Faculty Bibliography

Plasma lipids are mainly carried in apolipoprotein B (apoB) containing lipoproteins. High levels of these lipoproteins are associated with several metabolic diseases and lowering their plasma levels are associated with reduced incidence of atherosclerotic cardiovascular disease. MicroRNAs (miRs) are small non-coding RNAs that reduce protein expression of their target mRNAs and are potential therapeutic agents. Here, we identified a novel miR-615-3p that interacts with human 3'-UTR of apoB mRNA, induces post-transcriptional mRNA degradation, and reduces cellular and secreted apoB100 in human hepatoma Huh-7 cells. Reducing cellular miR-615-3p levels by CRISPR-sgRNA increased cellular and secreted apoB100 indicating endogenous miR regulates apoB expression. Overexpression of miR-615-3p along with or without palmitic acid treatment decreased cellular and media apoB and increased cellular triglyceride levels without inducing endoplasmic reticulum stress. These studies have identified miR-615-3p as a negative regulator of apoB expression in human liver derived cells. It is likely that there are more miRs that regulate apoB-containing lipoprotein assembly and secretion. Discovery of additional miRs may uncover novel mechanisms that control lipoprotein assembly and secretion.

PURPOSE/UNASSIGNED:Immune checkpoint inhibition (ICI) shows benefits in adjuvant (AT) and neoadjuvant melanoma treatments. However, ICI frequently induces severe immune-related adverse events (irAE). Unlike metastatic disease, in which irAEs are a clinical trade-off for treatment that improves survival, the toxicity burden from ICI in the AT setting is a substantial clinical problem urging for irAE-predictive biomarkers. EXPERIMENTAL DESIGN/UNASSIGNED:We assessed postsurgical, pre-ICI treatment peripheral CD4+ and CD8+ T cells from clinical trial patients (CheckMate 915) treated with AT nivolumab (n = 130) or ipilimumab/nivolumab (COMBO, n = 82). Performing RNA sequencing differential gene expression analysis, we tested baseline differences associated with severe (grades 3-5) irAEs and constructed an irAE-predictive model using least absolute shrinkage and selection operator-regularized logistic regression. RESULTS/UNASSIGNED:The analysis of predicted protein-protein interactions among differentially expressed genes in peripheral CD4+ cells revealed significant enrichment of the spleen tyrosine kinase (SYK) pathway, associated with severe irAEs in COMBO-treated patients. This gene expression signature predicted severe-irAE COMBO patients (χ2P value = 0.001) with 73% accuracy and was independent of disease recurrence (P = 0.79). The irAE-predictive model incorporating this gene expression signature demonstrated 82% accuracy (χ2P value = 8.91E-06). CONCLUSIONS/UNASSIGNED:We identified baseline gene expression differences in key immune pathways of peripheral blood T cells from COMBO-treated patients with grades 3 to 5 irAEs and defined a SYK-related gene signature correctly identifying ∼60% of COMBO-treated patients with grades 3 to 5 irAEs. This finding aligns with our previous work linking anti-CTLA4 irAEs with a germline variant associated with high SYK expression. This gene signature may serve as a baseline biomarker of severe grade 3 to 5 irAE risk, which is especially important in AT treatment.

INTRODUCTION/BACKGROUND:Understanding the trends among patients undergoing same-day discharge (SDD) total hip arthroplasty (THA) is imperative to highlight the progression of outpatient surgery and the criteria used for enrollment. The purpose of this study was to identify trends in demographic characteristics and outcomes among patients who participated in an academic hospital SDD THA program over 6 years. METHODS:We retrospectively reviewed all patients who enrolled in our institution's SDD THA program from January 2015 to October 2020. Patient demographics, failure-to-launch rate, as well as readmission and revision rates were evaluated. Trends for continuous variables were analyzed using analysis of variance, and categorical variables were analyzed using chi-square tests. RESULTS:In total, 1,334 patients participated in our SDD THA program between 2015 and 2020. Age (54.82 to 57.94 years; P < 0.001) and mean Charlson Comorbidity Index (2.15 to 2.90; P < 0.001) significantly differed over the 6-year period. More African Americans (4.3 to 12.3%; P = 0.003) and American Society of Anesthesiology class III (3.2% to 5.8%; P < 0.001) patients enrolled in the program over time. Sex ( P = 0.069), BMI ( P = 0.081), marital status ( P = 0.069), and smoking status ( P = 0.186) did not statistically differ. Although the failure-to-launch rate (0.0% to 12.0%; P < 0.001) increased over time, the 90-day readmissions ( P = 0.204) and 90-day revisions ( P = 0.110) did not statistically differ. CONCLUSION/CONCLUSIONS:More African Americans, older aged individuals, and patients with higher preexisting comorbidity burden enrolled in the program over this period. Our findings are a reflection of a more inclusive selection criterion for participation in the SDD THA program. These results highlight the potential increase in the number of patients and surgeons interested in SDD THA, which is paramount in the current incentivized and value-based healthcare environment. LEVEL EVIDENCE/METHODS:III, Retrospective Review.

We sought to determine what effect the size of a displaced coronoid fracture fragment in Monteggia injuries has on clinical outcome. Sixty-seven patients presented to an academic medical center for operative fixation of a Monteggia fracture. Radiographs were assessed for length and height of the displaced coronoid fragment using measuring tools in our center's imaging archive system. Data were analyzed using binary logistic or linear regression, as appropriate, controlling for sex, age, and Charlson Comorbidity Index. Outcome measurements included radiographic healing, range of motion, postoperative complications, and reoperation. The cohort had a mean follow-up of 16.7 months. Mean coronoid fragment area was 362.4±155.9 mm². Elbow range of motion decreased by 3.8° of elbow flexion (P<.001), 3.3° of elbow extension (P<.001), and 3.8° of forearm supination (P=.007) for every 1-cm² increase in coronoid fragment area. Complications (P=.012) and reoperation (P=.036) were associated with increasing coronoid fragment area. Nonunion rate, nerve injury, and pronation range of motion were not correlated to increasing coronoid fracture fragment area (P=.777, P=.123, and P=.351, respectively). As displaced coronoid fragment size increases in Monteggia fracture patterns, elbow range of motion decreases linearly. Coronoid displacement was also associated with increased rates of postoperative complication and need for reoperation. [Orthopedics. 2024;47(1):15-21.].

Inflammation can play a role in the pathophysiology of depression, and specific types of antidepressants may have inflammatory or anti-inflammatory properties. Furthermore, depression and antidepressant use has been linked to white blood cell (WBC) count, a routinely measured inflammatory marker. We examined the cross-sectional and longitudinal relationships of depressive symptoms and/or antidepressant use with WBC count among postmenopausal women. Analyses of cross-sectional data at enrollment were performed on 125,307 participants, 50-79 years of age, from the Women's Health Initiative Clinical Trials and Observational Studies who met eligibility criteria, and a subset of those with 3-year follow-up data were examined for longitudinal relationships. Depressive symptoms were defined using the Burnam Algorithm whereas antidepressant use was defined using therapeutic class codes. WBC count (Kcell/ml) was obtained through laboratory evaluations of fasting blood samples. Multivariable regression modeling was performed taking sociodemographic, lifestyle and health characteristics into consideration. At enrollment, nearly 85% were non-users of antidepressants with no depressive symptoms, 5% were antidepressant users with no depressive symptoms, 9% were non-users of antidepressants with depressive symptoms, and 2% were users of antidepressants with depressive symptoms. In fully-adjusted models, cross-sectional relationships were observed whereby women in the 2^nd (OR = 1.06, 95% CI: 1.01, 1.13), 3^rd (OR = 1.06, 95% CI: 1.00, 1.12) or 4^th (OR = 1.10, 95% CI: 1.05, 1.17) quartiles of WBC count were more likely to exhibit depressive symptoms, and women in the 4^th quartile were more likely to be users of antidepressants (OR = 1.07, 95% CI: 1.00, 1.15), compared to women in the 1^st quartile. Compared to women who exhibited no depressive symptoms at either visit, those with consistent depressive symptoms at enrollment and at 3-year follow-up had faster decline in WBC count (β = -0.73, 95% CI: -1.33, -0.14) over time. No significant bidirectional relationships were observed between changes in depressive symptoms score and WBC count over time. In conclusion, depressive symptoms and/or antidepressant use were cross-sectionally related to higher WBC counts among postmenopausal women. Further evaluation of observed relationships is needed in the context of prospective cohort studies involving older adult men and women, with repeated measures of depression, antidepressant use, and WBC count.

Pathways explaining racial/ethnic and socio-economic status (SES) disparities in white matter integrity (WMI) reflecting brain health, remain underexplored, particularly in the UK population. We examined racial/ethnic and SES disparities in diffusion tensor brain magnetic resonance imaging (dMRI) markers, namely global and tract-specific mean fractional anisotropy (FA), and tested total, direct and indirect effects through lifestyle, health-related and cognition factors using a structural equations modeling approach among 36,184 UK Biobank participants aged 40-70 y at baseline assessment (47% men). Multiple linear regression models were conducted, testing independent associations of race/ethnicity, socio-economic and other downstream factors in relation to global mean FA, while stratifying by Alzheimer's Disease polygenic Risk Score (AD PRS) tertiles. Race (Non-White vs. White) and lower SES predicted poorer WMI (i.e. lower global mean FA) at follow-up, with racial/ethnic disparities in FA_mean involving multiple pathways and SES playing a central role in those pathways. Mediational patterns differed across tract-specific FA outcomes, with SES-FA_mean total effect being partially mediated (41% of total effect = indirect effect). Furthermore, the association of poor cognition with FA_mean was markedly stronger in the two uppermost AD PRS tertiles compared to the lower tertile (T₂ and T₃: β±SE: -0.0009 ± 0.0001 vs. T₁: β±SE: -0.0005 ± 0.0001, P < 0.001), independently of potentially confounding factors. Race and lower SES were generally important determinants of adverse WMI outcomes, with partial mediation of socio-economic disparities in global mean FA through lifestyle, health-related and cognition factors. The association of poor cognition with lower global mean FA was stronger at higher AD polygenic risk.

OBJECTIVE/UNASSIGNED:The objective of this review is to discuss acid-base physiology, describe the essential steps for interpreting an arterial blood gas and relevant laboratory tests, and review the 4 distinct types of acid-base disorders. DATA SOURCES/UNASSIGNED:A comprehensive literature search and resultant bibliography review of PubMed from inception through March 7, 2023. STUDY SELECTION AND DATA EXTRACTION/UNASSIGNED:Relevant English-language articles were extracted and evaluated. DATA SYNTHESIS/UNASSIGNED:Critically ill patients are prone to significant acid-base disorders that can adversely affect clinical outcomes. Assessing these acid-base abnormalities can be complex because of dynamic aberrations in plasma proteins, electrolytes, extracellular volume, concomitant therapies, and use of mechanical ventilation. This article provides a systematic approach to acid-base abnormalities which is necessary to facilitate prompt identification of acid-base disturbances and prevent untoward morbidity and mortality. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE/UNASSIGNED:Many acid-base disorders result from medication therapy or are treated with medications. Pharmacists are uniquely poised as the medication experts on the multidisciplinary team to assist with acid-base assessments in the context of pharmacotherapy. CONCLUSION/UNASSIGNED:The use of a systematic approach to address acid-base disorders can be performed by all pharmacists to improve pharmacotherapy and optimize patient outcomes.