Faculty Bibliography

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation that results from maladaptive responses to lung epithelial injury; however, the underlying mechanisms remain unclear, and treatment options are limited. Here, we showed that deficiency in the innate immune receptor toll-like receptor 5 (TLR5) is associated with IPF in humans and with increased susceptibility to bleomycin-induced pulmonary fibrosis in mice and that activation of lung epithelial TLR5 through a synthetic flagellin analog protected mice from experimental fibrosis. Mechanistically, epithelial TLR5 activation induced antimicrobial gene expression and ameliorated lung dysbiosis after injury. In contrast, TLR5 deficiency in mice and patients with IPF was associated with lung dysbiosis. Elimination of the microbiome in mice through administration of antibiotics abolished the protective effect of TLR5, and reconstitution of the microbiome by fecal microbiota transplantation rescued the observed phenotype. In conclusion, these studies revealed that TLR5 protects against pulmonary fibrosis through effects on the lung microbiota, providing insight into therapeutic approaches that may ultimately benefit patients with IPF.

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.

BACKGROUND:Linkage to medical services enables timely diagnosis and treatment, yet racial/ethnic minority older adults with limited English proficiency (LEP) face substantial barriers. We tested Preparing Healthy Aging through Dementia Literacy Education and Navigation (PLAN), a language-concordant community health worker (CHW)-led intervention, to improve dementia linkage among Korean American (KA) older adults with undiagnosed probable dementia and to assess caregiver outcomes. METHODS:In a community-based randomized trial, 287 older adult-caregiver dyads were followed for 6 months. Trained Korean-speaking CHWs delivered a 1-h dementia literacy education session plus phone navigation. The primary outcome was linkage to medical services, verified through clinic documentation. Secondary outcomes included caregiver psychosocial measures. RESULTS:PLAN increased linkage to medical services versus control (16.7% vs 0%, chi-squared [df = 1] = 24.05, p < 0.001). Caregiver outcomes were largely unchanged, with self-efficacy favoring control. DISCUSSION/CONCLUSIONS:This language-concordant CHW model achieved verified community-to-clinic linkage at 6 months. Longer follow-up and testing across diverse LEP communities are needed to assess diagnosis, treatment initiation, and caregiver trajectories.

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 PURPOSE/UNASSIGNED:Radiotherapy is typically delivered in consecutive equi-dose fractions, but research suggests a non-uniform dose schedule may produce a higher tumor control probability (TCP). We developed an optimization method that automatically constructs the best dose schedule with variable fraction sizes and treatment breaks based on a tumor dose-response model calibrated to head-and-neck squamous cell carcinoma, which captures the impact of cellular resource competition and hypoxia. MATERIALS AND METHODS/UNASSIGNED:We formulated the dose scheduling problem as a finite-horizon optimal control problem. Fraction size was constrained by an upper bound on the biologically effective dose to normal tissue, along with a daily dose limit. This problem is nonconvex, so we employed a heuristic called the convex-concave procedure to solve a sequence of mixed-integer convex approximations that converges to a good estimate of the solution. RESULTS/UNASSIGNED:The optimal schedules adhered to a pattern consisting of an initial "primer shot", followed by a 1 week break, and concluding with six small equi-dose fractions and a final large fraction. The primer shot killed proliferating cells, freeing up resources so hypoxic cells could reoxygenate during the treatment break. These reoxygenated cells are more radiosensitive, therefore the schedule waited until all cells have reoxygenated before delivering its largest dose. In computational experiments, our schedule achieved a 12% higher TCP than the standard equi-dose weekday schedule. CONCLUSIONS/UNASSIGNED:An optimization method was developed to construct non-uniform dose schedules based on a model of tumor dose-response in the presence of hypoxia, yielding significant improvements in TCP.

Pericardial disease is common in patients with immune-mediated inflammatory diseases (IMIDs), especially in systemic lupus erythematosus. Pericardial disease may present as an asymptomatic pericardial effusion or acute and recurrent pericarditis, and may sometimes lead to complications (cardiac tamponade and constrictive pericarditis). Pathophysiology of pericarditis in IMIDs is likely related to the underlying immune dysregulation. Diagnosis of IMID-related pericarditis relies on general diagnostic criteria, supported by inflammatory biomarkers and non-invasive multimodality imaging. Initial management of IMID-related pericarditis overlaps with idiopathic pericarditis (nonsteroidal anti-inflammatory drugs and colchicine) together with treatment of the underlying IMID. Glucocorticoids are used in cases of poor response to first-line treatments. The use of immunosuppressive therapies is driven by the underlying IMID and systemic organ involvement beyond the pericardium. Multi-disciplinary care collaboration between cardiologists, radiologists, internists, and rheumatologists is pivotal to develop an appropriate, common treatment plan based on the individual features of each patient with IMIDs.

OBJECTIVES/OBJECTIVE:Congenital high airway obstruction syndrome (CHAOS) is characterized by over-distended lungs leading to impaired cardiac return and fetal hydrops. Survivors have been reported following prenatal spontaneous fistulization, fetal procedures to decompress the airway, or ex-utero intrapartum treatment (EXIT). The long-term outcomes of survivors are unclear. METHODS:We performed a retrospective chart review on patients diagnosed with CHAOS in our center between 2005-2025. RESULTS:Of the 28 patients with CHAOS, three (10.7%) underwent a fetal procedure to decompress the airway. Three patients (10.7%) had evidence of spontaneous fistulization. Four patients (14.3%) terminated the pregnancy and four (14.3%) had in-utero fetal demise. Twenty patients (71.4%) were live-born; of these, 14 (70%) died shortly after delivery and two (10%) died in the neonatal period. Seven patients (35%) underwent EXIT-to-tracheostomy at our center, of which four (57.1%) are long-term survivors ranging in age from 4 to 19 years old. Three patients have undergone airway reconstruction between 1.6 and 5.6 years of age; one remains tracheostomy-dependent due to recurrent airway stenosis, one patient has undergone reconstruction and is likely to be decannulated soon, and one patient had successful reconstruction and was decannulated. The fourth patient has not yet undergone airway reconstruction. CONCLUSIONS:CHAOS remains a highly morbid diagnosis, but long-term survivorship and liberation from tracheostomy is possible.