Citations

ABSTRACT Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi‐center retrospective cohort study to develop and validate a risk‐prediction model for early mortality (all‐cause death within 6 months) in patients treated with Dara‐based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6‐month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT‐proBN P > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), A ge > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on C ytogenetics (OR 3.0, p = 0.022), and E COG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6‐month mortality of 1.2% (low‐risk), 11.7% (intermediate‐risk), and 50.0% (high‐risk). The PACE score demonstrated superior discrimination (C‐index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C‐index 0.73) with corresponding 6‐month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara‐based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra‐high‐risk patients requiring intensive monitoring and novel therapies.

Importance Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear. Objective To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum. Design, Setting, and Participants This cohort study used longitudinal tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline. Exposure Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive. Main Outcomes and Measures Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment. Results Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P < .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women. Conclusions and Relevance In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.

Abstract Objective To estimate the incidence of de novo chronic rhinosinusitis and identify associated risk factors in kidney and liver transplant recipients without pre‐existing sinonasal complaints. Study design Retrospective cohort study. Setting Multisite study across Mayo Clinic Enterprise locations in Arizona, Florida, Minnesota, and Wisconsin. Methods Records of all patients who underwent kidney or liver transplantation between November 1, 2021, and November 1, 2022 were reviewed. Patients with documented sinonasal complaints prior to transplantation were excluded. Diagnoses were based on ICD‐10 codes assigned by board‐certified otolaryngologists, with follow‐up extending through November 2024. Demographic and clinical variables were collected, and multivariable logistic regression was used to identify predictors of de novo chronic rhinosinusitis. Results Among 1459 transplant recipients (mean age 55.1 years, 59.8% male), the cumulative 2‐year incidence of de novo chronic rhinosinusitis was 2.4% (24/986) in kidney and 2.3% (11/473) in liver transplant recipients ( P = .89). The overall incidence rate was 12.0 cases per 1000 person‐years, exceeding general population estimates. Transplant rejection (OR 3.2, 95% CI 2.5‐3.9, P < .001) and additional organ transplantation (OR 5.0, 95% CI 3.4‐6.5, P = .041) were independently associated with chronic rhinosinusitis development. Conclusion Kidney and liver transplant recipients experience a higher incidence of de novo chronic rhinosinusitis compared to the general population. Transplant rejection and additional organ transplantation significantly increase this risk. Early recognition and management of chronic rhinosinusitis in this population may support improved postoperative outcomes.

ABSTRACT Proteins are at the center of course content for Biochemistry, and thus it is critical for students to be familiar with amino acids and their structures. We aim to determine if the use of a kinesthetic learning tool will increase short‐ and long‐term undergraduate student knowledge retention of amino acids and their structures. The treatment group received a set of 3D printed amino acids to study and was assigned an amino acid to create using 3D modeling software. Quantitative assessment data were collected in quiz and exam formats. The treatment group completed a quantitative online survey and qualitative interview on their experience. Upper division undergraduate students overwhelmingly reported that designing a 3D amino acid provided a sense of accomplishment and added value to their experience in biochemistry. Short‐term structural knowledge retention was improved in the treatment group, as determined by quiz scores. Most students indicated they would recommend this assignment to future students. Through this work, we have shown that incorporating 3D printing as a kinesthetic learning tool in Biochemistry not only improves short‐term undergraduate student knowledge retention of amino acid structure, but also provides an engaging mechanism for students to interact hands‐on with content that adds value to their learning experience.

Abstract Background Tafamidis (meglumine 80 mg/free acid 61 mg) is approved to treat transthyretin amyloid cardiomyopathy (ATTR-CM). In the pivotal phase 3 study ATTR-ACT, tafamidis significantly reduced all-cause mortality (ACM) and cardiovascular-related hospitalisations in patients with ATTR-CM (1). Real-world data further extend and support the benefit of long-term tafamidis for improving survival in contemporary patients with ATTR-CM (2). Purpose To further compare survival in a contemporary, real-world, pooled, matched cohort of patients with ATTR-CM treated vs not treated with tafamidis, adjusted for potential prognosticators of treatment effect. Methods Data were pooled from 2 studies. One study included a contemporary cohort of patients with ATTR-CM who received early access to tafamidis in the ATTR-ACT long-term extension (LTE) study but did not participate in the parent study. The other study included a contemporary cohort of patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS; NCT00628745) with predominantly cardiac or mixed phenotype ATTR-CM enrolled between 2019–2023 who received tafamidis throughout the study or never received tafamidis. THAOS was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic gene carriers. Treated patients were pooled from the 2 studies; all received the approved dose of tafamidis. Untreated patients were from THAOS. A propensity score matching procedure was used to match treated and not treated patients 1:1 on 3 significant variables identified from a multivariate logistic regression analysis: baseline age, New York Heart Association (NYHA) class and phenotype (cardiac, mixed); other variables considered were sex, estimated glomerular filtration rate (eGFR), follow-up time and modified body mass index (mBMI). Results In all, 566 patients (283 treated, 283 not treated) were included; 85 treated patients were from the LTE study and 198 were from THAOS. In treated and not treated patients, respectively, median age at enrolment was 78.0 and 78.7 years, and 89.0% and 83.4% were male (Table). The estimated adjusted survival probabilities for ACM for treated vs not treated patients were 78.0% vs 67.9% at 30 months and 70.2% vs 57.9% at 42 months (Figure). The hazard ratio (HR) for time to event for ACM was 0.62 (95% CI 0.41–0.92), favouring tafamidis. Conclusions This matched-cohort analysis showed better survival in a contemporary, real-world cohort of patients with ATTR-CM receiving the approved dose of tafamidis vs those not treated. These findings further extend results of ATTR-ACT to contemporary populations of patients with ATTR-CM treated clinically with tafamidis. These data show greater effectiveness of tafamidis for ATTR-CM in clinical practice than observed in earlier clinical trials, which may reflect earlier diagnosis and treatment in contemporary patients.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1