Citations

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Introduction Endovascular abdominal aortic aneurysm repair (EVAR) is the primary treatment for abdominal aortic aneurysm (AAA). Despite favorable early outcomes, lifelong surveillance is essential as endoleaks remain a major cause of reintervention. Among these, type II endoleaks (T2E) remain controversial regarding optimal management. This study aimed to identify factors associated with intervention for T2E using time-to-event analysis and predefined anatomic thresholds. Secondary objectives included comparing outcomes between T2E patients with (intT2E) and without (nointT2E) intervention. Methods A retrospective review of EVAR procedures from 2011-2024 was performed. Patients with newly diagnosed or persistent T2E were identified on completion and follow-up CT angiography. Patients were categorized as intT2E or nointT2E. Multivariable Cox regression evaluated time to first intervention, and logistic regression served as sensitivity analysis. Kaplan-Meier curves assessed freedom from intervention by inferior mesenteric artery (IMA) size. Results Among 207 EVAR patients, 78 (37.6%) developed T2E over a mean 3.4 ± 2.4 years. Nineteen (24.3%) required intervention. IntT2E patients were younger (74.9 ± 6.8 vs 78.3 ± 7.9 years, P = 0.02), had more frequent anticoagulation use (47.4% vs 20.3%, P = 0.02), larger IMAs (4.2 ± 0.6 vs 3.3 ± 0.7 mm, P < 0.01), and more lumbar arteries (6.0 ± 1.2 vs 5.0 ± 1.3, P = 0.02). IMAs >4 mm occurred in 68.4% of intT2E vs 8.5% of nointT2E ( P < 0.01). Mean sac growth was greater in intT2E (9.7 ± 5.3 mm vs −1.9 ± 6.5 mm, P < 0.01). Thirty-day complications following the index EVAR procedure, mid-term reinterventions, and overall mortality were similar between groups. Post-embolization, T2E resolved in 36.9%, with sac regression in 63.1%. Among embolized patients, 26.3% required a second embolization and one patient required 3 attempts without achieving resolution. IMA >4 mm independently predicted intervention (HR 7.18, 95% CI 1.97-26.16, P < 0.01). Logistic regression confirmed IMA >4 mm (OR 23.4, 95% CI 6.17-88.6, P < 0.01), >6 lumbar arteries (OR 4.2, 95% CI 1.10-15.98, P = 0.02), and anticoagulation (OR 3.4, 95% CI 1.17-10.6, P = 0.02) as predictors. Conclusions Approximately one-quarter of T2E patients required embolization. IMA >4 mm was the strongest predictor of intervention, while anticoagulation and increased lumbar artery number also increased risk. Management should prioritize risk-stratified surveillance and selective intervention.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Background: Several special tests for detecting medial ulnar collateral ligament (MUCL) injuries of the elbow have been described, but data on the clinical utility of these tests are limited. Purpose: To determine the clinical utility of selected elbow special tests to detect MUCL injuries in an athletic population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 84 consecutive patients with sports-related elbow pain underwent a standardized clinical examination. Overall, 6 special tests (moving valgus stress test, static valgus stress test, modified valgus stress test, milking maneuver, pronation flexion resistance test, and temple/cheek press test) were performed. Sensitivity, specificity, accuracy, positive/negative predictive value, and positive/negative likelihood ratio (LR+ and LR–, respectively) were calculated for individual tests and combinations of tests to detect MUCL injuries. Higher values for the LR+ and lower values for the LR– represent stronger clinical utility. Results: For detecting MUCL injuries, the moving valgus stress test resulted in the highest sensitivity (98%) and accuracy (93%) with the lowest LR– (2%). The milking maneuver had the highest LR+ (5.1) with the second highest sensitivity (77%) and accuracy (79%). The pronation flexion resistance test and the temple/cheek press test had the lowest LR+ (1.5 and 1.8, respectively) and highest LR– (94% and 95%, respectively) in addition to the lowest sensitivity (16% and 9%, respectively) and accuracy (33% and 30%, respectively). No combination of tests resulted in increased clinical utility. Conclusion: The moving valgus stress test and milking maneuver demonstrated acceptable clinical utility in which the moving valgus stress test was better for ruling out MUCL injuries and the milking maneuver was better at ruling in MUCL injuries. There was no added value when combining the 2 tests together or with other maneuvers.

Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

Among patients with treatment-naive hepatocellular carcinoma, glass microsphere radiation segmentectomy before liver transplant achieved high rates of complete pathologic necrosis, which was positively associated with the number of optimized treatment parameter thresholds.

ABSTRACT Objective To evaluate intracochlear electrocochleography (ECochG) amplitude parameters during cochlear implantation (CI) using a novel multi‐frequency ECochG algorithm. Methods A multi‐institutional, prospective cohort study was performed at 18 high‐volume CI centers. The inclusion criteria were adults with sensorineural hearing loss and audiometric thresholds of ≤ 90 dB hearing level at 500 Hz undergoing CI with Advanced Bionics (Valencia, CA) Ultra 3D devices between 2024 and 2025. ECochG recordings were performed with simultaneous multi‐frequency stimulation of four frequencies between 125 and 4000 Hz during cochlear implant insertion. Concurrent multi‐frequency recording allowed extraction of amplitude and phase of each frequency individually. Post hoc analysis was performed to determine the difference in the number of drop alarms between single‐ and multi‐frequency ECochG. An ECochG amplitude drop of 6 dB was defined as a drop alarm. Insertion track patterns were compared between single‐ and multi‐frequency ECochG. Results One hundred ninety‐five ears were included. Mean number of drop alarms for the single‐frequency algorithm was 1.72 (95% CI: 1.52, 1.92; median 1) compared to 0.42 (95% CI: 0.31, 0.53; median 0) for multi‐frequency; p < 0.001. The number of Type C patterns (rise in amplitude during insertion followed by a drop) decreased with the multi‐frequency ECochG algorithm compared to the single‐frequency ECochG algorithm. The number of Type D patterns (no‐response) decreased, indicating that multi‐frequency ECochG generated more responses across the cochlea than single‐frequency ECochG. Conclusions A novel multi‐frequency ECochG algorithm during CI is associated with fewer drop alarms and altered insertion track patterns, which may provide a more accurate assessment of the cochlear microenvironment. Level of Evidence 3.

Background Strengthening emergency care systems could reduce death and disability in low- and middle-income countries (LMICs), yet many struggle to provide timely, high-quality care. LMICs also face growing risks from climate-related shocks and mass casualty events. This study identifies unmet emergency care needs in Nepal—one of the world’s most climate-vulnerable countries—using high-resolution geospatial data to estimate socioeconomic and climate-related inequalities. Methods We conducted a cross-sectional geospatial analysis using data from the 2022 Nepal Demographic and Health Survey (DHS), the 2021 DHS Service Provision Assessment and publicly available climate vulnerability data. Government hospitals were classified into three emergency care levels using World Health Organzation criteria: A (basic 24-hour services), B (A plus resuscitative capabilities) and C (B plus ≥50 beds and a surgeon). Household location and injury data were obtained from the DHS. Accessibility was defined as the proportion of the population within 1-hour and 2-hour travel times, estimated using AccessMod 5.8, incorporating road networks, rivers, land cover and elevation. Findings Most public hospitals (77.7%) met Level A criteria but only 49.3% met Level B and 10.8% met Level C. Nationally, 78.7% of households had 1-hour access to Level A care, 71.8% to Level B and 44.6% to Level C. Adjusted logistic regression showed rural, poorer and climate-vulnerable households had significantly lower 1-hour access compared with urban households, rural households had lower odds of access: Level A OR: 0.33 (95%CI 0.30 to 0.37), Level B OR: 0.33 (95%CI 0.30 to 0.36), Level C OR: 0.56 (95%CI 0.51 to 0.61). Households in high climate vulnerability areas had reduced access across all levels. Conclusions Substantial gaps and inequities in timely access to high-quality emergency care exist in Nepal. Rural, poorer and climate-vulnerable populations experience markedly lower access. Targeted, decentralised strengthening of emergency care capacity is essential both in Nepal and in other LMICs facing similar constraints.

Background: Contemporary data on trends in survival after incident atrial fibrillation (AF) are limited. Methods: Residents of a 27-county area in southern Minnesota and western Wisconsin with new-onset atrial fibrillation or atrial flutter between 2013 and 2023 were identified. An electronic algorithm requiring 1 inpatient code or 2 outpatient codes separated by >7 days but within 1 year was used to define AF. Patients were followed for all-cause mortality through March 31, 2025. Standardized mortality ratios of observed versus expected survival were calculated, and time trends in survival were examined using Cox regression adjusting for demographics, cardiovascular risk factors, comorbid conditions, and area-level measures of socioeconomic status and rurality. Results: There were 44,930 individuals identified with incident AF from 2013-2023 (56.4% male; mean (SD) age 72.8 (13.5) years; 95.8% were non-Hispanic white). Within the first 90 days, the risk of all-cause mortality was greatly elevated compared with individuals of a similar age and sex distribution in the general population (standardized mortality ratios 12.6, 95% CI, 12.1-13.0 and 3.8, 95% CI, 3.6-4.0 for the first 30 days and 31 to 90 days after diagnosis, respectively). This excess risk was observed for all age groups but was greatest in the youngest age group (standardized mortality ratios among 18-64 year olds for the first 30 days: 49.9, 95% CI, 44.6-55.7 and 31 to 90 days: 11.1, 95% CI: 9.4-13.1; Figure ). In the youngest age group, the excess risk persists through 5 years post AF, however, in the oldest age group the excess risk only persisted through 1 year. Survival within the first 90 days improved over the study period (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.79-0.99 for 2023 vs 2013); likewise, among 90-day survivors, survival improved between 2013 and 2023 (aHR,0.82; 95% CI, 0.76-0.88). These trends were driven by improvements in the younger age groups, particularly for death among 90-day survivors (aHR for 18-64 years, 0.66, 95% CI, 0.52-0.83; 65-74 years: 0.77, 95% CI: 0.65-0.90; 75-84 years, 0.84, 95% CI: 0.75-0.95; 85+ years, 0.99, 95% CI: 0.98-1.01). Conclusion: In a Midwestern community, the excess risk of death is high within the first 90 days after incident AF. Furthermore, survival after AF has improved between 2013 and 2023, with the improvement greatest in younger age groups.

ABSTRACT Background Cytomegalovirus (CMV) infection remains one of the most prevalent and consequential post solid organ transplant (SOT) infections. Treatment is often challenging, especially when dealing with refractory and resistant CMV infections. Methods We performed a retrospective multicenter cohort study of SOT recipients with clinically significant CMV infection (csCMVi) during 2010–2016. The primary outcome was early refractory CMV infection and secondary outcomes were drug resistance, CMV recurrence, and mortality. Analysis was done with Kaplan‐Meier, univariable logistic regression analysis, and multivariable Cox regression. Results We included 145 SOT recipients with csCMVi, majority were liver transplant (49%). Most common induction was an anti‐IL‐2 antibody (43.9%). The majority ( n = 82; 56.5%) were CMV D+/R‐ mismatch and presented asymptomatic infection (50.3%). After the initial 3 weeks of antiviral therapy, 13 (8.9%) patients had probable refractory csCMVi; most of them (10 [76.9%]) were CMV D+/R‐ mismatch. Longer time after transplant had lower risk (OR 0.68; CI 0.48–0.95, p = 0.029) while lower absolute lymphocyte count (ALC) had a higher risk of early refractory csCMVi (OR 1.54; CI 1.01–2.44, p = 0.048). Drug‐resistant csCMVi occurred in 7 patients (4.8%); a high initial CMV DNA level was associated with resistant csCMVi (OR 2.00; CI 1.08–3.93, p = 0.031). 25 patients (17.2%) experienced recurrent csCMVi within 6 months. 30 patients (20.7%) died; refractory, resistant or recurrent CMV infections were not associated with mortality. Conclusion Refractory csCMVi is associated with a low ALC and an earlier onset after transplant. Resistant csCMVi is associated with high initial CMV DNA levels. Recurrence of csCMVi is common and potentially associated with low ALC at the end of antiviral treatment.