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AbstractIntroductionThe Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50‐60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022.MethodsADNI4 will recruit URPs using community‐engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50‐60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in‐clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials.Results and DiscussionADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

Background: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. Objective: To study the cross-sectional associations of pulmonary function with structural brain variables. Methods: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. Results: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. Conclusion: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

A dementia friendly community allows people with dementia and their care partners to remain engaged in their community well into the disease. This study presents the results of primary research aimed at exploring perceptions regarding building a dementia friendly community in an African American neighborhood in northeast Florida. Twelve focus groups and five interviews were conducted with people living with dementia, informal and formal care partners, community stakeholders and neighborhood residents, and analyzed using a grounded theory approach. Three main themes emerged from the analyses, including (1) perceived needs, (2) facilitators and barriers to being dementia friendly, and (3) opportunities for the community to become more dementia friendly. Study findings highlight the unique needs of a single African American neighborhood and the importance of culturally tailoring the dementia friendly model to diverse communities.

ImportanceThere was a shift in patient volume from in-person to video telemedicine visits during the COVID-19 pandemic.ObjectiveTo determine the concordance of provisional diagnoses established at a video telemedicine visit with diagnoses established at an in-person visit for patients presenting with a new clinical problem.Design, Setting, and ParticipantsThis is a diagnostic study of patients who underwent a video telemedicine consultation followed by an in-person outpatient visit for the same clinical problem in the same specialty within a 90-day window. The provisional diagnosis made during the video telemedicine visit was compared with the reference standard diagnosis by 2 blinded, independent medical reviewers. A multivariate logistic regression model was used to determine factors significantly related to diagnostic concordance. The study was conducted at a large academic integrated multispecialty health care institution (Mayo Clinic locations in Rochester, Minnesota; Scottsdale and Phoenix, Arizona; and Jacksonville, Florida; and Mayo Clinic Health System locations in Iowa, Wisconsin, and Minnesota) between March 24 and June 24, 2020. Participants included Mayo Clinic patients residing in the US without age restriction. Data analysis was performed from December 2020 to June 2021.ExposuresNew clinical problem assessed via video telemedicine visit to home using Zoom Care Anyplace integrated into Epic.Main Outcomes and MeasuresConcordance of provisional diagnoses established over video telemedicine visits compared against a reference standard diagnosis.ResultsThere were 2393 participants in the analysis. The median (IQR) age of patients was 53 (37-64) years; 1381 (57.7%) identified as female, and 1012 (42.3%) identified as male. Overall, the provisional diagnosis established over video telemedicine visit was concordant with the in-person reference standard diagnosis in 2080 of 2393 cases (86.9%; 95% CI, 85.6%-88.3%). Diagnostic concordance by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision chapter ranged from 64.7% (95% CI, 42.0%-87.4%) for diseases of the ear and mastoid process to 96.8% (95% CI, 94.7%-98.8%) for neoplasms. Diagnostic concordance by medical specialty ranged from 77.3% (95% CI, 64.9%-89.7%) for otorhinolaryngology to 96.0% (92.1%-99.8%) for psychiatry. Specialty care was found to be significantly more likely than primary care to result in video telemedicine diagnoses concordant with a subsequent in-person visit (odds ratio, 1.69; 95% CI, 1.24-2.30; P < .001).Conclusions and RelevanceThis diagnostic study of video telemedicine visits yielded a high degree of diagnostic concordance compared with in-person visits for most new clinical concerns. Some specific clinical circumstances over video telemedicine were associated with a lower diagnostic concordance, and these patients may benefit from timely in-person follow-up.

AbstractClear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late‐stage CCOC is not responsive to gold‐standard chemotherapy and results in suboptimal outcomes for patients. In‐depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics for 192 cases of CCOC and compared these with other epithelial ovarian carcinoma subtypes. Our results showed distinct proteomic differences in CCOC compared with other epithelial ovarian cancer subtypes including alterations in lipid and purine metabolism pathways. Furthermore, we report potential clinically significant proteomic subgroups within CCOC, suggesting the biologic plausibility of stratified treatment for this cancer. Taken together, our results provide a comprehensive understanding of the CCOC proteomic landscape to facilitate future understanding and research of this disease. © 2022 The Pathological Society of Great Britain and Ireland.