Publications by Year: 2025

More than 50% of patients with kidney failure undergoing maintenance hemodialysis die within 5 years, a fate unexplained by traditional risk factors. To identify biological risk factors, we analyze 6287 circulating proteins and mortality in 893 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort (CRIC) and Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) studies. Proteins are measured shortly after (incident period) and one year after (prevalent period) dialysis initiation. In CRIC prevalent period, Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), R-spondin 4, tetranectin and 24 other proteins attain Bonferroni significance (p < 7 × 10-6). At false discovery rate<0.05, 184 proteins are significant in CRIC; 123/184 remain significant after adjustment for covariates including those linked to inflammation. Pathways related to insulin-like growth factor are prominent. In the pooled CRIC + PACE cohort, prevalent time period, AUC(95%CI) for a 3-protein model of 5-year mortality is 0.826 (0.742, 0.896), compared to 0.629 (0.528, 0.722) for a Cohort Clinical model (p < 0.001). Adding the 3 proteins (SVEP1, R-spondin 4 and tetranectin) to the Cohort Clinical model significantly improves the AUC (p < 0.001). These biomarkers should be validated in future studies and their roles as potential disease mediators elucidated.

Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.

Value in health care is defined as optimized patient-centered outcomes and streamlined costs of care. A patient-level value analysis (PLVA) is a novel value-based health care research method. In a PLVA, the ratio of outcomes to cost is calculated for each individual patient in a cohort, and factors that optimize value are investigated. We performed a PLVA in primary total knee arthroplasty (TKA). We conducted a retrospective analysis of a prospectively maintained multi-institutional arthroplasty registry. A total of 2,789 primary manual TKAs were analyzed. Knee Osteoarthritis Outcome Score-Physical Function Short-Form (KOOS-PS) scores and costs of care using time-driven activity-based costing (TDABC) were collected. All costs were converted from U.S. dollars to arbitrary cost units (CUs) to protect confidential hospital financial data. The primary outcome was the value quotient (Value KOOS-PS), or the ratio of 1-year improvement in KOOS-PS to the cost of care, which was converted to a scale with a maximum of 100. Multivariable forward linear regression determined factors impacting value in primary TKA. The mean improvement in KOOS-PS was 15.2. The mean cost of care was 859 CUs. The largest contributors to cost were the implant cost (378 CUs, 44.0%) and intraoperative personnel cost (173 CUs, 20.1%). Patient and hospital factors independently correlated with improved TKA Value KOOS-PS included home discharge (adjusted mean difference: +7.8; p < 0.001), outpatient surgery (adjusted mean difference: +3.6; p < 0.001), lower preoperative KOOS-PS score (adjusted mean difference: +0.6; p < 0.001), lower Charlson Comorbidity Index (adjusted mean difference: +0.6; p = 0.006), and lower body mass index (BMI; adjusted mean difference: +0.2; p = 0.001). Using TDABC and patient-reported outcome measures, we performed a PLVA. We found that the largest contributor to the cost of care was the implant cost. The highest value TKAs occurred in an outpatient setting with home discharges, for patients with more severe preoperative knee symptoms, fewer comorbidities, and lower BMI. Surgeons and hospital administrators can use these findings to inform strategies to optimize value in TKA.

BACKGROUND: Anorexia nervosa (AN) in older adults presents with medical complexity, psychiatric comorbidity, and diagnostic ambiguity, often overlapping with depression, cognitive decline, or anorexia of aging. A literature base dominated by case reports limits practical guidance for consultation-liaison (C-L) psychiatry.

OBJECTIVE: To describe key clinical features of AN in older adults, integrating systems-level barriers that shape diagnosis, care transitions, and prognosis.

METHODS: We describe 2 late-life AN cases and conducted a systematic review of studies including adults aged ≥60 years with AN defined by the Diagnostic and Statistical Manual of Mental Disorders. Two reviewers independently screened and extracted data and appraised quality using Joanna Briggs Institute tools. Extracted variables included demographics, Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria, psychiatric and medical comorbidities, care setting, and outcomes. We used narrative synthesis with descriptive statistics like n/N, %, median (interquartile range), and ranges to summarize case reports. The AN course was categorized as late-onset (≥60 years), chronic diagnosed, chronic undiagnosed, or recurrence.

RESULTS: Forty publications met criteria: 31 case reports/series, eight cross-sectional studies, and one cohort. Cross-sectional studies showed 3-6% prevalence of disordered eating behaviors with rare AN. Across 47 individually described patients, most were women in their early seventies with severe undernutrition and multimorbidity. Care most commonly occurred on medical units. Nutritional rehabilitation (e.g., supervised meals, enteral feeding) was the most common intervention. Outcomes were mixed, with many patients achieving weight gain, but mortality remained substantial. System-level barriers, such as insurance coverage and access constraints, were not reported in the literature but were prominent in our 2 cases.

CONCLUSIONS: In older adults, AN is rare in population samples but severe when clinically detected. The review highlights diagnostic complexity, medical risk, limited psychotherapy/medication detail, and systems barriers central to consultation-liaison practice. Consultation-liaison psychiatrists play a key role in identifying and coordinating treatment for this complex population.

BACKGROUND: The ARIES-HM3 trial demonstrated the safety and effectiveness of aspirin elimination from the antithrombotic regimen after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. We explored the interaction of atrial fibrillation, diabetes mellitus, and obesity (AF/DM/Ob) with aspirin elimination on hemocompatibility-related adverse events at 1-year postimplant.

METHODS: This prospective, double-blind, placebo-controlled trial randomized patients with an HM3 LVAD implant to receive aspirin (100 mg/d) or placebo, in addition to a vitamin K antagonist. The primary endpoint was survival free of nonsurgical (>14 days postimplant) hemocompatibility-related adverse events, including stroke, pump thrombosis, bleeding, and arterial peripheral thromboembolism at 12 months. The composite endpoint and individual components were compared between the arms for those with and without AF/DM/Ob; responsiveness to aspirin was assessed by measurement of thromboxane-B2 level suppression.

RESULTS: Among the 589 patients who contributed to the primary endpoint analysis, 1 or more AF/DM/Ob comorbidities were present in 78% (461/589), distributed as AF (259/461), DM (240/461), and Ob (204/461). The presence of 1 or more AF/DM/Ob comorbidities did not influence the effect of aspirin elimination on the primary endpoint outcome (interaction P = .60); patients with all 3 comorbidities (44/589, 7.5%) receiving aspirin had a significantly greater rate of primary endpoint events (difference: 30.6%; 95% confidence interval, 2.2%-59.0%). There was no treatment heterogeneity between the subgroups. Nonsurgical bleeding events were reduced similarly in patients with or without AF/DM/Ob who received placebo versus aspirin with similar reductions in thromboxane-B2 levels.

CONCLUSION: Among ARIES-HM3 trial patients with AF/DM/Ob, no comorbidity, alone or in combination, altered the safety or observed effect size on bleeding reduction with aspirin elimination in patients implanted with the HM3 LVAD.

Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of LRRK2 status, PD was associated with nominally lower levels of inflammatory analytes in CSF, with minimal changes observed in serum. Correlation analyses revealed distinct immune profiles between serum and CSF, suggesting compartmentalized immune responses. These findings highlight immune alterations in LRRK2 mutation carriers and PD, providing potential serum markers for monitoring immune responses and avenues for mechanistic studies.

PURPOSE: To evaluate whether left-sided transjugular intrahepatic portosystemic shunt (L-TIPS) placement offers an advantage over conventional right-sided transjugular intrahepatic portosystemic shunt (R-TIPS) in cirrhotic patients with a history of Grade 1 hepatic encephalopathy (HE), specifically in lowering the incidence and progression of HE.

MATERIALS AND METHODS: This institutional review board (IRB)-approved, single-center retrospective study analyzed 25 consecutive patients who underwent L-TIPS creation between January 2016 and March 2023 who had a history of Grade 1 HE. Using 1:2 matching for 5 variables (pre-transjugular intrahepatic portosystemic shunt HE grades, albumin levels, stent size, Model for End-stage Liver Disease [MELD] score, and age), 50 patients who received R-TIPS were selected for comparison of procedural and clinical outcomes.

RESULTS: Of the 75 patients, there were 25 in the L-TIPS group (age, 58.4 years [SD ± 6.8]; 72% male) and 50 in R-TIPS group (age, 58.8 years [SD ± 8.4]; 66% male; P = .828 for age; P = .600 for sex). Rates of HE stage escalation after transjugular intrahepatic portosystemic shunt placement were not significantly different between groups (48% L-TIPS vs 38% R-TIPS; P = .562). The rate of medically refractory HE was 4% in the L-TIPS group and 0% in the R-TIPS group. There was no significant difference in the number of adverse events between the 2 groups (P = .802).

CONCLUSIONS: L-TIPS demonstrates a similar safety profile and similar rates of HE as R-TIPS in patients with pre-existing Grade 1 HE.