycles 1-12 (days 1-21), and rituximab weekly during cycle 1 and monthly in cycles 2-5. The dual primary endpoints were overall response rate and progression-free survival by independent review committee. The data reported here are from a planned interim analysis carried out after 78% of progression-free survival events had occurred. This study is registered with ClinicalTrials.gov, NCT05409066, and EudraCT, 2021-000169-34, and is ongoing (closed to recruitment). FINDINGS/RESULTS:(grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved. INTERPRETATION/CONCLUSIONS:as a new standard of care for second-line or subsequent treatment of follicular lymphoma. FUNDING/BACKGROUND:AbbVie and Genmab.

Subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm is a highly fatal type of stroke. Cerebral vasospasm (CVS) is a major post-SAH complication leading to delayed ischemic neurological deficits, thereby worsening patient outcomes. Previously, we found that lower plasma levels of the soluble receptor for advanced glycation end products (RAGE) predict symptomatic CVS in patients with SAH. However, the molecular mechanisms underlying CVS remain unclear. Here, using an SAH mouse model with endovascular perforation, we found that neurological deficits, CVS in the circle of Willis, and impaired cortical microarterial perfusion were markedly ameliorated in RAGE-deficient mice. Neutrophils accumulated in the cerebral perivascular space of WT mice after SAH but were markedly reduced in RAGE-deficient mice. Myeloid lineage-targeted deletion of RAGE, including neutrophils, improved CVS after SAH. Inhibition of the high mobility group box 1 (HMGB1)/RAGE axis or neutrophil elastase ameliorated CVS. In a transwell assay, the HMGB1/RAGE axis drives neutrophil migration and NETosis. These findings indicate that neutrophil RAGE signaling contributes to cerebrovascular dysfunction after SAH and suggest that RAGE-mediated neutrophil inflammation may be a therapeutic target in the hyperacute phase to mitigate early brain injury.

PURPOSE/UNASSIGNED:Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC) and is a spectrum autoimmune disease of the gastrointestinal tract. Large scale real-world evidence studies could provide valuable evidence about IBD for personalized healthcare recommendations. The Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) standardizes electronic health record (EHR) data, allowing for research that incorporates multiple data sources. We are interested in whether OMOP CDM data on IBD are fit-for-use. METHODS/UNASSIGNED:We selected IBD diagnosis codes to define the phenotype. We used a data quality checklist to evaluate 5 domains: conformance, completeness, concordance, plausibility, and temporality. We also did sensitivity analyses for CD and UC that consisted of at least 2 diagnosis codes that were at least 30 days apart. RESULTS/UNASSIGNED:All of the phenotype-defining ICD source codes mapped to SNOMED. Many concept prevalences were low. A total of 78 (30.1%) out of 253 concept correlations were above our strength threshold (⍴ > 0.5). The age distribution of concepts and relative frequency of IBD medications were plausible. The median time between diagnosis and biopsy for the cohort was 4.43 [-0.05, 104.29] weeks. For the subgroup of participants who had sufficient data for the timeline analysis, IBD diagnosis concepts tended to occur first. In our sensitivity analyses, the completeness percentages of many variables in the UC and CD subgroups were similar to IBD, except for disease specific workup and treatment concepts. CONCLUSION/UNASSIGNED:We have shown a novel implementation of our data quality framework on IBD cohorts.

BackgroundFew studies have examined which patients with migraine might be responders for mind-body interventions. Thus, we examined whether certain baseline mindfulness traits and interest in physical exercise might predict response to treatment.MethodsThis is a planned exploratory analysis of a phase 2 randomized controlled study (N  =  50; 25 per arm) comparing a 6-week physical therapist (PT)-delivered biofeedback-assisted relaxation (BAR) program vs. an Enhanced Usual Care (EUC) migraine self-management program (diary tracking and emailed migraine-related educational materials). We conducted moderation analyses to determine whether the Multidimensional Assessment of Interoceptive Awareness (MAIA), Difficulties in Emotion Regulation Scale (DERS) and Physical Activity Enjoyment Scale (PACES) at baseline influenced the effect of BAR on migraine-related outcomes (Migraine-Specific Quality of Life Role Function Restrictive (MSQv2.1-RFR) and Migraine-Related Disability (MIDAS)) at 6 months.ResultsAmong the n = 40 participants (BAR = 19; EUC = 21), the majority were female (95%), non-Hispanic (77.5%) and white (67.5%). Mean (SD) age was 45.6 (11.2) years. For the MAIA Not-Worrying subscale, BAR produced the greatest improvement in 6-month MSQv2.1-RFR scores among participants with low baseline Not-Worrying scores (those who tended to worry about bodily sensations/discomfort more) (BAR = 77.1 ± 6.6 vs. EUC = 48.9 ± 5.0; p = 0.002, g = 4.75). The benefit diminished at average levels (p = 0.060, g = 2.72) and was absent at high baseline Not-Worrying (p = 0.528, g =  -0.91). For the MAIA Self-Regulation subscale, BAR was most effective among those low in baseline self-regulation (BAR = 71.7 ± 5.3 vs. EUC = 44.3 ± 7.2; p = 0.004, g = 4.27). The DERS total score showed that BAR demonstrated little benefit among participants with better baseline emotion regulation (i.e. lower DERS score; p = 0.907, g = 0.17) but was more effective as baseline emotion regulation difficulties increased, showing a moderate benefit at average levels (BAR = 69.2 ± 4.2 vs. EUC = 55.8 ± 4.0, p = 0.027, g = 3.25) and a large, significant difference at high levels (BAR = 70.6 ± 6.3 vs. EUC = 44.7 ± 5.7; p = 0.004, g = 4.22). The PACES total score indicated that BAR benefits were strongest among those with low (BAR = 76.1 ± 7.0 vs. EUC = 47.1 ± 5.3, p = 0.002, g = 4.60) to average (BAR = 71.2 ± 4.2 vs. EUC = 58.6 ± 4.0, p = 0.035, g = 3.07) enjoyment of physical activity.ConclusionsWe found subgroups of individuals with migraine who may be better responders to PT-delivered BAR, specifically those who tend to worry more about bodily sensations (lower MAIA Not-Worrying score), those with low self-regulation (lower MAIA Self-Regulation score), those with worse emotion regulation (higher DERS score) and those with lower levels of physical activity enjoyment (lower PACES score) at baseline. This may help us determine who may benefit most from BAR.Trial RegistrationClinicalTrials.gov Identifier: NCT06077812.

BACKGROUND:Transmural healing (TMH) indicates resolution of inflammation in all bowel wall layers and is an emerging therapeutic target in Crohn's disease (CD). Standardized sonographic criteria for TMH and early improvement, termed Transmural Response (TMR), have not been established. This systematic review synthesizes published definitions to provide an up-to-date overview of the current evidence base for intestinal ultrasound (IUS)-based assessment in CD. METHODS:This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comprehensive searches of databases identified full-text articles that pre-specified TMH, TMR or normal/abnormal bowel on trans-abdominal IUS in pediatric or adult participants with CD. Definitions were summarized descriptively. RESULTS:Eighty-three full-text studies (8033 patients) met eligibility criteria; 39 (47%) defined TMH and 22 (27%) defined TMR. TMH definitions most often included bowel-wall thickness (BWT) ≤ 3mm (31/39, 79%), absent or minimal Doppler flow (25/39, 64%), and preserved bowel wall stratification (10/39, 26%). All TMR definitions required BWT reduction, but thresholds varied (absolute ≥ 1 mm or relative ≥ 25% in 16/22, 73%). Nine studies (9/22, 41%) also required Doppler flow improvement and 4/22 (18%) included additional criteria. Pediatric-specific criteria were reported in 2 TMH and one TMR studies, extrapolating from adult BWT values. Heterogeneity precluded quantitative pooling. CONCLUSIONS:Standardized IUS definitions of TMH and TMR in CD are lacking. Consistent, validated criteria are essential to enable reproducible ultrasound endpoints, support treat-to-target strategies, and facilitate incorporation of IUS into CD clinical trials and routine care.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Congenital obstructive hydrocephalus (HCP) causes progressive, irreversible fetal brain damage through ventricular enlargement and increasing fetal cerebral tissue compression. Postnatal treatments of choice include ventriculoperitoneal shunting or endoscopic third ventriculostomy (ETV). Intrauterine treatments, such as ventriculoamniotic shunting, were attempted unsuccessfully 4 decades ago and failed to improve postnatal outcomes, likely due to inadequate fetal patient selection. The aim of this study was to evaluate the efficacy of prenatal ETV for early ventricular decompression and potential prevention of fetal brain damage in hydrocephalic fetal lambs. METHODS:HCP was induced in 24 fetal lambs by injecting BioGlue into the cisterna magna at E85. Three weeks later (E105-110), fetal ETV was successfully performed on 8 fetuses using a small rigid cystoscope. Fetal brain lateral ventricular diameters and cerebral mantle thicknesses were monitored by prenatal and postnatal ultrasounds and fetal MRI. RESULTS:According to the Cincinnati HCP Severity Scale, moderate and severe HCP subgroups responded positively to fetal ETV with reduced cerebral ventricular diameters. Ten days post-ETV, severe HCP fetal lambs improved to moderate levels, whereas those with moderate HCP normalized by birth. A similar improvement pattern was seen for the mechanical compression threshold (ventricular diameters/biparietal diameter). Biparietal diameter values did not significantly differ among nontreated, treated, and normal control groups during pregnancy. MRI revealed a significant increase in brain mantle thickness in the prenatally treated fetuses. CONCLUSION/CONCLUSIONS:Prenatal ETV is feasible in hydrocephalic fetal lambs and effectively reverses ventriculomegaly and brain compression in cases of severe or moderate fetal HCP in this ovine model.