Faculty Bibliography

PURPOSE/OBJECTIVE:The dependence of the long-time (tortuosity) limit of the extra-cellular diffusivity on the intra-cellular volume fraction is of fundamental importance for microstructure modeling. While such dependencies have been explored for the white matter, the tortuosity limit in gray matter is unknown due to complex cell composition and geometry. Here we rationalize and validate numerically the analytical relation between the extra-cellular diffusivity and intra-cellular fractions of cell bodies (somas) and neurites. METHODS:The tortuosity relation for extra-cellular diffusivity qualitatively follows from effective medium theory, coarse-grained by diffusion outside somas (spheres) and neurites (cylinders), respectively. This problem is equivalent to finding the overall conductivity in a medium of grains in a matrix, with methodology dating back to the 19th century. We extend the effective medium methodology to populations of impermeable spheres and randomly oriented cylinders with various volume fractions, yielding closed-form expressions corroborated by Monte Carlo simulations. RESULTS:We establish the power-law scaling of the extra-cellular diffusivity with the volume fractions of the extra-soma and extra-neurite spaces. We further evaluate the proposed framework using simulations in realistic tissue geometries, and by applying it to in vivo MRI data. CONCLUSION/CONCLUSIONS:Theory and simulations relate extra-cellular tortuosity to soma and neurite fractions, thereby offering a diffusion MRI protocol design optimized for in vivo assessment of soma size and soma/neurite fractions within clinical scan times. Such in vivo measurements can be used to study development, aging, and neurodegenerative disorders.

PURPOSE/UNASSIGNED:We report long-term follow-up on participants in the QUILT-3.032 study in BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) carcinoma in situ (CIS) +/- papillary disease utilizing nogapendekin alfa inbakicept (NAI) approved by the FDA (ANKTIVA) in combination with BCG. MATERIALS AND METHODS/UNASSIGNED:Participants received 400 mcg NAI in combination with 50 mg BCG via intravesical instillation weekly for six weeks, with optional re-induction if complete response (CR) was not achieved at month 3. Primary endpoints were CR rate at any time; secondary endpoints were duration of CR (DOR), progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS), and time to cystectomy. RESULTS/UNASSIGNED:The CR rate (n=100) was 71% (95% CI, 61.1, 79.6) with a median DOR of 26.6 months (range, 0.03-53.62). The cystectomy-free rate (CFR) in the 71 responders at 24- and 36-months was 90.3% (95% CI 79.7, 95.6) and 84.2% (95% CI 69.6, 92.1), respectively. DSS was 100% (95% CI 100.0, 100.0) at 12-months, and 98.2% (95% CI 88.2, 99.8) at 36-months. Treatment-related adverse events (TRAE) were largely grade 1 to 2 (61%), with 3% grade 3 and no grade 4 or 5 TRAE observed with this biological combination. CONCLUSIONS/UNASSIGNED:The CR rate and durability of responses that surpass 53 months reveal the efficacy of NAI in combination with BCG for treating BCG-unresponsive NMIBC with CIS +/- Ta/T1 disease. The high CFR of 84% and DSS of 98% at 36-months suggest that NAI plus BCG is a safe and efficacious option for NMIBC with CIS +/- Ta/T1 disease.

BACKGROUND/UNASSIGNED:Predominantly Dorsal Thoracic Spinal Arachnoid Webs (DAW/SAW: 90%-100%), attributed to arachnoidal scarring obstructing cerebrospinal fluid (CSF) dynamics, typically cause dorsal cord compression. Their multiple etiologies include; trauma, idiopathic/post-surgical, inflammatory/infection, subarachnoid hemorrhage, and/or congenital defects. METHODS/UNASSIGNED:Patients with DAW/SAW are typically in their early/mid-fifties, and present with; back pain (i.e., 41.2%-88.9%), motor deficits (i.e. 59%-77.8%), sensory loss (i.e., numbness 65%-66.7%), and/or sphincter dysfunction (i.e., 33.3%). RESULTS/UNASSIGNED:MR and Myelo-CT studies for DAW/SAW classically demonstrate the positive scalpel sign (i.e., single or multilevel dorsally compressive "fluid" collections often containing multiple loculations/fenestrations usually accompanied by Syrinxes (i.e., 44 - 83%), and/or Spinal Arachnoid Cyst (SAC) formation. Conservative treatment is rarely effective. Alternatively, surgery consisting of laminectomy/decompression, resection/ lysis, marsupialization and/or fenestration of loculated collections including attendant SAC resections, and decompression/shunting of Syrinxes, results in postoperative improvement in up to 91% of patients. CONCLUSION/UNASSIGNED:Patients with DAW/SAW typically present with MR/Myelo-CT studies that demonstrate the dorsal thoracic positive scalpel sign in conjunction with Syrinxes, and/or SAC. Surgery typically includes laminectomy/ decompression, lysis/resection of arachnoidal adhesions with marsupialization/fenestration, and/or shunting, to achieve up to a 91% incidence of postoperative neurological improvement.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common conditions among patients with cirrhosis whose development is associated with increased morbidity and mortality. Recurrent episodes of AKI within this population can ultimately lead to CKD, while patients with underlying CKD are in turn more likely to experience AKI. Determining the etiology of kidney dysfunction in the setting of cirrhosis is often challenging given the considerable limitations of currently available diagnostic tools. Ongoing research into the role of novel serum and urine biomarkers may allow for more timely diagnosis and treatment of kidney injury among patients with cirrhosis. This review provides an overview of kidney dysfunction in cirrhosis with a focus on the role of these emerging biomarkers for diagnosis of AKI and CKD.

PURPOSE/OBJECTIVE:To evaluate the effect of baseline dementia on postoperative outcomes in hip fracture patients undergoing hemiarthroplasty. METHODS:A retrospective review was conducted of patients aged 55 years or older who underwent hemiarthroplasty for displaced femoral neck fracture (AO/OTA 31B) between 2012 and 2024 at a large urban academic institution. Dementia was identified by ICD-10 codes and confirmed by chart review. A 3:1 propensity score matched cohort was created using the Score for Trauma Triage in Geriatric and Middle-aged (STTGMA). Demographics and baseline characteristics were compared to ensure similarity. Outcomes included total complications, major and minor complications, periprosthetic dislocation, length of stay, ICU admission, discharge location, 30- and 90-day readmission, revision surgery, inpatient, and 30-day and 1-year mortality. RESULTS:A total of 1,030 patients were included, with 241 patients with dementia and 839 controls. After 3:1 STTGMA propensity matching, baseline characteristics were comparable (mean age 82.75 vs. 83.0 years, P = 0.065; Charlson Comorbidity Index 1.96 vs. 1.92, P = 0.42; STTGMA 0.022 vs. 0.020, P = 0.50). Patients with dementia had increased major complications (17.92% vs. 10.93%, P = 0.013), including sepsis (5.00% vs. 2.21%, P = 0.027), urinary tract infections (13.33% vs. 6.78%, P = 0.002), and hip hemiarthroplasty dislocations (6.25% vs. 2.21%, P = 0.002). Patients with dementia also had longer length of stay (7.84 ± 5.83 vs. 6.80 ± 2.24 days, P = 0.030), increased 30-day readmissions (15.83% vs. 8.85%, P < 0.001), increased 90-day readmission (20.00% vs. 11.76%, P < 0.001), and higher 1-year mortality (16.25% vs. 8.02%, P < 0.001). No differences were observed in pneumonia, stroke, myocardial infarction, cardiac arrest, venothromboembolism, acute kidney injury, anemia, and revision surgery. CONCLUSION/CONCLUSIONS:Dementia was associated with increased major complications, hip hemiarthroplasty dislocations, higher readmission, and mortality after hemiarthroplasty. These findings highlight the need for targeted perioperative planning and multidisciplinary care pathways in cognitively impaired patients.

The September 11, 2001, terrorist attacks on the World Trade Center (9/11) exposed both disaster responders and community members to a complex mixture of environmental contaminants, resulting in long-term health consequences. While clinical and research efforts have characterized health effects among adult survivors (community members) and responders, less is known about individuals who were exposed in utero, during childhood, adolescence, or young adulthood. Recognizing this gap, Congress amended the Public Health Service Act (42 U.S.C. § 300mm-51(c)) to establish a Research Cohort for Emerging Health Impacts on Youth to promote research on those individuals who were 21 years of age or younger at the time of exposure. This Commentary reviews the historical development of post-9/11 monitoring, treatment, and research programs, and discusses the unique challenges of conducting research in such a youth cohort 25 years after the event. A central coordinating center supported by community-based field sites offers a promising approach to promoting research among this cohort and addressing critical gaps in understanding the lifelong impacts of 9/11 exposures.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia. METHODS:The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date. RESULTS:Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups. DISCUSSION/CONCLUSIONS:Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.

BACKGROUND:Anatomical variants of the anterior cerebral artery (ACA) may increase technical complexity during endovascular treatment of distal ACA aneurysms (DACA). However, their impact on treatment outcomes remains unclear. This study evaluated whether ACA variants influence angiographic and clinical outcomes following endovascular treatment. METHODS:A retrospective multicenter analysis was conducted using data from the CRETA Registry, including patients with ruptured and unruptured DACA treated endovascularly. Patients were grouped according to ACA anatomy (variant vs. conventional). Outcomes were compared after propensity score matching (PSM) to adjust for confounders including age, aneurysm rupture status, dome-to-neck ratio, branch origin, and treatment type. The primary outcome was aneurysm occlusion at last follow-up based on the Raymond-Roy classification. Secondary outcomes included ischemic and hemorrhagic complications, vasospasm, and clinical outcome measured by the modified Rankin Scale (mRS). RESULTS:After PSM, 128 patients were included (64 per group). Among patients with available imaging follow-up (54 in the conventional group and 55 in the variant group), adequate occlusion rates were comparable between the variant and conventional ACA groups (81.5% vs. 85.5%; p = 0.600). No significant differences were observed in ischemic or hemorrhagic complications, vasospasm, or long-term clinical outcomes. Sensitivity analyses confirmed the robustness of the findings. CONCLUSIONS:ACA anatomical variants do not adversely affect the safety or efficacy of endovascular treatment for DACA. With appropriate anatomical assessment and treatment selection, endovascular therapy remains effective even in the presence of complex ACA configurations.

Immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) have improved survival for patients with early-stage NSCLC who are candidates for surgical resection. ICIs enhance antitumor responses and improve a variety of perioperative outcomes when used in the neoadjuvant, adjuvant, or perioperative setting. This review summarizes immunotherapies currently approved for neoadjuvant, adjuvant, and perioperative treatment of resectable NSCLC and the supporting evidence for approval. Gaps in data and future areas of clinical interest of using immunotherapies to maximize survival outcomes are also discussed.