Citations

Abstract Background Acute kidney injury (AKI) frequently causes remote organ injury including hepatic steatosis, yet whether lipid accumulation reflects increased synthesis or impaired clearance has not been resolved. Methods We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24 hours after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two ICU databases (MIMIC-IV and eICU-CRD). Results AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (Scd1, Fasn, Acly, Acaca) were uniformly suppressed rather than upregulated. Proteins essential for VLDL assembly (ApoB, MTTP, ApoE) were significantly downregulated. Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR = 4.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. Conclusions These data support ER stress-mediated impairment of VLDL export as a primary driver of AKI-induced hepatic steatosis. Clinical validation across two independent ICU databases identifies a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury.

Objective(s): To (1) report on the long-term recurrence rate of surgically managed pleomorphic adenoma (PA) and (2) assess long-term surgical outcomes after parotidectomy Methods: Cross-sectional survey of all patients with a pathologic diagnosis of PA who underwent surgical management in a tertiary care center from 01/1997 to 12/2023 and had access to an electronic patient portal. Surveys were delivered via electronic patient portal or phone call with 6 questions to assess recurrence and long-term surgical outcomes. Time to first recurrence and recurrence free survival were analyzed using a Kaplan-Meier curve. Results: Seven hundred-forty-five patients met inclusion criteria and received the survey, with a 56% response rate (n = 420). The clinical median follow-up length was 51 days, which extended to a median length of 6.2 years following the survey. The median change in follow-up length was 5.37 years ( P < .001). The recurrence rate was 1% at 5 years, with a median time to first recurrence of 7.54 years. 13% and 9% of responders reported facial asymmetry and incisional cosmetic concerns, respectively. 33% of patients reported experiencing Frey syndrome, which increased from 5.2% of survey responders with documented Frey syndrome at their original post-operative assessment. Conclusion: Long-term assessment of PA outcomes confirms low recurrence rates, suggesting regular surveillance of recurrence is likely unnecessary. Complaints of Frey syndrome increased in frequency with longer term follow-up, which should be considered during patient counseling. Level of Evidence: 3

IgG4-related disease (IgG4-RD) is a relatively recently described condition whose etiology and pathophysiology remain unclear. Histopathological features include dense lymphoplasmacytic tissue infiltration with numerous IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Most individuals with IgG4-RD are asymptomatic; however, the disease can affect nearly any organ, leading to a wide range of clinical presentations. The four most common patterns are hepatopancreatobiliary disease, systemic disease, head and neck disease, and retroperitoneal disease. Diagnosis is challenging due to diverse organ involvement and is most often confirmed by biopsy. Elevated serum IgG4 concentration can support the diagnosis, though high IgG4 levels are neither highly sensitive nor specific for IgG4-RD. Immunohistochemical IgG4 staining is crucial, especially in patients without elevated serum IgG4. Differential diagnosis is necessary, as IgG4+ plasma cell infiltration is also seen in inflammatory and malignant conditions. First-line treatment consists of glucocorticoids (prednisone), although favorable outcomes have also been achieved with rituximab. Prognosis varies: the disease may resolve spontaneously or follow a relapsing–remitting course. If left untreated or undertreated, IgG4-RD can cause irreversible organ damage and even death. Finally, correlations have been made between IgG4 and different allergic reactions.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Aptamers are short single-stranded DNA or RNA ligands that fold into defined three-dimensional structures and bind targets with antibody-like affinity and specificity, yet retain key advantages for central nervous system (CNS) applications including chemical synthesis, low immunogenicity, thermal stability, and facile modular engineering. This review summarizes recent advances positioning aptamers as “theranostic” platforms for CNS disorders, spanning discovery, optimization, delivery, and integrated sensing. We highlight the evolution of selection technologies from classical protein-‘Systematic Evolution of Ligands by Exponential Enrichment’ (SELEX) to Cell-SELEX and in vivo SELEX, now increasingly coupled with high-throughput sequencing, bioinformatics, molecular docking/molecular dynamics, and emerging artificial intelligence/machine learning (AI/ML) approaches that learn sequence–structure–function relationships and accelerate candidate prioritization and de novo design. We discuss chemical strategies that address nuclease degradation and rapid renal clearance, while noting trade-offs between stability and folding-dependent affinity. Since blood–brain barrier (BBB) transport remains the dominant translational barrier, we evaluate non-invasive intranasal delivery, receptor-mediated transcytosis via endothelial shuttles, intrathecal administration, and vector-enabled intracellular expression for sustained neuroimmune modulation. Finally, we discuss multifunctional conjugates and carriers and CNS-focused aptamer-based sensors for neurotransmitters and misfolded proteins, alongside multiplexed aptamer proteomics for biomarker discovery and monitoring. Collectively, converging advances in selection, computation, chemistry, and delivery are enabling aptamer-based closed-loop theranostics tailored to CNS disease biology.

ABSTRACT Pulmonary arterial hypertension (PAH) is associated with significant symptoms and impaired health‐related quality of life (HRQOL) and survival. Specialty palliative care (SPC), an intervention delivered by a multidisciplinary team, is focused on improving HRQOL. We performed a randomized controlled trial (RCT) of SPC among adults with PAH and impaired HRQOL to determine the impact of SPC on HRQOL as assessed by PAH‐SYMPACT. PAH‐SYMPACT is a validated PAH disease‐specific patient‐reported outcome measure that assesses HRQOL across four domains: cardiopulmonary symptoms, cardiovascular symptoms, physical impact, and cognitive/emotional impact. Sixty‐two patients were included (36 usual care, 26 SPC plus usual care), but only 58% of patients randomized to SPC completed their SPC visits. In the intention‐to‐treat analysis, SPC was associated with similar changes in total, symptom, and physical impact domain scores and increased cognitive/emotional impact scores, indicative of worse HRQOL. In the per‐protocol analysis, SPC was not associated with significant changes in total or individual domain scores. According to a survey of patients who completed SPC visits, most were satisfied with their visit and were likely to recommend SPC for other patients with PAH. In conclusion, limited SPC visits in this single‐center RCT were not associated with significant improvements in HRQOL among patients with PAH and impaired HRQOL, but the majority of patients who participated in a SPC intervention were satisfied and would recommend SPC to other PAH patients. Future studies of SPC in PAH are needed to determine the appropriate patient selection and timing for SPC. www.clinicaltrials.gov (NCT03905421).

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract INTRODUCTION Research into cognitive dispersion – a cognitive process score measuring the intra‐individual variability (IIV) across a single testing session – suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early‐onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition. METHODS A total of 309 participants (188 amyloid‐positive EOAD, 43 amyloid‐negative early‐onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion‐related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain‐specific cognitive trajectories, and its convergence with imaging biomarkers. RESULTS EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD‐specific biomarkers. Additionally, cognitive dispersion was associated with 12‐month reliable change across several cognitive domains. DISCUSSION These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.

Objective: To compare disease-specific quality of life (QOL) among patients with sporadic vestibular schwannoma (VS) by tumor management strategy using the recently developed and validated Mayo Clinic VSQOL Index relative to established minimal important difference (MID) thresholds. Study design: Cross-sectional cohort. Setting: Acoustic Neuroma Association and tertiary care center. Patients: Adults with sporadic VS. Interventions: Microsurgery, radiation, or observation. Main outcome measures: VSQOL Index scores were compared by tumor management strategy adjusting for age, sex, setting, tumor size at diagnosis, and duration of follow-up. Scores range from 0 to 100; higher scores indicate better QOL. Results: Of the 652 patients included, 333 (51%) were managed with microsurgery, 175 (27%) with radiation, and 144 (22%) with observation. The mean (SD) duration of follow-up was 6.2 (2.7) years. Global QOL adjusted mean scores (95% CI) differed significantly ( P <0.001) by management group: 70 (67-72) for microsurgery, 73 (70-77) for radiation, and 79 (75-83) for observation. Hearing Problems ( P <0.001), Dizziness and Imbalance ( P <0.001), Problems with Face or Eyes ( P <0.001), and Difficulty with Thinking and Memory ( P =0.03) domain scores also differed significantly by group. Pairwise comparisons that exceeded at least the lower bound of published MIDs included Global QOL scores (microsurgery versus observation) and Hearing Problems scores (microsurgery and radiation versus observation). Conclusions: At a mean follow-up of 6.2 years, several notable statistically and clinically significant differences in QOL were identified. These findings may be used to guide patient counseling regarding management options and require validation in future prospective studies.