Faculty Bibliography

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.

BACKGROUND:Enteric infectious diseases claim more than 1 million lives annually and are among the top ten causes of death in children younger than 5 years. Remarkable global investment has been dedicated to enteric infectious disease prevention and control; however, the shifting global health landscape is testing the continuance of progress. To evaluate the current status and guide future interventions, we present the latest epidemiological estimates of enteric infectious diseases from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 and assess progress towards the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) mortality target of fewer than 20 deaths per 100 000 children younger than 5 years by 2025. METHODS:We quantified the incidence, mortality, and disability-adjusted life-years (DALYs) of enteric infectious diseases by age, sex, and year across 204 countries and territories from 1990 to 2023. In GBD 2023, the following were considered under the category of enteric infectious diseases: diarrhoeal diseases, enteric fever (typhoid and paratyphoid), invasive non-typhoidal Salmonella spp (iNTS) infections, and other intestinal infectious diseases. We also examined 15 aetiologies contributing to diarrhoeal diseases. Incidence and prevalence were estimated with DisMod-MR (version 2.1), a Bayesian meta-regression tool, drawing on data from systematic reviews, population-based surveys, claims data, and hospital sources. Cause-specific mortality was modelled with Cause of Death Ensemble Modelling based on data from sources including vital registration, mortality surveillance, verbal autopsy, and minimally invasive tissue sampling. Years of life lost and years lived with disability were computed and combined to derive DALYs. For aetiology-specific estimation, population-attributable fractions (PAFs) for 15 pathogens were derived with a counterfactual framework. Point estimates and 95% uncertainty intervals (UIs) were generated from 250 draws from the posterior distribution. FINDINGS/RESULTS:In 2023, enteric infectious diseases resulted in an estimated 1·27 million (95% UI 0·963-1·68) deaths globally, declining from 3·69 million (3·04-4·56) in 1990. The global age-standardised mortality rate (ASMR) decreased from 74·1 (62·0-92·9) per 100 000 population to 16·4 (12·6-21·3) per 100 000 population during the same period. Diarrhoeal diseases accounted for most deaths in 2023 (1·11 million [0·811-1·54]), followed by enteric fever and iNTS. South Asia and sub-Saharan Africa remained the most affected regions in 2023, with 599 000 (441 000-882 000) and 501 000 (373 000-648 000) deaths due to enteric infectious diseases, respectively, predominantly from diarrhoeal disease. Rotavirus was the leading cause of all-age diarrhoeal disease deaths (PAF 16·3% [12·0-21·5]), followed by norovirus (10·2% [2·4-17·0]) and Shigella spp (9·3% [5·4-15·2]). Among children younger than 5 years, PAFs of deaths due to diarrhoeal diseases were 40·2% (32·5-48·5) for rotavirus, 24·0% (15·1-36·7) for Shigella spp, and 23·4% (13·7-34·3) for adenovirus. Across 204 countries and territories, 141 met the GAPPD mortality target in 2023. The driving aetiologies among countries that did not meet the target in 2023 varied slightly by GBD super-region, but the highest or second-highest number of deaths in children younger than 5 years were consistently attributed to rotavirus. Astrovirus and sapovirus, newly included in GBD 2023, were responsible for 24 600 (6290-49 000) and 18 800 (4650-44 400) deaths, respectively, in 2023, mainly in children younger than 5 years. INTERPRETATION/CONCLUSIONS:Our findings show that mortality and ASMRs of enteric infectious diseases declined substantially between 1990 and 2023. This decline is consistent with the expansion of public health measures and broader socioeconomic development. However, the burden in 2023 remains considerably high, with the highest mortality concentrated in sub-Saharan Africa and south Asia. Considering that more than a quarter of all countries had yet to meet the GAPPD mortality target in 2023, sustained efforts are needed to address the persistent burden in affected countries and to adapt to the changing global health landscape. FUNDING/BACKGROUND:Gates Foundation.

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.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness that arises from disrupted retinal vascular development in premature infants. Oxygen exposure remains a central driver of treatment-warranted ROP, as higher saturation levels suppress early retinal vascular growth and later promote pathological neovascularization. Large, randomized trials of oxygen targeting show that lower oxygen saturation ranges reduce the incidence of treatment-requiring ROP, though with trade-offs in mortality. Observational cohorts, including the CRYO-ROP, ETROP, and e-ROP trials, consistently report lower rates of treatment-warranted ROP and reduced treatment need among Black infants despite similar or greater prematurity risk. Multiple explanations have been proposed to account for the paradoxically lower rates of treatment-warranted ROP observed among Black infants. Although biologic variations in angiogenic pathways have been proposed, evidence suggests that structural and clinical factors may offer an alternative explanation for these patterns. Black race is strongly correlated with residence in neighborhoods with greater socioeconomic disadvantage, which is associated with increased risk of prematurity and missed ROP follow-up visits. In addition, pulse oximeters may overestimate oxygen saturation in individuals with darker skin pigmentation, potentially altering targeted oxygen exposure. Survival-related selection bias may further contribute to this paradox, as infants at the highest risk of both mortality and treatment-warranted ROP may not survive long enough to develop treatment-requiring disease. This review examines racial differences in ROP severity and examines how oxygen exposure and structural factors may contribute to these disparities, while acknowledging the limited evidence supporting biologic explanations.

BACKGROUND:Remote patient monitoring (RPM) and telehealth improve hypertension management but remain underutilized in resource-constrained settings. The Advancing Long-term Improvements in Hypertension Outcomes through a Team-based Care Approach (ALTA) intervention integrates RPM and virtual health coaching into routine care across a large urban FQHC network and has improved blood pressure outcomes. OBJECTIVE:Explore contextual and mechanistic factors shaping ALTA's implementation outcomes from the perspective of intervention deliverers. DESIGN/METHODS:Following 1 year of ALTA implementation, we conducted a realist-informed qualitative evaluation to examine factors influencing intervention uptake using semi-structured interviews and focus groups conducted from September to November 2023. PARTICIPANTS/METHODS:Practice leadership, clinicians, and staff. APPROACH/METHODS:Participants were recruited through convenience sampling. Transcripts were analyzed using a stepwise deductive and inductive coding approach. Deductive codes were drawn from Proctor's taxonomy of implementation outcomes. Themes were developed using context-mechanism-outcome (C-M-O) configurations. KEY RESULTS/RESULTS:Analysis of 32 semi-structured interviews and four focus groups with a total of 46 intervention deliverers revealed five primary C-M-O-oriented themes: (1) Appropriateness, determined by perceptions of fit, drives acceptability. (2) Demanding workflows raise concerns around ALTA's additional burden, influencing perceptions of appropriateness. (3) Intervention challenges are mitigated by practice facilitation and team-based problem-solving, enhancing acceptability, feasibility, and fidelity. (4) Repeated exposure promotes workflow optimizations, fostering intervention penetration over time. (5) Staff desire insight into ALTA's impact, and communication about intervention progress increases motivation and buy-in. Five of Proctor's implementation outcomes emerged most prominently: appropriateness, acceptability, feasibility, fidelity, and penetration. Notably, these outcomes were interdependent, with one acting as an important contextual factor or mechanistic element for another. CONCLUSIONS:This evaluation highlights important contextual factors, mechanisms, and interconnected outcomes underlying implementation of ALTA. Shared understanding and peer learning, workflow optimization, and communication of outcomes with frontline staff improve reach, equity, and sustainability of RPM-enabled interventions for hypertension management in FQHCs. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT03713515, date of registration: October 19, 2018, https://classic. CLINICALTRIALS/RESULTS:gov/ct2/show/NCT03713515.

Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) where its allosteric regulation depends on homodimerization. Using affinity capture, FRET, and blue native gels, we show that KRAS4A enhances oligomerization of HK1 on the OMM. Modeling the HK1/KRAS4A complex with AlphaFold3 predicts that the membrane association sequences of both HK1 and KRAS4A are oriented toward the OMM. Super-resolution microscopy showed colocalization of HK1 and KRAS4A on the OMM with HK1 enriched at discrete locations. Single-molecule tracking reveals HK1 diffusing freely along the OMM and dwelling at discrete regions where two molecules can be seen to colocalize transiently. KRAS4A expression decreased the diffusion coefficient of HK1 on the organelle. Thus, KRAS4A alters the dynamics of HK1 on the OMM and promotes oligomerization.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications, such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON-OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or control-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood-brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD-iNs, suggesting a compensatory mechanism. In addition, MXRA8 showed altered protein-protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology, and thus, site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.

INTRODUCTION/BACKGROUND:The purpose of this study was to determine whether CT Hounsfield units (HUs) as a proxy for bone quality can predict postoperative mechanical complications following surgical treatment of distal humerus fractures. METHODS:One hundred fifty-three patients with both column distal humerus fractures who underwent surgical fixation at single institution and had complete radiographic data available were included. Radiographic measurements included the HU value from the surgical distal humerus as determined by measuring the metaphyseal/supracondylar at the midaxial/coronal/sagittal CT image an average of 1 cm from the articular surface using a freehand region of interest. Zones with fracture lines and cortical impaction were avoided for all measurements. Postoperative complications recorded were implant failure, nonunion, and acute periprosthetic fracture. Patients with and without complications were statistically compared, and binary logistic regression was done to determine if CT HU measurements from the distal humerus were predictive of complications. RESULTS:Five patients (3.3%) developed five mechanical complications, including peri-prosthetic humerus fracture (one), implant failure (two), and nonunion (two). Patients with mechanical complications were more likely to be current smokers (40% vs. 6.8%, P = 0.010). Otherwise, no difference was observed in demographics or AO/Orthopedic Trauma Association classification between the cohorts. Patients with complications had markedly lower HU in the coronal plane (P = 0.031). Regression analysis found that current smoking was associated with an increased risk of mechanical complications (P = 0.041, OR = 1.102, 95% confidence interval [CI], 1.087 to 1.710), whereas a higher coronal HU was associated with a decreased risk of complications (P = 0.048, OR = 0.973, 95% CI, 0.961 to 0.991). CONCLUSION/CONCLUSIONS:A thorough smoking history and CT HU measurements in the coronal plane may identify patients with poorer bone quality at higher risk for postoperative mechanical complications following distal humerus fracture fixation.

Advances in MRI hardware and acceleration strategies have enabled substantial reductions in musculoskeletal MRI acquisition times over the past decade. Advanced acceleration techniques have facilitated four- to eightfold acceleration but are often limited by noise amplification and reconstruction artifacts at higher acceleration factors. The clinical introduction of deep learning (DL)-based image reconstruction addresses traditional constraints by improving SNRs, reducing artifacts, and enhancing image quality, thereby enabling higher acceleration factors than previously achievable with conventional reconstruction methods. DL reconstruction and superresolution techniques allow comprehensive musculoskeletal MRI protocols to be performed in less than 10 minutes across a range of applications, field strengths, and vendors. Successful implementation requires consideration of hardware capabilities, anatomic constraints, protocol design, and workflow adaptation to fully realize efficiency gains. In addition to technical factors, operational considerations-including scheduling logistics and infrastructure adjustments-are important to translate scan time reductions into clinical value. Early validation studies show preserved or improved diagnostic performance of DL-accelerated MRI compared with conventional protocols, supporting their growing integration into clinical practice. Continued technical development and clinical validation will further define the role of DL reconstruction and potentially facilitate even greater acceleration and efficiency gains.

Comparing outcomes across treatments is essential in medicine and public policy. To do so, researchers typically estimate a set of parameters, possibly counterfactual, each targeting adifferent treatment. Treatment-specific means are commonly used, but their identification requires a positivity assumption: every subject has a nonzero probability of receiving each treatment. This assumption is often implausible, especially when treatment can take many values. Causal parameters based on dynamic stochastic interventions offer robustness to positivity violations. However, comparing these parameters may fail to reflect the effects of the underlying target treatments because the parameters can depend on outcomes under nontarget treatments. To clarify when two parameters targeting different treatments yield a useful comparison of treatment efficacy, we propose a comparability criterion: if the conditional treatment-specific mean for one treatment is greater than that for another, then the corresponding causal parameter should also be greater. Many standard parameters fail to satisfy this criterion, but we show that only a mild positivity assumption is needed to identify parameters that yield useful comparisons. We then provide two simple examples that satisfy this criterion and are identifiable under the milder positivity assumption: trimmed and smooth-trimmed treatment-specific means with multivalued treatments. For smooth-trimmed treatment-specific means, we develop doubly robust-style estimators that attain parametric convergence rates under nonparametric conditions. We illustrate our methods with an analysis of dialysis providers in New York State.