Citations

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 < .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 < .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.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

OBJECTIVE Achieving submillimetric accuracy in stereotactic neurosurgery remains critical for safely targeting deep brain structures. Current workflows rely on intraoperative CT to register stereotactic frames to preoperative imaging, but this introduces additional radiation exposure, cost, and workflow complexity. Three-dimensional surface scanning (3DSS) potentially offers a fast radiation-free alternative capable of capturing detailed craniofacial anatomy and frame geometry. Therefore, the aim of this cadaveric study was to evaluate the feasibility, accuracy, and navigational compatibility of integrating 3DSS into stereotactic workflows as a potential replacement for intraoperative CT. METHODS A human cadaveric head was imaged with both thin-slice CT and structured-light 3DSS after mounting stereotactic frame components. CT, 3DSS, and computer-aided design (CAD) models were registered using a multistep point cloud alignment pipeline involving the fast point feature histogram, the random sample consensus method, and the iterative closest point algorithm. Accuracy was assessed using surface deviation error, root mean square error (RMSE), and fiducial registration error within a commercial neuronavigation platform. RESULTS Fusion of the 3D facial scan with CT provided a mean surface deviation error of approximately 0.4 mm. Registration of the 3DSS-derived N-bar localizer to its CAD reference model produced a frame alignment RMSE of 1.3 mm. Within the navigation system, the 3DSS-based workflow achieved a mean fiducial registration error of 0.14 mm (range 0.02–0.20 mm), outperforming the conventional CT-based method (mean error 0.20 mm, range 0.09–0.40 mm). CONCLUSIONS The 3DSS-based method enabled precise submillimetric stereotactic registration without the need for intraoperative CT, reducing radiation exposure and operative complexity. This workflow is fully compatible with existing navigation systems and could serve as a practical radiation-free alternative in stereotactic neurosurgery. Future work will focus on automating frame detection, incorporating artificial intelligence–driven fusion methods, and validating this approach in live surgical settings.