Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum.

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Trends in smoking initiation and cessation over a century in two Australian cohorts.

BACKGROUND: Historical data on smoking can enhance our comprehension of the effectiveness of past tobacco control policies and play a key role in developing targeted public health interventions. This study was undertaken to assess trends in smoking initiation and cessation in Australia for the period 1910-2005. METHODS: Rates of smoking initiation and cessation were calculated for participants in two population-based cohorts, the Busselton Health Study and the Tasmanian Longitudinal Health Study. The effects of time trends, gender and age group were evaluated. RESULTS: Of the 29,971 participants, 56.8% ever smoked. In males, over the period 1910-1999, the rate of smoking initiation in young adolescents remained high with a peak in the 1970s; in older adolescents it peaked in the 1940s and then declined; in young adults it showed a steady decline. In females, the rate of smoking initiation in young adolescents rose sharply in the 1960s and peaked in the 1970s, in older adolescents it increased throughout the period, and in young adults it declined after 1970. In the period 1930-2005, 27.3% of 9,605 people aged 36-50 years who smoked ceased smoking. Rates of cessation in this age group increased throughout but decreased in males after 1990 and plateaued around 2000 in females. CONCLUSION: Our findings show substantial variation in the efficacy of tobacco control policies across age groups, with a notable lack of success among the younger population.

Confronting the Medical Leviathan: Reading a Report from the Front Lines.

This essay discusses how two physicians in Britain's National Health Service describe and analyze the conditions of their work: how algorithms and protocols structure the care they can provide and create the dilemmas they and their patients face. In these issues, the NHS is a canary in the mineshaft of contemporary Western health care. NHS practices are understood as how states and state-like entities, Leviathans, seek to render their subjects legible; in this instance, to make both physicians and patients transparently visible to surveillance and administration by standardizing medical work and patient need. Physicians respond by engaging in workarounds, finding ways to provide care despite systemic restrictions.

Decreased functional connectivity is associated with increased levels of Cerebral Spinal Fluid soluble-PDGFRß, a marker of blood brain barrier breakdown, in older adults.

Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. For instance, studies in pre-clinical AD subjects have shown increases of cerebral spinal fluid soluble platelet-derived growth factor receptor-ß (CSF sPDGFRß, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRß in the CSF may correlate with impaired FC in metabolically demanding brain regions (i.e. Default Mode Network, DMN). Our study aimed to investigate the relationship between these two markers in older individuals that were cognitively normal and had cognitive impairment. Eighty-nine older adults without dementia from the University of Southern California were selected from a larger cohort. Region of interest (ROI) to ROI analyses were conducted using DMN seed regions. Linear regression models measured significant associations between BOLD FC strength among seed-target regions and sPDGFRß values, while covarying for age and sex. Comparison of a composite ROI created by averaging FC values between seed and all target regions among cognitively normal and impaired individuals was also examined. Using CSF sPDGFRß as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, specifically the PCC, and while the hippocampus exhibited an interaction effect using CDR score, this was an exploratory analysis that we feel can lead to further research. Ultimately, we found that BBB breakdown, as measured by CSF sPDGFRß, is associated with neural networks, and decreased functional connections.

Anxiety in late-life depression is associated with poorer performance across multiple cognitive domains.

OBJECTIVE: Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains. METHOD: Older adults with major depressive disorder (N = 228, ages 65-91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning. RESULTS: Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity. CONCLUSIONS: Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.

Enhancing Health Literacy: Evaluating the Readability of Patient Handouts Revised by ChatGPT's Large Language Model.

OBJECTIVE: To use an artificial intelligence (AI)-powered large language model (LLM) to improve readability of patient handouts. STUDY DESIGN: Review of online material modified by AI. SETTING: Academic center. METHODS: Five handout materials obtained from the American Rhinologic Society (ARS) and the American Academy of Facial Plastic and Reconstructive Surgery websites were assessed using validated readability metrics. The handouts were inputted into OpenAI's ChatGPT-4 after prompting: "Rewrite the following at a 6th-grade reading level." The understandability and actionability of both native and LLM-revised versions were evaluated using the Patient Education Materials Assessment Tool (PEMAT). Results were compared using Wilcoxon rank-sum tests. RESULTS: The mean readability scores of the standard (ARS, American Academy of Facial Plastic and Reconstructive Surgery) materials corresponded to "difficult," with reading categories ranging between high school and university grade levels. Conversely, the LLM-revised handouts had an average seventh-grade reading level. LLM-revised handouts had better readability in nearly all metrics tested: Flesch-Kincaid Reading Ease (70.8 vs 43.9; P < .05), Gunning Fog Score (10.2 vs 14.42; P < .05), Simple Measure of Gobbledygook (9.9 vs 13.1; P < .05), Coleman-Liau (8.8 vs 12.6; P < .05), and Automated Readability Index (8.2 vs 10.7; P = .06). PEMAT scores were significantly higher in the LLM-revised handouts for understandability (91 vs 74%; P < .05) with similar actionability (42 vs 34%; P = .15) when compared to the standard materials. CONCLUSION: Patient-facing handouts can be augmented by ChatGPT with simple prompting to tailor information with improved readability. This study demonstrates the utility of LLMs to aid in rewriting patient handouts and may serve as a tool to help optimize education materials. LEVEL OF EVIDENCE: Level VI.

Brain aging patterns in a large and diverse cohort of 49,482 individuals.

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.

Immune Checkpoint Inhibitor (ICI) Induced Sinonasal Disease: Review of Literature and FDA Database.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of oncologic therapies whose mechanism of action can result in unique immune-related adverse events (irAEs) not seen in other cancer therapeutics. The objective of this study was to determine the presence of sinonasal irAEs with these medications. METHODS: A case report of chronic rhinosinusitis with nasal polyps (CRSwNP) caused by an ICI is presented and was the impetus for this review. Review of the literature using Pubmed and Cochrane Database of Systematic Reviews was performed. Additionally, we searched the FDA adverse event reporting system (FAERS) database for sinonasal AEs in the 7 FDA-approved ICIs. RESULTS: We demonstrate an emerging scientific literature describing cases of CRS associated with multiple ICIs with a particular predilection toward TH2 driven phenotypes. Review of the FAERS also demonstrates a small percentage of patients who report sinonasal complaints after initiating ICI therapy. CONCLUSION: Sinonasal symptoms and the development of CRS, in particular, are not currently well recognized as potential irAEs for ICIs. Increased awareness and further study may help to elucidate if these are more common than currently reported and if irAE-related CRS is a unique phenotype.

Three Types of Stories About Encountering Bioethics.

This commentary discusses 12 stories about receiving ethics consultation in hospitals. Five stories are by physicians, three by nurses, and four by family members; three of the writers have training in bioethics. Some writers requested the consultation, others experienced the consultation as an imposition forced upon them, and in two cases, the story is about the absence of any consultation service. Three types of narrative are found to structure the stories: the genuine dilemma narrative, the institutional intransigence narrative, and the relational care narrative. Throughout, the question is what makes for a valuable consultation, and the general answer is whether consultation enables the development of mutually supportive relationships.

The informatics of ADNI.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) has revolutionized the landscape of Alzheimer's research through its Informatics Core, which has facilitated unprecedented data standardization and sharing. Over 20 years, ADNI established a robust informatics framework, enabling the validation of biomarkers and supporting global research efforts. The Informatics Core, centered at the Laboratory of Neuro Imaging (LONI), provides a comprehensive data hub that ensures data quality, accessibility, and security, fostering over 5600 publications and significant scientific advancements. By embracing open data sharing principles, ADNI set a gold standard in data transparency, allowing over 26,000 investigators from 169 countries to access and download a wealth of multimodal data. This collaborative approach not only accelerated biomarker discovery and drug development and advanced our understanding of Alzheimer's disease but also has served as a model for other research initiatives, demonstrating the transformative potential of carefully designed informatics models and shared data in driving global scientific progress. HIGHLIGHTS: Accelerating biomarker discovery and drug development for Alzheimer's disease. Alzheimer's Disease Neuroimaging Initiative's (ADNI's) open data sharing drives scientific progress. Data exploration and coupled analytics to data archives.

Field-of-view extension for brain diffusion MRI via deep generative models.

Purpose: In brain diffusion magnetic resonance imaging (dMRI), the volumetric and bundle analyses of whole-brain tissue microstructure and connectivity can be severely impeded by an incomplete field of view (FOV). We aim to develop a method for imputing the missing slices directly from existing dMRI scans with an incomplete FOV. We hypothesize that the imputed image with a complete FOV can improve whole-brain tractography for corrupted data with an incomplete FOV. Therefore, our approach provides a desirable alternative to discarding the valuable brain dMRI data, enabling subsequent tractography analyses that would otherwise be challenging or unattainable with corrupted data. Approach: We propose a framework based on a deep generative model that estimates the absent brain regions in dMRI scans with an incomplete FOV. The model is capable of learning both the diffusion characteristics in diffusion-weighted images (DWIs) and the anatomical features evident in the corresponding structural images for efficiently imputing missing slices of DWIs in the incomplete part of the FOV. Results: For evaluating the imputed slices, on the Wisconsin Registry for Alzheimer's Prevention (WRAP) dataset, the proposed framework achieved PSNR b 0 = 22.397 , SSIM b 0 = 0.905 , PSNR b 1300 = 22.479 , and SSIM b 1300 = 0.893 ; on the National Alzheimer's Coordinating Center (NACC) dataset, it achieved PSNR b 0 = 21.304 , SSIM b 0 = 0.892 , PSNR b 1300 = 21.599 , and SSIM b 1300 = 0.877 . The proposed framework improved the tractography accuracy, as demonstrated by an increased average Dice score for 72 tracts ( p < 0.001 ) on both the WRAP and NACC datasets. Conclusions: Results suggest that the proposed framework achieved sufficient imputation performance in brain dMRI data with an incomplete FOV for improving whole-brain tractography, thereby repairing the corrupted data. Our approach achieved more accurate whole-brain tractography results with an extended and complete FOV and reduced the uncertainty when analyzing bundles associated with Alzheimer's disease.

Features of Importance in Nasal Endoscopy: Deriving a Meaningful Framework.

OBJECTIVE: Critical components of the nasal endoscopic examination have not been definitively established for either the normal examination or for clinical disorders. This study aimed to identify concordance among rhinologists regarding the importance of examination findings for various nasal pathologies. STUDY DESIGN: A consortium of 19 expert rhinologists across the United States was asked to rank the importance of findings on nasal endoscopy for 5 different sinonasal symptom presentations. SETTING: An online questionnaire was distributed in July 2023. METHODS: The questionnaire utilized JotForm® software and featured 5 cases with a set of 4 identical questions per case, each covering a common indication for nasal endoscopy. Rankings were synthesized into Normalized Attention Scores (NASs) and Weighted Normalized Attention Scores (W-NASs) to represent the perceived importance of each feature, scaled from 0 to 1. RESULTS: General concordance was found for examination findings on nasal endoscopy within each case. The perceived features of importance differed between cases based on clinical presentation. For instance, in evaluating postnasal drip, the middle meatus was selected as the most important structure to examine (NAS, 0.73), with mucus selected as the most important abnormal finding (W-NAS, 0.66). The primary feature of interest for mucus was whether it was purulent or not (W-NAS, 0.67). Similar analyses were performed for features in each case. CONCLUSION: The implicit framework existing among rhinologists may help standardize examinations and improve diagnostic accuracy, augment the instruction of trainees, and inform the development of artificially intelligent algorithms to enhance clinical decision-making during nasal endoscopy.

Current otolaryngologic applications of the novel self-assembling RADA-16 peptide matrix.

A novel bioresorbable agent on the market is PuraGel® (3-D Matrix, Tokyo, Japan), a RADA-16 product that acts as a synthetic hemostatic and space-filling gel that promotes wound healing and prevents adhesion formation. Given the reported benefits of accelerated wound healing and scar tissue prevention, there are multiple otolaryngologic applications where RADA-16 might improve outcomes. Our study highlights current utilization and associated post-operative complications with this product.

Histopathologic evaluation of Asian-American patients with chronic rhinosinusitis with nasal polyps.

KEY POINTS: Asian-American (AA) patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have comparable rates of tissue eosinophilia compared to Caucasians when defined as >10 eosinophils/high-powered field (HPF). AA patients with CRSwNP have significantly higher incidence of mixed inflammation defined as >10 eosinophils/HPF and >10 neutrophils/HPF.

Donor-derived Mycoplasma and Ureaplasma infections in lung transplant recipients: A prospective study of donor and recipient respiratory tract screening and recipient outcomes.

Mycoplasma hominis and Ureaplasma species are urogenital mollicutes that can cause serious donor-derived infections in lung transplant recipients. Best practices for mollicute screening remain unknown. We conducted a single-center prospective study analyzing lung transplants performed from October 5, 2020, to September 25, 2021, whereby donor and recipient bronchoalveolar lavage (BAL) samples obtained at time of transplant underwent mollicute screening via culture and polymerase chain reaction (PCR). Of 115 total lung transplants performed, 99 (86%) donors underwent combined mollicute BAL culture and PCR testing. The study cohort included these 99 donors and their matched recipients. In total, 18 (18%) of 99 donors screened positive via culture or PCR. Among recipients, 92 (93%) of 99 had perioperative BAL screening performed, and only 3 (3%) had positive results. After transplant, 9 (9%) recipients developed mollicute infection. Sensitivity of donor screening in predicting recipient mollicute infection was 67% (6/9) via culture and 56% (5/9) via PCR. Positive predictive value for donor culture was 75% (6/8), compared with 33% (5/15) for PCR. Donor screening via culture predicted all serious recipient mollicute infections and had better positive predictive value than PCR; however, neither screening test predicted all mollicute infections. Independent of screening results, clinicians should remain suspicious for posttransplant mollicute infection.