Prediction of early postoperative pain using sleep quality and heart rate variability.

PURPOSE: Accurate predictions of postoperative pain intensity are necessary for customizing analgesia plans. Insomnia is a risk factor for severe postoperative pain. Moreover, heart rate variability (HRV) can provide information on the sympathetic-parasympathetic balance in response to noxious stimuli. We developed a prediction model that uses the insomnia severity index (ISI), HRV, and other demographic factors to predict the odds of higher postoperative pain. METHODS: We recruited gynecological surgery patients classified as American Society of Anesthesiologists class 1-3. An ISI questionnaire was completed 1 day before surgery. HRV was calculated offline using intraoperative electrocardiogram data. Pain severity at the postanesthesia care unit (PACU) was assessed with the 0-10 numerical rating scale (NRS). The primary outcome was the model's predictive ability for moderate-to-severe postoperative pain. The secondary outcome was the relationship between individual risk factors and opioid consumption in the PACU. RESULTS: Our study enrolled 169 women. Higher ISI scores (p = 0.001), higher parasympathetic activity (rMSSD, pNN50, HF; p < 0.001, p < 0.001, p < 0.001), loss of fractal dynamics (SD2, alpha 1; p = 0.012, p = 0.039) in HRV analysis before the end of surgery were associated with higher NRS scores, while laparoscopic surgery (p = 0.031) was associated with lower NRS scores. We constructed a multiple logistic model (area under the curve = 0.852) to predict higher NRS scores at PACU arrival. The five selected predictors were age (OR: 0.94; p = 0.020), ISI score (OR: 1.14; p = 0.002), surgery type (laparoscopic or open; OR: 0.12; p < 0.001), total power (OR: 2.02; p < 0.001), and alpha 1 (OR: 0.03; p < 0.001). CONCLUSION: We employed a multiple logistic regression model to determine the likelihood of moderate-to-severe postoperative pain upon arrival at the PACU. Physicians could personalize analgesic regimens based on a deeper comprehension of the factors that contribute to postoperative pain.

The cysteine-altering p.R544C variant in the NOTCH3 gene is a probable candidate for blood pressure and relevant traits in the Taiwan Biobank.

BACKGROUND: The cysteine-altering variants in NOTCH3 have been suggested to be associated with stroke, dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), where aberrant blood pressure levels represent the characteristics of these diseases. We aimed to assess whether the cysteine-altering p.Arg544Cys (p.R544C; rs201118034) variant and common single nucleotide variants (SNVs) in NOTCH3 could contribute to systolic and diastolic blood pressure and related phenotypes in the Taiwan Biobank. METHODS: We employed a discovery sample of 68,925 individuals, an independent replication sample of 45,676 individuals, and a combined/total sample of 114,601 individuals; all from the Taiwan Biobank. Blood pressure, such as systolic and diastolic blood pressure, was measured for all participants. Association was evaluated using a general linear model, where results were considered statistically significant if the P value < 0.05 divided by the number of independent tests per model. RESULTS: From our analysis, we identified and replicated three novel candidates for blood pressure that have not previously been reported: the cysteine-altering p.R544C variant for systolic blood pressure, the common SNV rs11669950 for diastolic blood pressure, and the common SNV rs4808235 for diastolic blood pressure. We also generalized two previously identified SNVs (i.e., rs10418305 and rs7408868) in NOTCH3 for blood pressure in European and non-Taiwanese East Asian populations to the Taiwanese population. Moreover, the participants with NOTCH3 p.R544C had an increased stroke frequency (P < 1.0 × 10-5) and a higher dementia frequency (P = 2.0 × 10-4) compared with the whole Taiwan Biobank population in the combined/total sample. CONCLUSION: NOTCH3 is a strong candidate for a role in stroke, dementia, and CADASIL, which has previously been linked to blood pressure changes. While our preliminary study suggests that NOTCH3 p.R544C may influence blood pressure, stroke, and dementia in the Taiwan Biobank, replication in a well-powered external sample is required. This study also underlines considerable prospects of detecting novel genetic biomarkers in underrepresented worldwide populations.

Dietary profile of pediatric obstructive sleep apnea patients, effects of routine educational counseling, and predictors for outcomes.

Background: Dietary behavior is a main contributing yet modifiable factor to the body weight status of children and may be involved in the pathophysiology of childhood obstructive sleep apnea (OSA). This study aimed to investigate the dietary profile of pediatric OSA patients, effects of educational counseling after adenotonsillectomy, and predictor for disease resolution. Methods: This observational study included 50 pediatric OSA patients undergoing adenotonsillectomy with routine educational counseling (Group 1), 50 pediatric OSA patients undergoing adenotonsillectomy without formal educational counseling (Group 2), and 303 healthy children without OSA (Control). The three groups were matched by age. The consumption frequency of 25 food items/groups was assessed by the Short Food Frequency Questionnaire. Quality of life was evaluated by the OSA-18 questionnaire. Sleep architecture and OSA severity were measured by standard polysomnography. Between- and within-group comparisons were analyzed by non-parametric approaches and generalized estimating equations. Prediction of disease recovery was performed by multivariable logistic regression models. Results: Group 1 children consumed fruit drinks with sugar, vegetables, sweets, chocolate, rice, and noodles more frequently than Control Group children. At baseline, the distributions of sex, weight status, OSA-18 scores, and polysomnographic variables were comparable between Group 1 and Group 2. After a 12-month follow-up, Group 1 had better improvements in physical suffering, caregiver concerns, sleep architecture, and mean peripheral oxygen saturation compared to Group 2. Furthermore, Group 1 no longer had excessive consumption of fruit drinks with sugar, chocolate, and noodles; however, food consumption frequencies did not change significantly. Notably, younger age and reduced intake of butter/margarine on bread and noodles were independent predictors of cured OSA in Group 1. Conclusion: The present study preliminarily characterized an unhealthy dietary profile among pediatric OSA patients and suggested that routine educational counseling in addition to adenotonsillectomy yielded some clinical benefits. Certain items/groups of food frequencies may be associated with disease recovery and further investigations are warranted.

Rapid detection of nicotine and benzoic acid in e-liquids with surface-enhanced Raman scattering and artificial intelligence-assisted spectrum interpretation.

Electronic cigarettes have rapidly gained acceptance recently. Nicotine-containing electronic cigarette liquids (e-liquids) are prohibited in some countries, but are permitted and simply available online in others. A rapid detection method is therefore required for on-site inspection or screening of a large amount of samples. Our previous study demonstrated a surface-enhanced Raman scattering (SERS)-based approach to identify nicotine-containing e-liquids; without any pre-treatment, e-liquid can be directly tested on our solid-phase SERS substrates, made of silver nanoparticle arrays embedded in anodic aluminium oxide nanochannels (Ag/AAO). However, this approach required manual determination of spectral signatures and negative samples should be validated in the second round detection. Here, after examining 406 commercial e-liquids, we refined this approach by developing artificial intelligence (AI)-assisted spectrum interpretations. We also found that nicotine and benzoic acid can be simultaneously detected in our platform. This increased test sensitivity because benzoic acid is usually used in nicotine salts. Around 64% of nicotine-positive samples in this study showed both signatures. Using either cutoffs of nicotine and benzoic acid peak intensities or a machine learning model based on the CatBoost algorithm, over 90% of tested samples can be correctly discriminated with only one round of SERS measurement. False negative and false positive rates were 2.5-4.4% and 4.4-8.9%, respectively, depending on the interpretation method and thresholds applied. The new approach takes only 1 microliter of sample and can be performed in 1-2 min, suitable for on-site inspection with portable Raman detectors. It could also be a complementary platform to reduce samples that need to be analyzed in the central labs and has the potential to identify other prohibited additives.

Using sleep heart rate variability to investigate the sleep quality in children with obstructive sleep apnea.

Background: Obstructive sleep apnea (OSA) is associated with impaired sleep quality and autonomic dysfunction. Adenotonsillectomy significantly improves subjective and objective sleep quality in children with OSA. However, the postoperative changes in heart rate variability (HRV) indices (indicators of cardiac autonomic function) and their importance remain inconclusive in childhood OSA. This retrospective case series aimed to investigate the association of sleep HRV indices, total OSA-18 questionnaire score (a subjective indicator of sleep quality) and polysomnographic parameters (objective indicators of sleep quality), and effects of adenotonsillectomy on HRV indices, total OSA-18 questionnaire score and polysomnographic parameters in children with OSA. Methods: Seventy-six children with OSA were included in baseline analysis, of whom 64 (84%) completed at least 3 months follow-up examinations after adenotonsillectomy and were included in outcome analysis. Associations between baseline variables, and relationships with treatment-related changes were examined. Results: Multivariable linear regression models in the baseline analysis revealed independent relationships between tonsil size and obstructive apnea-hypopnea index (OAHI), adenoidal-nasopharyngeal ratio and very low frequency (VLF) power of HRV (an indicator of sympathetic activity), and normalized low frequency power (an indicator of sympathetic activity) and OAHI. The outcome analysis showed that adenotonsillectomy significantly improved standard deviation of all normal-to-normal intervals, and high frequency power, QoL (in terms of reduced total OSA-18 questionnaire score), OAHI and hypoxemia. Using a conceptual serial multiple mediation model, % change in OSA-18 questionnaire score and % change in VLF power serially mediated the relationships between change in tonsil size and % change in OAHI. Conclusions: The improvement in OAHI after adenotonsillectomy was serially mediated by reductions in total OSA-18 questionnaire score and VLF power. These preliminary findings are novel and provide a direction for future research to investigate the effects of VLF power-guided interventions on childhood OSA.

Adenotonsillectomy-related changes in systemic inflammation among children with obstructive sleep apnea.

BACKGROUND: Adenotonsillar hypertrophy is the most common cause of pediatric obstructive sleep apnea (OSA). Although adenotonsillectomy considerably reduces OSA and systemic inflammation, whether and how systemic inflammation influences the effects of adenotonsillectomy on OSA has yet to be determined. METHODS: This study investigated the associations between changes in anatomical variables, % changes in subjective OSA-18 questionnaire scores, % changes in 11 polysomnographic parameters, and % changes in 27 systemic inflammatory biomarkers in 74 children with OSA. RESULTS: Fifty-six (75.6%) boys and 18 (24.4%) girls with the mean age of 7.4 ± 2.2 years and apnea-hypopnea index (AHI) of 14.2 ± 15.9 events/h were included in the statistical analysis. The mean period between before and after adenotonsillectomy was 5.6 ± 2.6 months. After adenotonsillectomy, the OSA-18 score, eight of 11 polysomnographic parameters, and 20 of 27 inflammatory biomarkers significantly improved (all p < 0.005). Notably, there were significant associations between change in tonsil size and % change in AHI ( r = 0.23), change in tonsil size and % changes in interleukin-8 (IL-8) ( r = 0.34), change in tonsil size and % change in and IL-10 ( r = -0.36), % change in IL-8 and % change in C-C chemokine ligand 5 (CCL5) ( r = 0.30), and % change in CCL5 and % change in AHI ( r = 0.38) (all p < 0.005). Interestingly, % change in IL-8 and % change in CCL5 serially mediated the relationship between change in tonsil size and % change in AHI (total effect: ß = 16.672, standard error = 8.274, p = 0.048). CONCLUSION: These preliminary findings suggest that systemic inflammation is not only a complication of OSA but also that it mediates the surgical effects, which may open avenues for potential interventions to reduce tonsil size and OSA severity through the regulation of IL-8 and CCL5.

Ten-year trends in depression care in Taiwan.

BACKGROUND/PURPOSE: The number of psychiatrists working in community clinics in Taiwan has increased dramatically in the recent decade. This study aimed to investigate the trend of prevalence and incidence of depressive disorders and assess the quality of depression care between 2007 and 2016 in Taiwan. METHODS: We used the claims database derived from Taiwan's National Health Insurance (NHI) program, in which approximately 23.0 million individuals were enrolled, translating to a coverage rate of 99%. Patients with depressive disorders were identified based on International Classification of Diseases codes. The process indicators of depression care quality included visit, duration, and dose adequacy. The outcome indicators included the rate of psychiatric hospitalisation, emergency visit, self-harm hospitalisation, and suicide. RESULTS: The prevalence of treated depressive disorders increased from 1.61% in 2007 to 1.92% in 2016, i.e., a 25% increase, whereas the incidence of first-ever or recurrent depressive disorder did not change significantly. The number of patients treated by psychiatrists and in community clinics also increased. The quality of depression care improved, the proportion of patients receiving minimum psychiatric clinic follow-up and adequate medication increased, and the rate of emergency visits, psychiatric hospitalisation, and self-harm hospitalisation declined. CONCLUSION: The community-based psychiatric services increased and the quality indicators of depression care in Taiwan improved during 2007-2016. The causality warrants further investigations.

An association study in the Taiwan Biobank elicits the GABAA receptor genes GABRB3, GABRA5, and GABRG3 as candidate loci for sleep duration in the Taiwanese population.

BACKGROUND: Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans. METHODS: We determined the association between single-nucleotide polymorphisms (SNPs) in the GABAA receptor genes GABRA1, GABRA2, GABRB3, GABRA5, and GABRG3 and sleep duration, sleep quality, and sleep timing in the Taiwan Biobank with a sample of 10,127 Taiwanese subjects. There were 10,142 subjects in the original study cohort. We excluded 15 subjects with a medication history of sedative-hypnotics. RESULTS: Our data revealed an association of the GABRB3-GABRA5-GABRG3 gene cluster with sleep duration, which has not been previously identified: rs79333046 (beta = - 0.07; P = 1.21 × 10-3) in GABRB3, rs189790076 (beta = 0.92; P = 1.04 × 10-3) in GABRA5, and rs147619342 (beta = - 0.72; P = 3.97 × 10-3) in GABRG3. The association between rs189790076 in GABRA5 and sleep duration remained significant after Bonferroni correction. A variant (rs12438141) in GABRB3 was also found to act as a potential expression quantitative trait locus. Additionally, we discovered interactions between variants in the GABRB3-GABRA5-GABRG3 gene cluster and lifestyle factors, such as tea and coffee consumption, smoking, and physical activity, that influenced sleep duration, although some interactions became nonsignificant after Bonferroni correction. We also found interactions among GABRB3, GABRA5, and GABRG3 that affected sleep duration. Furthermore, we identified an association of rs7165524 (beta = - 0.06; P = 2.20 × 10-3) in GABRA5 with sleep quality and an association of rs79465949 (beta = - 0.12; P = 3.95 × 10-3) in GABRB3 with sleep timing, although these associations became nonsignificant after Bonferroni correction. However, we detected no evidence of an association of individual SNPs in GABRA1 and GABRA2. CONCLUSIONS: Our results indicate that rs189790076 in GABRA5 and gene-gene interactions among GABRB3, GABRA5, and GABRG3 may contribute to sleep duration in the Taiwanese population.

CUX2, BRAP and ALDH2 are associated with metabolic traits in people with excessive alcohol consumption.

Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts. This genome-wide association study aims to identify the susceptibility gene loci for excessive alcohol consumption by jointly measuring weekly alcohol consumption and γ-GT levels. We analysed the Taiwan Biobank data of 18,363 Taiwanese people, including 1945 with excessive alcohol use. We found that one or two copies of the G allele in rs671 (ALDH2) increased the risk of excessive alcohol consumption, while one or two copies of the C allele in rs3782886 (BRAP) reduced the risk of excessive alcohol consumption. To minimize the influence of extensive regional linkage disequilibrium, we used the ridge regression. The ridge coefficients of rs7398833, rs671 and rs3782886 were unchanged across different values of the shrinkage parameter. The three variants corresponded to posttranscriptional activity, including cut-like homeobox 2 (a protein coded by CUX2), Glu504Lys of acetaldehyde dehydrogenase 2 (a protein encoded by ALDH2) and Glu4Gly of BRCA1-associated protein (a protein encoded by BRAP). We found that Glu504Lys of ALDH2 and Glu4Gly of BRAP are involved in the negative regulation of excessive alcohol consumption. The mechanism underlying the γ-GT-catalytic metabolic reaction in excessive alcohol consumption is associated with ALDH2, BRAP and CUX2. Further study is needed to clarify the roles of ALDH2, BRAP and CUX2 in the liver-brain endocrine axis connecting metabolic shifts with excessive alcohol consumption.

Active Cigarette Smoking Is Associated With an Exacerbation of Genetic Susceptibility to Diabetes.

The heritability levels of two traits for diabetes diagnosis, serum fasting glucose (FG) and glycated hemoglobin (HbA1c), were estimated to be 51-62%. Studies have shown that cigarette smoking is a modifiable risk factor for diabetes. It is important to uncover whether smoking may modify the genetic risk of diabetes. This study included unrelated Taiwan Biobank subjects in a discovery cohort (TWB1) of 25,460 subjects and a replication cohort (TWB2) of 58,774 subjects. Genetic risk score (GRS) of each TWB2 subject was calculated with weights retrieved from the TWB1 analyses. We then assessed the significance of GRS-smoking interactions on FG, HbA1c, and diabetes while adjusting for covariates. A total of five smoking measurements were investigated, including active smoking status, pack-years, years as a smoker, packs smoked per day, and hours as a passive smoker per week. Except for passive smoking, all smoking measurements were associated with FG, HbA1c, and diabetes (P < 0.0033) and were associated with an exacerbation of the genetic risk of FG and HbA1c (P Interaction < 0.0033). For example, each 1 SD increase in GRS is associated with a 1.68% higher FG in subjects consuming one more pack of cigarettes per day (P Interaction = 1.9 × 10-7). Smoking cessation is especially important for people who are more genetically predisposed to diabetes.

An association study in the Taiwan Biobank reveals RORA as a novel locus for sleep duration in the Taiwanese Population.

BACKGROUND: Sleep is a key factor for health-related quality of life since sleep disturbances are a significant and common problem for patients with various human diseases such as psychiatric disorders. While single nucleotide polymorphisms (SNPs) in circadian clock genes have been indicated to be associated with sleep duration, most of the association studies have been investigated in populations with European ancestry. It is believed that no studies have been conducted to investigate a link between sleep duration and the circadian clock genes RORA and RORB, which play a key role, with NR1D1, in an additional feedback loop for the circadian rhythm machinery. METHODS: In this study, we assessed the relationships between sleep duration and SNPs in the circadian clock genes NR1D1, RORA, and RORB in the Taiwan Biobank with a sample of 10,112 Taiwanese subjects. RESULTS: From our data, we revealed a novel significant association in sleep duration with the rs75981965 SNP (P = 9.93 × 10-5) in the RORA gene that has not been previously identified. The association of sleep duration with this SNP remained significant after performing Bonferroni correction. RORA is a potential candidate for sleep duration as RORA has been suggested to play a key role in the regulation of sleep disorders. Additionally, we pinpointed the effects of interactions between RORA rs75981965 and environmental factors such as tea consumption (P = 0.0015), coffee consumption (P = 0.0029), physical activity (P = 0.011), alcohol consumption (P = 0.0146), and smoking (P = 0.0223) in influencing sleep duration. We also found interactions between RORA and NR1D1 (P = 0.0023) as well as between RORA and RORB (P = 0.0061) in affecting sleep duration. CONCLUSIONS: Our results indicate that the circadian clock gene RORA may contribute to sleep duration independently as well as through gene-gene and gene-environment interactions in the Taiwanese population.

Role of Interleukin-6 in Depressive Disorder.

Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the IL6 genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.

Association between polygenic liability for schizophrenia and substance involvement: A nationwide population-based study in Taiwan.

Schizophrenia and substance involvement frequently co-occur in individuals, and a bidirectional relationship between the two has been proposed; shared underlying genetic factors could be an alternative explanation. This study investigated the genetic overlap between schizophrenia and substance involvement, including tobacco, alcohol and betel nut use. The study subjects were recruited from the Taiwan Biobank, and genome-wide genotyping data was available for 18 327 participants without schizophrenia. We calculated the Psychiatric Genomics Consortium-derived polygenic risk score (PRS) for schizophrenia in each participant. The significance of the schizophrenia PRS associated with substance involvement was evaluated using a regression model with adjustments for gender, age and population stratification components. The modified effect of gender or birth decade was also explored. The schizophrenia PRS was positively associated with lifetime tobacco smoking in women (OR in per SD increase in PRS = 1.12 with 95% CI 1.04-1.20, P = .002), but not in men (OR = 0.99 with 95% CI 0.95-1.04, P = .74), and the gender-PRS interaction reached significance (P = .006). The OR between PRS and lifetime tobacco smoking increased with the birth decade (P of birth decade-PRS interaction = .0002). In women, OR increased from 0.97 (P = .85) for subjects with a birth decade before 1950 to 1.21 (P = .04) for subjects with a birth decade after 1980; in men, the corresponding OR increased from 0.88 (P = .04) to 1.13 (P = .11). There was no association between schizophrenia PRS and alcohol/betel nut use phenotypes. This study provides evidence for the genetic overlap between schizophrenia and tobacco use in women, and this overlap was stronger in the younger population.

Heart rate variability and surgical pleth index under anesthesia in poor and normal sleepers.

Poor sleep quality is associated with autonomic dysfunctions and altered pain perception and tolerance. To investigate whether autonomic dysregulations related to insomnia would still exist under general anesthesia, we adopt heart rate variability (HRV) analysis to evaluate ANS activity and surgical pleth index (SPI) to compare nociceptive/anti-nociceptive balance. We enrolled 61 adult females scheduled for gynecological surgeries under general anesthesia. All the subjects were ASA Class I to III without using medicines affecting HRV. We used the Insomnia Severity Index to evaluate sleep qualities. ECG data were recorded and signals which denote four different surgical stages were extracted (baseline, incision, mid-surgery, and end of surgery). We analyzed the HRV changes across the whole surgical period and differences among good and poor sleepers. We also compared the SPI differences among groups. For baseline HRV analysis, we found significant differences in the RMSSD (p = 0.043), pNN50 (p = 0.029), VLF power (p = 0.035), LF power (p = 0.004), and HF power (p = 0.037) between the good and poor sleeper groups. However, all intergroup differences disappeared after anesthesia induction. Temporal HRV changes significantly among different perioperative stages (RMSSD, p < 0.001; pNN50, p = 0.004; LF, p < 0.001; and HF, p < 0.001). Patients with different sleep qualities did not exhibit different SPI levels in all four periods. Poor sleepers exhibited attenuated parasympathetic activities at the baseline but no differences after the induction. Nociceptive/anti-nociceptive balance seems not be altered by poor sleep condition under general anesthesia.

Avaliação de assimetria hemisférica funcional em pacientes com doença de Alzheimer / Evaluation of functional hemispheric asymmetry in Alzheimer's disease patients

Introdução: as assimetrias cerebrais constituem aspectos fundamentais para a organização funcional e o processamento cognitivo. Estudos prévios têm reportado que alterações no padrão de assimetria hemisférica existentes em algumas patologias reduzem a eficiência no processamento de informação. Objetivos: avaliar a assimetria hemisférica funcional a partir de padrões de homofilia e heterofilia; analisar a assimetria da conectividade funcional de redes dinâmicas em portadores de Alzheimer. Metodologia: foram construídas redes funcionais dinâmicas do córtex cerebral de pacientes com diferentes níveis de Alzheimer (muito leve, leve e moderado a grave) e do grupo de controle a partir de EEG (19 eletrodos, Sistema 10-20). Tais redes foram geradas a partir do método de associação sincronização por motifs e representadas através de grafos variantes no tempo e de redes estáticas agregadas. Essas redes foram avaliadas por meio de índices de assimetria e conectividade. Resultados: os resultados mostram uma tendência à redução da homofilia com a progressão da enfermidade, quando se compara ao controle, além de um leve aumento do índice para o último estágio, se comparado aos estágios iniciais da doença. A assimetria para a conectividade funcional, por sua vez, mostrou uma propensão a maior conectividade para o hemisfério direito, salvo para o estágio moderado a grave. Conclusão: embora os resultados não tenham apresentado diferenças significativas, eles indicam tendências de alteração no padrão de homofilia e na assimetria da conectividade funcional em redes funcionais dinâmicas de pacientes com Alzheimer.

Introduction: brain asymmetries are fundamental aspects for functional organization and cognitive processing. Previous studies have reported that changes in the hemispheric asymmetry pattern of some pathologies reduce the efficiency of information processing. Objectives: to evaluate functional hemispheric asymmetry based on homophilia and heterophilia patterns; to analyze the asymmetry of functional connectivity of dynamic networks in Alzheimer patients. Methodology: dynamic functional networks of the cerebral cortex were constructed from patients with different levels of Alzheimer's (very mild, mild and moderate to severe) and the control group from EEG (19 electrodes, System 10-20). Such networks were generated from the motif synchronization association method and represented by time-varying graphs and aggregate static networks. These networks were evaluated using asymmetry and connectivity indices. Results: the results show a tendency towards a reduction in homophilia with disease progression, when compared to the control, besides a slight increase in the index for the last stage, compared to the initial stages of the disease. Asymmetry for functional connectivity, in turn, showed a propensity for greater connectivity to the right hemisphere, except for the moderate to severe stage. Conclusion: although results did not show significant differences, they indicate trends of change in homophily pattern and functional connectivity asymmetry in dynamic functional networks of patients with Alzheimer's.

Gene-based analysis of genes related to neurotrophic pathway suggests association of BDNF and VEGFA with antidepressant treatment-response in depressed patients.

It is well established that brain-derived neurotrophic factor (BDNF) signaling pathway plays a key role in the pathophysiology of major depressive disorder (MDD) and in therapeutic mechanisms of antidepressants. We aim to identify genetic vairiants related to MDD susceptibility and antidepressant therapeutic response by using gene-based association analysis with genes related to the neurotrophic pathway. The present study investigated the role of genetic variants in the 10 neurotrophic-related genes (BDNF, NGFR, NTRK2, MTOR, VEGFA, S100A10, SERPINE1, ARHGAP33, GSK3B, CREB1) in MDD susceptibility through a case-control (455 MDD patients and 2,998 healthy controls) study and in antidepressant efficacy (n = 455). Measures of antidepressant therapeutic efficacy were evaluated using the 21-item Hamilton Rating Scale for Depression. Our single-marker and gene-based analyses with ten genes related to the neurotrophic pathway identified 6 polymorphisms that reached a significant level (p-value < 5.0 × 10-3) in both meta- and mega-analyses in antidepressant therapeutic response. One polymorphism was mapped to BDNF and 5 other polymorphisms were mapped to VEGFA. For case-control association study, we found that all of these reported polymorphisms and genes did not reach a suggestive level. The present study supported a role of BDNF and VEGFA variants in MDD therapeutic response.

Effects of circadian clock genes and environmental factors on cognitive aging in old adults in a Taiwanese population.

Previous animal studies have indicated associations between circadian clock genes and cognitive impairment . In this study, we assessed whether 11 circadian clockgenes are associated with cognitive aging independently and/or through complex interactions in an old Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to evaluate cognitive function. Our data showed associations between cognitive aging and single nucleotide polymorphisms (SNPs) in 4 key circadian clock genes, CLOCK rs3749473 (p = 0.0017), NPAS2 rs17655330 (p = 0.0013), RORA rs13329238 (p = 0.0009), and RORB rs10781247 (p = 7.9 x 10-5). We also found that interactions between CLOCK rs3749473, NPAS2 rs17655330, RORA rs13329238, and RORB rs10781247 affected cognitive aging (p = 0.007). Finally, we investigated the influence of interactions between CLOCK rs3749473, RORA rs13329238, and RORB rs10781247 with environmental factors such as alcohol consumption, smoking status, physical activity, and social support on cognitive aging (p = 0.002 ~ 0.01). Our study indicates that circadian clock genes such as the CLOCK, NPAS2, RORA, and RORB genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-environment interactions.

Effects of circadian clock genes and health-related behavior on metabolic syndrome in a Taiwanese population: Evidence from association and interaction analysis.

Increased risk of developing metabolic syndrome (MetS) has been associated with the circadian clock genes. In this study, we assessed whether 29 circadian clock-related genes (including ADCYAP1, ARNTL, ARNTL2, BHLHE40, CLOCK, CRY1, CRY2, CSNK1D, CSNK1E, GSK3B, HCRTR2, KLF10, NFIL3, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, REV1, RORA, RORB, RORC, SENP3, SERPINE1, TIMELESS, TIPIN, VIP, and VIPR2) are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing MetS and its individual components. A total of 3,000 Taiwanese subjects from the Taiwan Biobank were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our data showed a nominal association of MetS with several single nucleotide polymorphisms (SNPs) in five key circadian clock genes including ARNTL, GSK3B, PER3, RORA, and RORB; but none of these SNPs persisted significantly after performing Bonferroni correction. Moreover, we identified the effect of GSK3B rs2199503 on high fasting glucose (P = 0.0002). Additionally, we found interactions among the ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, RORA rs8034880, and RORB rs972902 SNPs influenced MetS (P < 0.001 ~ P = 0.002). Finally, we investigated the influence of interactions between ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, and RORB rs972902 with environmental factors such as alcohol consumption, smoking status, and physical activity on MetS and its individual components (P < 0.001 ~ P = 0.002). Our study indicates that circadian clock genes such as ARNTL, GSK3B, PER3, RORA, and RORB genes may contribute to the risk of MetS independently as well as through gene-gene and gene-environment interactions.

Increased Risk of Myofascial Pain Syndrome Among Patients with Insomnia.

OBJECTIVE: The aim of this study is to evaluate the risk of developing myofascial pain syndrome among patients diagnosed with insomnia. METHODS: We conducted a population-based longitudinal study of a matched cohort with 7,895 participants (1,579 patients with insomnia and 6,316 controls) who were selected from the Taiwan National Health Insurance Research Database. The patients were observed for a maximum of 10 years to determine the incidence of newly diagnosed myofascial pain syndrome. A Cox regression analysis was performed to identify the risk factors associated with myofascial pain syndrome in patients with insomnia. RESULTS: During the 10-year follow-up period, 182 insomnia patients (14.9 per 1,000 person-years) and 379 controls (7.5 per 1,000 person-years) were diagnosed with myofascial pain syndrome. The incidence risk ratio of myofascial pain syndrome between the insomnia and control patients was 2.00 (95% confidence interval [CI] = 1.67-2.38, P < 0.001). After adjusting for age, sex, monthly income, urbanization, and comorbidities, the insomnia patients were 1.93 times more likely to develop myofascial pain syndrome (95% CI = 1.62-2.31, P < .001) than the control patients. Malignant neoplasm (hazard ratio = 3.08) and living in urban areas (hazard ratio = 3.05) were identified as independent risk factors for myofascial pain syndrome in patients with insomnia. CONCLUSIONS: Patients with insomnia had a higher risk of developing myofascial pain syndrome than controls. This study adds to the understanding of the complex relationship between sleep disturbance and pain.

Association and interaction effects of Alzheimer's disease-associated genes and lifestyle on cognitive aging in older adults in a Taiwanese population.

Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer's diseases (AD) has been associated with the ABCA7, APOE, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB1, HLA-DRB4, INPP5D, MEF2C, MS4A4A, MS4A4E, MS4A6E, NME8, PICALM, PLD3, PTK2B, RIN3, SLC24A4, SORL1, and ZCWPW1 genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. We also analyzed the interactions between lifestyle and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to evaluate cognitive functions. Out of the 588 SNPs tested in this study, only the association between CASS4-rs911159 and cognitive aging persisted significantly (P = 2.2 x 10-5) after Bonferroni correction. Our data also showed a nominal association of cognitive aging with the SNPs in six more key AD-associated genes, including EPHA1-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, PLD3-rs11672825, RIN3-rs1885747, and SLC24A4-rs67063100 (P = 0.0018~0.0097). Additionally, we found the interactions among CASS4-rs911159, EPHA-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, or SLC24A4-rs67063100 on cognitive aging (P = 0.004~0.035). Moreover, our analysis suggested the interactions of SLC24A4-rs67063100 or MEF2C-rs9293506 with lifestyle such as alcohol consumption, smoking status, physical activity, or social support on cognitive aging (P = 0.008~0.041). Our study indicates that the AD-associated genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-lifestyle interactions.