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Objectives: Quantifying interdependence in multiple patient-centered outcomes is important for understanding health declines among older adults., Methods: Medicare-linked National Health and Aging Trends Study data (2011-2015) were used to estimate a joint longitudinal logistic regression model of disability in activities of daily living (ADL), fair/poor self-rated health (SRH), and mortality. We calculated personalized concurrent risk (PCR) and typical concurrent risk (TCR) using regression coefficients., Results: For fair/poor SRH, highest odds were associated with COPD. For mortality, highest odds were associated with dementia, hip fracture, and kidney disease. Dementia and hip fracture were associated with highest odds of ADL disability. Hispanic respondents had highest odds of ADL disability. Hispanic and NH Black respondents had higher odds of fair/poor SRH, ADL disability, and mortality. PCRs/TCRs demonstrated wide variability for respondents with similar sociodemographic-multimorbidity profiles., Discussion: These findings highlight the variability of personalized risk in examining interdependent outcomes among older adults., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hospitalizations are increasing among persons who use opioids, secondary to overdose and infections. Our study identified acute hospitalization as a reachable moment for engaging people who use drugs in increased screening and education about human immunodeficiency virus risk and prevention (preexposure prophylaxis)., Competing Interests: Potential conflicts of interest. S. A. S. has provided paid scientific consultation to Alkermes Inc and has received in-kind study drug donations from Alkermes Inc and Indivior Pharmaceutical Company for National Institutes of Health (NIH)–funded research. Sublocade was donated in-kind by Indivior Inc after an investigator-initiated application was approved. F. R. L. receives grant support from the NIDA, NCATS, Substance Abuse and Mental Health Services Administration, US World Meds; receives research support from Aelis Pharmaceuticals; receives medication from Indivior for research; receives royalties from APA Publishing; served as an unpaid member of a scientific advisory board for Alkermes, Indivior, Novartis, Teva, and US WorldMeds; and is a consultant to Major League Baseball. S. S.’s spouse worked for Merck pharmaceuticals from 1997 to 2007 and retains company stock in his retirement account. There is no conflict of interest, but it is included in the interest of full disclosure. K. B. receives grant support from NIDA, NCATS, and the Duke Foundation. A. H. L. has served on advisory boards for Gilead Sciences and Merck Pharmaceuticals and received research funding from Gilead Sciences. E. N. has served as an investigator on NIH-funded studies that received donated medication or digital therapeutics from Alkermes, Braeburn, Camurus, Indivior, Chess Health, and Pear Therapeutics, and has served as a consultant without compensation to Alkermes, Camurus, Indivior, and Pear Therapeutics. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Importance: Nationally representative estimates of hospital readmissions within 30 and 180 days after major surgery, including both fee-for-service and Medicare Advantage beneficiaries, are lacking., Objectives: To provide population-based estimates of hospital readmission within 30 and 180 days after major surgery in community-living older US residents and examine whether these estimates differ according to key demographic, surgical, and geriatric characteristics., Design, Setting, and Participants: A prospective longitudinal cohort study of National Health and Aging Trends Study data (calendar years 2011-2018), linked to records from the Centers for Medicare & Medicaid Services (CMS). Data analysis was conducted from April to August 2023. Participants included community-living US residents of the contiguous US aged 65 years or older who had at least 1 major surgery from 2011 to 2018. Data analysis was conducted from April 10 to August 28, 2023., Main Outcomes and Measures: Major operations and hospital readmissions within 30 and 180 days were identified through data linkages with CMS files that included both fee-for-service and Medicare Advantage beneficiaries. Data on frailty and dementia were obtained from the annual National Health and Aging Trends Study assessments., Results: A total of 1780 major operations (representing 9 556 171 survey-weighted operations nationally) were identified from 1477 community-living participants; mean (SD) age was 79.5 (7.0) years, with 56% being female. The weighted rates of hospital readmission were 11.6% (95% CI, 9.8%-13.6%) for 30 days and 27.6% (95% CI, 24.7%-30.7%) for 180 days. The highest readmission rates within 180 days were observed among participants aged 90 years or older (36.8%; 95% CI, 28.3%-46.3%), those undergoing vascular surgery (45.8%; 95% CI, 37.7%-54.1%), and persons with frailty (36.9%; 95% CI, 30.8%-43.5%) or probable dementia (39.0%; 95% CI, 30.7%-48.1%). In age- and sex-adjusted models with death as a competing risk, the hazard ratios for hospital readmission within 180 days were 2.29 (95% CI, 1.70-3.09) for frailty and 1.58 (95% CI, 1.15-2.18) for probable dementia., Conclusions and Relevance: In this nationally representative cohort study of community-living older US residents, the likelihood of hospital readmissions within 180 days after major surgery was increased among older persons who were frail or had probable dementia, highlighting the potential value of these geriatric conditions in identifying those at increased risk.

Seasonal infection rates of individual viruses are influenced by synergistic or inhibitory interactions between coincident viruses. Endemic patterns of SARS-CoV-2 and influenza infection overlap seasonally in the Northern hemisphere and may be similarly influenced. We explored the immunopathologic basis of SARS-CoV-2 and influenza A (H1N1pdm09) interactions in Syrian hamsters. H1N1 given 48 h prior to SARS-CoV-2 profoundly mitigated weight loss and lung pathology compared to SARS-CoV-2 infection alone. This was accompanied by the normalization of granulocyte dynamics and accelerated antigen-presenting populations in bronchoalveolar lavage and blood. Using nasal transcriptomics, we identified a rapid upregulation of innate and antiviral pathways induced by H1N1 by the time of SARS-CoV-2 inoculation in 48 h dual-infected animals. The animals that were infected with both viruses also showed a notable and temporary downregulation of mitochondrial and viral replication pathways. Quantitative RT-PCR confirmed a decrease in the SARS-CoV-2 viral load and lower cytokine levels in the lungs of animals infected with both viruses throughout the course of the disease. Our data confirm that H1N1 infection induces rapid and transient gene expression that is associated with the mitigation of SARS-CoV-2 pulmonary disease. These protective responses are likely to begin in the upper respiratory tract shortly after infection. On a population level, interaction between these two viruses may influence their relative seasonal infection rates.

Dementia can be difficult for married couples for many reasons, including the introduction of caregiving burden, loss of intimacy, and financial strain. In this study, we investigated the impact of dementia staging and neuropsychiatric behavioral symptoms on the likelihood of divorce or separation for older adult married couples. For this case-control study, we used data from the National Alzheimer's Coordinating Center (NACC) Uniform dataset (UDS) versions 2 and 3. This dataset was from 2007 to 2021 and contains standardized clinical information submitted by NIA/NIH Alzheimer's Disease Research Centers (ADRCs) across the United States (US). This data was from 37 ADRCs. We selected participants who were married or living as married/domestic partners at their initial visit. Cases were defined by a first divorce/separation occurring during the follow-up period, resulting in 291 participants. We selected 5 controls for each married/living as married case and matched on age. Conditional logistic regression estimated the association between overall Neuro Psychiatric Inventory (NPI) score and severity of individual symptoms of the NPI with case/control status, adjusted for education, the CDR® Dementia Staging Instrument score, living situation, symptom informant, sex, and race. Separate analyses were conducted for each symptom. Multiple comparisons were accounted for with the Hochberg method. Later stage of dementia was negatively associated with divorce/separation with an adjusted odds ratio (AOR) = 0.68 (95%CI = 0.50 to 0.93). A higher overall NPI score was positively associated with divorce/separation AOR = 1.08 (95% CI = 1.03 to 1.12,). More severe ratings of agitation/aggression, depression/dysphoria, disinhibition, and elation/euphoria were associated with greater odds of divorce/separation. Among older adults in the US, a later stage of dementia is associated with a lower likelihood of divorce or separation, while having more severe neuropsychiatric behavioral symptoms of agitation/aggression, depression/dysphoria, disinhibition, and elation/euphoria are associated with a higher likelihood of divorce or separation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Monin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology., Competing Interests: Declaration of interests X.P. is a consultant for the Brain Electrophysiology Laboratory Company., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Platelets are uniquely positioned as mediators of not only hemostasis but also innate immunity. However, how age and geriatric conditions such as frailty influence platelet function during an immune response remains unclear. We assessed the platelet transcriptome at baseline and following influenza vaccination in Younger (age 21-35) and Older (age ≥65) adults (including community-dwelling individuals who were largely non-frail and skilled nursing facility (SNF)-resident adults who nearly all met criteria for frailty). Prior to vaccination, we observed an age-associated increase in the expression of platelet activation and mitochondrial RNAs and decrease in RNAs encoding proteins mediating translation. Age-associated differences were also identified in post-vaccination response trajectories over 28 days. Using tensor decomposition analysis, we found increasing RNA expression of genes in platelet activation pathways in young participants, but decreasing levels in (SNF)-resident adults. Translation RNA trajectories were inversely correlated with these activation pathways. Enhanced platelet activation was found in community-dwelling older adults at the protein level, compared to young individuals both prior to and post-vaccination; whereas SNF residents showed decreased platelet activation compared to community-dwelling older adults that could reflect the influence of decreased translation RNA expression. Our results reveal alterations in the platelet transcriptome and activation responses that may contribute to age-associated chronic inflammation and the increased incidence of thrombotic and pro-inflammatory diseases in older adults., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Critical illness often leads to persistent functional impairment among older Intensive Care Unit (ICU) survivors. Identification of high-risk survivors prior to discharge from their ICU hospitalization can facilitate targeting for restorative interventions after discharge, potentially improving the likelihood of functional recovery. Our objective was to develop and validate a prediction model for persistent functional impairment among older adults in the year after an ICU hospitalization., Methods: The analytic sample included community-living participants enrolled in the National Health and Aging Trends Study 2011 cohort who survived an ICU hospitalization through December 2017 and had a follow-up interview within 1 year. Persistent functional impairment was defined as failure to recover to the pre-ICU level of function within 12 months of discharge from an ICU hospitalization. We used Bayesian model averaging to identify the final predictors from a comprehensive set of 17 factors. Discrimination and calibration were assessed using area-under-the-curve (AUC) and calibration plots., Results: The development cohort included 456 ICU admissions (2,654,685 survey-weighted admissions) and the validation cohort included 227 ICU admissions (1,350,082 survey-weighted admissions). In the development cohort, the median age was 81.0 years (interquartile range [IQR] 76.0, 86.0) and 231 (50.7%) participants were women; demographic characteristics were comparable in the validation cohort. The rates of persistent functional impairment were 49.3% (development) and 50.2% (validation). The final model included age, pre-ICU disability, probable dementia, frailty, prior hospitalizations, vision impairment, depressive symptoms, and hospital length of stay. The model demonstrated good discrimination (AUC 71%, 95% confidence interval [CI] 0.66-0.76) and good calibration. When applied to the validation cohort, the model demonstrated comparable discrimination (AUC 72%, 95% CI 0.66-0.78) and good calibration., Conclusions: Application of the model prior to discharge from an ICU hospitalization may identify older adults at the highest risk of persistent functional impairment in the subsequent year, thereby facilitating targeted interventions and follow-up., (© 2022 The American Geriatrics Society.)

Objective: The objective of this study was to estimate the incidence and cumulative risk of major surgery in older persons over a 5-year period and evaluate how these estimates differ according to key demographic and geriatric characteristics., Background: As the population of the United States ages, there is considerable interest in ensuring safe, high-quality surgical care for older persons. Yet, valid, generalizable data on the occurrence of major surgery in the geriatric population are sparse., Methods: We evaluated data from a prospective longitudinal study of 5571 community-living fee-for-service Medicare beneficiaries, aged 65 or older, from the National Health and Aging Trends Study from 2011 to 2016. Major surgeries were identified through linkages with Centers for Medicare and Medicaid Services data. Population-based incidence and cumulative risk estimates incorporated National Health and Aging Trends Study analytic sampling weights and cluster and strata variables., Results: The nationally representative incidence of major surgery per 100 person-years was 8.8, with estimates of 5.2 and 3.7 for elective and nonelec-tive surgeries. The adjusted incidence of major surgery peaked at 10.8 in persons 75 to 79 years, increased from 6.6 in the non-frail group to 10.3 in the frail group, and was similar by sex and dementia. The 5-year cumulative risk of major surgery was 13.8%, representing nearly 5 million unique older persons, including 12.1% in persons 85 to 89 years, 9.1% in those ≥90 years, 12.1% in those with frailty, and 12.4% in those with probable dementia., Conclusions: Major surgery is a common event in the lives of community-living older persons, including high-risk vulnerable subgroups., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Estimating relationships between multiple incomplete patient measurements requires methods to cope with missing values. Multiple imputation is one approach to address missing data by filling in plausible values for those that are missing. Multiple imputation procedures can be classified into two broad types: joint modeling (JM) and fully conditional specification (FCS). JM fits a multivariate distribution for the entire set of variables, but it may be complex to define and implement. FCS imputes missing data variable-by-variable from a set of conditional distributions. In many studies, FCS is easier to define and implement than JM, but it may be based on incompatible conditional models. Imputation methods based on multilevel modeling show improved operating characteristics when imputing longitudinal data, but they can be computationally intensive, especially when imputing multiple variables simultaneously. We review current MI methods for incomplete longitudinal data and their implementation on widely accessible software. Using simulated data from the National Health and Aging Trends Study, we compare their performance for monotone and intermittent missing data patterns. Our simulations demonstrate that in a longitudinal study with a limited number of repeated observations and time-varying variables, FCS-Standard is a computationally efficient imputation method that is accurate and precise for univariate single-level and multilevel regression models. When the analyses comprise multivariate multilevel models, FCS-LMM-latent is a statistically valid procedure with overall more accurate estimates, but it requires more intensive computations. Imputation methods based on generalized linear multilevel models can lead to biased subject-level variance estimates when the statistical analyses involve hierarchical models., (© 2022 John Wiley & Sons Ltd.)

Importance: Despite their importance to guiding public health decision-making and policies and to establishing programs aimed at improving surgical care, contemporary nationally representative mortality data for geriatric surgery are lacking., Objective: To calculate population-based estimates of mortality after major surgery in community-living older US adults and to determine how these estimates differ according to key demographic, surgical, and geriatric characteristics., Design, Setting, and Participants: Prospective longitudinal cohort study with 1 year of follow-up in the continental US from 2011 to 2018. Participants included 5590 community-living fee-for-service Medicare beneficiaries, aged 65 years or older, from the National Health and Aging Trends Study (NHATS). Data analysis was conducted from February 22, 2021, to March 16, 2022., Main Outcomes and Measures: Major surgeries and mortality over 1 year were identified through linkages with data from the Centers for Medicare & Medicaid Services. Data on frailty and dementia were obtained from the annual NHATS assessments., Results: From 2011 to 2017, of the 1193 major surgeries (from 992 community-living participants), the mean (SD) age was 79.2 (7.1) years; 665 were women (55.7%), and 30 were Hispanic (2.5%), 198 non-Hispanic Black (16.6%), and 915 non-Hispanic White (76.7%). Over the 1-year follow-up period, there were 206 deaths representing 872 096 survey-weighted deaths and 13.4% (95% CI, 10.9%-15.9%) mortality. Mortality rates were 7.4% (95% CI, 4.9%-9.9%) for elective surgeries and 22.3% (95% CI, 17.4%-27.1%) for nonelective surgeries. For geriatric subgroups, 1-year mortality was 6.0% (95% CI, 2.6%-9.4%) for persons who were nonfrail, 27.8% (95% CI, 21.2%-34.3%) for those who were frail, 11.6% (95% CI, 8.8%-14.4%) for persons without dementia, and 32.7% (95% CI, 24.3%-41.0%) for those with probable dementia. The age- and sex-adjusted hazard ratios for 1-year mortality were 4.41 (95% CI, 2.53-7.69) for frailty with a reduction in restricted mean survival time of 48.8 days and 2.18 (95% CI, 1.40-3.40) for probable dementia with a reduction in restricted mean survival time of 44.9 days., Conclusions and Relevance: In this study, the population-based estimate of 1-year mortality after major surgery among community-living older adults in the US was 13.4% but was 3-fold higher for nonelective than elective procedures. Mortality was considerably elevated among older persons who were frail or who had probable dementia, highlighting the potential prognostic value of geriatric conditions after major surgery.

Multimorbidity (≥2 chronic conditions) is a common and important marker of aging. To better understand racial differences in multimorbidity burden and associations with important health-related outcomes, we assessed differences in the contribution of chronic conditions to hospitalization, skilled nursing facility admission, and mortality among non-Hispanic Black and non-Hispanic White older adults in the United States. We used data from a nationally representative study, the National Health and Aging Trends Study, linked to Medicare claims from 2011-2015 (n = 4,871 respondents). This analysis improved upon prior research by identifying the absolute contributions of chronic conditions using a longitudinal extension of the average attributable fraction for Black and White Medicare beneficiaries. We found that cardiovascular conditions were the greatest contributors to outcomes among White respondents, while the greatest contributor to outcomes for Black respondents was renal morbidity. This study provides important insights into racial differences in the contributions of chronic conditions to costly health-care utilization and mortality, and it prompts policy-makers to champion delivery reforms that will expand access to preventive and ongoing care for diverse Medicare beneficiaries., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Persons who inject drugs are at increased risk for acquiring hepatitis C virus (HCV). Medications for opioid use disorder (MOUD) are associated with reduced injection drug use (IDU) frequency among persons with opioid use disorder (OUD). However, whether HCV treatment uptake or changes in IDU frequency differ by HIV serostatus among persons receiving MOUD is incompletely understood., Methods: A secondary analysis was performed of data collected from 2 prospective cohort studies of participants with (PWH) or without HIV with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-diagnosed OUD who were initiated on methadone, buprenorphine, or naltrexone., Results: Of 129 participants, 78 (60.5%) were HCV antibody positive. PWH underwent increased HCV viral load testing (76.7% vs 43.3%; P = .028), but HCV treatment rates did not differ (17.6% vs 10.0%; P = .45) by HIV status. Participants without HIV reported a greater reduction in mean opioid IDU at 90 days (10.7 vs 2.0 fewer days out of 30; P < .001), but there were no group differences at 90 days. Stimulant use did not differ between groups. Urine opioid positivity declined from baseline to 90 days among the entire cohort (61.4% to 38.0%; P < .001) but did not differ by HIV serostatus., Conclusions: PWH who received MOUD underwent higher rates of follow-up HCV testing, but HCV treatment rates did not significantly differ by HIV serostatus. Participants without HIV on MOUD reported a greater reduction in opioid IDU. Improved integration of concomitant OUD with HCV and HIV screening, linkage to care, and treatment are needed for persons without HIV., Competing Interests: Potential conflicts of interest. Dr. Sandra Springer has provided scientific consultation with paid honoraria from Alkermes, Inc., and has received in-kind study donations of Vivitrol for NIDA-funded research and in-kind study donations of SUBLOCADE from Indivior for NCATS- and NIDA-funded research. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Opioid use disorder (OUD) and injection drug use (IDU) place justice-involved individuals at increased risk for acquiring or transmitting HIV or hepatitis C virus (HCV). Methadone and buprenorphine have been associated with reduced opioid IDU; however, the effect of extended-release naltrexone (XR-NTX) on this behavior is incompletely studied., Methods: This study examined injection opioid use and shared injection equipment behavior from a completed double-blind placebo-controlled trial of XR-NTX among 88 justice-involved participants with HIV and OUD. Changes in participants' self-reported daily injection opioid use and shared injection equipment was evaluated pre-incarceration, during incarceration, and monthly post-release for 6 months. The study also assessed differences in time to first opioid injection post-release. The research team performed intention to treat and "as treated" (high treatment versus low treatment) analyses., Results: Fifty-eight of 88 participants (69.5 %) endorsed IDU and 26 (29.5 %) reported sharing injection equipment in the 30 days pre-incarceration; 2 participants (2.2 %) reported IDU during incarceration; 19 (21.6 %) reported IDU one month post-release from prison or jail. Fifty-four (61.4 %) participants had an HIV RNA below 200 copies/mL and 62 (70.5 %) were baseline HCV antibody positive. The 6-month follow-up rate was 49.5 % and 50.5 % for those who received XR-NTX and placebo, respectively, which was not significantly different (p = 0.822). Participants in the XR-NTX and placebo groups had similar low mean opioid injection use post-release and time to first injection opioid use in the Intention-to-treat analysis. In the as-treated analysis, participants in the high treatment group had significantly lower mean proportion of days injecting opioids (13.8 % high treatment versus 22.8 % low treatment, p = 0.02) by month 1, which persisted up to 5 months post-release (0 % high treatment vs 24.3 % low treatment, p < 0.001) and experienced a longer time to first opioid injection post-release (143.8 days high treatment vs 67.4 days low treatment, p < 0.001)., Conclusions: Injection opioid use was low during incarceration and remained low post-release in this justice-involved population. Retention on XR-NTX was associated with reduced intravenous opioid use, which has important implications for reducing transmission of HIV and HCV., Competing Interests: Declaration of competing interest Author SAS has provided scientific consultation to Alkermes Inc. and received NIH and VA grant funding. SAS has received in-kind study drug donations from Alkermes Inc. and Indivior Pharmaceutical Company for NIH-funded research. The authors alone are responsible for the content and writing of this paper., (Published by Elsevier Inc.)

Background: The correlations between skilled nursing facility (SNF) admissions, number of hospitalizations, and informal caregiving hours received after adjusting for physical and cognitive function and sociodemographic covariates are not well understood., Objective: The objective of this study was to better understand risk factors for SNF admissions and the interrelation with hospitalizations and amount of informal caregiving received, this study applied a novel joint modeling analysis to simultaneously explore the correlation and shared information between the 3 outcomes., Research Design: This was an observational follow-up study., Subjects: Data from 4836 older Americans included in the 2011-2015 rounds of the National Health and Aging Trends Study were linked with Centers for Medicare & Medicaid Services., Measures: We jointly modeled SNF admission, hospital admissions, and informal caregiving hours received while accounting for possible risk factors. We addressed missing values by multiple imputation with chained equations., Results: SNF admission evidenced a strong positive correlation with hospital admission, and SNF admission evidenced a weak positive correlation with the informal caregiving hours received after adjustment for important risk factors. Non-Hispanic White race/ethnicity, living alone, not being Medicaid eligible, Alzheimer disease and related dementias diagnosis, activities of daily living disabilities, and frailty were associated with increased risk of SNF admissions and any/number of hospital admission. Lower educational level was also associated with the latter. Medicaid eligibility was the only factor not associated with any nor numbers of informal caregiving hours received., Conclusions: Sociodemographic and health factors were important for predicting SNF admissions. After adjustment for important risk factors, SNF evidenced a strong positive correlation with the number of hospitalizations and a weak positive correlation with the hours of informal caregiving received., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Medication treatment for opioid use disorder (OUD) (MOUD; buprenorphine and methadone) reduces opioid use and overdose. Discontinuation of MOUD can quickly lead to relapse, overdose and death. Few persons who initiate MOUD are retained on treatment, thus it is critical to identify factors associated with retention., Methods: Evaluated data was from an ongoing prospective cohort study of adults aged 18 or older with DSM-5 moderate to severe OUD seeking MOUD in the community and followed for 6 months. Participants were considered retained on MOUD through 6 months if they reported taking MOUD at every study interview without discontinuation. A high dose of MOUD was defined as a methadone dose > 85 mg or buprenorphine dose ≥ 16 mg. Multivariable logistic regression was conducted to assess factors associated with 6-month MOUD retention., Results: A total of 118 participants (73% male, 58% white, 36% with HIV) were included. Buprenorphine was initiated by 58% and 42% started methadone. MOUD retention was 49% and 58% among buprenorphine and methadone, respectively, at 6-months. In adjusted models, a high MOUD dose (OR = 4.71, 95% CI 2.05-10.84) and higher pain interference (OR = 1.59, 95% CI 1.15-2.19) was associated with MOUD retention., Conclusions: Adequate dosing of MOUD leads to improved retention on MOUD. Further, persons with high pain interference at baseline had higher odds of retention on MOUD. Both methadone and buprenorphine have analgesic effects, thus those with high pain interference could have dual benefits of MOUD for treating OUD and pain. Interventions should be tailored to improve adequate MOUD dosing to improve retention on MOUD., (© 2022. The Author(s).)

At present, global immunity to SARS-CoV-2 resides within a heterogeneous combination of susceptible, naturally infected and vaccinated individuals. The extent to which viral shedding and transmission occurs on re-exposure to SARS-CoV-2 is an important determinant of the rate at which COVID-19 achieves endemic stability. We used Sialodacryoadenitis Virus (SDAV) in rats to model the extent to which immune protection afforded by prior natural infection via high risk (inoculation; direct contact) or low risk (fomite) exposure, or by vaccination, influenced viral shedding and transmission on re-exposure. On initial infection, we confirmed that amount, duration and consistency of viral shedding, and seroconversion rates were correlated with exposure risk. Animals were reinfected after 3.7-5.5 months using the same exposure paradigm. 59% of seropositive animals shed virus, although at lower amounts. Previously exposed seropositive reinfected animals were able to transmit virus to 25% of naive recipient rats after 24-hour exposure by direct contact. Rats vaccinated intranasally with a related virus (Parker's Rat Coronavirus) were able to transmit SDAV to only 4.7% of naive animals after a 7-day direct contact exposure, despite comparable viral shedding. Cycle threshold values associated with transmission in both groups ranged from 29-36 cycles. Observed shedding was not a prerequisite for transmission. Results indicate that low-level shedding in both naturally infected and vaccinated seropositive animals can propagate infection in susceptible individuals. Extrapolated to COVID-19, our results suggest that continued propagation of SARS-CoV-2 by seropositive previously infected or vaccinated individuals is possible., Competing Interests: The authors have declared that no competing interests exist.

[ 11 C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer's disease (AD). We compared [ 11 C]UCB-J binding for synaptic density and [ 18 F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K 1 or R 1 for [ 11 C]UCB-J perfusion, V T (volume of distribution) or DVR to cerebellum for [ 11 C]UCB-J binding to SV2A; and K i or K i R to cerebellum for [ 18 F]FDG metabolism. [ 11 C]UCB-J binding and [ 18 F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD -compared to CN participants. However, the magnitude of reduction of [ 11 C]UCB-J binding in neocortical regions was less than that observed with [ 18 F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [ 11 C]UCB-J perfusion showed a similar pattern to [ 18 F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.

Background: Multimorbidity is common in adults aged 65 and older and is associated with health care utilization and mortality, but most methods ignore the interrelationship among concurrent outcome nor provide person-specific probabilities., Method: A longitudinal cohort of 5300 older Americans from the 2011-2015 rounds of the National Health and Aging Study was linked to Center for Medicare and Medicaid Services claims. Odds ratios for 15 chronic conditions adjusted for sociodemographic factors were estimated using a joint model of hospitalization, skilled nursing facility (SNF) admission, and mortality. Additionally, we estimated the person-specific probability of an outcome while currently at risk for other outcomes for different chronic disease combinations demonstrating the heterogeneity across persons with identical chronic conditions., Results: During the 4-year follow-up period, 2867 (54.1%) individuals were hospitalized, 1029 (19.4%) were admitted to a SNF, and 1237 (23.3%) died. Chronic kidney disease, dementia, heart failure, and chronic obstructive pulmonary disease had significant increased odds for all 3 outcomes. By incorporating a person-specific random intercept, there was considerable range of person-specific probabilities for individuals with hypertension, diabetes, and depression with dementia, (hospitalization: 0.14-0.61; SNF admission: 0.04-0.28) and without dementia (hospitalization: 0.07-0.44; SNF admission: 0.02-0.15). Such heterogeneity was found among individuals with heart failure, ischemic heart disease, chronic kidney disease, hypertension, hyperlipidemia, and osteoarthritis with and without Medicare., Conclusions: This approach of joint modeling of interrelated concurrent health care and mortality outcomes not only provides a cohort-level odds and probabilities but addresses the heterogeneity among otherwise similarly characterized persons identifying those with above-average probability of poor outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Polypharmacy (use of ≥5 medications) and increasing Drug Burden Index (DBI) score (measure of person's total exposure to anticholinergic/sedative medications) are associated with impaired physical function in observational studies of older adults. Deprescribing, the supervised withdrawal of medications for which harms outweigh benefits for an individual, may be a useful intervention. Current knowledge is limited to clinical observational studies that are unable to determine causality. Here, we establish a preclinical model that investigates the effects of chronic polypharmacy, increasing DBI, and deprescribing on global health outcomes in aging. In a longitudinal study, middle-aged (12 months) male C57BL/6J (B6) mice were administered control feed or feed and/or water containing polypharmacy or monotherapy with different DBI scores. At 21 months, each treatment group was subdivided (stratified by frailty at 21 months) to either continue on treatment for life or to have treatment withdrawn (deprescribed). Frailty and physical function were evaluated at 12, 15, 18, and 24 months, and were analyzed using a mixed modeling approach. Polypharmacy with increasing DBI and monotherapy with citalopram caused mice to become frailer, less mobile, and impaired their strength and functional activities. Critically, deprescribing in old age reversed a number of these outcomes. This is the first preclinical study to demonstrate that chronic polypharmacy with increasing DBI augments frailty and impairs function in old age, and that drug withdrawal in old age reversed these outcomes. It was not the number of drugs (polypharmacy) but the type and dose of drugs (DBI) that caused adverse geriatric outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The genus Flavivirus contains many mosquito-borne human pathogens of global epidemiological importance such as dengue virus, West Nile virus, and Zika virus, which has recently emerged at epidemic levels. Infections with these viruses result in divergent clinical outcomes ranging from asymptomatic to fatal. Myriad factors influence infection severity including exposure, immune status and pathogen/host genetics. Furthermore, pre-existing infection may skew immune pathways or divert immune resources. We profiled immune cells from dengue virus-infected individuals by multiparameter mass cytometry (CyTOF) to define functional status. Elevations in IFNβ were noted in acute patients across the majority of cell types and were statistically elevated in 31 of 36 cell subsets. We quantified response to in vitro (re)infection with dengue or Zika viruses and detected a striking pattern of upregulation of responses to Zika infection by innate cell types which was not noted in response to dengue virus. Significance was discovered by statistical analysis as well as a neural network-based clustering approach which identified unusual cell subsets overlooked by conventional manual gating. Of public health importance, patient cells showed significant enrichment of innate cell responses to Zika virus indicating an intact and robust anti-Zika response despite the concurrent dengue infection., Competing Interests: The authors have declared that no competing interests exist.

Discovery studies in animals constitute a cornerstone of biomedical research, but suffer from lack of generalizability to human populations. We propose that large-scale interrogation of these data could reveal patterns of animal use that could narrow the translational divide. We describe a text-mining approach that extracts translationally useful data from PubMed abstracts. These comprise six modules: species, model, genes, interventions/disease modifiers, overall outcome and functional outcome measures. Existing National Library of Medicine natural language processing tools (SemRep, GNormPlus and the Chemical annotator) underpin the program and are further augmented by various rules, term lists, and machine learning models. Evaluation of the program using a 98-abstract test set achieved F1 scores ranging from 0.75-0.95 across all modules, and exceeded F1 scores obtained from comparable baseline programs. Next, the program was applied to a larger 14,481 abstract data set (2008-2017). Expected and previously identified patterns of species and model use for the field were obtained. As previously noted, the majority of studies reported promising outcomes. Longitudinal patterns of intervention type or gene mentions were demonstrated, and patterns of animal model use characteristic of the Parkinson's disease field were confirmed. The primary function of the program is to overcome low external validity of animal model systems by aggregating evidence across a diversity of models that capture different aspects of a multifaceted cellular process. Some aspects of the tool are generalizable, whereas others are field-specific. In the initial version presented here, we demonstrate proof of concept within a single disease area, Parkinson's disease. However, the program can be expanded in modular fashion to support a wider range of neurodegenerative diseases., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: To assess whether medically supportive care partners modify the associations of symptomatic chronic conditions with the number of functional disabilities in a cohort of multimorbid older adults with cognitive impairment., Research Design and Methods: The research design is a prospective study of a nationally representative cohort of Medicare beneficiaries. National Health and Aging Trends Study (NHATS) data were linked with Medicare claims for years 2011-2015. Participants were aged 65 or older and had cognitive impairment with at least 2 chronic conditions ( N = 1,003). Annual in-person interviews obtained sociodemographic information at baseline and time-varying variables for caregiving, hospitalization, and 6 activities of daily living (ADL); these variables were merged with Center for Medicare and Medicaid Services data to ascertain 16 time-varying chronic conditions. A care partner was defined as a person who sat with their care recipient during doctor visits in the past year and/or who helped them with prescribed medications in the last month. Chronic condition associations and their potential effect modifications by care partner status were assessed using weighted generalized estimating equations accounting for the complex survey design of the longitudinal analytical sample., Results: Chronic kidney disease, depression, and heart failure were associated with an increased number of functional disabilities. Among these, only the association of chronic kidney disease with the number of functional disabilities (interaction p value = .001) was weakened by the presence of a care partner., Discussion and Implications: The presence of care partners showed limited modification of the associations of symptomatic chronic conditions with functional disability.

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain's reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation-one that could, in future, be harnessed to augment behavioral treatments for ASD.

Object: Sagittal nonsyndromic craniosynostosis (sNSC) is the most common form of NSC. The condition is associated with a high prevalence (> 50%) of deficits in executive function. The authors employed diffusion tensor imaging (DTI) and functional MRI to evaluate whether hypothesized structural and functional connectivity differences underlie the observed neurocognitive morbidity of sNSC., Methods: Using a 3-T Siemens Trio MRI system, the authors collected DTI and resting-state functional connectivity MRI data in 8 adolescent patients (mean age 12.3 years) with sNSC that had been previously corrected via total vault cranioplasty and 8 control children (mean age 12.3 years) without craniosynostosis. Data were analyzed using the FMRIB Software Library and BioImageSuite., Results: Analyses of the DTI data revealed white matter alterations approaching statistical significance in all supratentorial lobes. Statistically significant group differences (sNSC < control group) in mean diffusivity were localized to the right supramarginal gyrus. Analysis of the resting-state seed in relation to whole-brain data revealed significant increases in negative connectivity (anticorrelations) of Brodmann area 8 to the prefrontal cortex (Montreal Neurological Institute [MNI] center of mass coordinates [x, y, z]: -6, 53, 6) and anterior cingulate cortex (MNI coordinates 6, 43, 14) in the sNSC group relative to controls. Furthermore, in the sNSC patients versus controls, the Brodmann area 7, 39, and 40 seed had decreased connectivity to left angular gyrus (MNI coordinates -31, -61, 34), posterior cingulate cortex (MNI coordinates 13, -52, 18), precuneus (MNI coordinates 10, -55, 54), left and right parahippocampus (MNI coordinates -13, -52, 2 and MNI coordinates 11, -50, 2, respectively), lingual (MNI coordinates -11, -86, -10), and fusiform gyri (MNI coordinates -30, -79, -18). Intrinsic connectivity analysis also revealed altered connectivity between central nodes in the default mode network in sNSC relative to controls; the left and right posterior cingulate cortices (MNI coordinates -5, -35, 34 and MNI coordinates 6, -42, 39, respectively) were negatively correlated to right hemisphere precuneus (MNI coordinates 6, -71, 46), while the left ventromedial prefrontal cortex (MNI coordinates 6, 34, -8) was negatively correlated to right middle frontal gyrus (MNI coordinates 40, 4, 33). All group comparisons (sNSC vs controls) were conducted at a whole brain-corrected threshold of p < 0.05., Conclusions: This study demonstrates altered neocortical structural and functional connectivity in sNSC that may, in part or substantially, underlie the neuropsychological deficits commonly reported in this population. Future studies combining analysis of multimodal MRI and clinical characterization data in larger samples of participants are warranted.

Pivotal response treatment (PRT) is an empirically validated behavioral treatment that has widespread positive effects on communication, behavior, and social skills in young children with autism spectrum disorder (ASD). For the first time, functional magnetic resonance imaging was used to identify the neural correlates of successful response to PRT in two young children with ASD. Baseline measures of social communication, adaptive behavior, eye tracking and neural response to social stimuli were taken prior to treatment and after 4 months of PRT. Both children showed striking gains on behavioral measures and also showed increased activation to social stimuli in brain regions utilized by typically developing children. These results suggest that neural systems supporting social perception are malleable through implementation of PRT.