Faculty Bibliography

A key conceptual issue in the resilience literature centers on whether the presence of resilience in one domain corresponds to positive adaptation in other areas. The present studies investigated whether an individual's likelihood of demonstrating resilience in their trajectory of depressive symptoms would be associated with positive adjustment in psychological, functional, and health-related domains following exposure to spinal cord injury, bereavement, and heart attack. In each study, we utilized growth mixture and robust linear mixed-effects modeling to examine the associations between depression-based trajectories and multiple domains of positive adjustment. Results from all three studies indicated that, on average, individuals who exhibited trajectories of resilience in relation to depressive symptoms concurrently experienced better quality of life, perceived manageability, self-esteem, cognition, and body mass index (BMI). Further, a higher probability of belonging to the resilient trajectory class was linked to higher quality of life, B = 33.78, 95% CI [24.31, 42.91]; perceived manageability, B = 3.44, 95% CI [1.54, 5.21]; cognitive functioning, B = 2.30, 95% CI [1.32, 3.27]; and healthier BMI, B = -1.02, 95% CI [-1.89, -0.17]. Together, these findings illustrate that it is possible to utilize symptoms of depression to predict patterns of resilience across several clinically meaningful domains.

Xylose constitutes the second major sugar fraction of the plant-derived lignocellulosic biomass, which is the most abundantly available and renewable feedstock for microbial fermentations. Hence, comprehensive utilization of xylose is crucial from the perspective of sustainable development of bio-based products, such as fuels, fine chemicals, and high-value compounds. Due to several inherent advantages, various species and strains of yeast are employed to produce these biomolecules. With the advancement of genetic engineering in yeast, lignocellulosic biomass has begun to be commercialized for producing various bioproducts required in the food, fuel, pharmaceutical, chemical, and cosmetics industries. The increasing demands of these bioproducts worldwide lead to a necessity of utilizing xylose efficiently for yeast fermentation strategies together with/replacing glucose for more economic sustainability. However, yeast fermentation processes mostly employ glucose; hence, our understanding of xylose utilization by yeast has not been as scrupulous as it should have been. There has been a remarkable increase in the number of studies conducted on xylose utilization and metabolism in yeasts in the past decade. Our objective in this chapter is to highlight the key advancements and novel approaches in this area and to integrate our understanding of xylose metabolism in yeasts, which can help culminate into commercializing strategies in the future for the development of important bioproducts.

BACKGROUND:Most donor hearts offered for heart transplant (HT) in the United States (US) are turned down. We aimed to understand the reasons for this - focusing on those related to the potential recipient and HT center (i.e. donor-unrelated reasons for refusal). METHODS:The Donor Heart Study (DHS) enrolled 4,333 adult potential heart donors in US from 2015 - 2020. Separately by donor, each HT center who refused an offer for that donor was surveyed on their reason(s) for refusal. We measured the prevalences of 18 distinct donor-unrelated reasons for refusal and their association with the timing of offers (weekend vs. weekday). RESULTS:Our analytic sample included 14,132 unique surveys, each representing a declined offer for one of 3083 donors (mean per donor: 2.56; range: 1 - 17). Donor-unrelated reasons were cited in 24.3% (n = 3441) of surveys; among these, recipient issues (i.e. "recipient ill) were most common (cited in 7%) while resource-related issues (e.g. "logistics", "surgeon unavailable") were rare (<1%). Neither showed a significant time trend; however, other reasons ("already considering another offer", "distance too far") did so, with an abrupt uptick after 2018. We found that several donor-related (but no donor-unrelated) reasons for refusal (e.g. left ventricular hypertrophy, social risk behaviors) were significantly more common on weekends. Their "weekend-predominance" was not explained by differences in objective donor characteristics. CONCLUSIONS:Nearly one quarter of donor heart offer refusals are due to donor-unrelated reasons. Weekend-predominant reasons for offer refusal signal the highly subjective nature of donor assessment and warrant further scrutiny.

PURPOSE/OBJECTIVE:The purpose of this study is to compare the quality and clinical outcomes of patients who underwent open reduction internal fixation for a proximal humerus fracture in a "timely manner" which was defined to be within 5 days of injury compared to those with "delayed intervention" (>5 Days) to determine the effect this had. METHODS:This IRB-approved study evaluated patients who sustained a proximal humerus fracture treated with plate and screw fixation (ORIF) between January 2004 and October 2022 and had time from injury to surgery documented. Patients were grouped based on the time to surgery (TTS) - Less than 5 Days (L5) vs. More than 5 Days (M5). TTS was also evaluated as a continuous variable. Univariable and multivariable analysis compared patient demographics, injury/surgical characteristics, postoperative complications, and clinical outcomes to determine effect of TTS. Clinical outcomes included shoulder range of motion (ROM) and Disabilities of the Arm, Shoulder, and Hand (DASH) score at least 1 year following the date of injury. Standard statistical tests were used (p<0.05 considered significant). RESULTS:, p=0.03, β= -0.27, 95% CI = -41.71- -2.89) surgery was associated with less passive forward elevation. CONCLUSION/CONCLUSIONS:Timing of surgery did not impact outcomes of patients who underwent open reduction internal fixation for proximal humerus fractures. Surgical intervention after 14 days was associated with diminished passive forward elevation only.

Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β₂ that dimerizes with integrin α_X and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β₂ decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β₂ levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β₂ as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

Gliomas are the most common primary brain tumors and a major source of mortality and morbidity in adults and children. Recent genomic studies have identified multiple molecular subtypes; however metabolic characterization of these tumors has thus far been limited. We performed metabolic profiling of 114 adult and pediatric primary gliomas and integrated metabolomic data with transcriptomics and DNA methylation classes. We identified that pediatric tumors have higher levels of glucose and reduced lactate compared to adult tumors regardless of underlying genetics or grade, suggesting differences in availability of glucose and/or utilization of glucose for downstream pathways. Differences in glucose utilization in pediatric gliomas may be facilitated through overexpression of SLC2A4, which encodes the insulin-stimulated glucose transporter GLUT4. Transcriptomic comparison of adult and pediatric tumors suggests that adult tumors may have limited access to glucose and experience more hypoxia, which is supported by enrichment of lactate, 2-hydroxyglutarate (2-HG), even in isocitrate dehydrogenase (IDH) wild-type tumors, and 3-hydroxybutyrate, a ketone body that is produced by oxidation of fatty acids and ketogenic amino acids during periods of glucose scarcity. Our data support adult tumors relying more on fatty acid oxidation, as they have an abundance of acyl carnitines compared to pediatric tumors and have significant enrichment of transcripts needed for oxidative phosphorylation. Our findings suggest striking differences exist in the metabolism of pediatric and adult gliomas, which can provide new insight into metabolic vulnerabilities for therapy.

Mutations that accumulate in the human male germline with age are a major driver of genetic diversity and contribute to genetic diseases. However, aging-related male germline mutation rates have not been measured directly in germline cells (sperm) at the level of individuals. We developed a study design in which we recalled 23 sperm donors with prior banked samples to provide new sperm samples. The old and new sequential sperm samples were separated by long timespans, ranging from 10 to 33 years. We profiled these samples by high-fidelity duplex sequencing and demonstrate that direct high-fidelity sequencing of sperm yields cohort-wide mutation rates and patterns consistent with prior family-based (trio) studies. In every individual, we detected an increase in sperm mutation burden between the two sequential samples, yielding individual-specific measurements of germline mutation rate. Deep whole-genome sequencing of sequential sperm samples from two individuals followed by targeted validation measured remarkably stable mosaicism of clonal mutations that likely arose during embryonic and germline development, suggesting that age did not substantially impact the diversity of spermatogonial stem cell pools in these individuals. Our application of high-fidelity and deep whole-genome sequencing to sequential sperm samples provides insight into aging-related mutation processes in the male germline.

As the opioid crisis continues, now driven by use of fentanyl, naloxone is an increasingly important intervention to reverse overdoses. More research is needed on the willingness of populations at risk for unintentional fentanyl exposure (through adulterated drugs) to accept naloxone to reverse potential overdoses. Adults (n = 991) entering randomly selected nightclubs in New York City (NYC) were surveyed at the point-of-recruitment in 2024 and were asked about their willingness to accept a free naloxone kit. We examined the prevalence of reported willingness to accept naloxone and reasons for refusal, and we examined prevalence and correlates of participants accepting naloxone. During the survey, 65.2% of participants reported being familiar with naloxone, 62.1% agreed to accept naloxone, and 49.6% were recorded as accepting a kit. Those residing in NYC, compared to visitors, had a higher prevalence of recorded acceptance (aPR = 1.41, 95% CI: 1.11-1.79), as did those reporting familiarity with naloxone (aPR = 1.27, 95% CI: 1.02-1.58), and those with an average higher readiness to intervene in an opioid overdose (aPR = 1.18, 95% CI: 1.04-1.33). The majority who refused (56.1%) reported not being interested; 10.1% reported that they were not worried about overdoses, and 8.2% reported that they already had naloxone. Although 83.4% agreed that naloxone is used to reverse opioid overdoses, 35.4% reportedly thought that naloxone is used to reverse the effects of cocaine or any drug. While at least half of attendees were willing to accept a naloxone kit, lack of interest and lack of knowledge about naloxone were potential barriers to carrying naloxone.

OBJECTIVES/UNASSIGNED:To evaluate the incidence and degree of rectal wall infiltration (RWI) of spacer gel used during prostate radiotherapy among two practitioners experienced in using rectal spacers. MATERIALS AND METHODS/UNASSIGNED:Consecutive patients with prostate cancer who received prostate radiotherapy after hydrogel rectal spacer insertion in August 2023-August 2024 by two experienced practitioners were retrospectively included. Post-implant magnetic resonance imaging examinations were evaluated by two radiologists for RWI: 0 (no abnormality), 1 (rectal wall edema), 2 (superficial RWI), and 3 (deep RWI). Scores 2-3 were considered positive for RWI and their location and degree of RWI (radial, longitudinal, and circumferential) were also categorized. Inter-reader agreement was assessed with Cohen's Kappa. RESULTS/UNASSIGNED:215 men were included. Agreement was substantial between the radiologists for RWI scores (Kappa, 0.697; 95% confidence interval, 0.594-0.800). RWI scores were 0 in 80.5% (173/215), 1 in 7.9% (17/215), 2 in 10.7% (23/215), and, 3 in 0.9% (2/215) of the men. Altogether, RWI was present (scores 2-3) in 11.6% (25/215), most commonly in the mid-gland and apex with median radial, longitudinal, and circumferential involvement of 3.2 mm, 8.6 mm, and 11.5%. None of these patients demonstrated any significant rectal toxicity. CONCLUSION/UNASSIGNED:RWI was very uncommon for experienced practitioners. The degree of RWI was focal and not associated with increased complications.