San Francisco VA Health Care System

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration-approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

Since the World Health Organization launched its commission on the social determinants of health (SDOH) over a decade ago, a large body of research has proven that social determinants-defined as the conditions in which people are born, grow, live, work, and age-are significant drivers of disease risk and susceptibility within clinical care and public health systems. Unfortunately, the term has lost meaning within systems of care because of misuse and lack of context. As many disparate health outcomes remain, including higher risk of maternal mortality among Black women, a deeper understanding of the SDOH-and what forces underlie their distribution-is needed. In this article, we will expand our review of social determinants of maternal health to include the terms "structural determinants of health" and "root causes of inequities" as we assess the literature on this topic. We hypothesize that the addition of structural determinants and root causes will identify racism as a cause of inequities in maternal health outcomes, as many of the social and political structures and policies in the United States were born out of racism, classism, and gender oppression. We will conclude with proposed practice and policy solutions to end inequities in maternal health outcomes.

Individuals who are exposed to traumatic events that violate their moral values may experience severe distress and functional impairments known as "moral injuries." Over the last decade, moral injury has captured the attention of mental health care providers, spiritual and faith communities, media outlets, and the general public. Research about moral injury, especially among military personnel and veterans, has also proliferated. For this article, we reviewed scientific research about moral injury. We identified 116 relevant epidemiological and clinical studies. Epidemiological studies described a wide range of biological, psychological/behavioral, social, and religious/spiritual sequelae associated with exposure to potentially morally injurious events. Although a dearth of empirical clinical literature exists, some authors debated how moral injury might and might not respond to evidence-based treatments for posttraumatic stress disorder (PTSD) whereas others identified new treatment models to directly address moral repair. Limitations of the literature included variable definitions of potentially morally injurious events, the absence of a consensus definition and gold-standard measure of moral injury as an outcome, scant study of moral injury outside of military-related contexts, and clinical investigations limited by small sample sizes and unclear mechanisms of therapeutic effect. We conclude our review by summarizing lessons from the literature and offering recommendations for future research.

BACKGROUND/OBJECTIVES: Advance care planning (ACP) has shown benefit in some, but not all, studies. It is important to understand the utility of ACP. We conducted a scoping review to identify promising interventions and outcomes. DESIGN: Scoping review. MEASUREMENTS: We searched MEDLINE/PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science for ACP randomized controlled trials from January 1, 2010, to March 3, 2020. We used standardized Preferred Reporting Items for Systematic Review and Meta-Analyses methods to chart study characteristics, including a standardized ACP Outcome Framework: Process (e.g., readiness), Action (e.g., communication), Quality of Care (e.g., satisfaction), Health Status (e.g., anxiety), and Healthcare Utilization. Differences between arms of P < .05 were deemed positive. RESULTS: Of 1,464 articles, 69 met eligibility; 94% were rated high quality. There were variable definitions, age criteria (≥18 to ≥80 years), diseases (e.g., dementia and cancer), and settings (e.g., outpatient and inpatient). Interventions included facilitated discussions (42%), video only (20%), interactive, multimedia (17%), written only (12%), and clinician training (9%). For written only, 75% of primary outcomes were positive, as were 69% for multimedia programs; 67% for facilitated discussions, 59% for video only, and 57% for clinician training. Overall, 72% of Process and 86% of Action outcomes were positive. For Quality of Care, 88% of outcomes were positive for patient-surrogate/clinician congruence, 100% for patients/surrogate/clinician satisfaction with communication, and 75% for surrogate satisfaction with patients' care, but not for goal concordance. For Health Status outcomes, 100% were positive for reducing surrogate/clinician distress, but not for patient quality of life. Healthcare Utilization data were mixed. CONCLUSION: ACP is complex, and trial characteristics were heterogeneous. Outcomes for all ACP interventions were predominantly positive, as were Process and Action outcomes. Although some Quality of Care and Health Status outcomes were mixed, increased patient/surrogate satisfaction with communication and care and decreased surrogate/clinician distress were positive. Further research is needed to appropriately tailor interventions and outcomes for local contexts, set appropriate expectations of ACP outcomes, and standardize across studies.

Importance: Traumatic brain injury (TBI) is common in both veteran and civilian populations. Prior studies have linked moderate and severe TBI with increased dementia risk, but the association between dementia and mild TBI, particularly mild TBI without loss of consciousness (LOC), remains unclear. Objective: To examine the association between TBI severity, LOC, and dementia diagnosis in veterans. Design, Setting, and Participants: This cohort study of all patients diagnosed with a TBI in the Veterans Health Administration health care system from October 1, 2001, to September 30, 2014, and a propensity-matched comparison group. Patients with dementia at baseline were excluded. Researchers identified TBIs through the Comprehensive TBI Evaluation database, which is restricted to Iraq and Afghanistan veterans, and the National Patient Care Database, which includes veterans of all eras. The severity of each TBI was based on the most severe injury recorded and classified as mild without LOC, mild with LOC, mild with LOC status unknown, or moderate or severe using Department of Defense or Defense and Veterans Brain Injury Center criteria. International Classification of Diseases, Ninth Revision codes were used to identify dementia diagnoses during follow-up and medical and psychiatric comorbidities in the 2 years prior to the index date. Main Outcomes and Measures: Dementia diagnosis in veterans who had experienced TBI with or without LOC and control participants without TBI exposure. Results: The study included 178 779 patients diagnosed with a TBI in the Veterans Health Administration health care system and 178 779 patients in a propensity-matched comparison group. Veterans had a mean (SD) age of nearly 49.5 (18.2) years at baseline; 33 250 (9.3%) were women, and 259 136 (72.5%) were non-Hispanic white individuals. Differences between veterans with and without TBI were small. A total of 4698 veterans (2.6%) without TBI developed dementia compared with 10 835 (6.1%) of those with TBI. After adjustment for demographics and medical and psychiatric comobidities, adjusted hazard ratios for dementia were 2.36 (95% CI, 2.10-2.66) for mild TBI without LOC, 2.51 (95% CI, 2.29-2.76) for mild TBI with LOC, 3.19 (95% CI, 3.05-3.33) for mild TBI with LOC status unknown, and 3.77 (95% CI, 3.63-3.91) for moderate to severe TBI. Conclusions and Relevance: In this cohort study of more than 350 000 veterans, even mild TBI without LOC was associated with more than a 2-fold increase in the risk of dementia diagnosis. Studies of strategies to determine mechanisms, prevention, and treatment of TBI-related dementia in veterans are urgently needed.

Importance: Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer's Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. Objective: To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states. Evidence Review: PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms "biomarker" OR "amyloid" OR "tau" OR "neurodegeneration" OR "preclinical" OR "CSF" OR "PET" OR "plasma" AND "Alzheimer's disease." The references of relevant articles were also searched. Findings: In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease. Conclusions and Relevance: The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

BACKGROUND: Patients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear. OBJECTIVE: To determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID. DESIGN: Prospective observational cohort study. SETTING: Two U.S. CID referral centers. PARTICIPANTS: Volunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination. MEASUREMENTS: binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination. RESULTS: = 11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies. LIMITATIONS: Small sample that lacked demographic diversity, and residual confounding. CONCLUSION: Compared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study. PRIMARY FUNDING SOURCE: The Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

OBJECTIVE To examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Using claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) &amp;lt;6%, 6 to &amp;lt;7%, 7 to &amp;lt;8%, 8 to &amp;lt;9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18–44, 45–64, 65–74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more). RESULTS From 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P &amp;lt; 0.001). The proportion of patients with HbA1c &amp;lt;7% declined (from 56.4 to 54.2%; P &amp;lt; 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P &amp;lt; 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P &amp;lt; 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36). CONCLUSIONS During the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged.

Background. Patient comprehension is fundamental to valid informed consent. Current practices often result in inadequate patient comprehension. Purpose. An updated review to evaluate the characteristics and outcomes of interventions to improve patient comprehension in clinical informed consent. Data Sources. Systematic searches of MEDLINE and EMBASE (2008–2018). Study Selection. We included randomized and nonrandomized controlled trials evaluating interventions to improve patient comprehension in clinical informed consent. Data Extraction. Reviewers independently abstracted data using a standardized form, comparing all results and resolving disagreements by consensus. Data Synthesis. Fifty-two studies of 60 interventions met inclusion criteria. Compared with standard informed consent, a statistically significant improvement in patient comprehension was seen with 43% (6/14) of written interventions, 56% (15/27) of audiovisual interventions, 67% (2/3) of multicomponent interventions, 85% (11/13) of interactive digital interventions, and 100% (3/3) of verbal discussion with test/feedback or teach-back interventions. Eighty-five percent of studies (44/52) evaluated patients’ understanding of risks, 69% (41/52) general knowledge about the procedure, 35% (18/52) understanding of benefits, and 31% (16/52) understanding of alternatives. Participants’ education level was reported heterogeneously, and only 8% (4/52) of studies examined effects according to health literacy. Most studies (79%, 41/52) did not specify participants’ race/ethnicity. Limitations. Variation in interventions and outcome measures precluded conduct of a meta-analysis or calculation of mean effect size. Control group processes were variable and inconsistently characterized. Nearly half of studies (44%, 23/52) had a high risk of bias for the patient comprehension outcome. Conclusions. Interventions to improve patient comprehension in informed consent are heterogeneous. Interactive interventions, particularly with test/feedback or teach-back components, appear superior. Future research should emphasize all key elements of informed consent and explore effects among vulnerable populations.

STUDY OBJECTIVES: To evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA). METHODS: Participants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study. RESULTS: In the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs. CONCLUSIONS: This study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified. TRIAL REGISTRATION: NCT02348632.

Coronavirus disease 2019 (COVID-19) continues to impact older adults disproportionately with respect to serious consequences ranging from severe illness and hospitalization to increased mortality risk. Concurrently, concerns about potential shortages of healthcare professionals and health supplies to address these issues have focused attention on how these resources are ultimately allocated and used. Some strategies, for example, misguidedly use age as an arbitrary criterion that disfavors older adults in resource allocation decisions. This is a companion article to the American Geriatrics Society (AGS) position statement, "Resource Allocation Strategies and Age-Related Considerations in the COVID-19 Era and Beyond." It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations that should be considered when developing strategies for allocation of scarce resources during an emergency involving older adults. This review presents the legal and ethical background for the position statement and discusses these issues that informed the development of the AGS positions: (1) age as a determining factor, (2) age as a tiebreaker, (3) criteria with a differential impact on older adults, (4) individual choices and advance directives, (5) racial/ethnic disparities and resource allocation, and (6) scoring systems and their impact on older adults. It also considers the role of advance directives as expressions of individual preferences in pandemics. J Am Geriatr Soc 68:1143-1149, 2020.

Importance: Previous estimates suggested that 1 in 3 cases of Alzheimer disease and related dementia (ADRDs) in the US are associated with modifiable risk factors, the most prominent being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences by sex or race and ethnicity. Objective: To update estimates of the proportion of ADRDs in the US that are associated with modifiable risk factors and to assess for differences by sex and race and ethnicity. Design, Setting, and Participants: For this cross-sectional study, risk factor prevalence and communality were obtained from the nationally representative US Behavioral Risk Factor Surveillance Survey data from January 2018 to December 2018, and relative risks for each risk factor were extracted from meta-analyses. Data were analyzed from December 2020 to August 2021. Respondents included 378 615 noninstitutionalized adults older than 18 years. The number before exclusion was 402 410. Approximately 23 795 (~6%) had missing values on at least 1 of the variables of interest. Exposures: Physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. Main Outcomes and Measures: Individual and combined population-attributable risks (PARs) associated with ADRDs, accounting for nonindependence between risk factors. Results: Among 378 615 individuals, 171 161 (weighted 48.7%) were male, and 134 693 (weighted 21.1%) were 65 years and older. Race and ethnicity data were self-reported and defined by the US Behavioral Risk Factor Surveillance System Data; 6671 participants (weighted 0.9%) were American Indian and Alaska Native, 8043 (weighted 5.1%) were Asian, 29 956 (weighted 11.7%) were Black, 28 042 (weighted 16.0%) were Hispanic (any race), and 294 394 (weighted 64.3%) were White. Approximately 1 in 3 of ADRD cases (36.9%) in the US were associated with 8 modifiable risk factors, the most prominent of which were midlife obesity (17.7%; 95% CI, 17.5-18.0), physical inactivity (11.8%; 95% CI, 11.7-11.9), and low educational attainment (11.7%; 95% CI, 11.5-12.0). Combined PARs were higher in men (35.9%) than women (30.1%) and differed by race and ethnicity: American Indian and Alaska Native individuals, 39%; Asian individuals, 16%; Black individuals, 40%; Hispanic individuals (any race), 34%; and White individuals, 29%. The most prominent modifiable risk factors regardless of sex were midlife obesity for American Indian and Alaska Native individuals, Black individuals, and White individuals; low education for Hispanic individuals; and physical inactivity for Asian individuals. Conclusions and Relevance: The findings suggest that risk factors associated with ADRDs have changed over the past decade and differ based on sex and race and ethnicity. Alzheimer risk reduction strategies may be more effective if they target higher-risk groups and consider current risk factor profiles.

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.

Importance: Although randomized clinical trials are considered to be the criterion standard for generating clinical evidence, the use of real-world evidence to evaluate the efficacy and safety of medical interventions is gaining interest. Whether observational data can be used to address the same clinical questions being answered by traditional clinical trials is still unclear. Objective: To identify the number of clinical trials published in high-impact journals in 2017 that could be feasibly replicated using observational data from insurance claims and/or electronic health records (EHRs). Design, Setting, and Participants: In this cross-sectional analysis, PubMed was searched to identify all US-based clinical trials, regardless of randomization, published between January 1, 2017, and December 31, 2017, in the top 7 highest-impact general medical journals of 2017. Trials were excluded if they did not involve human participants, did not use end points that represented clinical outcomes among patients, were not characterized as clinical trials, and had no recruitment sites in the United States. Main Outcomes and Measures: The primary outcomes were the number and percentage of trials for which the intervention, indication, trial inclusion and exclusion criteria, and primary end points could be ascertained from insurance claims and/or EHR data. Results: Of the 220 US-based trials analyzed, 33 (15.0%) could be replicated using observational data because their intervention, indication, inclusion and exclusion criteria, and primary end points could be routinely ascertained from insurance claims and/or EHR data. Of the 220 trials, 86 (39.1%) had an intervention that could be ascertained from insurance claims and/or EHR data. Among the 86 trials, 62 (72.1%) had an indication that could be ascertained. Forty-five (72.6%) of 62 trials had at least 80% of inclusion and exclusion criteria data that could be ascertained. Of these 45 studies, 33 (73.3%) had at least 1 primary end point that could be ascertained. Conclusions and Relevance: This study found that only 15% of the US-based clinical trials published in high-impact journals in 2017 could be feasibly replicated through analysis of administrative claims or EHR data. This finding suggests the potential for real-world evidence to complement clinical trials, both by examining the concordance between randomized experiments and observational studies and by comparing the generalizability of the trial population with the real-world population of interest.

Importance: The racial and ethnic diversity of the US, including among patients receiving their care at the Veterans Health Administration (VHA), is increasing. Dementia is a significant public health challenge and may have greater incidence among older adults from underrepresented racial and ethnic minority groups. Objective: To determine dementia incidence across 5 racial and ethnic groups and by US geographical region within a large, diverse, national cohort of older veterans who received care in the largest integrated health care system in the US. Design, Setting, and Participants: Retrospective cohort study within the VHA of a random sample (5% sample selected for each fiscal year) of 1 869 090 participants aged 55 years or older evaluated from October 1, 1999, to September 30, 2019 (the date of final follow-up). Exposures: Self-reported racial and ethnic data were obtained from the National Patient Care Database. US region was determined using Centers for Disease Control and Prevention (CDC) regions from residential zip codes. Main Outcomes and Measures: Incident diagnosis of dementia (9th and 10th editions of the International Classification of Diseases). Fine-Gray proportional hazards models were used to examine time to diagnosis, with age as the time scale and accounting for competing risk of death. Results: Among the 1 869 090 study participants (mean age, 69.4 [SD, 7.9] years; 42 870 women [2%]; 6865 American Indian or Alaska Native [0.4%], 9391 Asian [0.5%], 176 795 Black [9.5%], 20 663 Hispanic [1.0%], and 1 655 376 White [88.6%]), 13% received a diagnosis of dementia over a mean follow-up of 10.1 years. Age-adjusted incidence of dementia per 1000 person-years was 14.2 (95% CI, 13.3-15.1) for American Indian or Alaska Native participants, 12.4 (95% CI, 11.7-13.1) for Asian participants, 19.4 (95% CI, 19.2-19.6) for Black participants, 20.7 (95% CI, 20.1-21.3) for Hispanic participants, and 11.5 (95% CI, 11.4-11.6) for White participants. Compared with White participants, the fully adjusted hazard ratios were 1.05 (95% CI, 0.98-1.13) for American Indian or Alaska Native participants, 1.20 (95% CI, 1.13-1.28) for Asian participants, 1.54 (95% CI, 1.51-1.57) for Black participants, and 1.92 (95% CI, 1.82-2.02) for Hispanic participants. Across most US regions, age-adjusted dementia incidence rates were highest for Black and Hispanic participants, with rates similar among American Indian or Alaska Native, Asian, and White participants. Conclusions and Relevance: Among older adults who received care at VHA medical centers, there were significant differences in dementia incidence based on race and ethnicity. Further research is needed to understand the mechanisms responsible for these differences.

Healthcare systems worldwide are responding to Coronavirus Disease 2019 (COVID-19), an emerging infectious syndrome caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus. Patients with COVID-19 can progress from asymptomatic or mild illness to hypoxemic respiratory failure or multisystem organ failure, necessitating intubation and intensive care management. Healthcare providers, and particularly anesthesiologists, are at the frontline of this epidemic, and they need to be aware of the best available evidence to guide therapeutic management of patients with COVID-19 and to keep themselves safe while doing so. Here, the authors review COVID-19 pathogenesis, presentation, diagnosis, and potential therapeutics, with a focus on management of COVID-19-associated respiratory failure. The authors draw on literature from other viral epidemics, treatment of acute respiratory distress syndrome, and recent publications on COVID-19, as well as guidelines from major health organizations. This review provides a comprehensive summary of the evidence currently available to guide management of critically ill patients with COVID-19.

BACKGROUND: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker. METHODS: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. RESULTS: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. CONCLUSIONS: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

There is evidence from observational studies for a role of a number of environmental exposures and lifestyle habits in modulating the risk for Parkinson's disease. Environmental and lifestyle associations, if causal, represent opportunities for Parkinson's disease prevention or disease modification at individual and population levels. In the past decade, additional evidence has been published that improves causal inference and/or enhances our understanding of the complexity of these associations. A number of gene-environment interactions have been elucidated, and our understanding of the roles of physical activity, pesticide and other chemical exposures, dietary habits, emotional stress, head injury, and smoking has been refined. In the next decade, better techniques will help us to close the gaps in our knowledge, including taking into account Parkinson's disease heterogeneity and gene and risk factor interactions in observational studies. To do this, larger datasets, global consortia, genomewide environment interaction studies, prospective studies throughout the lifespan, and improvements in the methodology of clinical trials of physical activity will be key. Despite the caveats of observational studies, a number of low-risk and potentially high-yield recommendations for lifestyle modification could be made to minimize the individual and societal burdens of Parkinson's disease, including dietary modifications, increasing physical activity, and head injury avoidance. Furthermore, a reduction in pesticide use could have a major impact on global health related to and beyond Parkinson's disease. Given the increasing prevalence of this disorder, formulating and promoting these recommendations should be a high priority. © 2019 International Parkinson and Movement Disorder Society.