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Abstract Background Diffusion MRI (dMRI) measures are increasingly being used as biomarkers for aging and dementia in multi‐center studies. Measurements in longitudinal studies are often acquired on different systems, which can result in systematic differences of machine origin (e.g. vendor, hardware, algorithms). This may warrant harmonization prior to pooling multi‐site data. However, harmonization algorithms may introduce a risk of removing valuable information content and reducing sensitivity to physiological factors (e.g. sex, age, disease). Here, we tested the hypothesis that protocol standardization may minimize machine‐origin differences, obviating a need for post‐acquisition harmonization in a two‐site (Mississippi‐MS and Minnesota‐MN) cohort of the longitudinal Mayo Clinic Study of Aging (MCSA). Methods Two data sets were analyzed: first, a crossover dataset with 80 participants (scanned within 2 days) bridging two different protocols on GE and Siemens scanners; second, participants scanned using standardized protocols from the ongoing MCSA ( N MN‐MCSA =204; N MS‐MCSA =52). Parameters are listed in Figure 1. For crossover data, analyses were repeated with GE data resampled to 2‐mm isotropic resolution, and discarding Siemens‐only b‐shells to artificially reduce protocol disparities. Analysis encompassed visualization of overlain subjectwise histogram‐derived densities obtained from whole‐brain masks for dMRI measures; and median dMRI measures from within the genu of the corpus callosum (GCC) with nonparametric statistical testing. When available, both DTI and NODDI measures were compared. Results Pronounced visual distributional differences seen between MD and FA in crossover data were reduced with resampling of GE data and including only b‐shells shared across acquisitions. For the resampled/reshelled data, significant differences remained for all GCC‐FA comparisons, but not all GCC‐MD (Figure 2). For the ongoing MCSA data from two sites, MD and FA whole‐brain densities were more closely aligned, with GCC‐FA and GCC‐MD showing no significant differences (Figure 3). NODDI measures showed more discordant densities than DTI measures, including shifts in most probable values and differences in distributional arrangement. Conclusions Our work provides further evidence supporting protocol and processing standardization for minimizing machine‐origin differences prior to considering harmonization. Differences in dMRI metrics seen when comparing across unstandardized protocols were reduced when protocols were standardized. NODDI metrics had more apparent sensitivity to site than DTI measures.

Abstract Background PET visual reads for multi‐center studies are conducted centrally by one or a few experts. In CLARiTI, a broader network of raters will perform the reads, necessitating methods to ensure their accuracy and reliability. Method All ADRC sites ( N = 37) will prospectively acquire amyloid PET scans for 800 cognitively unimpaired and 1200 cognitively impaired participants. Each site can use one of four amyloid PET tracers ([ 18 F]florbetaben, [ 18 F]florbetapir, [ 11 C]PIB, [ 18 F]NAV4694). PET scans will be visually interpreted by ten PET neuroimaging experts located across eight ADRCs, using their preferred hardware, software, and file format (DICOM, NIFTI). Calibration requires readers to perform blinded, independent visual interpretation of 180 amyloid PET scans (30 unique and 15 duplicate scans per tracer), previously read and selected by an expert (Table 1). An even mix of visually non‐elevated and elevated scans were selected, with quantitation spanning ‐26‐123 Centiloids (Figure 1), and 15% were visually borderline (similar proportion to ADNI4), with quantitation spanning 4‐48 Centiloids (mean 21). Kruskal‐Wallis H test showed no significant difference in the distribution of Centiloid values for scans in each tracer group, Χ 2 (3)=2.133, p = 0.545. Result Calibration scans were read by a second expert not serving in CLARiTI. There was 97% concordance and almost perfect agreement between readers (κ=0.932, p <0.001; Figure 2). Discordantly read scans were visually borderline elevated ( N = 2), borderline non‐elevated ( N = 1), and negative ( N = 1), with quantitation of 8‐21 Centiloids (mean 14). Intra‐rater reads were 98% concordant and had almost perfect agreement (κ=0.966, p <0.001). These findings hold promise for scaling‐up visual reads in CLARiTI, and we expect ≥80% concordance and substantial to almost perfect agreement (κ≥0.7) for inter/intra‐rater reliability. Conclusion Calibration is essential for accurate/reliable amyloid PET visual reads in large multi‐center studies with multiple raters. Through the calibration process, we will develop methods to improve the adjudication of borderline/challenging scans and formalize methods for visual reads of amyloid PET tracers that are investigational (i.e., [ 11 C]PIB, [ 18 F]NAV4694). Involving multiple raters across different sites, who use diverse hardware/software/file format combinations, will mirror the natural heterogeneity present in real‐world clinical practice. This calibration set can also serve as a standardized training tool for other studies incorporating amyloid PET visual reads.

Abstract Background Plasma neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) are blood‐based biomarkers of axonal injury and astrocytic activation, respectively, that are elevated in those with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) relative to cognitively unimpaired (CU) individuals. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method capable of evaluating tissue microstructure at the axonal and dendritic level. We evaluated associations between temporal cortex orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (ISOVF) and plasma NfL and GFAP concentrations. Method We included Mayo Clinic Study of Aging (MCSA) participants (ages 60‐95 years) with diagnoses or CU ( n = 356) or MCI ( n = 60), and Alzheimer’s Dementia Research Center (ADRC) participants with dementia ( n = 51). NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. NfL and GFAP were measured using the Simoa® Neurology 4‐Plex E Advantage kit. We fit separate linear regression models within each MCALT_ADIR122 cortical ROI with regional NODDI as the primary predictor and log‐transformed plasma concentration as the outcome. Models were adjusted for age, sex, BMI, cortical thickness (or hippocampal & amygdalar volume) and total intracranial volume. Result The Table displays demographic data. Figures 1 & 2 show the relationship of NDI and ISOVF measures to plasma NfL concentrations across participants in individual ROIs (similar findings were noted with GFAP). A significant inverse relationship between NfL concentrations and NDI was observed in hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus as well as all temporal neocortical regions except the superior temporal gyrus ( p <0.001) (Figure 1), whereas higher NfL concentrations were associated with higher ISOVF in all regions ( p <0.001) (Figure 2). Fewer significant associations were also seen with ODI. After adjusting for age, cortical thickness/volume and other confounds, significant associations with NDI remain, particularly in hippocampal and amygdalar regions. Conclusion NODDI‐derived measures (NDI and ISOVF) within the temporal lobe cortical regions demonstrate significant associations with plasma biomarkers of axonal and astrocytic dysfunction that are elevated during cognitive decline. This association provides preliminary validation of the utility of NODDI in assessing cortical microstructural changes associated with cognitive decline.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Importance Little is known about food insecurity (FI) among graduate medical education (GME) trainees or how FI might relate to well-being outcomes in this population. Objectives To assess the prevalence of and factors associated with FI among GME trainees and to investigate the associations of FI with well-being outcomes such as burnout and social isolation in this population. Design, Setting, and Participants In this cross-sectional study, a survey was distributed among 3408 resident and fellow physicians at 4 geographically distinct sites within 2 US academic institutions from May 2 to June 21, 2023. All resident and fellow physicians appointed at both institutions were eligible and were invited by email to participate. Main Outcomes and Measures The primary outcome was prevalence of FI. Measurement instruments included a 2-item FI screening tool, a 2-item measure of burnout, items addressing intent to stay at one’s institution, social isolation, and demographic characteristics. Univariable analysis and multivariable Poisson and linear regression were used to characterize prevalence and factors associated with FI and associations with well-being outcomes and intent to stay at the institution. Results Of those eligible, 1656 residents and fellows participated in the survey (a response rate of 48.6%). Of these respondents, 735 of 1458 (50.4%) who indicated their gender identified as men and 365 of 1402 (26.0%) who indicated their parental status reported having children. Of the 1551 respondents who reported their age, 519 (33.5%) were younger than 30 years, 770 (49.6%) were aged 31 to 35 years, 169 (10.9%) were aged 36 to 40 years, and 53 (3.4%) were older than 40 years. Among 1457 respondents indicating their race and ethnicity, the majority were Asian (310 [21.3%]) or White (654 [44.9%]). The overall prevalence of FI was 13.7%. FI proportions differed across training sites, with higher levels in large metropolitan locations (15.6%, 17.0%, and 21.3% for the 3 sites in large metropolitan areas vs 4.5% for the site in a small metropolitan area; P &amp;lt; .001). There were also differences by postgraduate year (16.9% for postgraduate year 1 vs 10.1% for postgraduate year ≥5; P = .003) and race and ethnicity (22.4% for Black or African American trainees compared with 8.4% for White trainees; P = .04). Those with FI were more likely to experience burnout (adjusted relative risk, 1.37 [95% CI, 1.18-1.60]; P &amp;lt; .001), were less likely to consider remaining at their institution after training (adjusted relative risk, 0.81 [95% CI, 0.68-0.98]; P = .02), and had higher social isolation scores (T-score parameter estimate 2.37 [95% CI, 0.89-3.86]; P = .002). Conclusions and Relevance In this cross-sectional study, nearly 1 in 7 GME trainees screened positive for FI. FI was associated with important well-being outcomes including burnout. These findings suggest that academic medical institutions should pursue systemic solutions to address FI among resident and fellow physicians as a means of supporting their well-being.

PURPOSE To compare patient-reported and clinical outcomes between radical cystectomy (RC) and bladder-sparing therapy (BST) in patients with recurrent high-grade non–muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS This pragmatic, prospective observational cohort study was designed with patients, who selected and prioritized outcomes. Eligible adults were candidates for both RC or BST, had previous induction Bacillus Calmette-Guérin (BCG), and received their last treatment within 12 months. The primary outcome was the EORTC-QLQ-C30 physical function scale at 12 months. Secondary outcomes included other EORTC-QLQ-C30 scales, depression, anxiety, bladder cancer–specific quality of life (QOL), financial burden, and cancer-specific outcomes. Targeted maximum likelihood estimation (TMLE) was used to calculate average treatment effect (ATE) estimates between arms. Inverse probability weighted risk ratios (wRR) were calculated using quasi-Poisson regression. RESULTS Of 570 participants (mean age 71.4 years; 21% female), 371 selected BST and 199 selected RC. Physical function was significantly worse in the RC arm at 3 months; by 9 months, there was no difference between arms, and at 12 months, physical function did not differ (ATE, 0.9; 95% CI, –0.6 to 2.4; P = .22). RC was associated with better emotional function, generic health-related QOL, and financial burden, and lower depression and anxiety, while BST was associated with better bowel and sexual health. Cancer-specific survival was 99% for BST versus 96% for RC (wRR, 0.99; 95% CI, 0.97 to 1.01). RC was associated with a higher risk of adverse events and serious adverse events, including a 90-day mortality rate of 2.5%. CONCLUSION Most patient-prioritized outcomes were similar or better among participants who chose RC compared with BST. These findings support the continued role of RC in managing recurrent high-grade NMIBC.

Spinal sarcomas are rare, aggressive tumors requiring wide resection that creates large, challenging defects. Conventional reconstruction using allografts or metallic implants is prone to failure in compromised settings like irradiated or infected tissue. This narrative review synthesizes the literature on biologic reconstruction strategies, focusing on vascularized bone grafts (VBGs) and the ‘spinoplastic’ reconstruction approach, to provide a clinical framework for their application. We performed a narrative literature review using PubMed and Scopus to synthesize clinical studies describing biologic spinal reconstruction in compromised host beds. The main findings show that pedicled VBGs (e.g., rib, iliac crest) and free VBGs (e.g., fibula) function as living structural components. ‘Spinoplastic’ reconstruction leverages these grafts to promote biologic fusion, with clinical series reporting high union rates, even in irradiated or revision settings, offering a durable alternative to avascular constructs. Biologic reconstruction using VBGs is a critical strategy for achieving durable spinal stability in these challenging scenarios, and future directions point toward hybrid strategies combining 3D-printed implants with the biologic power of VBGs.

Background: Clozapine is the preferred medication for treatment-resistant schizophrenia with therapeutic drug monitoring (TDM) suggested to mediate its safe and effective use. However, clozapine TDM is not a ubiquitous element of care in clinical practice. Understanding the current state of clinicians' perceptions of and barriers to clozapine TDM is a crucial step in improving its use. Methods: A survey related to the use, perceptions, and barriers of clozapine TDM was distributed across multiple national organizations in the United States, representing several disciplines. Results: Most of the 190 respondents were consultants or attending physicians (42.5%) or pharmacists (52.3%). Nearly 80% of respondents had ordered clozapine level measurements in the year before completing the survey but identified slow turnaround time (TaT) as an important barrier; 73.5% of respondents noted that level measurements were performed at an offsite laboratory. Although 86.8% agreed that clozapine levels should be checked once an initial target dose was reached, less than half would subsequently order clozapine level measurements routinely, unless clinical factors such as nonadherence (96.5% agreement), new interaction (94.5% agreement), or change in smoking status (94.5% agreement) occurred. More pharmacists than prescribers indicated confidence in interpreting and clinically applying clozapine TDM results (84.6% versus 70.1%, P = 0.024), with a similar finding between the groups regarding faster clozapine TDM TaT, resulting in improved patient safety (89.0% versus 68.7% agreement, P = 0.003). In addition, more pharmacists would also conduct clozapine TDM in the setting of an acute inflammatory or infectious process (84.9% versus 61.2%, P = 0.002). Conclusions: These data provide insights into clozapine TDM perception, availability, TaT, and barriers. Further research is required to assess whether a faster TaT and more frequent clozapine TDM positively influence patient outcomes from a safety and effectiveness perspective.