Publications by Year: 2025

BACKGROUND: Replacing added sugars with nonnutritive sweeteners, such as sucralose, may help reduce weight gain in adults over time. Because sucralose is primarily excreted in the stool, its consumption could lead to changes in the gut microbiome.

OBJECTIVES: We aimed to explore whether replacing sucrose used in beverages with small quantities of sucralose led to gut microbiome changes among Asian Indian adults with type 2 diabetes (T2D) or overweight/obesity (BMI ≥23 kg/m2) without T2D.

METHODS: In 2 analogous substudies nested within two 12-wk, open-label parallel-arm randomized controlled trials, adults with T2D (n = 49) or overweight/obesity and no T2D (n = 48) were instructed to replace sucrose in their daily coffee and tea with sucralose or to continue their use of sucrose. We examined changes in gut microbiome community structure and taxonomic composition profiled using 16S rRNA sequencing in stool samples collected before and after the 12-wk interventions. The false discovery rate was controlled using the Benjamini-Hochberg method (q < 0.20).

RESULTS: Compared with the control group, the sucralose intervention decreased α diversity (Shannon index: P = 0.02; Simpson index: P = 0.03) and increased β diversity (P = 0.001) in gut microbiome communities of adults with T2D, but not among adults with overweight/obesity (all between-group P > 0.05). Among 185 genera tested in the T2D trial, compared with the control, relative abundances of 14 primarily sugar-fermenting or short-chain fatty-acid-producing Firmicutes bacteria in the Lachnospiracae family were reduced, whereas Enterococcus and Pediococcus increased during the intervention (q < 0.20). In contrast, adults with overweight/obesity and no T2D showed no similar changes.

CONCLUSIONS: Replacing daily sucrose added to coffee and tea with sucralose resulted in changes in gut microbiome community structure and taxonomic composition among Asian Indian adults with T2D, but not those with overweight/obesity and no T2D. Further studies are needed to understand potential health implications and the underlying drivers of these gut microbiome changes.Clinical Trial Register No. (India Trial Register): CTRI/2021/04/032686, CTRI/2021/04/032809.

White matter alterations are increasingly implicated in neurological diseases and their progression. Diffusion-weighted magnetic resonance imaging (DW-MRI) has been included in many international-scale studies to identify alterations in white matter microstructure and connectivity. Yet, quantitative investigation of DW-MRI data is hindered by a lack of consistency due to variations in acquisition protocols, sites, and scanners. Specifically, there is a need to harmonize the preprocessing of DW-MRI datasets to ensure that compatible and reproducible quantitative metrics are derived from each site, including (1) bundle-wise microstructure measures, (2) features of white matter fiber bundles, and (3) connectomics measures. In the MICCAI CDMRI 2023 QuantConn challenge, participants are provided raw data from the same individuals taken with two different acquisition protocols on a single 4 tesla scanner in the same scanning session and asked to preprocess the data in order to minimize acquisition differences while retaining biological variation. Here, we outline the testing framework, provide baseline pre-harmonized results, and discuss the learning implications of this challenge.

BACKGROUND: The CXCR4 and CXCR2 chemokine receptor axes play critical but opposing roles in regulating neutrophil retention and release from the bone marrow (BM). Gain-of-function (GOF) variants in CXCR4 are associated with WHIM syndrome, characterized by neutropenia, lymphopenia, frequent infections, warts, and myelokathexis. Similarly, loss-of-function (LOF) variants in CXCR2 also result in neutropenia, increased infection susceptibility and myelokathexis. Mavorixafor, an orally bioavailable CXCR4 antagonist, has shown meaningful increases in absolute neutrophil count and reduced infections in WHIM syndrome patients. However, it remains unclear whether CXCR4 antagonism can mitigate the pathogenic characteristics observed in individuals with CXCR2 LOF mutations.

METHODS: This study investigated the effects of chronic oral administration of a CXCR4 antagonist on neutrophil abnormalities and infection susceptibility in a CXCR2 LOF mouse model. Mice received the CXCR2 antagonist navarixin orally and then the CXCR4 antagonist compound 1 or vehicle control daily for 7 days. Blood and BM samples were collected for analysis. Treated mice were inoculated with Streptococcus pneumoniae to induce pneumonia. Lung tissues were harvested to assess bacterial load and neutrophil counts, and overall survival was monitored.

RESULTS: Pharmacologically induced CXCR2 LOF in mice recapitulated multiple phenotypic features analogous to those observed in patients with CXCR2 LOF, including peripheral blood neutropenia, an elevated myeloid/erythroid ratio (M/E ratio), and neutrophil accumulation with myelokathexis-like (MK-like) morphology in BM, and increased pneumonia susceptibility. Treatment with the CXCR4 antagonist resulted in the correction of these pathologic features, as evidenced by normalization of absolute neutrophil count in peripheral blood, reversal of neutrophil accumulation in BM, normalization of the M/E ratio in BM and reduced the frequency of MK-like neutrophils in BM, and the incidence of myelokathexis. Furthermore, CXCR4 antagonism ameliorated the severity of pneumonia and facilitated the emigration of neutrophils into infected tissues in the CXCR2 LOF mice.

CONCLUSIONS: Our findings provide evidence that oral administration of a CXCR4 antagonist can effectively correct blood and BM neutrophil abnormalities and reduce infection susceptibility in a CXCR2 LOF mouse model. These findings suggest potential therapeutic benefits of CXCR4 antagonist therapy in addressing peripheral blood neutropenia and other pathogenic phenotypes in patients with CXCR2 LOF variants.

PURPOSE: Retinoblastoma is the most common intraocular cancer in infants and children, with a significant potential for metastasis. The mini-peptide ribosomal protein L41 (RPL41) has demonstrated extensive antitumor effects in vitro by promoting the degradation of activating transcription factor 4 (ATF4). This study aims to evaluate the therapeutic effect of RPL41 on retinoblastoma and elucidate its potential mechanisms.

METHODS: A xenografted retinoblastoma model was constructed in nude mice. The effects of xenografted RPL41 on tumor proliferation, invasion and metastasis were evaluated by local injection. Mass spectrometry identified differentially expressed genes in Y79 and Weri-RB1 retinoblastoma cells pre- and post-treatment. We utilized quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry to assess the expression levels of ARL5B(ADP ribosylation factor like GTPase 5B) in retinoblastoma cell lines and tissues. We also explored ATF4's regulatory role on ARL5B expression through chromatin immunoprecipitation (ChIP) experiments and luciferase reporter gene assays.

RESULTS: RPL41 inhibits the growth of subcutaneous retinoblastoma xenografts. ARL5B expression was significantly downregulated in treated Y79 and Weri-RB1 cells. ARL5B was upregulated in retinoblastoma cells and clinicopathological tissues. RPL41 treatment led to ATF4 degradation, reducing the expression levels of ARL5B and lysotransfer-related molecules. Knocking down ATF4 decreased ARL5B protein levels. ChIP experiments and dual-luciferase assays confirmed ATF4 positively regulates ARL5B. Rescue experiments indicated that ARL5B overexpression partially reversed the effects of RPL41 therapy or ATF4 knockdown on lysosomal pathways and cell migration.

CONCLUSIONS: RPL41 down-regulates the expression of ARL5B by degrading ATF4 and the impaired ARL5B-related lysosomal trafficking is a mechanism to inhibit the metastasis of retinoblastoma.

OBJECTIVE: Develop a new hospital surgery report card for use in performance improvement.

BACKGROUND: When evaluating quality, a surgical program is aided by benchmark comparisons with outcomes achieved at other hospitals. To be credible, benchmarking should be based on the same surgical procedures and patient risk, despite there being many types of patients and procedures.

METHODS: Using Medicare patients undergoing general, orthopedic, or vascular surgery, each patient in a hospital is closely matched to 10 control patients from typical hospitals and to 10 control patients from well-resourced hospitals throughout the United States. Patients were matched on 200 characteristics, including procedure, comorbidities, socio-demographics, and the presence of multimorbidity. Hospitals were graded based on the differences in outcomes between matched sets of patients. As an illustration, we examine the 20 highest volume hospitals in Pennsylvania and provide detailed report cards on 2 example hospitals.

RESULTS: The hospitals studied differed in quality and grades, with better outcomes than matched controls for Hospital A and significantly worse outcomes than controls for Hospital B, depending on the type of surgery and patient. For the 20 largest hospitals in Pennsylvania, 5 had significantly elevated mortality, and 2 had significantly lower mortality than matched controls.

CONCLUSIONS: Surgical programs benefit from knowing how their outcomes compare with those of other hospitals, both their overall outcomes and their outcomes for subsets of patients, such as patients with or without multimorbidity. Detailed reports based on matching can help identify meaningful deficiencies and strengths in programs concerning specific surgeries and patient types.

BACKGROUND: Acute myeloid leukemia (AML) progresses by the accumulation of somatic mutations and clonal expansion of pre-leukemic cells. Patients may respond to initial therapy, but often relapse, underscoring an evolving disease. Next generation sequencing technologies are being applied to AML for risk stratification and monitoring treatment response. We aimed to evaluate the efficiency of whole exome sequencing (WES) and single-cell DNA sequencing (scDNA-seq) for determining clonal heterogeneity and evolution in AML induced by treatment, assessing strengths and limitations of each technology.

METHODS: We conducted WES and scDNA-seq on samples from 6 patients with AML, including sequential samples from four patients. We identified somatic variants, clonal composition and phylogeny using both technologies and compared the results.

RESULTS: WES detected more variants and clones due to broader coverage, while scDNA-seq provided clonality results for targeted genes revealing zygosity and rare clones. Both techniques missed clinically important variants, posing challenges for clinical application. However, they identified similar founding clones and strong correlation of variant allele frequencies and clonal prevalences.

CONCLUSIONS: As both technologies can overlook variants, multiple technologies should be utilized to understand clonality in heterogeneous diseases such as AML. Careful scDNA-seq target panel planning, utilizing knowledge obtained from bulk sequencing, can offer more information on clonal heterogeneity. One limitation of our study is the small sample size which may limit the generalizability of the conclusions.

Congenital heart disease (CHD) is a complex group of cardiac abnormalities arising during fetal development. Despite advancements in diagnostics and surgery, CHD mechanisms remain elusive due to inadequate disease models. Recent innovations in artificial intelligence (AI)-assisted organoid construction, which replicate tissue architecture and function, provide a promising in vitro platform for modeling cardiac development and CHD progression with high precision. This review summarizes AI-driven approaches in CHD organoid construction, focusing on machine learning (ML) applications in self-assembly, three-dimensional (3D) bioprinting, tissue engineering, and microfluidic organ-on-a-chip (OOC) technologies. We also discuss refinements in AI algorithms - such as support vector machines (SVMs), decision trees, and neural networks - to enhance cell-cell interaction analysis, optimize drug screening, and improve toxicity/efficacy assessments. Looking ahead, AI is poised to accelerate CHD organoid translation to clinical practice, advancing precision medicine.

OBJECTIVE: Child sexual abuse is associated with mental health (MH) challenges across the lifespan. Black and Latino children are less likely to receive MH services than children of other backgrounds. We aimed to identify facilitators and barriers to MH services for Black and Latino children after sexual abuse.

METHODS: We conducted semistructured interviews with 30 Black and Latino, English- and Spanish-speaking caregivers of children who have experienced sexual abuse. Interviews were completed in caregivers' preferred language and modality (phone, video conferencing, or in person). Caregivers were asked about their opinions and experiences with initiating child MH services after sexual abuse. Interviews were audio-recorded, transcribed, and analyzed using thematic analysis.

RESULTS: Caregivers (27% Black, 47% Latino, 27% Black and Latino) were mostly biological mothers (87%). Half were born outside the United States. Caregivers reported 3 facilitators to MH services after sexual abuse: 1) perceived benefits of MH services; 2) trust in MH providers; and 3) support from frontline professionals and systems. Caregivers reported timely support when there was cross-system care coordination. Caregivers described 5 barriers to MH services after sexual abuse: 1) perceived harms of MH services; 2) concerns about misjudgment and discrimination by MH providers; 3) stigma of sexual abuse; 4) youth's lack of engagement in MH services; and 5) structural obstacles to MH services.

CONCLUSIONS: Black and Latino caregivers identified multiple facilitators and barriers to MH services after sexual abuse. Our findings can inform the development and testing of evidence-based strategies to improve MH engagement and outcomes after sexual abuse.

OBJECTIVE: Although complex endovascular repairs are becoming increasingly common, complication rates are less well studied, and published rates of technical success vary widely. In addition, whether high volume surgeons are more able to rescue intra-operative complications has not been well studied.

METHODS: This study analysed all complex abdominal aortic aneurysm (AAA) repairs in the Vascular Quality Initiative from 2014 to 2023. Multilevel logistic regression with inverse probability weighting was used to identify factors associated with lack of technical success (defined as successful introduction of the main graft, incorporation of all target vessels without occlusion or stenosis > 50%, and no type I or III endoleaks). Secondary analyses assessed the differential impact of type I and III endoleaks compared with graft and target vessel complications.

RESULTS: There were 6 556 repairs (3 246 para- or juxtarenal AAAs and 3 310 thoraco-abdominal aortic aneurysms) with an overall technical success rate of 82.7%; technical failures were due to type I or III endoleak in 9.6%, target vessel complications in 5.6%, and complications with the main body in 4.0%. Technical success increased in concert with volume in crude and adjusted analyses. Technical failure was associated with a markedly higher adjusted odds of peri-operative death, thoraco-abdominal life altering events, acute kidney injury, dialysis, spinal cord ischaemia, and re-operation. Repairs with technical failure at the hands of higher volume surgeons were less likely to experience death than cases of technical failure in the hands of lower volume surgeons (p < .006 for interaction). Technical success was similarly associated with higher 5 year survival (86% vs. 65%; p < .001). Both type I and III endoleaks, and target vessel and main body complications were associated with worse peri-operative outcomes and lower 5 year survival. However, although type I and III endoleaks had less impact than target vessel and main body complications in elective repairs, in symptomatic and ruptured settings these endoleaks had simlarly poor outcomes to target vessel and main body complications.

CONCLUSION: Technical success had a strong association with outcomes of endovascular complex AAA repair, especially in non-elective settings. Higher volume surgeons had higher rates of technical success, and their outcomes were less negatively impacted by technical failures, suggesting a potential benefit to centralising more urgent and complex cases.

INTRODUCTION: Transgender and gender-diverse adults have worse mental health than cisgender adults, yet few studies assess unmet mental health needs. This study compares frequent mental distress, access to care, and barriers among transgender and gender-diverse and cisgender adults.

METHODS: Using the 2022 KFF/The Washington Post Trans Survey of U.S. adults (n=1,338), unadjusted prevalence differences in frequent mental distress, unmet mental health need, and reasons for unmet mental health need were described. Logistic regression models assessed unmet mental health need likelihood, adjusting for sociodemographic characteristics and distress. Data were analyzed in 2024.

RESULTS: Among transgender and gender-diverse adults, 64% were nonbinary or gender nonconforming, 22% were transgender women, 12% were transgender men, and 2% were of another gender. Transgender and gender-diverse adults were more likely to have Medicaid (21% vs 14%, p=0.01) or be uninsured (15% vs 10%, p=0.04) and less likely to have Medicare (6% vs 25%, p<0.001) than cisgender adults. Transgender and gender-diverse adults reported more frequent mental distress (47% vs 21%, p<0.001) and unmet mental health need (48% vs 26%, p<0.001) than cisgender adults. In multivariable models, transgender and gender-diverse adults had higher unmet mental health need than cisgender adults (OR=1.62, 95% CI=1.08, 2.43). Transgender and gender-diverse adults were more likely to report cost as the main care barrier than cisgender adults (30% vs 15%, p=0.01).

CONCLUSIONS: Transgender and gender-diverse adults reported higher rates of frequent mental distress, unmet mental health need, and cost-related barriers to mental health care than cisgender adults. Efforts to improve the affordability and availability of mental health treatment could reduce high levels of unmet need among transgender and gender-diverse adults.