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Network meta-analysis is an extension of standard meta-analysis. It allows researchers to build a network of evidence to compare multiple interventions that may have not been compared directly in existing publications. With a Bayesian approach, network meta-analysis can be used to obtain a posterior probability distribution of all the relative treatment effects, which allows for the estimation of relative treatment effects to quantify the uncertainty of parameter estimates, and to rank all the treatments in the network. Ranking treatments using both direct and indirect evidence can provide guidance to policy makers and clinicians for making decisions. The purpose of this paper is to introduce fundamental concepts of Bayesian network meta-analysis (BNMA) to researchers in psychology and social sciences. We discuss several essential concepts of BNMA, including the assumptions of homogeneity and consistency, the fixed and random effects models, prior specification, and model fit evaluation strategies, while pointing out some issues and areas where researchers should use caution in the application of BNMA. Additionally, using an automated R package, we provide a step-by-step demonstration on how to conduct and report the findings of BNMA with a real dataset of psychological interventions extracted from PubMed.

To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline.

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions.

Older adults experiencing dual decline in memory and gait have greater dementia risk than those with memory or gait decline only, but mechanisms are unknown. Dual decline may indicate specific pathophysiological pathways to dementia which can be reflected by circulating metabolites. We compared longitudinal changes in plasma metabolite biomarkers of older adults with and without dual decline in the Baltimore Longitudinal Study of Aging (BLSA). Participants were grouped into 4 phenotypes based on annual rates of decline in verbal memory and gait speed: no decline in memory or gait, memory decline only, gait decline only, and dual decline. Repeated measures of plasma metabolomics were measured by biocrates p500 kit during the same time of memory and gait assessments. In BLSA, 18 metabolites differed across groups (q-value

Stress, social isolation, and changes in health behaviors during the COVID-19 pandemic period may have a lasting influence on health. Here, the correlation between current or prior demographic, social and health related characteristics, including psychosocial factors with perceived impact of the COVID-19 pandemic assessed by questionnaire during the early pandemic period is evaluated among 770 participants of the Baltimore Longitudinal Study of Aging. In multinomial logistic regression models participants with higher pre-pandemic personal mastery, a construct related to self-efficacy, were more likely to report "both positive and negative" impact of the pandemic than a solely "negative" impact (OR: 2.17, 95% CI: 1.29-3.65). Higher perceived stress and frequent contact with family prior to the pandemic were also associated with pandemic impact. These observations highlight the relevance of psychosocial factors in the COVID-19 pandemic experience and identify characteristics that may inform interventions in future public health crises.

Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood borne immune cell types (naïve B, naïve CD4+and CD8+T cells, granulocytes, monocytes and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousand of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In-silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor motifs respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to transcription factor motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.

Tongue fungiform papillae contain taste buds crucial for taste and hormone-producing taste receptor cells; therefore, they may be considered as endocrine organs and have important age-associated physiological implications. We examine the cross-sectional and longitudinal trajectories of fungiform papillae density in 1084 participants from the Baltimore Longitudinal Study of Aging using linear regression models and mixed effects models. At baseline, the mean age was 67.86 ± 14.20 years, with a mean follow-up time among those with repeat visits of 4.24 ± 1.70 years. Women (53%) were younger (66.85 ± 13.78 vs. 69.04 ± 14.61 years, p < 0.001) and had a higher fungiform papillae density than men (16.14 ± 9.54 vs. 13.77 ± 8.61 papillae/cm2, p < 0.001). Whites (67%) had a lower fungiform papillae density than non-Whites after adjusting for age and sex. Factors cross-sectionally associated with a lower fungiform papillae density included a higher waist-hip ratio (β = −8.525, p = 0.029), current smoking status (β = −5.133, p = 0.014), and alcohol use within the past 12 months (β = −1.571, p = 0.025). Longitudinally, fungiform papillae density decreased linearly with follow-up time (β = −0.646, p < 0.001). The rate of decline was not affected by sex, race, BMI, waist-hip ratio, smoking, or alcohol use. The longitudinal decline of fungiform papillae density over time needs to be explored further in order to identify other possible age-associated physiological determinants.

Background Human motor function is optimised for energetic efficiency, however, age-related neurodegenerative changes affects neuromotor control of walking. Energy utilisation has been associated with motor performance, but its association with cognitive performance is unknown. Methods The study population included 979 Baltimore Longitudinal Study of Aging participants aged $\ge$50 years (52% female, mean age: 70$\pm$10.2 years) with a median follow-up time of 4.7 years. Energy utilisation for walking was operationalised as a ratio of the energy cost of slow walking to peak walking energy expenditure during standardised tasks (‘cost-ratio’). Cognitive functioning was measured using the Trail Making Tests, California Verbal Learning Test, Wechsler Adult Intelligence Scale (WAIS), letter and category fluency and card rotation tests. Linear mixed models adjusted for demographics, education and co-morbidities assessed the association between baseline cost-ratio and cognitive functioning, cross-sectionally and longitudinally. To investigate the relationship among those with less efficient energy utilisation, subgroup analyses were performed. Results In fully adjusted models, a higher cost-ratio was cross-sectionally associated with poorer performance on all cognitive tests except WAIS (P Conclusions These findings suggest cross-sectional and longitudinal links between energy utilisation and cognitive performance, highlighting an intriguing link between brain function and the energy needed for ambulation. Future research should examine this association earlier in the life course to gauge the potential for interventive mechanisms.

OBJECTIVE The concept of frailty has been proposed to capture the vulnerability resulting from aging and has been implemented for the prediction of perioperative outcomes. Carotid artery stenting (CAS) is considered an appropriate minimally invasive procedure for patients considered to high risk to undergo carotid endarterectomy. Recently, the predictive accuracy for perioperative outcomes using the five-item modified frailty index (5mFI) has been reported to be relatively poor for cardiovascular surgery compared with other surgeries. The effects of functional status and the 5mFI on the outcomes after CAS remain unknown. Thus, in the present study, we investigated the relationship between 5mFI, functional status, and perioperative outcomes. METHODS All the patients who had undergone CAS in the Vascular Quality Initiative from November 15, 2016 to December 31, 2018 were included. Good functional status was defined as the ability to perform all predisease activities without restriction using a new variable added to the Vascular Quality Initiative from November 15, 2016 onward. The 5mFI was calculated using functional status and a history of diabetes, chronic obstructive pulmonary disease, congestive heart failure, and hypertension. The perioperative outcomes included in-hospital stroke or death within 30 days after CAS, a prolonged postoperative stay (≥2 days), and nonhome discharge. The associations between functional status, 5mFI, and perioperative outcomes were examined using univariate and multivariable logistic regression, adjusting for sex, age, race, degree of stenosis, symptomatic status, and the usage of preoperative medications. An analysis stratified by functional status was also performed. RESULTS Of the 7836 patients, 188 (2.4%) had experienced perioperative stroke or death, 765 (9.8%) had required a nonhome discharge, and 2584 (33.0%) had required a prolonged postoperative stay. A higher (≥0.6 vs

OBJECTIVES: Acute bronchiolitis commonly causes respiratory failure in children ≤ 2 years, and is particularly severe in those with Down syndrome (DS). Obstructive sleep apnea (OSA), common in DS, is also associated with respiratory complications. However, it is unknown whether OSA is associated with worse outcomes in children with and without DS, hospitalized with bronchiolitis. We hypothesized that in children with bronchiolitis, OSA is associated with worse outcomes in those with DS, independent of DS-related comorbidities. METHODS: Hospital discharge records of children with bronchiolitis aged ≤ 2 years were obtained for 1997–2012 from the Kid’s Inpatient Database. The primary outcome was invasive mechanical ventilation (IMV), and secondary outcomes were non-invasive mechanical ventilation (NIMV), length of hospital stay, and inflation-adjusted cost of hospitalization (IACH). Multivariable regression was conducted to ascertain the associations between OSA and primary and secondary outcomes accounting for DS-associated comorbidities. RESULTS: There were 928,961 hospitalizations for bronchiolitis. The DS group with bronchiolitis (n=8,697) was more likely to have OSA [241 (2.77%) vs 1,293 (0.14%), p

Background Physical activity becomes increasingly fragmented with age, which may be an early marker of functional decline. Energetic cost of walking and energy capacity are also linked with functional decline, but their associations with activity fragmentation, and the potential modifying roles of total daily physical activity and age, remains unclear. Method A total of 493 participants (50–93 years) from the Baltimore Longitudinal Study of Aging underwent measures of energetic cost of usual-paced overground walking (mL/kg/m), energy demand during slow walking (mL/kg/min) on a treadmill (0.67 m/s, 0% grade), and average peak walking energy expenditure (mL/kg/min) during a fast-paced 400-m walk. A ratio of slow walking to peak walking energy expenditure (“cost-to-capacity ratio”) was calculated. Activity fragmentation was quantified as an active-to-sedentary transition probability (ASTP) using Actiheart accelerometer data. Linear regression models with ASTP as the dependent variable were used to test whether poorer energy cost and capacity were associated with higher ASTP and whether the associations differed by daily physical activity or age. Results After adjusting for demographics, body composition, comorbidities, and daily physical activity, every 10% higher cost-to-capacity ratio was associated with 0.4% greater ASTP (p = .005). This association was primarily driven by the least active participants (pinteraction = .023). Peak walking energy expenditure was only associated with ASTP among participants aged ≥70 years. Conclusions Higher cost-to-capacity ratio and lower energy capacity may manifest as more fragmented physical activity, especially among those less active or aged ≥70 years. Future studies should examine whether an increasing cost-to-capacity ratio or declining energy capacity predicts subsequent activity fragmentation.

BACKGROUND: Place of death is important to patients and caregivers, and often a surrogate measure of health care disparities. While recent trends in place of death suggest an increased frequency of dying at home, data is largely unknown for older adults with cancer. METHODS: Deidentified death certificate data were obtained via the National Center for Health Statistics. All lung, colon, prostate, breast, and pancreas cancer deaths for older adults (defined as >65 years of age) from 2003 to 2017 were included. Multinomial logistic regression was used to test for differences in place of death associated with sociodemographic variables. RESULTS: From 2003 through 2017, a total of 3,182,707 older adults died from lung, colon, breast, prostate and pancreas cancer. During this time, hospital and nursing home deaths decreased, and the rate of home and hospice facility deaths increased (all p

OBJECTIVE To determine the impact of obstructive sleep apnea (OSA) on asthma exacerbation severity in children hospitalized for asthma exacerbation. HYPOTHESIS OSA is associated with greater use of invasive mechanical ventilation (IMV) and noninvasive mechanical ventilation (NIMV) in children hospitalized for asthma exacerbation. STUDY DESIGN A retrospective cohort study. PATIENT-SUBJECT SELECTION Hospitalization records of children aged 2-18 years admitted for acute asthma exacerbation were obtained for 2000, 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. METHODOLOGY The primary exposure was OSA, the primary outcome was IMV, and secondary outcomes were NIMV, length of hospital stay (LOS), and inflation-adjusted cost of hospitalization. Multivariable logistic regression, negative binomial, and linear regression were conducted to ascertain the impact of OSA on primary and secondary outcomes. Exploratory analyses investigated the impact of obesity on primary and secondary outcomes. RESULTS Among 564,467 hospitalizations for acute asthma exacerbation, 4209 (0.75%) had OSA. Multivariable regression indicated that OSA was associated with IMV (adjusted odds ratio [OR], 5.33 [95% confidence interval, CI: 4.35-6.54], p

Human aging is a complex multifactorial process associated with a decline of physical and cognitive function and high susceptibility to chronic diseases, influenced by genetic, epigenetic, environmental, and demographic factors. This chapter will provide an overview on the use of epidemiological models with proteomics data as a method that can be used to identify factors that modulate the aging process in humans. This is demonstrated with proteomics data from human plasma and skeletal muscle, where the combination with epidemiological models identified a set of mitochondrial, spliceosome, and senescence proteins as well as the role of energetic pathways such as glycolysis, and electron transport pathways that regulate the aging process.

Although a persistent inflammatory state has long been associated with aging and negative health outcomes, the underlying mechanisms remain unclear. Mitochondrial dysfunction has been proposed as a cause of inflammaging, but evidence of an association in humans is lacking. In this study, we analyzed the cross-sectional association between inflammatory biomarkers and mitochondrial oxidative capacity in skeletal muscle, assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy, in a population of 669 adults (mean age 67 years) from the Baltimore Longitudinal Study of Aging. We observed that participants with lower mitochondrial oxidative capacity exhibited hallmarks of inflammation, specifically markedly higher levels of interleukin-6 and C-reactive protein, as well as increased erythrocyte sedimentation rate when compared with participants with better oxidative capacity, independent of age and sex. We speculate that this association reflects the observation that products of damaged mitochondria, such as mitochondrial DNA, activate multiple pathways that lead to inflammation. Furthermore, excess production of oxidative species (ROS) by dysfunctional mitochondria could trigger inflammation either directly via NF-κB or through oxidative damage to proteins, lipids, and nucleic acids. Longitudinal studies are necessary to ascertain whether and through which mechanisms mitochondrial dysfunction activate inflammation or whether both these phenomena derive from a common root.

Carotid artery stenting (CAS) was introduced as an alternative carotid revascularization procedure in patients deemed to be at high risk for carotid endarterectomy. Although techniques and selection criteria for patients have dramatically improved, CAS continues to have higher risk of stroke and death in comparison to carotid endarterectomy. Several risk factors are known to be associated with worse outcomes. Whereas knowledge of these independent factors is helpful, clinical decision-making is further refined when these are considered in aggregate. This study aimed to develop a score to predict the risk of stroke/death after transfemoral CAS (TFCAS).We analyzed the Vascular Quality Initiative CAS data set from 2010 to 2018. Lesions due to trauma, dissection, or transcarotid artery stenting and cases performed without an embolic protection device were excluded. Univariable and multivariable logistic regression methods with bootstrapping (1000 repetitions) were used to identify predictors associated with 30-day stroke/death. Stepwise backward selection for variables was used to achieve model parsimony. A risk score was made by converting regression coefficients for each predictor to integers from which probability was calculated. Scores were grouped into simplified categories.We identified 10,753 patients undergoing TFCAS during the study period with a combined 30-day stroke/death rate of 4.1%. On multivariable adjustment, independent predictors of 30-day stroke/death included age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.06; P .001), nonwhite race (OR, 1.42; 95% CI, 1.16-1.74; P = .001), diabetes (OR,1.34; 95% CI, 1.08-1.67; P = .01), coronary artery disease (OR, 1.40; 95% CI, 1.13-1.73; P = .001), congestive heart failure (OR, 1.41; 95% CI, 1.07-1.85; P = .02), symptomatic status (OR, 2.11; 95% CI, 1.64-2.72; P .001), and contralateral occlusion (OR, 1.64; 95% CI, 1.22-2.19; P = .001). On the other hand, preoperative use of statins (OR, 0.074; 95% CI, 0.59-0.93; P = .02) and dual antiplatelet therapy (P2YIn an analysis of 10,753 patients undergoing TFCAS between 2010 and 2018, significant predictors of perioperative stroke or death included old age, nonwhite race, symptomatic status, diabetes, coronary artery disease, congestive heart failure, and contralateral occlusion in addition to perioperative dual antiplatelet therapy and statin use. These variables were used to develop a risk score calculator that estimates the probability of 30-day stroke/death after TFCAS. External validation of this tool in different populations of patients and data sets is warranted to evaluate its predictive performance.

Objective Although up to 90% of systemic sclerosis (SSc) patients are affected by gastrointestinal (GI) dysmotility, the clinical phenotype of patients with pseudo-obstruction is not well-defined. We sought to identify this phenotype by studying a large cohort of SSc patients with and without pseudo-obstruction. Methods We performed a retrospective analysis of patients seen at the Johns Hopkins Scleroderma Center between February 2003 and September 2017. All SSc patients had clinical data prospectively collected in a longitudinal database. Cross-sectional analyses were performed comparing autoantibody status and clinical and demographic features of patients with and without pseudo-obstruction. Cox proportional hazards regression was used to identify risk factors for pseudo-obstruction. Results 175 patients with SSc had a history of pseudo-obstruction, and 2,637 SSc patients did not. After adjusting for significant variables from the univariate analysis and potential confounders, the Cox proportional hazards multivariable analysis demonstrated that older age (HR 1.02; 95%CI 1.00–1.04), male sex (HR 1.75; 95%CI 1.42–2.43), diffuse cutaneous disease (HR 2.52; 95%CI 1.59–3.99), myopathy (HR 1.83, 95%CI 1.09–3.08), and opioid use (HR 2.38; 95%CI 1.50–3.78) were predictive of pseudo-obstruction. Autoantibodies to RNA polymerase-3 were negatively associated with pseudo-obstruction (HR 0.34; 95%CI 0.17–0.66). Conclusion We identified clinical features associated with pseudo-obstruction in a large US SSc cohort. This study identifies characteristics of patients with SSc who are at a higher risk of developing pseudo-obstruction and suggests that opioids may be a modifiable risk factor. These clinical features may allow for earlier diagnostic evaluation and/or therapeutic intervention for patients at risk for pseudo-obstruction.

Opening of the cystic fibrosis transmembrane conductance regulator (CFTR) channel is coupled to the motion of its two nucleotide-binding domains: they form a heterodimer sandwiching two functionally distinct ATP-binding sites (sites 1 and 2). While active ATP hydrolysis in site 2 triggers rapid channel closure, the functional role of stable ATP binding in the catalysis-incompetent (or degenerate) site 1, a feature conserved in many other ATP-binding cassette (ABC) transporter proteins, remains elusive. Here, we found that CFTR loses its prompt responsiveness to ATP after the channel is devoid of ATP for tens to hundreds of seconds. Mutants with weakened ATP binding in site 1 and the most prevalent disease-causing mutation, F508del, are more vulnerable to ATP depletion. In contrast, strengthening ligand binding in site 1 with N6 -(2-phenylethyl)-ATP, a high-affinity ATP analogue, or abolishing ATP hydrolysis in site 2 by the mutation D1370N, helps sustain a durable function of the otherwise unstable mutant channels. Thus, tight binding of ATP in the degenerate ATP-binding site is crucial to the functional stability of CFTR. Small molecules targeting site 1 may bear therapeutic potential to overcome the membrane instability of F508del-CFTR. KEY POINTS: During evolution, many ATP-binding cassette transporters - including the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, whose dysfunction causes cystic fibrosis (CF) - lose the ability to hydrolyse ATP in one of the two ATP-binding sites. Here we show that tight ATP binding at this degenerate site in CFTR is central for maintaining the stable, robust function of normal CFTR. We also demonstrate that membrane instability of the most common CF-causing mutant, F508del-CFTR, can be rescued by strengthening ATP binding at CFTR's degenerate site. Our data thus explain an evolutionary puzzle and offer a potential therapeutic strategy for CF.

Screening programs for lung cancer aim to allow diagnosis at the early stage, and therefore the decline in mortality rates. Thus, the aim of this retrospective cohort study was to the comparison of screened and non-screened lung cancer in terms of lung cancer characteristics, overdiagnosis and survival rate. A retrospective study in which 2883 patients with 2883 lung cancer diagnosed according to the hospital-based lung cancer register database between 2007 and 2017. A comparison was performed in term of clinical characteristics and outcomes of lung cancer between the screened and non-screening patient groups. 2883 subjects were identified (93 screened and 2790 non-screened). Screened group patients were younger (59.91 ± 8.14 versus 67.58 ± 12.95; p 0.0001), and were more likely to be female than non-screened group (61.3% versus 36.8%; p 0.0001). The screened group showed significantly better outcomes in overall mortality than the non-screened group (10.75% versus 79.06%; 0.0001). In a Cox proportional hazard model, lung cancer in the screened group proved to be an independent prognostic factor in lung cancer subjects. Our findings point to the improved survival outcome in the screened group and might underline the benefit of low-dose computed tomography (LDCT) screening program in Asian populations with the high prevalence of non-smoking-related lung cancer. Further study aimed at the LDCT mass screening program targeting at light smokers and non-smoker outside of existing screening criteria is warranted.

187 Background: Place of death (PoD) is a surrogate determinant of health care inequity in patients with cancer. Aggregation of Asian Americans, a diverse group, may mask significant health disparities in end-of-life care. Methods: De-identified death certificate data were obtained via the National Center for Health Statistics. All adult (> 18 years of age) prostate cancer deaths from 2018 to 2019 were included. Multinomial logistic regression was used to test for differences in place of death associated with sociodemographic variables. Results: From 2018 through 2019, 81,292 adults died from prostate cancer. Overall, most Asians were less likely to die at home (p < 0.05) or nursing facility (p < 0.05) compared to White patients. Significant differences in nursing facility use was noted in disaggregated analysis, with Samoan patients 12.44 times more likely to die in a hospice facility compared to hospital (CI 2.89, 53.6; p < 0.001) and Chinese patients 100 times less likely to die in a hospice facility (CI 0.01, 0.02; p < 0.001) to give two notable examples. Chinese (OR 0.26), Guamanian (OR 0.2), and Vietnamese race (OR 0.05) had the lowest likelihood of dying at home, with odds ratio lower than Black race (OR 0.3) (Table). Conclusions: Increased attention to PoD over recent years has highlighted issues around equity in end-of-life care. Overall, our data underscore important differences among Asian subpopulations and possible barriers to quality end of life care that would otherwise be masked with data aggregation. It is well known that resources are needed to allow death at home or at a nursing facility. Further qualitative work is planned to investigate culture differences contributing to PoD differences for patients with cancer through the lens of the social determinants of health.

Objective: To investigate whether APOE ε4 genotype—an established risk factor for dementia—is associated with earlier age at diagnosis in addition to increased risk overall and in secondary analysis by race and sex. Methods: We followed up 13,782 dementia-free individuals (n = 10,137 White, n = 3,645 Black, baseline age 60–66 years) in the Atherosclerosis Risk in Communities study for up to 30 years. Dementia was operationalized using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. We used a mixture of generalized gamma distributions to simultaneously estimate time to dementia, time to dementia-free death, and the proportion of individuals with dementia, by APOE ε4 status (≥1 vs. no alleles). Results: Median age of dementia onset among APOE ε4 carriers was 81.7 (Blacks) and 83.3 years (Whites) compared with 82.6 (Blacks) and 85.7 years (Whites) in non-APOE ε4 carriers (p > 0.05 Blacks; p < 0.01 Whites). Age of dementia diagnosis did not differ by sex in ε4 carriers, but among non-carriers, average age was earlier in males than females regardless of race. APOE ε4 carriers had on average a higher proportion of diagnoses; results did not differ by race or sex. Conclusions: APOE ε4 carrier status is associated with earlier age of dementia diagnosis with differences across race and sex. These findings clarify the causal role of APOE in dementia etiology, which could help better identify at-risk subgroups and may help facilitate better research trial recruitment and design.

Importance Hearing impairment, a common treatable condition, may contribute to poorer physical function with aging. Objective To assess whether hearing impairment is associated with poorer physical function, reduced walking endurance, and faster decline in physical function. Design, Setting, and Participants In this cohort study, cross-sectional and longitudinal analyses were performed using data from the 2011 to 2019 period of the Atherosclerosis Risk in Communities study, a population-based study of community-dwelling adults at 4 sites in the US. Exposures Hearing thresholds (per 10 dB) assessed with pure tone audiometry and categorized as normal hearing or mild, moderate, or severe hearing impairment. Main Outcomes and Measures Physical function was assessed using the short physical performance battery (SPPB), with composite scores ranging from 0 to 12. A composite score of 6 or less and a score for each component (balance, gait speed, and chair stands) of 2 or less indicated poor performance. Walking endurance was assessed using a 2-minute fast-paced walk test. Tobit regression models adjusted for sociodemographic factors and medical history were used to calculate the mean differences in SPPB composite scores; logistic regression models, to estimate the odds ratios (ORs) of low SPPB composite and component scores; and linear mixed-effects models, to estimate the mean rate of change in SPPB composite scores over time. Results Of the 2956 participants (mean [SD] age, 79 [4.6] years) who attended study visit 6 between 2016 and 2017, 1722 (58.3%) were women, and 2356 (79.7%) were White. As determined by pure tone audiometry, 973 (33%) participants had normal hearing, 1170 (40%) had mild hearing impairment, 692 (23%) had moderate hearing impairment, and 121 (4%) had severe hearing impairment. In the Tobit regression model, severe hearing impairment was associated with a lower mean SPPB score (β, –0.82; 95% CI, –0.34 to –1.30) compared with normal hearing. In fully adjusted logistic regression models, hearing impairment was associated with higher odds of low physical performance scores (severe impairment vs normal hearing: OR for composite physical performance, 2.51 [95% CI, 1.47-4.27]; OR for balance, 2.58 [95% CI, 1.62-4.12]; OR for gait speed, 2.11 [95% CI, 1.03-4.33]). Over time (2 to 3 visits; maximum, 8.9 years), participants with hearing impairment had faster declines in SPPB compared with those with normal hearing (moderate hearing impairment × time interaction, –0.34 [–0.52 to –0.16]). In adjusted models for walking endurance, participants with moderate or severe hearing impairment walked a mean distance of –2.81 m (95% CI, –5.45 to –0.17 m) and –5.31 m (95% CI, –10.20 to –0.36 m) than those with normal hearing, respectively, during the 2-minute walk test. Conclusions and Relevance In this cohort study, hearing impairment was associated with poorer performance, faster decline in physical function, and reduced walking endurance. The results of the longitudinal analysis suggest that hearing impairment may be associated with poorer physical function with aging. Whether management of hearing impairment could delay decline in physical function requires further investigation.

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

BACKGROUND Childhood pneumonia is a leading cause of mortality worldwide. Growing evidence suggests that lung ultrasound (LUS) may be a reliable diagnostic alternative to chest x-ray for childhood pneumonia. However, it is unclear whether sonographer experience affects the diagnostic accuracy of LUS. We summarize the diagnostic accuracy of LUS for pneumonia and compare the performance between novice and advanced sonographers with a systematic review and meta-analysis. METHODS We searched PubMed and EMBASE from inception to February 2018 for eligible studies that evaluated the utility of LUS in children suspected of having pneumonia against the reference standard of either imaging results alone or a combination of clinical, laboratory, and imaging results. We reported the study using the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies. We used QUADAS-2 to appraise the included studies' methodologic quality. We employed a random-effect bivariate model and a hierarchical summary receiver operating characteristic curve to evaluate LUS's performance characteristics. We conducted subgroup analyses and meta-regression based on level of sonographer training to summarize and compare LUS's diagnostic accuracy for pneumonia between novice (training ≤ 7 days) and advanced sonographers. RESULTS Twenty-five studies (n = 3,353) were included in the meta-analysis. For diagnosing pneumonia, LUS demonstrated an overall sensitivity of 0.94 (95% confidence interval [CI] = 0.89 to 0.97), specificity of 0.92 (95% CI = 0.78 to 0.98), positive likelihood ratio of 12.40 (95% CI = 4.00 to 38.10), and negative likelihood ratio of 0.07 (95% CI = 0.04 to 0.12), with an area under ROC curve of 0.97 (95% CI = 0.95 to 0.98). Meta-regression revealed a significant difference in the diagnostic accuracy for pneumonia for LUS between novice and advanced sonographers (p

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data. Unfortunately, measurements for individual CpGs can be surprisingly unreliable due to technical noise, and this may limit the utility of epigenetic clocks. We report that noise produces deviations up to 3 to 9 years between technical replicates for six major epigenetic clocks. The elimination of low-reliability CpGs does not ameliorate this issue. Here, we present a novel computational multi-step solution to address this noise, involving performing principal component analysis on the CpG-level data followed by biological age prediction using principal components as input. This method extracts shared systematic variation in DNAm while minimizing random noise from individual CpGs. Our novel principal-component versions of six clocks show agreement between most technical replicates within 0 to 1.5 years, equivalent or improved prediction of outcomes, and more stable trajectories in longitudinal studies and cell culture. This method entails only one additional step compared to traditional clocks, does not require prior knowledge of CpG reliabilities, and can improve the reliability of any existing or future epigenetic biomarker. The high reliability of principal component-based epigenetic clocks will make them particularly useful for applications in personalized medicine and clinical trials evaluating novel aging interventions.

Key Points Question Is there an association between hearing loss and physical activity? Findings In this cross-sectional study that included 291 adults aged 60 to 69 years, hearing loss was associated with a worse physical activity profile, including less moderate-to-vigorous physical activity, less light-intensity activity, and a more fragmented physical activity pattern. Meaning These findings suggest that promoting physical activity among older adults with hearing loss is important, and further research is needed to investigate whether hearing loss interventions could improve physical health profiles., This cross-sectional study examines the association of hearing loss with objectively measured physical activity, including moderate-to-vigorous physical activity, light-intensity physical activity, sedentary behavior, and physical activity fragmentation., Importance Hearing loss may be a modifiable factor associated with decreased physical activity in older adults. Objective To examine the association of hearing loss with objectively measured physical activity, including moderate-to-vigorous physical activity, light-intensity physical activity, sedentary behavior, and pattern of physical activity (physical activity fragmentation). Design, Setting, and Participants This population-based cross-sectional study used National Health and Nutrition Examination Survey (NHANES) data collected in the 2003 to 2004 cycle and analyzed in 2017 to 2020. Participants aged 60 to 69 years with complete audiometry, physical activity, and comorbidity data were included in the analysis. Data analysis was performed from January 2017 to December 2020. Exposures Hearing defined by the pure tone average (PTA; range, 0.5-4 kHz) in the better ear, with normal PTA defined as less than 25 dB hearing loss, mild hearing loss defined as PTA 25 to less than 40 dB hearing loss, and moderate or greater hearing loss defined as a PTA greater than or equal to 40 dB hearing loss. Main Outcomes and Measures The primary outcomes were comprehensive metrics of objectively measured physical activity, including time spent in moderate-to-vigorous physical activity, light-intensity physical activity, and sedentary behavior, and physical activity fragmentation. Linear regression was used to model the association between hearing loss and physical activity. Results Of the 291 participants (mean [SD] age, 64.53 [2.96] years), 139 (47.8%) were male, 48 (16.5%) had mild hearing loss, and 22 (7.6%) had moderate or greater hearing loss. After adjusting for age, sex, education, race/ethnicity, and comorbidities, hearing loss (vs normal hearing) was significantly associated with less time spent in moderate-to-vigorous physical activity by 5.53 minutes per day (95% CI, −10.15 to −0.90 minutes per day), less time spent in light-intensity physical activity by 28.55 minutes per day (95% CI, −53.07 to −4.02 minutes per day), more time spent in sedentary behaviors by 34.07 minutes per day (95% CI, 8.32 to 59.82 minutes per day), and more fragmented physical activity pattern by 0.38 SD higher in active-to-sedentary transition probability (95% CI, to 0.10 to 0.65). The magnitude of the association of hearing loss (vs normal hearing) with physical activity metrics was equivalent to 7.28 years (95% CI, 3.19 to 11.37 years) of accelerated age for moderate-to-vigorous physical activity, 5.84 years (95% CI, 1.45 to 10.23 years) of accelerated age for light-intensity physical activity, and 10.53 years (95% CI, 2.89 to 18.16 years) of accelerated age for degree of physical activity fragmentation. Conclusions and Relevance These findings suggest that hearing loss is associated with a worse physical activity profile. Whether interventions to address hearing loss in adults could improve physical activity profiles will require further study.

Background Although hearing impairment (HI) is linked to poorer physical functioning, the longitudinal associations between HI and higher-level functional measures are unclear. Method Data are from the Baltimore Longitudinal Study of Aging (2012–2019). Using pure-tone audiometry, we categorized hearing into normal, mild, and moderate or greater HI. Physical function was assessed with the expanded Short Physical Performance Battery (eSPPB) and walking endurance with time to walk 400 m. Multivariable and mixed-effects linear models tested the hypotheses that participants with HI, at baseline, have poorer physical performance and walking endurance, and faster decline over time (up to 6 measurements). In a subset (n = 526), we further adjusted for vestibular function. Among participants with HI, we evaluated the differences in eSPPB scores and walking endurance between hearing aid users and nonusers. Results Of 831 participants, 26% had mild, and 17% moderate or greater HI. After adjustment for demographics and medical history, moderate or greater impairment versus normal hearing was associated with poorer function (0.17 [95% CI: 0.09, 0.26] lower eSPPB score, and 13.3 [95% CI: 3.31, 23.4] seconds slower 400-m walk time) and faster decline in these parameters over 6 years. Adjustment for vestibular function did not attenuate these associations. Hearing aid users walked 400 m 24 seconds faster than nonusers (p = .001). Conclusion Moderate or greater HI is associated with poorer initial and greater decline in higher-level physical performance. The observation that hearing aid users had better walking endurance suggests that screening for and treatment of HI may delay or slow progression of hearing-related functional decline.

Key Points Question What is the prevalence of functional dual sensory impairment and is it associated with dementia risk among community-dwelling older adults in the US? Findings In this cohort study of adults over the age of 65 years, 14.9% of adults aged 90 years or older reported functional dual sensory impairment. Functional dual sensory impairment was associated with a higher 7-year risk of dementia compared with no sensory impairment. Meaning The results of this study suggest that functional sensory impairments are prevalent among older adults, and interventions to address multiple sensory impairments may be a potential target to reduce dementia risk., This cohort study of community-dwelling older adults in the US examined the age-specific prevalence of functional dual sensory impairment and assessed cross-sectional and longitudinal associations between functional dual impairment and dementia., Importance Impairments in vision or hearing are common and have been independently linked to higher risk of dementia in older adults. There is a limited understanding of the prevalence of concurrent functional vision and hearing impairment (dual sensory impairment) and its contribution to dementia risk. Objective To examine the age-specific prevalence of functional dual sensory impairment among older adults, and to investigate the cross-sectional and 7-year longitudinal associations between functional dual sensory impairment and dementia. Design, Setting, and Participants This cohort study of 7562 older adults used data from the US National Health and Aging Trends Study (NHATS), a nationally representative cohort study of community-dwelling, Medicare beneficiaries aged 65 years and older in the US. Participants in the study with complete data on hearing, vision, and dementia were included in analysis. Data were collected between 2011 and 2018, and between March 2018 and May 2020. Exposures Self-reported functional sensory impairments (ie, no sensory impairment, functional vision impairment only, functional hearing impairment only, and functional dual sensory impairment). Main Outcomes and Measures Age-specific prevalence of functional sensory impairments was calculated. Generalized linear regression with a complementary log-log link and a discrete time proportional hazards model with a complementary log-log link were used to assess the cross-sectional and 7-year longitudinal hazard of dementia. Results Of 7562 participants, 3073 (40.7%) were ages 80 years or older and 4411 (58.3%) were women. Overall, 5.4% (95% CI, 4.7%-6.1%) of participants reported functional vision impairment only, 18.9% (95% CI, 18.9%-17.8%) reported functional hearing impairment only, and 3.1% (95% CI, 2.7%-3.5%) reported functional dual sensory impairment (prevalence estimates are weighted). Participants reporting sensory impairments were older (no impairment: age ≥90 years, 2.12% [95% CI, 1.79%-2.46%] vs functional dual sensory impairment: age ≥90 years, 20.06% [95% CI, 16.02%-24.10%]), had lower education (no impairment

Study ObjectivesObstructive sleep apnea (OSA) is associated with cardiovascular and cerebrovascular morbidity. Patients with sickle cell disease (SCD) are at increased risk for both neurologic complications (NC) and OSA. However, the relationship between OSA and SCD complications is unclear. We hypothesized that there would be an association between OSA diagnosis and SCD complications.MethodsHospital discharge records of patients with SCD aged < 19 years were obtained for the years 1997, 2000, 2003, 2006, 2009, and 2012 from the Kid’s Inpatient Database. The primary outcome, NC, a composite of stroke, transient ischemic attack, and seizures. Secondary outcomes included acute chest syndrome (ACS), vaso-occlusive crisis, length of hospital stay, and inflation-adjusted cost of hospitalization. Multivariable regression was conducted to ascertain the association of OSA with primary and secondary outcomes. Analyses were adjusted for the use of noninvasive mechanical ventilation (NIMV) to determine its role as NC risk modifier.ResultsThere were 203,705 SCD discharges included in the analysis, of which 2,820 (1.4%) and 4,447 (2.2%) also included OSA and NC diagnoses. Multivariable logistic regression indicated that OSA was associated with NC (adjusted odds ratio [OR], 1.50 [95% CI 1.02–2.21], p = 0.039) and ACS (OR, 1.34 [95% CI 1.08–1.67], p = 0.009) in children with SCD. In the multivariable analysis adjusted for NIMV, the significant association between OSA and NC was no longer observed (OR, 1.39 [95% CI 0.94–2.05], p = 0.100).ConclusionsOSA is associated with a 50% increase of odds of NC in children with SCD in this nationwide dataset. The use of NIMV to treat OSA may modify the risk of OSA-associated NC.

Biological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

Over the past three decades, considerable effort has been dedicated to quantifying the pace of ageing yet identifying the most essential metrics of ageing remains challenging due to lack of comprehensive measurements and heterogeneity of the ageing processes. Most of the previously proposed metrics of ageing have been emerged from cross-sectional associations with chronological age and predictive accuracy of mortality, thus lacking a conceptual model of functional or phenotypic domains. Further, such models may be biased by selective attrition and are unable to address underlying biological constructs contributing to functional markers of age-related decline. Using longitudinal data from the Baltimore Longitudinal Study of Aging (BLSA), we propose a conceptual framework to identify metrics of ageing that may capture the hierarchical and temporal relationships between functional ageing, phenotypic ageing and biological ageing based on four hypothesized domains: body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity. We explored the longitudinal trajectories of key variables within these phenotypes using linear mixed-effects models and more than 10 years of data. Understanding the longitudinal trajectories across these domains in the BLSA provides a reference for researchers, informs future refinement of the phenotypic ageing framework and establishes a solid foundation for future models of biological ageing.

The study of aging relates to changes in physical and functional dimensions that occur over time in living organisms. Yet, a model that establishes the hierarchical relationship and interlaced time courses of molecular, phenotypic, and functional hierarchical domains of aging in humans has not been established. We propose that studying the mechanisms and consequences of aging through the lens of these hierarchical domains and their connections will provide clarity in semantics and enhance a translational perspective. The study of human aging would be most informative from a life course, longitudinal perspective, given that manifestations of aging are already detectable early in life at the molecular level, yet the phenotypic responses remain masked by compensatory/resiliency mechanisms. Understanding the nature of these mechanisms is paramount for developing interventions that reduce the burden of disease and disability in older persons.

Screening programs for lung cancer aim to allow diagnosis at the early stage, and therefore the decline in mortality rates. Thus, the aim of this retrospective cohort study was to the comparison of screened and non-screened lung cancer in terms of lung cancer characteristics, overdiagnosis and survival rate. A retrospective study in which 2883 patients with 2883 lung cancer diagnosed according to the hospital-based lung cancer register database between 2007 and 2017. A comparison was performed in term of clinical characteristics and outcomes of lung cancer between the screened and non-screening patient groups. 2883 subjects were identified (93 screened and 2790 non-screened). Screened group patients were younger (59.91 ± 8.14 versus 67.58 ± 12.95; p

The longitudinal associations between hearing impairment and higher-level functional measures and the potential confounding role of vestibular function have not been assessed. We investigated these associations in 831 participants of the Baltimore Longitudinal Study of Aging (2012–2019). Hearing was measured using pure-tone audiometry and categorized using WHO standards. Physical function was assessed with the Health Aging and Body Composition Physical Performance Battery (HABCPPB, higher=better) and walking endurance with time to walk 400 meters. Multivariable regression models tested the hypotheses that participants with hearing impairment have poorer physical outomes. In a subset, we further adjusted for vestibular function. Hearing impairment was associated with decrements in higher-level physical performance and walking endurance, and faster decline over time, regardless of vestibular function. Among participants with any hearing impairment, hearing aid users were faster in the 400-m walk. Early screening for higher-level functional loss among older adults with hearing loss is warranted.

Renal function declines markedly with age due to normal aging and/or disease processes and impacts multiple systems. Diminished renal function may manifest as low exercise tolerance and fatigue threshold. Using data on 951 well-functioning (usual gait speed >.67m/s and no difficulty walking ¼ mile) men and women (51%) aged 60-89 years in the Baltimore Longitudinal Study of Aging, we evaluated the cross-sectional association between perceived fatigability (Rating Perceived Exertion after 5-minute treadmill walk at 1.5mph) categorized as 6-7, 8-9, 10-11 and 12+ and GFR using Cockcroft-Gault. For each fatigability increment, likelihood of suboptimal (GFR=75-89, 21%), diminished (GFR=60-74, 26%) and poor renal function (GFR=15-59, 30%) relative to GFR≥90 was respectively OR(95%CI)p-value 1.51(1.16-1.96).002, 1.38(1.04-1.83).027 and 1.68(1.22-2.31).002 adjusted for demographics, weight, height, smoking, exercise and anemia. Findings were similar for men and women. Perceived fatigability may facilitate identification of apparently well-functioning older adults on the precipice of suboptimal to poor renal function.