Natural history of sleep disordered breathing in prepubertal children transitioning to adolescence.

Because there is a lack of agreed upon diagnostic criteria, it is critical to understand the natural history of obstructive sleep apnoea (OSA) in children in order to establish treatment strategies based on objective data.The Penn State Child Cohort is a representative, general-population sample of 700 elementary school children at baseline, of whom 421 were reassessed 8 years later, during adolescence.The remission of childhood apnoea-hypopnoea index (AHI) ≥2 events per h in adolescence was 52.9%. Using the higher threshold of AHI ≥5 events per h, remission was 100.0%, with 50.0% partially remitting to AHI 2- <5 events per h and the other half remitting to AHI <2 events per h. The incidence of adolescent AHI ≥2 events per h in those with childhood AHI <2 events per h was 36.5%, while the incidence of AHI ≥5 events per h in those with childhood AHI <5 events per h was 10.6%. This longitudinal study confirms that prepubertal OSA tends to resolve naturally during the transition to adolescence, and that primary snoring and mild sleep disordered breathing (SDB) do not appear to be strongly associated with progression to more severe SDB.The key risk factors for SDB in adolescence are similar to those found in middle-aged adults (i.e. male sex, older age and obesity). Moreover, consistent with recent studies in adults, this study includes the novel cross-sectional finding that visceral fat is associated with SDB as early as adolescence.

Assessing the Feasibility of a Faith-Based Colorectal Cancer Education and Screening Intervention for Latino Men in Pennsylvania.

Introduction: Limited health knowledge, literacy, engagement in preventive health services, participation in health promotion behaviors, and cultural factors place Latino men at high risk for colorectal cancer (CRC). This pilot study aimed to determine the feasibility and acceptability of a faith-based cancer education intervention focusing on Latino men between 45 and 74 years old. Methods: This pilot study used a single group pre- and post-intervention research design to compare changes in knowledge, perceived benefit of screening, perceived susceptibility and severity of CRC, and the completion of CRC screening after the intervention. Results: In this study, Latino men were willing to participate in a CRC educational intervention supported by a faith-based institution. The participants had limited knowledge about CRC, yet most recognized that screening is beneficial and that getting CRC is serious. Sixty percent of the participants completed the fecal immunochemical screening test, which showed that the intervention impacted the screening uptake among this group. Conclusion: The findings of this study support the further development of faith-based interventions focusing on Latino men.

Insulin resistance and circadian rhythm of cardiac autonomic modulation.

BACKGROUND: Insulin resistance (IR) has been associated with cardiovascular diseases (CVD). Heart rate variability (HRV), an index of cardiac autonomic modulation (CAM), is also associated with CVD mortality and CVD morbidity. Currently, there are limited data about the impairment of IR on the circadian pattern of CAM. Therefore, we conducted this investigation to exam the association between IR and the circadian oscillations of CAM in a community-dwelling middle-aged sample. METHOD: Homeostasis models of IR (HOMA-IR), insulin, and glucose were used to assess IR. CAM was measured by HRV analysis from a 24-hour electrocardiogram. Two stage modeling was used in the analysis. In stage one, for each individual we fit a cosine periodic model based on the 48 segments of HRV data. We obtained three individual-level cosine parameters that quantity the circadian pattern: mean (M), measures the overall average of a HRV index; amplitude (Â), measures the amplitude of the oscillation of a HRV index; and acrophase time (θ), measures the timing of the highest oscillation. At the second stage, we used a random-effects-meta-analysis to summarize the effects of IR variables on the three circadian parameters of HRV indices obtained in stage one of the analysis. RESULTS: In persons without type diabetes, the multivariate adjusted ß (SE) of log HOMA-IR and M variable for HRV were -0.251 (0.093), -0.245 (0.078), -0.19 (0.06), -4.89 (1.76), -3.35 (1.31), and 2.14 (0.995), for log HF, log LF, log VLF, SDNN, RMSSD and HR, respectively (all P < 0.05). None of the IR variables were significantly associated with  or θ of the HRV indices. However, in eight type 2 diabetics, the magnitude of effect due to higher HOMA-IR on M, Â, and θ are much larger. CONCLUSION: Elevated IR, among non-diabetics significantly impairs the overall mean levels of CAM. However, the  or θ of CAM were not significantly affected by IR, suggesting that the circadian mechanisms of CAM are not impaired. However, among persons with type 2 diabetes, a group clinically has more severe form of IR, the adverse effects of increased IR on all three HRV circadian parameters are much larger.

Examining Older Adults' Attitudes and Perceptions of Cancer Screening and Overscreening: A Qualitative Study.

INTRODUCTION/OBJECTIVES: Screening guidelines for breast, cervical, and colorectal cancer (CRC) are less clear for older adults due to the potential harms that may result from screening. Understanding older adults' attitudes and perceptions, especially racial/ethnic minority and underserved adults, of cancer screening can help health care providers determine how best to communicate with older adults about cancer screening and screening cessation. The objective of this study was to determine how older adults primarily from minority/underserved backgrounds perceive cancer screening and overscreening. METHODS: Four focus groups (n = 39) were conducted with adults (>=65 years of age) in 3 community settings in south-central Pennsylvania. Two focus groups were conducted in Spanish and translated to English upon transcription. Focus group data was managed and analyzed using QSR NVivo 12. Inductive thematic analysis was used to analyze the data where themes emerged following the coding process. RESULTS: The focus group participants had an average age of 74 years and were primarily female (74%) and Hispanic (69%), with 69% reporting having less than a high school degree. Four key themes were identified from the focus groups: (1) importance of tailored and targeted education/information; (2) impact of physician/patient communication; (3) impact of barriers and facilitators to screening on cancer screening cessation; and (4) awareness of importance of screening. Participants were more likely to be agreeable to screening cessation if they received specific information regarding their health status and previous medical history from their physician as to why screening should be stopped and told by their physician that the screening decision is up to them. CONCLUSIONS: Older adults prefer individualized information from their physician in order to justify screening cessation but are against incorporating life expectancy into the discussion. Future research should focus on developing interventions to test the effectiveness of culturally tailored screening cessation messages for older adults.

Metabolic syndrome clusters and the risk of incident stroke: the atherosclerosis risk in communities (ARIC) study.

BACKGROUND AND PURPOSE: Little is known about the metabolic syndrome (MetS) and the risk of incident stroke. This study is designed to identify particular clusters of MetS components that carry the highest risk of incident stroke. METHODS: We analyzed the public use data from the population-based Atherosclerosis Risk in Communities study. At baseline, 14 993 stroke-free middle-aged individuals were followed-up over 9 years for incident stroke. MetS components were defined according to the National Heart, Lung, and Blood Institute/American Heart Association criteria. Incident stroke was identified using a standardized incident events identification and classification protocol. Proportional hazard models were used to assess the RRs and 95% CIs of ischemic stroke associated with MetS and its different clusters. RESULTS: At baseline, the prevalence of MetS was 39%. The mean age was 54, with 26% blacks and 55% females. The hazard ratio of incident ischemic stroke associated with MetS among women (hazard ratio, 2.41; 95% CI, 1.69 to 3.49) and men (hazard ratio, 2.11; 95% CI, 1.56-2.85) was similar. There was a dose-response relationship between the numbers of MetS components and the risk of incidence stroke. Persons with either elevated blood pressure or elevated fasting glucose in the clusters to form a MetS had the highest risk for incident stroke (hazard ratio, 2.74-4.16 comparing to the reference group) than MetS without these 2 components (hazard ratio,

Infectivity of herpes simplex virus type-1 (HSV-1) amplicon vectors in dendritic cells is determined by the helper virus strain used for packaging.

Herpes simplex virus type-1 (HSV-1) amplicon vectors are being explored for a wide range of potential applications, including vaccine delivery and immunotherapy of cancer. While extensive effort has been directed towards the improvement of the amplicon "payload" in these vectors, relatively little attention has been paid to the effect of the packaging HSV-1 strains on the biological properties of co-packaged amplicon vectors. We therefore compared the biological properties of amplicon stocks prepared using a panel of primary HSV-1 isolates, a molecularly cloned strain used to package helper-free amplicons (designated here as F5), and two laboratory isolates (KOS and strain 17, which is the parent of the F5 clone). This analysis revealed considerable inter-strain variability in the ability of amplicon stocks packaged by different primary HSV-1 isolates to efficiently transduce established cell lines and primary human dendritic cells (DC). Amplicons packaged by both the F5 molecularly cloned virus and its laboratory-adapted parent (strain 17) were very inefficient at transducing DC, when compared to amplicons packaged by KOS or by several of the primary virus isolates. These finding have important implications for the future development of improved amplicon-based vaccine delivery systems and suggest that DC tropism may be an instrinsic property of some HSV-1 strains, independent of passage history or molecular cloning.

Sleep variability and cardiac autonomic modulation in adolescents - Penn State Child Cohort (PSCC) study.

OBJECTIVE: To investigate the effects of objectively measured habitual sleep patterns on cardiac autonomic modulation (CAM) in a population-based sample of adolescents. METHODS: We used data from 421 adolescents who completed the follow-up examination in the Penn State Children Cohort study. CAM was assessed by heart rate (HR) variability (HRV) analysis of beat-to-beat normal R-R intervals from a 39-h electrocardiogram, on a 30-min basis. The HRV indices included frequency domain (HF, LF, and LF/HF ratio), and time domain (SDNN, RMSSD, and heart rate or HR) variables. Actigraphy was used for seven consecutive nights to estimate nightly sleep duration and time in bed. The seven-night mean (SD) of sleep duration and sleep efficiency were used to represent sleep duration, duration variability, sleep efficiency, and efficiency variability, respectively. HF and LF were log-transformed for statistical analysis. Linear mixed-effect models were used to analyze the association between sleep patterns and CAM. RESULTS: After adjusting for major confounders, increased sleep duration variability and efficiency variability were significantly associated with lower HRV and higher HR during the 39-h, as well as separated by daytime and nighttime. For instance, a 1-h increase in sleep duration variability is associated with -0.14(0.04), -0.12(0.06), and -0.16(0.05) ms(2) decrease in total, daytime, and nighttime HF, respectively. No associations were found between sleep duration, or sleep efficiency and HRV. CONCLUSION: Higher habitual sleep duration variability and efficiency variability are associated with lower HRV and higher HR, suggesting that an irregular sleep pattern has an adverse impact on CAM, even in healthy adolescents.

Metabolic syndrome burden in apparently healthy adolescents is adversely associated with cardiac autonomic modulation--Penn State Children Cohort.

BACKGROUND: Reduced cardiac autonomic modulation (CAM) has been associated with metabolic syndrome (MetS) in adults. However, the association between MetS component cluster and CAM has not been examined in adolescents. METHODS: We conducted a cross-sectional analysis using data from the Penn State Child Cohort follow-up examination. CAM was assessed by heart rate variability (HRV) analysis of 39-h RR intervals, including frequency (high frequency, HF; low frequency, LF; and LF/HF ratio) and time (SDNN, standard deviation of all RR intervals; RMSSD, square root of the mean of the sum of the squares of differences between adjacent RR intervals; and HR, heart rate) domain variables. To assess the MetS burden, we used continuous MetS score (cMetS)--sum of the age and sex-adjusted standardized residual (Z-score) of five established MetS components. Linear mixed-effect models were used to analyze the association between cMetS and CAM in the entire population and stratified by gender. RESULTS: After adjusting for age, sex, and race, cMetS was significantly associated with reduced HRV and higher HR. With 1 standard deviation increase in cMetS, there was a significant decrease in HF (-0.10 (SE = 0.02)), LF (-0.07 (SE = 0.01)), SDNN (-1.97 (SE = 0.50)), and RMSSD (-1.70 (SE = 0.72)), and increase in LF/HF (0.08 (SE = 0.02)) and HR (1.40 (SE = 0.26)). All cMetS components, with the exception of high-density lipoprotein (HDL), were associated with significantly decreased HRV and increased HR. High blood pressure (MAP) and triglyceride (TG) levels were also associated with an increase in LF/HF and decrease in RMSSD. An increase in high-density lipoprotein was only associated with higher LF and SDNN. Moreover, cMetS and HRV associations were more pronounced in males than in females. The associations between HRV and. MAP, TG, and HDL were more pronounced in females. CONCLUSIONS: cMetS score is associated with lower HRV, suggesting an adverse impact on CAM, even in apparently healthy adolescents.

Therapeutic levels of factor IX expression using a muscle-specific promoter and adeno-associated virus serotype 1 vector.

Extensive studies in animal models of the X-linked bleeding disorder hemophilia B (deficiency in functional coagulation factor IX, F.IX) have shown that muscle-directed adeno-associated (AAV)-mediated F.IX gene transfer can be used to treat this disease. However, large vector doses of AAV-2 vector are required for therapeutic levels of expression, and the number of vector doses that can be injected per intramuscular site is limited. Several studies have shown that some of these limitations can be overcome by use of AAV serotype 1 vector. Here, we demonstrate levels of F.IX transgene expression from a synthetic muscle-specific promoter (C5-12) that were higher than from the cytomegalovirus (CMV) immediate-early enhancer-promoter in cultured muscle cells in vitro and approximately 50% of CMV-driven expression in vivo in murine skeletal muscle after AAV-1 gene transfer. These data show for the first time that a tissue-specific promoter can be used to achieve therapeutic levels of muscle-derived F.IX expression in the context of viral gene transfer. However, use of a muscle-specific promoter did not prevent antibody formation in response to a murine F.IX transgene product in mice with F.IX gene deletion, indicating that the risk of humoral immune responses remains in the context of an immunologically unfavorable mutation.

Childhood obesity and autonomic dysfunction: risk for cardiac morbidity and mortality.

OPINION STATEMENT: The epidemic of childhood obesity is becoming a major predictor for risk of cardiovascular diseases (CVD) and mortality during adulthood. Alterations in the morphology of the heart due to obesity could be a predictor for the dysfunction of cardiac autonomic modulation (CAM). A number of epidemiologic studies have evaluated the effect of obesity and CAM in children, finding that obesity impaired the balance of CAM toward a sympathetic overflow and reduced parasympathetic modulation, a significant predictor of CVD morbidity and mortality in adults. Lifestyle modifications, for example long-term exercise programs, have been shown to improve CAM in the obese. This review discusses the recent evidence on childhood and adolescent obesity and its impact on CAM, as well as how early lifestyle changes could help improve CAM, which may in turn reduce the burden of CVD in adults.

Obesity is associated with impaired cardiac autonomic modulation in children.

OBJECTIVE: To examine the cross-sectional association between measurements of obesity and subclinical impairment of cardiac autonomic modulation (CAM) in a population-based sample of children. METHODS: Data from 616 grade K-5 children randomly selected from Central Pennsylvania were utilized. Obesity was defined using the International Obesity Task Force (IOTF) age- and sex-specific cut-off criteria and classified as normal weight, overweight, and obese. CAM was measured by heart rate variability (HRV) analysis of beat-to-beat RR intervals, including time domain measures i.e., the standard deviation of all RR intervals (SDNN), the square root of the mean of the sum of squares of differences between adjacent RR intervals (RMSSD), and mean heart rate (HR); and frequency domain measures i.e., high frequency power (HF), low frequency power (LF), and LF/HF ratio. RESULTS: The prevalence of obesity and overweight in children was 12.3%, and 16.5%, respectively. Age, race, sex, and sleep disorder breathing (SDB) adjusted means (standard error, SE) of SDNN were 98 (1.24), 90.2 (2.58), and 81.9 (3.03) milliseconds (ms) in normal weight, overweight, and obese groups, respectively; and that for (log) HF were 6.83 (0.04), 6.56 (0.08), and 6.35 (0.09) ms(2), respectively. Comparing the magnitude of effects from body mass index (BMI), weight, and height percentiles, and waist circumference on HRV indices revealed that body weight was the strongest correlate of HRV indices. CONCLUSION: Childhood obesity is significantly associated with lower HRV, indicative of sympathetic overflow unopposed by parasympathetic modulation. These findings support the need to target childhood-obesity before traditional "high risk age" for cardiac events.

Systemic inflammation and circadian rhythm of cardiac autonomic modulation.

Systemic inflammation (SI) is associated with impairment of cardiac autonomic modulation (CAM), which is associated with cardiac disease. However, there is limited data about SI on CAM circadian pattern, which this study aimed to investigate in a middle-aged sample. C-reactive protein (CRP) was used as a SI marker. We performed HRV analysis on each 5-min segment RRs from a 24-h 12-lead ECG to obtain time and frequency domain HRV indices as measures of CAM. The circadian pattern of CAM was analyzed by a two-stage modeling. Stage one, for each individual we fit a cosine periodic model based on the 288 segments of 5-min HRV data to produce three individual-level cosine parameters that quantity the circadian pattern: mean (M), amplitude (Â), and acrophase time (θ), measure the overall average, the amplitude of the oscillation, and the timing of the highest oscillation, respectively. Stage two, we used random-effects-meta-analysis to summarize the effects of CRP on the three circadian parameters obtained in stage one. CRP was adversely associated with lower M of log-HF, log-LF, SDNN, and RMSSD [ß (SE): -0.22 (0.07) ms(2), -0.20 (0.06) ms(2), -3.62 (0.99) ms, and -2.32 (0.73) ms, respectively, with all p-values <0.01]. More importantly, CRP was also adversely associated with lower  of SDNN and RMSSD [ß (SE): -0.84 (0.44) ms and -0.86 (0.38) ms, respectively, both p-values <0.05]. SI is adversely associated with circadian pattern of CAM, suggesting that the cardiac risk associated with SI may be partially mediated via inflammation-related changes in CAM.

Sleep-disordered breathing and cardiac autonomic modulation in children.

OBJECTIVES: To investigate the adverse cardiac autonomic effects of sleep-disordered breathing (SDB) in a large population-based sample and a clinical sample of children. METHODS: Subjects included a population-based sample of 700 and a clinically diagnosed sample of 43 SDB children. SDB was defined based on an apnea hypopnea index (AHI) 1 during one night of polysomnography. Cardiac autonomic modulation was measured by heart rate variability (HRV) analysis of the beat-to-beat RR interval data collected during polysomnography. RESULTS: The mean (SD) age was 112 (21) months, with 49% male and 25% non-white. About 73.0% had AHI<1 (no SDB), 25.8% had 1-5 AHI (mild SDB), and 1.2% had 5 AHI (moderate SDB). Among individuals with moderate SDB in the population-based sample and the clinically diagnosed SDB patients, the mean (SE) of HRV-high frequency power (HF) was significantly lower compared to children without SDB [6.00 (0.32) and 6.24 (0.14), respectively, vs. 6.68 (0.04) ms(2), p<0.05 and p<0.01, respectively], whereas the low frequency power to high frequency power ratio (LF/HF) was significantly higher [1.62 (0.20) and 1.74 (0.09), respectively, vs. 0.99 (0.02), both p<0.01)]. CONCLUSIONS: SDB in healthy young children and in clinical patients is significantly associated with impaired cardiac autonomic modulation, i.e., sympathetic overflow and weaker parasympathetic modulation, which may contribute to increased risk of acute cardiac events in persons with SDB, even before reaching the "high risk age."

Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 Gag.

Helper-free herpes simplex virus type-1 (HSV-1) amplicon vectors elicit robust immune responses to encoded proteins, including human immunodeficiency virus type-1 (HIV-1) antigens. To improve this vaccine delivery system, seven amplicon vectors were constructed, each encoding HIV-1 Gag under the control of a different promoter. Gag expression levels were analyzed in murine and human cell lines, as well as in biopsied tissue samples from injected mice; these data were then compared with Gag-specific T cell responses in BALB/c mice. The magnitude of the amplicon-induced immune response was found to correlate strongly with the level of Gag production both in vitro and in vivo. Interestingly, the best correlation of the strength of the amplicon-induced immune response was with antigen expression in cultured DC rather than expression at the tissue site of injection or in cultured cell lines. These findings may have implications for the generation of improved HSV-1 amplicon vectors for HIV-1 vaccine delivery.

Recombinant adenovirus type 5 vectors that target DC-SIGN, ChemR23 and alpha(v)beta3 integrin efficiently transduce human dendritic cells and enhance presentation of vectored antigens.

Recombinant adenoviruses (rAds) represent a promising system for vaccine delivery but transduce dendritic cells (DC) relatively poorly. To address this concern, we used a biotin-avidin linkage to conjugate rAd vectors to ligands which bind with high affinity to selected receptors on DC (ChemR23, alpha(v)beta3 integrin, and DC-SIGN). The targeted vectors had an enhanced ability to transduce human monocyte-derived DC compared to untargeted virus. In addition, DC transduced with targeted rAd vectors were more efficient at stimulating cytokine production by autologous memory CD8+ T cells, against a vector-encoded antigen. These results expand the range of cell surface receptors that can be used to target rAd5 vectors to DC, and may facilitate future development of rAd-based vaccines.