Faculty Bibliography

The clinical translation of diffusion magnetic resonance imaging (dMRI)-derived quantitative contrasts hinges on robust reproducibility, minimizing both same-scanner and cross-scanner variability. As multi-site data sets, including multi-shell dMRI, expand in scope, enhancing reproducibility across variable MRI systems and MRI protocols becomes crucial. This study evaluates the reproducibility of diffusion kurtosis imaging (DKI) metrics (beyond conventional diffusion tensor imaging (DTI)), at the voxel and region-of-interest (ROI) levels on magnitude and complex-valued dMRI data, using denoising with and without harmonization. We compared same-scanner, cross-scanner, and cross-protocol variability for a multi-shell dMRI protocol (2-mm isotropic resolution, b = 0, 1000, 2000 s/mm²) in 20 subjects. We first evaluated the effectiveness of Marchenko-Pastur Principal Component Analysis (MPPCA) based denoising strategies for both magnitude and complex data to mitigate noise-induced bias and variance, to improve dMRI parametric maps and reproducibility. Next, we examined the impact of denoising under different population analysis approaches, specifically comparing voxel-wise versus region of interest (ROI)-based methods. We also evaluated the role of denoising when harmonizing dMRI across scanners and protocols. The results indicate that DTI and DKI maps visually improve after MPPCA denoising, with noticeably fewer outliers in kurtosis maps. Denoising, either using magnitude or complex dMRI, enhances voxel-wise reproducibility, with test-retest variability of kurtosis indices reduced from 15%-20% without denoising to 5%-10% after denoising. Complex dMRI denoising reduces the noise floor by up to 60%. Denoising not only reduced variability across scans and protocols, but also increased statistical power for low SNR voxel-wise comparisons when comparing cross sectional groups. In conclusion, MPPCA denoising, either over magnitude or complex dMRI data, enhances the reproducibility and precision of higher-order diffusion metrics across same-scanner, cross-scanner, and cross-protocol assessments. The enhancement in data quality and precision facilitates the broader application and acceptance of these advanced imaging techniques in both clinical practice and large-scale neuroimaging studies.

BACKGROUND:Results from national surveys indicate that many older adults reported delayed medical care during the acute phase of the COVID-19 pandemic, yet few studies have used objective data to characterize healthcare utilization among vulnerable older adults in that period. In this study, we characterized healthcare utilization during the acute pandemic phase (March 7-October 6, 2020) and examined risk factors for total disruption of care among older adults with multiple chronic conditions (MCC) in New York City. METHODS:This retrospective cohort study used electronic health record data from NYC patients aged ≥ 50 years with a diagnosis of either hypertension or diabetes and at least one other chronic condition seen within six months prior to pandemic onset and after the acute pandemic period at one of several major academic medical centers contributing to the NYC INSIGHT clinical research network (n=276,383). We characterized patients by baseline (pre-pandemic) health status using cutoffs of systolic blood pressure (SBP) < 140mmHg and hemoglobin A1C (HbA1c) < 8.0% as: controlled (below both cutoffs), moderately uncontrolled (below one), or poorly controlled (above both, SBP > 160, HbA1C > 9.0%). Patients were then assessed for total disruption versus some care during shutdown using recommended care schedules per baseline health status. We identified independent predictors for total disruption using logistic regression, including age, sex, race/ethnicity, baseline health status, neighborhood poverty, COVID infection, number of chronic conditions, and quartile of prior healthcare visits. RESULTS:Among patients, 52.9% were categorized as controlled at baseline, 31.4% moderately uncontrolled, and 15.7% poorly controlled. Patients with poor baseline control were more likely to be older, female, non-white and from higher poverty neighborhoods than controlled patients (P < 0.001). Having fewer pre-pandemic healthcare visits was associated with total disruption during the acute pandemic period (adjusted odds ratio [aOR], 8.61, 95% Confidence Interval [CI], 8.30-8.93, comparing lowest to highest quartile). Other predictors of total disruption included self-reported Asian race, and older age. CONCLUSIONS:This study identified patient groups at elevated risk for care disruption. Targeted outreach strategies during crises using prior healthcare utilization patterns and disease management measures from disease registries may improve care continuity.

Health equity is the fair and just opportunity for every individual to achieve their full potential in all aspects of health and well being. The combination of the COVID-19 pandemic and increased awareness of social injustice shed critical light on health inequities. DEI efforts in health care directly affect patient outcomes and quality of life. By creating and implementing high-quality DEI programs, our orthopedic surgery practices and organizations can help ameliorate healthcare inequities and deliver inclusive, person-centered, and culturally competent patient care. Substantial variability in definition, data collection, methodology, and goals exist between organizations that measure health equity. DEI metrics and targets will be used to measure quality, but reliance on data acquired through patient questionnaires or through their interaction with technology may exclude the most at-risk populations. The purpose of this review is to outline the various organizations involved in evaluating DEI metrics so that orthopaedic teams can better measure and more effectively report the effect of DEI efforts on patient outcomes.

PURPOSE/OBJECTIVE:Circulating tumor DNA (ctDNA) is an emerging tool in the evaluation of GI cancers. Challenges remain in defining its utility and role as a primary end point in therapeutic trials. The National Cancer Institute (NCI) ctDNA GI working group was created to evaluate current data and provide guidance on the inclusion of ctDNA in GI cancer trials. METHODS:The NCI GI steering committee assigned four task force members to serve as co-chairs for the working group. Co-chairs identified experts within each GI disease group to form a panel that convened to review data and provide recommendations. The group focused on ctDNA's role as a potential surrogate for assessing prognosis and guiding treatment decisions that may enhance GI cancer trials. A manuscript was drafted, circulated, revised, and voted on by the panel. The final draft was reviewed by the Cancer Therapy Evaluation Program. RESULTS:Further data are required to support ctDNA as a primary end point for late-phase therapeutic trials, particularly in studies that could change the standard-of-care. However, the group supports ctDNA as a primary efficacy end point for phase II studies and as a noninvasive evaluation strategy for new drug development. Incorporation of ctDNA as a biomarker in trial design must consider the specific context of disease biology of the GI cancer subtypes. ctDNA should be incorporated as an exploratory end point across a variety of disease settings and indications. Several practical considerations were identified to optimize the incorporation of ctDNA in future trial design. CONCLUSION/CONCLUSIONS:Prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.

Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.

PURPOSE/UNASSIGNED:To assess corneal resistance to enzymatic digestion after rose bengal (RB)/green light and RB/green light followed by riboflavin (RF)/ultraviolet A (UV-A) cross-linking (CXL), with or without oxygen. METHODS/UNASSIGNED:Ex vivo porcine corneal buttons (n = 144) underwent CXL with RB/green or RB/green-RF/UV-A under atmospheric 21% oxygen conditions or in a nitrogen chamber with 0.1% oxygen (hypoxic conditions) to test 10- and 15-J/cm2 fluences. After CXL, corneas were digested with 0.3% collagenase A, and mean digestion times (MDTs) were recorded. RESULTS/UNASSIGNED:For the non-irradiated control group, the MDT was 19.75 ± 1.34 hours. Under atmospheric oxygen conditions, RB/green CXL yielded MDTs of 33.69 ± 1.4 and 34.38 ± 1.31 hours with fluences of 10 and 15 J/cm2, respectively. RB/green + RF/UV-A showed MDTs of 39.56 ± 1.93 and 51.94 ± 4.2 hours for combined fluences of 10 + 10 J/cm2 and 15 + 15 J/cm2, respectively. Hypoxic RB/green MDTs were 33.88 ± 1.02 and 34.06 ± 1.57 hours, and RB/green + RF/UV-A MDTs were 39.62 ± 2.5 and 50.35 ± 1.59 hours for the same respective fluences. No significant differences were observed between the control groups and corresponding intervention groups (all P > 0.05). CONCLUSIONS/UNASSIGNED:CXL via RB/green and RB/green-RF/UV-A significantly enhanced corneal collagenase digestion resistance, irrespective of oxygen presence. These findings could help optimize infectious keratitis therapy CXL protocols. TRANSLATIONAL RELEVANCE/UNASSIGNED:Our findings aid the understanding of the molecular mechanisms underlying the therapeutic effect of CXL and may contribute to refining accelerated PACK-CXL protocols and other CXL treatment strategies.

OBJECTIVE:We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and nonstimulants. METHOD/METHODS:February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multilevel meta-analytic models were conducted with R 4.3.1. RESULTS:We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedge's g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults. CONCLUSION/CONCLUSIONS:In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and nonstimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and nonpharmacological interventions is likely to further improve QoL in people with ADHD. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:From a prior dataset of a network meta-analysis, 17 randomized controlled trials (RCTs) were included in a meta-analysis to investigate if attention-deficit/hyperactivity disorder (ADHD) medication improves quality of life (QoL) in people with ADHD. The analysis showed that medications such as amphetamines, methylphenidate, and atomoxetine improved QoL compared to placebo, with moderate effect sizes. This study underscores the importance of ADHD medications, both stimulants and nonstimulants, not only in alleviating core ADHD symptoms but also in enhancing overall QoL for individuals with ADHD. STUDY PREREGISTRATION INFORMATION/UNASSIGNED:Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/; qvgps.

Dyadic assessment is an essential component of understanding a young child's mental health, providing critical information about the contexts within which they live and develop. This article describes how to observe the behaviors of a child and caregiver together, either by systematically reviewing key domains of the dyadic interaction or by using a formal observation procedure. Though challenged by issues of training and time to complete them, cultural responsiveness, and the balance of making them both naturalistic and feasible, dyadic assessments are indispensable. They can provide a foundation and jumping-off point for therapy and healing.

Pathogenic Enterobacter species are of increasing clinical concern due to the multidrug-resistant nature of these bacteria, including resistance to carbapenem antibiotics. Our understanding of Enterobacter virulence is limited, hindering the development of new prophylactics and therapeutics targeting infections caused by Enterobacter species. In this study, we assessed the virulence of contemporary clinical Enterobacter hormaechei isolates in a mouse model of intraperitoneal infection and used comparative genomics to identify genes promoting virulence. Through mutagenesis and complementation studies, we found two porin-encoding genes, ompC and ompD, to be required for E. hormaechei virulence. These porins imported clinically relevant carbapenems into the bacteria, and thus loss of OmpC and OmpD desensitized E. hormaechei to the antibiotics. Our genomic analyses suggest porin-related genes are frequently mutated in E. hormaechei, perhaps due to the selective pressure of antibiotic therapy during infection. Despite the importance of OmpC and OmpD during infection of immunocompetent hosts, we found the two porins to be dispensable for virulence in a neutropenic mouse model. Moreover, porin loss provided a fitness advantage during carbapenem treatment in an ex vivo human whole blood model of bacteremia. Our data provide experimental evidence of pathogenic Enterobacter species gaining antibiotic resistance via loss of porins and argue antibiotic therapy during infection of immunocompromised patients is a conducive environment for the selection of porin mutations enhancing the multidrug-resistant profile of these pathogens.