Publications

INTRODUCTION: Contrasting active treatment against a placebo has long been the gold standard in clinical medicine. The possible impact of placebo responses in surgery has recently been investigated using sham surgery. Despite indications that both genuine and placebo surgeries may lead to positive outcomes, no investigation into the differential routes to improvement has been performed.

OBJECTIVES: To assess the mechanisms involved in improvements seen in patients with sacroiliac joint pain who undergo genuine or placebo surgery.

METHODS: This randomized controlled trial incorporated both subjective and objective assessments, including functional magnetic resonance imaging and experimental pain testing, at baseline and 6-month follow-up in a surgical trial including patients with chronic pain. Twenty-three patients were randomized to receive genuine surgery (sacroiliac joint fusion) or placebo (sham). An additional 7 patients were included as observational controls.

RESULTS: There was a significant reduction in weekly pain intensity for both the genuine and placebo groups at follow-up, with greater reductions in the genuine group compared with placebo (P = 0.04). The difference was driven by a few "super-responders" in the genuine group. Clinical improvements correlated with experimental pain outcomes at the operated sacroiliac joint. Functional brain connectivity between the somatosensory cortex and the default mode network decreased more in the genuine group compared with the placebo group.

CONCLUSION: Preliminary findings indicate decreased connectivity between somatosensory and default mode networks for patients in the genuine vs sham group, demonstrating the first findings of differential neural processing in pain-relevant brain networks after genuine vs placebo surgery using objective measures. Understanding the active mechanisms of surgery may lead to personalized treatments, more effective pain reduction, and less side effects for patients with pain.

INTRODUCTION: Dementia has been strongly linked with cardiovascular disease, but the relationships between cardiovascular disease and brain health at subclinical stages have not been fully explored. We investigated the associations between subclinical cardiac dysfunction, defined by cardiac biomarkers and echocardiography, and novel neurobiomarkers associated with the brain injury in older adults.

METHODS: We included 962 participants from the Cardiovascular Health Study who had no history of stroke, transient ischemic attack, atrial fibrillation, heart failure, or myocardial infarction. We analyzed cross-sectional associations using linear regression. Outcomes variables were serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), two markers of subclinical brain injury. Exposure variables were serum N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) and subclinical cardiac measures including echocardiographic left atrial reservoir strain, left ventricular average longitudinal strain, early diastolic strain rate of the left ventricle, decreased left ventricular ejection fraction, average E/e', percent predicted left ventricular mass, and left atrial diameter.

RESULTS: Among 844 participants with serum biomarkers, hs-cTnT was significantly associated with NfL (β = 1.881, 95 % CI: (0.729, 3.032), p = 0.001), and this association remained significant even after mutual adjustment for NT-proBNP (β = 1.781, 95 % CI: (0.626, 2.937), p = 0.003). NT-proBNP was also associated with NfL (β = 1.170, 95 % CI: (0.047, 2.293), p = 0.041), although this association was slightly attenuated and not statistically significant after adjustment for hs-cTnT (β = 1.004, 95 % CI: (-0.119, 2.126), p = 0.08). There were no significant associations observed for either circulating marker with GFAP, nor were echocardiographic variables associated with NfL or GFAP.

CONCLUSIONS: In older adults without clinically identified cardiovascular disease, subclinical cardiac dysfunction identified through hs-cTnT and, to a lesser extent, NT-proBNP, was associated with higher levels of NfL, a marker of brain injury. This novel insight suggests that even subclinical cardiac disease is linked to brain health.

BACKGROUND: While mindfulness meditation (MM) apps have gained popularity as a tool for promoting sleep, research focusing on bedtime mindfulness practice and app usage is limited.

OBJECTIVE: As the first step toward understanding the efficacy and mechanisms of such bedtime practice and to inform future investigations, the goal of this pilot study was to explore the feasibility of app-guided bedtime MM practice with both in-lab and at-home physiological and self-report sleep remote assessments.

METHODS: We conducted a single-arm, prospective mixed methods pilot study that included both standard in-lab sleep studies and remote at-home assessments of individuals with insomnia disorder with self-reported difficulty falling asleep. Participants practiced MM guided by a commercially available smartphone app at bedtime for 4 weeks. Pre-post assessments included a battery of sleep-related and psychological health questionnaires, objective physiological sleep measures (polysomnography and actigraphy), and daily sleep logs. We also conducted qualitative exit interviews to further assess feasibility and acceptability. Transcripts were analyzed for dominant themes using inductive and deductive qualitative methods.

RESULTS: We recruited 13 participants with chronic insomnia (symptoms ≥3 nights weekly for ≥3 months) to complete the study protocol within 8 months (retention rate 77%). We were able to collect analyzable physiological and psychometric data with overall completion rates of more than 90%. The study was deemed feasible, meeting a priori benchmarks including recruitment, retention, completion, and adherence. The 10 participants retained in the program had excellent engagement (95% completion of in-lab studies, 100% completion of questionnaires, and 91% compliance with use of the app). Our preliminary analysis of subjective measures indicated improvement in sleep quality, insomnia severity, and presleep arousal, including Pittsburgh Sleep Quality Index change of -3.7 (95% CI -6.7 to -0.7), Insomnia Severity Index change of -4.5 (95% CI -7.7 to -1.4), Pre-Sleep Arousal Scale change of -7.7 (95% CI -13.1 to -2.3), and trend toward improvement in the Ford Insomnia Response to Stress Test indicated by a change of -2.5 (95% CI -5.9 to 0.9). From qualitative data, we identified domains that inform the feasibility and acceptability of the study, including (1) barriers to sleep prior to the study, (2) benefits and skills imparted by mindfulness, and (3) feedback on app use. Benefits and skills imparted by mindfulness included decreased catastrophizing, acceptance and nonreactivity, body awareness and relaxation, self-kindness, awareness of sleep hygiene and bedtime routine, earlier defusing of stress, increased focus and presence, and calm throughout the day.

CONCLUSIONS: Bedtime app-guided MM as an intervention in patients with insomnia and the hybrid study design with in-lab and at-home assessments are feasible and acceptable. This study informs the design of future clinical and mechanistic research examining app-guided MM to impact insomnia severity and presleep arousal.

BACKGROUND: Exposure to lipopolysaccharide (LPS), a potent proinflammatory glycolipid derived from gut microbiota, may be linked to the development of coronary heart disease (CHD). However, evidence from human studies is limited.

OBJECTIVES: We aimed to investigate prospective relationships between 2 plasma biomarkers of LPS exposures-LPS-binding protein (LBP) and soluble cluster of differentiation 14 (sCD14)-in relation to incident CHD among United States males and females.

METHODS: A prospective nested 1:1 matched case-control study of CHD was conducted among participants in the Nurses' Health Study II (NHSII) and Health Professionals Follow-up Study (HPFS). Plasma concentrations of LBP and sCD14 were measured in 496 HPFS male CHD case-control pairs and 212 NHSII female pairs.

RESULTS: Among controls, plasma concentrations of LBP exhibited positive correlations with age, body mass index, and C-reactive protein (CRP) concentrations and an inverse correlation with high-density lipoprotein cholesterol concentrations. For sCD14, positive correlations with age and CRP were only observed in HPFS controls. Neither elevated LBP nor sCD14 concentrations were significantly associated with incident CHD in HPFS. In NHSII, higher sCD14 concentrations, but not LBP, were significantly associated with higher risk of CHD, with a risk ratio of 3.01 [95% confidence interval (CI): 1.28, 7.11] when comparing extreme quintiles. Collectively, CRP and the total cholesterol/ high-density lipoprotein cholesterol ratio explained 27.9% (95% CI: 7.1%, 66.1%; P = 0.01) of the positive association between sCD14 and CHD in NHSII females. These associations were not modified by physical activity, alcohol intake, body mass index, inflammation markers, family history of CHD, or the presence of hypertension, hyperlipidemia, or type-2 diabetes.

CONCLUSION: Higher concentrations of sCD14 may be associated with an increased risk of CHD in females, whereas LBP concentrations are not associated with CHD in either sex. These data do not support that LPS exposure in initially healthy individuals is a contributing CHD risk factor, although the potential sex difference should be explored further.

AIMS: Circulating ketone bodies (KB) are an important source of metabolic fuel for the myocardium under physiological and pathological conditions. Prior studies have linked KB levels with adverse cardiovascular outcomes. However, their relationship with atrial fibrillation (AF) risk remains unknown. The objective is to evaluate the association of KB levels with the risk of incident AF.

METHODS AND RESULTS: This prospective, multicentre cohort study recruited patients without baseline AF from the Multi-Ethnic Study of Atherosclerosis (MESA) and the UK Biobank (UKB), respectively. Total KB levels were measured by nuclear magnetic resonance spectroscopy in both studies. The associations between total and individual KB and incident AF were evaluated using multivariable-adjusted Cox proportional hazard models. Prespecified interaction analyses were performed for smoking status, history of diabetes mellitus, history of hypertension, body mass index, and self-reported race/ethnicity (to represent a social construct). A total of 6783 participants [mean (standard deviation, SD) age 62 (10) years, 52% women, 38% White, 27.5% Black, 21.8% Hispanic, and 11.6% Chinese American] from MESA and 116 480 participants [mean (SD) age 56.5 (8) years, 54% women, 94% White] from the UKB were included. Over a median follow-up of 16.5 (10.3-17.4) years in MESA and 13.6 (12.8-14.4) years in the UKB, higher levels of total KB were associated with a higher risk of incident AF. In MESA, each doubling of baseline total KB levels was associated with a 1.08-fold increased hazard of incident AF on follow-up [95% confidence interval (CI): 1.00-1.16] after adjustment for confounding factors. Consistent results were obtained in a subgroup analysis stratified by different types of KB (β-hydroxybutyrate, acetoacetate, and acetone). There was a significant interaction with current smoking, such that per doubling of total KB levels was associated with a 1.32-fold increased hazard for incident AF in current smokers (95% CI: 1.08-1.61), but this association was not seen among former/never smokers [hazard ratio (95% CI): 1.05 (0.95-1.13)]. These results were replicated in the UKB.

CONCLUSION: Higher concentrations of KB are associated with an increased risk of AF in predominantly healthy, community-based cohorts, acknowledging that many participants also had comorbidities such as hypertension and diabetes, particularly among smokers. Ketone bodies could serve as a potential biomarker for identifying populations at risk for AF.

We investigated the associations of pregnancy levels of heavy metals and trace elements with the risk of gestational diabetes mellitus (GDM). Participating pregnant women were from the Boston Birth Cohort. We measured levels of mercury, lead, cadmium, selenium, and manganese in maternal red blood cells collected after delivery. We verified the GDM diagnosis using ICD codes, medication history, and plasma glucose profile abstracted from medical records. We used modified Poisson regression and Bayesian kernel machine regression models to examine associations of metals and elements, individually and as a mixture, with GDM. We stratified the analyses by race and ethnicity. Among 1256 pregnant women, 58% were non-Hispanic Black and 22% were Hispanic. Overall, each doubling of mercury and manganese levels was associated with 1.14 (95% CI: 1.01-1.28) and 0.65 (95% CI: 0.50-0.84) times the risk of GDM, respectively. In the race- and ethnicity-stratified analyses, the mercury-GDM association was stronger among Black women, and higher selenium levels were associated with higher GDM risk only among Hispanic women (Pinteraction = 0.01). In conclusion, women with higher mercury or lower manganese levels during pregnancy were more likely to develop GDM. An increased GDM risk associated with higher selenium levels was observed only in Hispanic women.

INTRODUCTION: The present study examined the dimensional structure of the neuropsychological test batteries from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) versions 2.0 and 3.0 and measurement equivalence across UDS versions and race/ethnicity groups.

METHODS: There were 49,895 participants included in the present study. The best-fitting model was developed and tested in separate samples. Multiple group confirmatory factor analysis (CFA) evaluated measurement equivalence across UDS versions and race/ethnicity groups.

RESULTS: Results identified a best-fitting four-factor model with residual structure. Multiple group CFA supported partial scalar invariance by UDS version and race/ethnicity group. Regarding race/ethnicity groups, the Language and Attention domains had more non-invariant intercepts, which most affected the White group.

DISCUSSION: A four-factor model effectively summarizes the UDS neuropsychological test batteries across UDS versions and race/ethnicity groups. Crucial differences in measurement parameters must be accounted for in studies using these neuropsychological tests as outcomes.

HIGHLIGHTS: A four-factor model summarizes cognition across Uniform Data Set (UDS) versions and race/ethnicity groups. Measurement invariance exists across race/ethnicity groups. Model fit differs between cognitively impaired and unimpaired samples. Accounting for differences in measurement parameters across groups is essential. Tailored normative data are crucial for certain UDS tests, including category fluency.

STUDY OBJECTIVES: Circulating non-esterified fatty acids (NEFAs) have been associated with impaired glucose metabolism but their modifiable determinants remain uncertain. We sought to determine the association between objectively-measured sleep disordered breathing (SDB), which is also associated with dysglycemia, and NEFA levels among community-dwelling older adults.

METHODS: We analyzed 787 older adults who had total fasting and post-load NEFAs measured in 1996-1997 in the Cardiovascular Health Study and underwent polysomnography between 1995 and 1997 in the Sleep Heart Health Study. We used multivariable linear regression to model NEFAs as a function of four SDB parameters: apnea-hypopnea index, arousal index, hypoxemia, and slow-wave sleep, and tested formal mediating effects by insulin sensitivity estimated with the Gutt index.

RESULTS: The mean age of study participants was 77.5 ± 4.3 years. The proportion of females and non-Hispanic whites was 58.7 per cent and 84.2 per cent, respectively. We did not find statistically significant associations between any of the SDB parameters and fasting NEFAs, but higher amounts of slow-wave sleep were significantly associated in a linear fashion with lower total post-load NEFAs in unadjusted and adjusted models [adjusted: β = -0.004, SE = 0.001, p = .02]. In mediation analyzes, 10 per cent of the slow wave sleep-NEFA association was mediated by Gutt-estimated insulin sensitivity (p = .45 for the indirect effect).

CONCLUSIONS: Among the SDB measures studied, only higher levels of objectively measured slow-wave sleep were significantly associated with lower levels of post-load NEFAs, although the underlying mechanism is uncertain. Establishing a causal link would make SDB interventions a promising target for NEFA regulation.

BACKGROUND: Heart rate variability (HRV) is a measure of autonomic function that has been associated with worse lung function and worse respiratory health. Using data from a community-based cohort, we aimed to test if HRV is associated with lung function and self-reported chronic lung disease (CLD).

METHODS: The Atherosclerosis Risk in Communities (ARIC) study is a community-based cohort that collected HRV measurements from 14-day continuous ECG patches and self-reported CLD at visit 6 (2016-2017). Pulmonary function testing was performed a prior visit (visit 5; 2011-2013). We used multivariate linear regression to test cross-sectional associations between HRV and lung function, and logistic regression to test associations between HRV and self-reported CLD. All analyses were adjusted for important confounders including smoking, demographics, and medications.

RESULTS: HRV and lung function measurements were available for 1456 participants. Included participants had a mean ± standard deviation (SD) age of 78.7 ± 4.5 years, 59.6 % were female, and 30.1 % were African American. Higher HRV reflective of overall HRV (standard deviation of normal RR intervals) and sympathetic activity [low frequency (LF) to high frequency (HF) ratio (LF/HF)] were associated with better lung function and lower odds of self-reported CLD. Higher HRV reflective of parasympathetic function (HF) was associated with worse lung function and higher odds of self-reported CLD.

CONCLUSIONS: We confirmed associations between HRV and respiratory health outcomes. Our data from a community-based cohort demonstrate the importance of utilizing several HRV measurements to capture multiple components of autonomic function when analyzing respiratory health outcomes.