Biomarker panel discriminates diabetics with and without periodontitis pre- and post-therapy.

BACKGROUND AND OBJECTIVE: Biological regulators of periodontal inflammation, collagen degradation, and insulin resistance have not been determined in association with severity of periodontitis and response to periodontal treatment in diabetics. Our objective was to determine whether type 2 diabetes (T2DM) patients with periodontal disease present a distinct salivary biomarker profile compared with T2DM patients without periodontal disease and healthy subjects (without diabetes and periodontitis) pre- and post-nonsurgical therapy. METHODS: Clinical parameters of periodontal health and whole unstimulated saliva were collected from 92 participants (31 Not Periodontitis, NP; 32 T2DM without periodontitis, DWoP; and 29 with T2DM with periodontitis, DWP) at baseline. The T2DM groups received scaling and root planning (SRP) and provided saliva at 6-week follow-up. Salivary concentrations of interleukin (IL)-1ß, IL-6, matrix metalloproteinase-8 (MMP-8), and resistin were measured by immunoassay. RESULTS: The DWP group had significantly more disease and higher salivary concentrations at baseline for IL-1ß, MMP-8, and resistin (p's < .01) compared with DWoP and NP. SRP resulted in significant improvement in periodontal parameters for the T2DM groups; however, more disease persisted (p < .001), and IL-1ß, MMP-8, and resistin concentrations remained significantly higher in the DWP than the DWoP group (p < .01) at 6 weeks post-treatment. Principal component analysis demonstrated the DWoP group appeared more biologically similar to the NP group than the DWP group. Concentrations of these salivary biomarkers increased with increasing periodontal disease severity (p < .05) in this study population. CONCLUSION: Salivary concentrations of IL-1ß, MMP-8, and resistin appear to serve as biomarkers of periodontal status pre- and post-treatment, irrespective of diabetes status.

Facilitators and Barriers to Attendance in a Nursing Home Exercise Program.

Women and residents in Certified Nursing Homes (CNHs) with higher star ratings had better attendance in exercise and social engagement programming (ie, Bingocize) than men and residents in CNHs with lower ratings. OBJECTIVE: The purpose of the current study was to determine whether resident factors and nursing home star ratings influenced attendance in Bingocize, a therapeutic exercise program that incorporates opportunities for social engagement in nursing homes. DESIGN: This is a descriptive study of data collected across multiple nursing homes over 17 months. SETTING AND PARTICIPANTS: Data were collected from residents in 25 certified nursing homes in the mid-southern United States. METHODS: The program consisted of two 45-60-minute sessions each week. Bingocize attendance was recoded as number of sessions attended each month from September 2017 to February 2019 in 25 nursing homes. The impact of gender, age, cognitive functioning, and Nursing Home Star Ratings on adherence to the program based on percentage of Bingocize sessions attended was analyzed. RESULTS: A total of 1165 residents of certified nursing homes were recruited and participated in Bingocize; 55% of participants attended Bingocize infrequently or had poor attendance, 21% of the participants had average attendance, and 24% had good attendance. The association between gender and level of attendance was significant (P = .045). The star rating of the nursing home also affected attendance. As star level of the nursing home increased, the percentage of good attendance increased (P < .001): 19.12% (1 star), 20.69% (2 stars), 23.57% (3 stars), 33.76% (4 stars), and 36.63% (5 stars). Neither age nor cognitive functioning [based on Brief Interview of Mental Status (BIMS)] had a significant impact on attendance. CONCLUSIONS AND IMPLICATIONS: We examined adherence to an exercise program called Bingocize based on percentage of sessions attended in 25 nursing homes. Women and residents in nursing homes with higher star ratings were reported to have better attendance in Bingocize than men or residents in nursing homes with lower ratings, respectively. Residents of all ages and cognitive ability can successfully participate in the Bingocize program.

Salivary biomarkers for discriminating periodontitis in the presence of diabetes.

AIM: Salivary biomarkers can help in assessment of periodontitis; however, concentrations may be altered in the presence of diabetes. Hence, the ability of salivary biomarkers to discriminate periodontally healthy type II diabetics (T2DM) from T2DM who have periodontitis was examined. METHODS: Ninety-two participants (29 with T2DM with chronic periodontitis, DWP; 32 T2DM without chronic periodontitis, DWoP; and 31 Not Periodontitis, NP) provided saliva and clinical parameters of periodontal health were recorded. Salivary concentrations of interleukin (IL)-1ß, IL-6, matrix metalloproteinase-8 (MMP-8), macrophage inflammatory protein-1α (MIP-1α), adiponectin and resistin were measured by immunoassay. RESULTS: Salivary analyte concentrations for IL-1ß, MMP-8 and resistin correlated with clinical parameters of periodontitis, with MMP-8 demonstrating the strongest positive correlation with PD ≥5 mm (p < 0.0001). Periodontal health was reflected in salivary analyte concentrations by group, with concentrations of IL-1ß and MMP-8 showing significant associations with periodontitis (p ≤ 0.04) that increased in concentration from health to DWoP to DWP. Odds ratio (OR) analyses showed that MMP-8 discriminated periodontitis from NP (OR of 8.12; 95% CI: 1.01-65.33; p = 0.03) and in the presence of T2DM (DWP vs DWoP, OR = 5.09; 95% CI: 1.24-20.92; p = 0.03). CONCLUSION: Salivary MMP-8 and IL-1ß discriminate periodontitis in T2DM.

Evaluating trajectories of episodic memory in normal cognition and mild cognitive impairment: Results from ADNI.

BACKGROUND: Memory assessment is a key factor for the diagnosis of cognitive impairment. However, memory performance over time may be quite heterogeneous within diagnostic groups. METHOD: To identify latent trajectories in memory performance and their associated risk factors, we analyzed data from Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who were classified either as cognitively normal or as Mild Cognitive Impairment (MCI) at baseline and were administered the Rey Auditory Verbal Learning test (RAVLT) for up to 9 years. Group-based trajectory modeling on the 30-minute RAVLT delayed recall score was applied separately to the two baseline diagnostic groups. RESULTS: There were 219 normal subjects with mean age 75.9 (range from 59.9 to 89.6) and 52.5% male participants, and 372 MCI subjects with mean age 74.8 (range from 55.1 to 89.3) and 63.7% male participants included in the analysis. For normal subjects, six trajectories were identified. Trajectories were classified into three types, determined by the shape, each of which may comprise more than one trajectory: stable (~30% of subjects), curvilinear decline (~ 28%), and linear decline (~ 42%). Notably, none of the normal subjects assigned to the stable stratum progressed to dementia during the study period. In contrast, all trajectories identified for the MCI group tended to decline, although some participants were later re-diagnosed with normal cognition. Age, sex, and education were significantly associated with trajectory membership for both diagnostic groups, while APOE ɛ4 was only significantly associated with trajectories among MCI participants. CONCLUSION: Memory trajectory is a strong indicator of dementia risk. If likely trajectory of memory performance can be identified early, such work may allow clinicians to monitor or predict progression of individual patient cognition. This work also shows the importance of longitudinal cognitive testing and monitoring.

Functional human GRIN2B promoter polymorphism and variation of mental processing speed in older adults.

We investigated the role of a single nucleotide polymorphism rs3764030 (G>A) within the human GRIN2B promoter in mental processing speed in healthy, cognitively intact, older adults. In vitro DNA-binding and reporter gene assays of different allele combinations in transfected cells showed that the A allele was a gain-of-function variant associated with increasing GRIN2B mRNA levels. We tested the hypothesis that individuals with A allele will have better memory performance (i.e. faster reaction times) in older age. Twenty-eight older adults (ages 65-86) from a well-characterized longitudinal cohort were recruited and performed a modified delayed match-to-sample task. The rs3764030 polymorphism was genotyped and participants were grouped based on the presence of the A allele into GG and AA/AG. Carriers of the A allele maintained their speed of memory retrieval over age compared to GG carriers (p = 0.026 slope of the regression line between AA and AG versus GG groups). To validate the results, 12 older adults from the same cohort participated in a different version of the short-term memory task. Reaction times were significantly slower with age in older adults with G allele (p < 0.001). These findings support a role for rs3764030 in maintaining faster mental processing speed over aging.

Self-Reported Sleep Apnea and Dementia Risk: Findings from the Prevention of Alzheimer's Disease with Vitamin E and Selenium Trial.

OBJECTIVES: To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADViSE) study and to explore whether the association depends on apolipoprotein E (APOE) ɛ4 allele status. DESIGN: Secondary analysis based on data collected during PREADViSE. SETTING: Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location. PARTICIPANTS: Men enrolled in PREADViSE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = 7,547). MEASUREMENTS: Participants were interviewed at baseline for sleep apnea. The Memory Impairment Screen (MIS) was administered to each participant annually. Subjects who failed this initial screen were tested with secondary screening tests. Medical history and medication use were determined, and the AD8 dementia screening instrument was used. RESULTS: The effect of self-reported sleep apnea on dementia risk depended on APOE ɛ4 status. When the allele was absent, baseline self-reported sleep apnea was associated with a 66% higher risk of developing dementia (95% confidence interval = 2-170%), whereas self-reported sleep apnea conferred no additional risk for participants with an ɛ4 allele. CONCLUSION: Sleep apnea may increase risk of dementia in the absence of APOE ɛ4. This may help inform prevention strategies for dementia or AD in older men with sleep apnea. Registration: PREADViSE is registered at ClinicalTrials.gov: NCT00040378.

A 2-step penalized regression method for family-based next-generation sequencing association studies.

Large-scale genetic studies are often composed of related participants, and utilizing familial relationships can be cumbersome and computationally challenging. We present an approach to efficiently handle sequencing data from complex pedigrees that incorporates information from rare variants as well as common variants. Our method employs a 2-step procedure that sequentially regresses out correlation from familial relatedness and then uses the resulting phenotypic residuals in a penalized regression framework to test for associations with variants within genetic units. The operating characteristics of this approach are detailed using simulation data based on a large, multigenerational cohort.

Identifying genetic variants for heart rate variability in the acetylcholine pathway.

Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n = 3429, discovery stage). Second, findings were replicated in three independent cohorts (n = 3311, replication stage), and finally the two stages were combined in a meta-analysis (n = 6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study.

Comparison of BMI, AHI, and apolipoprotein E ε4 (APOE-ε4) alleles among sleep apnea patients with different skeletal classifications.

STUDY OBJECTIVES: This case-control study investigated whether variations within the APOE-ε gene were associated with having a convex facial profile (skeletal Class II) compared to exhibiting a straight or concave facial profile (Class I or Class III) among patients with obstructive sleep apnea (OSA). Associations between the apnea-hypopnea index (AHI) and body mass index (BMI) scores for these OSA patients were also examined in the context of facial profile. METHOD: OSA patients with an AHI ≥ 15 were recruited from a sleep clinic and classified by facial and dental occlusal relationships based on a profile facial analysis, lateral photographs, and dental examination. Saliva was collected as a source of DNA. The APOE-ε1-4 allele-defining single nucleotide polymorphisms (SNPs) rs429358 and rs7412 were genotyped. A χ(2) analysis was used to assess Hardy-Weinberg equilibrium and for association analysis (significance at p < 0.05). ANOVA and Fisher exact test were also used. RESULT: Seventy-six Caucasian OSA patients participated in the study-25 Class II cases and 51 non-Class II cases. There was no association of the APOE-ε4 allele with facial profile among these OSA patients. Class II OSA patients had significantly lower BMIs (30.7 ± 5.78) than Class I (37.3 ± 6.14) or Class III (37.8 ± 6.17) patients (p < 0.001), although there was no statistical difference in AHI for Class II patients compared with other groups. CONCLUSION: OSA patients with Class II convex profile were more likely to have a lower BMI than those in other skeletal groups. In fact 20% of them were not obese, suggesting that a Class II convex profile may influence or be associated with OSA development independent of BMI.

Salivary biomarkers associated with gingivitis and response to therapy.

BACKGROUND: Salivary biomarkers are potentially important for determining the presence, risk, and progression of periodontal disease. However, clinical translation of biomarker technology from lab to chairside requires studies that identify biomarkers associated with the transitional phase between health and periodontal disease (i.e., gingivitis). METHODS: Eighty participants (40 with gingivitis, 40 healthy) provided saliva at baseline and 7 to 30 days later. An additional sample was collected from gingivitis participants 10 to 30 days after dental prophylaxis. Clinical parameters of gingival disease were recorded at baseline and the final visit. Salivary concentrations of interleukin (IL)-1ß, IL-6, matrix metalloproteinase (MMP)-8, macrophage inflammatory protein (MIP)-1α, and prostaglandin E2 (PGE2) were measured. RESULTS: Clinical features of health and gingivitis were stable at both baseline visits. Participants with gingivitis demonstrated significantly higher bleeding on probing (BOP), plaque index (PI), and gingival index (GI) (P ≤0.002) and a significant drop in BOP, PI, and GI post-treatment (P ≤0.001). Concentrations of MIP-1α and PGE2 were significantly higher (2.8 times) in the gingivitis group than the healthy group (P ≤0.02). After dental prophylaxis, mean biomarker concentrations did not decrease significantly from baseline in the gingivitis group, although concentrations of IL-1ß, IL-6, and MMP-8 approached healthy levels, whereas MIP-1α and PGE2 concentrations remained significantly higher than in the healthy group (P ≤0.04). Odds ratio analyses showed that PGE2 concentrations, alone and in combination with MIP-1α, readily discriminated gingivitis from health. CONCLUSIONS: Salivary PGE2 and MIP-1α discriminate gingivitis from health, and patients with gingivitis who return to clinical health continue to produce inflammatory mediators for weeks after dental prophylaxis.

Assessment of Appalachian region pediatric hearing healthcare disparities and delays.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to examine the timing of diagnostic and therapeutic services in cochlear implant recipients from a rural Appalachian region with healthcare disparity. STUDY DESIGN: Retrospective analysis. METHODS: Cochlear implant recipients from a tertiary referral center born with severe congenital sensorineural hearing loss were examined. Rural status and Appalachian status of their county of origin were recorded. A log-rank test was used to examine differences in the distributions of time to definitive diagnosis of hearing loss, initial amplification fitting, and cochlear implantation in these children. Correlation analysis of the rural status of each county and the timing of services was assessed. RESULTS: A total of 53 children born with congenital hearing loss were included in the study (36 from rural counties and 17 from urban/suburban counties). The distribution of weeks after birth to diagnosis (P=.006), amplification (P=.030), and cochlear implantation (P=.002) was delayed in rural children compared with urban children. An analysis factoring in the effect of implementation of mandatory infant hearing screening in 2000 demonstrated a similar delay in rural children for weeks to diagnosis (P=.028), amplification (P=.087), and cochlear implantation (P<.0001). CONCLUSIONS: Children with severe hearing loss in very rural areas, such as Appalachia, may have significant delays in diagnostic and rehabilitative services. Further investigation is warranted to assess causative factors in delays of cochlear implantation and to develop interventions to promote timely diagnosis and care. LEVEL OF EVIDENCE: 3b.

Genetic and environmental influences on blood pressure variability: a study in twins.

OBJECTIVES: Blood pressure variability (BPV) and its reduction in response to antihypertensive treatment are predictors of clinical outcomes; however, little is known about its heritability. In this study, we examined the relative influence of genetic and environmental sources of variance of BPV and the extent to which it may depend on race or sex in young twins. METHODS: Twins were enrolled from two studies. One study included 703 white twins (308 pairs and 87 singletons) aged 18-34 years, whereas another study included 242 white twins (108 pairs and 26 singletons) and 188 black twins (79 pairs and 30 singletons) aged 12-30 years. BPV was calculated from 24-h ambulatory blood pressure recording. RESULTS: Twin modeling showed similar results in the separate analysis in both twin studies and in the meta-analysis. Familial aggregation was identified for SBP variability (SBPV) and DBP variability (DBPV) with genetic factors and common environmental factors together accounting for 18-40% and 23-31% of the total variance of SBPV and DBPV, respectively. Unique environmental factors were the largest contributor explaining up to 82-77% of the total variance of SBPV and DBPV. No sex or race difference in BPV variance components was observed. The results remained the same after adjustment for 24-h blood pressure levels. CONCLUSIONS: The variance in BPV is predominantly determined by unique environment in youth and young adults, although familial aggregation due to additive genetic and/or common environment influences was also identified explaining about 25% of the variance in BPV.

Genetic influence on blood pressure measured in the office, under laboratory stress and during real life.

To determine to what extent the genetic influences on blood pressure (BP) measured in the office, under psychologically stressful conditions in the laboratory and during real life are different from each other. Office BP, BP during a video game challenge and a social stressor interview, and 24-h ambulatory BP were measured in 238 European American and 186 African American twins. BP values across the two tasks were averaged to represent stress levels. Genetic model fitting showed no ethnic or gender differences for any of the measures. The model fitting resulted in heritability estimates of 63, 75 and 71% for office, stress and 24-h systolic BP (SBP) and 59, 67 and 69% for diastolic BP (DBP), respectively. Up to 81% of the heritability of office SBP and 71% of office DBP were attributed to genes that also influenced stress BP. However, only 45% of the heritability of 24-h SBP and 49% of 24-h DBP were attributed to genes that also influence office BP. Similarly, about 39% of the heritability of 24-h SBP and 42% of 24-h DBP were attributed to genes that also influence stress BP. Substantial overlap exists between genes that influence BP measured in the office, under laboratory stress and during real life. However, significant genetic components specific to each BP measurement also exist. These findings suggest that partly different genes or sets of genes contribute to BP regulation in different conditions.

Genetic and environmental influences on blood pressure and body mass index in Han Chinese: a twin study.

The familial aggregation of blood pressure (BP) may be partly due to the familial aggregation of obesity, caused by genetic and/or environmental factors that influence both. Gene-obesity interactions are expected to result in different heritability estimates for BP at different obesity levels. However, the latter hypothesis has never been tested. The present study included 1243 monozygotic and 833 dizygotic Han Chinese twins (mean±s.d. age: 37.81 ± 9.82; range: 19.1-81.4) from the Chinese National Twin Registry. Body mass index (BMI) was used as the index of general obesity. The outcome measures were systolic BP (SBP) and diastolic BP (DBP). Quantitative genetic modeling was performed using Mx software. The SBP and DBP heritabilities were 46 and 30%, respectively. The positive correlations of BMI with SBP (r=0.26) and with DBP (r=0.27) were largely due to genetic factors (approximately 85%). Genetic factors, which also influence BMI, account for 6 and 7% of the total variance for SBP and DBP, respectively. The gene-obesity interaction analysis showed that both common and unique environmental influences on SBP increased with increasing levels of BMI, resulting in a lower heritability at higher BMI levels, whereas for DBP the heritability remained unchanged at higher BMI levels. Our results suggest that higher BMIs may reduce SBP heritability through a larger impact of environmental effects. These conclusions may be valuable for gene-finding studies.

Genetic influences on daytime and night-time blood pressure: similarities and differences.

OBJECTIVE: To examine whether the genetic influences on blood pressure (BP) during night-time are different from those during daytime and the extent to which they depend on ethnicity or sex. METHODS: Ambulatory BP was measured in 240 European-American and 190 African-American twins (mean +/- SD age, 17.2 +/- 3.4). Individuals with night-time BP falls more than 10% of the daytime values were defined as dippers. A bivariate analysis of the daytime and the night-time BP levels, as well as a liability-threshold model of dippers vs. nondippers were used. RESULTS: Bivariate model fitting showed no ethnic or sex differences for any of the measures, with heritabilities of 0.70 and 0.68 for SBP and 0.70 and 0.64 for DBP at daytime and at night-time. The genetic influences on daytime and night-time were not significantly different for SBP or DBP. The bivariate analysis also indicated that about 56 and 33% of the heritabilities of night-time SBP and DBP could be attributed to genes that also influenced daytime levels. The specific heritabilities due to genetic effects only influencing night-time values were 0.30 for SBP and 0.43 for DBP. The heritabilities of systolic and diastolic dipping were 0.59 and 0.81, respectively. CONCLUSION: Independent of ethnicity and sex, an overlap exists between genes that influence daytime and night-time BP, as well as a significant genetic component that is specific to the night-time BP. These findings suggest that different genes or sets of genes contribute to BP regulation at daytime and night-time.

A longitudinal study in youth of heart rate variability at rest and in response to stress.

BACKGROUND: Few longitudinal studies have examined ethnic and sex differences, predictors and tracking stabilities of heart rate variability (HRV) at rest and in response to stress in youths and young adults. METHODS: Two evaluations were performed approximately 1.5 years apart on 399 youths and young adults (189 European Americans [EAs] and 210 African Americans [AAs]; 190 males and 209 females). HRV was measured at rest and during a video game challenge. RESULTS: AAs showed significantly higher resting root mean square of successive differences (RMSSD) of normal R-R intervals and high-frequency (HF) power than EAs (ps<0.01). Females displayed larger decrease of RMSSD and HF during video game challenge than males (ps<0.05). These ethnic and sex differences were consistent across 1.5 years. No significant sex difference of resting HRV or ethnic difference of HRV response to stress was observed. In addition to age, ethnicity or sex, baseline resting HRV or HRV response to stress are predictors of the corresponding variables 1.5 years later (ps<0.01). Furthermore, weight gain indexed by either body mass index or waist circumference predicts declined resting HRV levels during follow up (ps<0.05). Tracking stabilities were high (>0.5) for resting HRV, but relatively low (<0.3) for HRV in response to stress. CONCLUSION: AAs show higher resting HRV than EAs, and females display greater HRV response to stress than males; and these ethnic and sex differences are consistent across 1.5 years. Resting HRV declines with weight gain.

Genetic influences on heart rate variability at rest and during stress.

We tested whether the heritability of heart rate variability (HRV) under stress is different from rest and its dependency on ethnicity or gender. HRV indexed by root mean square of successive differences (RMSSD) and high-frequency (HF) power was measured at rest and during 3 stressors in 427 European and 308 African American twins. No ethnic or gender differences were found for any measures. There was a nonsignificant increase in heritability of RMSSD (from 0.48 to 0.58) and HF (from 0.50 to 0.58) under stress. Up to 81% and 60% of the heritabilities of RMSSD and HF under stress could be attributed to genes influencing rest levels. The heritabilities due to genes expressed under stress were 0.11 for RMSSD and 0.23 for HF. The findings suggest that, independent of ethnicity and gender, HRV regulation at rest and under stress is largely influenced by the same genes with a small but significant contribution of stress-specific genetic effects.