Serum albumin, genetic susceptibility, and risk of venous thromboembolism.

Background: Previous research on the association between serum albumin (ALB) and venous thromboembolism (VTE) has produced inconclusive results. The polygenic risk score is constructed from a set of independent risk variants associated with a disorder, enabling the identification of a larger fraction of the population at comparable or greater disease risk. It is still unknown whether ALB and genetic factors jointly contribute to the incidence of VTE. Objectives: The present study aimed to explore ALB, genetic susceptibility, and the risk of VTE. Methods: The present investigation was an analysis of prospectively collected data from UK Biobank, a population-based, longitudinal cohort. Cox proportional models were used to calculate hazard ratios and 95% CIs for VTE. The Kaplan-Meier curve was utilized to visualize the cumulative risk of VTE according to different serum ALB levels, and the restricted cubic spline model was leveraged to explore the exposure-response relationship among ALB levels and VTE risk. Results: During median follow-up of 13.5 years, 11,502 cases with VTE were diagnosed among 417,113 participants in the UK Biobank. The lower ALB levels were associated with a higher risk for VTE. Individuals with both a high genetic risk and lowest ALB level had the highest risk of VTE (hazard ratio, 3.89; 95% CI, 3.41-4.43), compared with those with low genetic risk and highest ALB level. The positive joint effects of low ALB and polygenic risk score increased the risk of VTE in individuals with high genetic risk. This study excluded non-European patients and primarily focused on the European population, which may limit the generalizability of the findings. Conclusion: Low serum ALB levels were linked to an increased risk of VTE, which was in accordance with a linear dose-response relationship. There was a positive additive effect of ALB and genetic susceptibility on the risk of VTE. ALB could serve as a biomarker for predicting the risk of VTE.

Joint and interactive associations of body mass index and genetic factors with cardiovascular disease: a prospective study in UK Biobank.

BACKGROUND: Both body mass index (BMI) and genetic factors independently contribute to cardiovascular disease (CVD). However, it is unclear whether genetic risk modifies the association between BMI and the risk of incident CVD. This study aimed to investigate whether BMI categories and genetic risk jointly and interactively contribute to incident CVD events, including hypertension (HTN), atrial fibrillation (AF), coronary heart disease (CHD), stroke, and heart failure (HF). METHODS: A total of 496,851 participants from the UK Biobank with one or more new-onset CVD events were included in the analyses. BMI was categorized as normal weight (< 25.0 kg/m2), overweight (25.0-29.9 kg/m2), and obesity (≥ 30.0 kg/m2). Genetic risk for each outcome was defined as low (lowest tertile), intermediate (second tertile), and high (highest tertile) using polygenic risk score. The joint associations of BMI categories and genetic risk with incident CVD were investigated using Cox proportional hazard models. Additionally, additive interactions were evaluated. RESULTS: Among the 496,851 participants, 270,726 (54.5%) were female, with a mean (SD) age was 56.5 (8.1) years. Over a median follow-up (IQR) of 12.4 (11.5-13.1) years, 102,131 (22.9%) participants developed HTN, 26,301 (5.4%) developed AF, 32,222 (6.9%) developed CHD, 10,684 (2.2%) developed stroke, and 13,304 (2.7%) developed HF. Compared with the normal weight with low genetic risk, the obesity with high genetic risk had the highest risk of CVD: HTN (HR: 3.96; 95%CI: 3.84-4.09), AF (HR: 3.60; 95%CI: 3.38-3.83), CHD (HR: 2.76; 95%CI: 2.61-2.91), stroke (HR: 1.44; 95%CI: 1.31-1.57), and HF (HR: 2.47; 95%CI: 2.27-2.69). There were significant additive interactions between BMI categories and genetic risk for HTN, AF, and CHD, with relative excess risk of 0.53 (95%CI: 0.43-0.62), 0.67 (95%CI: 0.51-0.83), and 0.37 (95%CI: 0.25-0.49), respectively. CONCLUSIONS: BMI and genetic factors jointly and interactively contribute to incident CVD, especially among participants with high genetic risk. These findings have public health implications for identifying populations more likely to have cardiovascular benefit from weight loss interventions.

Improving life's essential 8 mitigates myocardial infarction risk attributed to abnormal birth weight in later life.

Background: To prospectively assess the individual and joint effects of birth weight and the life's essential 8 (LE8)-defined cardiovascular health (CVH) on myocardial infarction (MI) risk in later life. Methods: In 144,803 baseline MI-free participants who were recruited in the UK Biobank cohort between 2006 and 2010, Cox proportional hazard models were used to estimate the associations of birth weight, LE8 score, and their interactions with incident MI. LE8 was defined on the basis of diet, physical activity, nicotine exposure, sleep health, body mass index, blood pressure, blood glucose, and blood lipids. Results: Low birth weight was associated with higher risk of MI [hazard ratio (HR) 1.17, 95% confidence interval 1.02-1.35, P = 0.025], while no significant correlation between high birth weight and MI was observed after adjustment. Low CVH was associated with higher MI risk [HR 6.43 (3.71-11.15), P < 0.001). Participants with low birth weight and low CVH (vs. participants with normal birth weight and high CVH) had HR of 5.97 (2.94-12.14) for MI incidence. The relative excess risk due to interaction of low birth weight and low CVH on MI was -4.11 (-8.12, -0.11), indicating a negative interaction on an additive scale. A consistent decreasing trend of MI risk along with increased LE8 score was observed across all three birth weight groups. Conclusion: Low birth weight was associated with increased MI risk, emphasizing the importance of the prenatal factor in risk prediction and prevention of MI. Improving LE8 can mitigate MI risk attributed to low birth weight.

Estimating Additive Interaction in Two-Stage Individual Participant Data Meta-Analysis.

Individual participant data (IPD) meta-analysis provides important opportunities to study interaction and effect modification for which individual studies often lack power. While previous meta-analyses have commonly focused on multiplicative interaction, additive interaction holds greater relevance for public health and may in certain contexts better reflect biological interaction. Methodological literature on interaction in IPD meta-analysis does not cover additive interaction for models including binary or time-to-event outcomes. We aimed to describe how the Relative Excess Risk due to Interaction (RERI) and other measures of additive interaction or effect modification can be validly estimated within two-stage IPD meta-analysis. First, we explain why direct pooling of study-level RERI estimates may lead to invalid results. Next, we propose a three-step procedure to estimate additive interaction: 1) estimate effects of both exposures and their product term on the outcome within each individual study; 2) pool study-specific estimates using multivariate meta-analysis; 3) estimate an overall RERI and 95% confidence interval based on the pooled effect estimates. We illustrate this procedure by investigating interaction between depression and smoking and risk of smoking-related cancers using data from the PSYchosocial factors and Cancer (PSY-CA) consortium. We discuss implications of this procedure, including the application in meta-analysis based on published data.

Intergenerational transmission of psychopathology across three generations: the role of social support.

Psychopathology runs in families and affects functioning of individuals and their family members. This study assessed the intergenerational transmission of psychopathology risk across three generations, and the extent to which social support factors may protect against this transmission from parents to their offspring. This study was embedded in Generation R, a multi-ethnic population-based cohort from fetal life onwards. Lifetime psychiatric disorders of grandparents were assessed with the Family Informant Schedule Criteria- updated for DSM-IV. Parental psychopathology was repeatedly measured by the Brief Symptom Inventory. Offspring psychopathology (ages 10 and 14) was assessed with the Brief Problem Monitor. Maternal and child social factors were assessed using questionnaire measures and a computerized peer nomination assessment. Our results show that the estimated additive interaction effect for the risk transmission of grandparental and pre- and postnatal parental psychopathology to offspring psychopathology was 23% (95% CI 19; 27). The joint effect of grandparental and parental psychopathology combined with maternal and child social support factors was 13% (95% CI 08; 17)], suggesting that social support factors diminished the intergenerational transmission of psychopathology from (grand)parents (G1 and G2) to offspring (G3). Transmission of psychopathology risk may have long-lasting developmental effects across generations. Social support factors reduced the vulnerability to the effects of psychopathology risk, underscoring the importance of the identification of buffering factors associated with good mental health in adolescents who are at high familial risk.

The Interaction Effect of Adverse Childhood Experiences and Socioeconomic Circumstances in Adolescent Depressive Symptomatology.

PURPOSE: Limited research has examined the combined effects of psychosocial and material adversities experienced in childhood during adolescence, a sensitive period of rapid social, emotional, and cognitive development. We investigated the interaction effect of adverse childhood experiences (ACEs) and socioeconomic circumstances (SECs) during childhood on emerging self-reported depressive symptomatology among 13-year-old Portuguese adolescents. METHODS: We utilized data from 4,280 participants in the Generation XXI birth cohort, collected during the baseline (2005-2006), third (2016-2017), and fourth waves (2018-2020). Adjusted odds ratios and 95% confidence intervals (CIs) were obtained from binary logistic regression analyses to estimate the likelihood of depressive symptoms based on exposure to ACEs and adverse family SECs. The interaction effect of ACEs and SECs was evaluated in terms of departure from additive and multiplicative models. RESULTS: Adolescents who reported experiences of abuse, school-related problems, and household dysfunction, as well as those from less advantaged family SECs at age 10, were more likely to report moderate to severe depressive symptoms at age 13, compared to their more affluent counterparts. We observed a significant additive interaction between low household income and abuse in the development of moderate to severe depressive symptoms [relative excess risk due to interaction, 0.69, 95% CI: 0.11, 1.26]. This interaction remained statistically significant on a multiplicative scale [OR = 1.61, 95% CI: 0.99, 2.69]. DISCUSSION: ACEs and low family SECs during the first decade of life are associated with an elevated risk of moderate to severe depressive symptoms in adolescence.

Assessing Additive Interactions between Protective Factors Using Relative Risk Reduction Due to Interaction.

Background and Objectives: In the context of disease prevention, interaction on an additive scale is commonly assessed to determine synergistic effects between exposures. While the "Relative Excess Risk due to Interaction" represents the main measure of additive interaction between risk factors, in this study we aimed to extend this approach to assess additive interaction between factors known to prevent the event's occurrence, such as medical interventions and drugs. Materials and Methods: We introduced and described the "Relative Risk Reduction due to Interaction" (RRRI) as a key measure to assess additive interactions between preventive factors, such as therapeutic interventions and drug combinations. For RRRI values closer to 1, the combination of exposures has a greater impact on reducing the event risk due to their interaction. As a purely illustrative example, we re-evaluated a previous investigation of the synergistic effect between statins and blood pressure-lowering drugs in preventing major adverse cardiovascular events (MACE). Moreover, simulation studies were used to empirically evaluate the performance of a robust Poisson regression model to estimate RRRI across different scenarios. Results: In our example, the drug combination revealed a positive additive interaction in further reducing MACE risk (RRRI > 0), even if not statistically significant. This result is more straightforward to interpret as compared to the original one based on the RERI. Additionally, our simulations highlighted the importance of large sample sizes for detecting significant interaction effects. Conclusion: We recommend RRRI as the main measure to be considered when exploring additive interaction effects between protective exposures, such as the investigation of synergistic effects between drug combinations or preventive treatments.

Did childhood adversity increase the vulnerability of university students to the negative mental health impact of the COVID-19 pandemic?

OBJECTIVE: To examine a potential synergistic effect of history of childhood adversity and COVID-19 pandemic exposure on the association with mental health concerns in undergraduate students. Participants: We used U-Flourish Survey data from 2019 (pre-pandemic) and 2020 (during-pandemic) first-year cohorts (n = 3,149) identified at entry to a major Canadian University. METHODS: Interactions between childhood adversity (physical and sexual abuse, and peer bullying) and COVID-19 pandemic exposure regarding mental health concern (depressive and anxiety symptoms, suicidality, and non-suicidal self-harm) were examined on an additive scale. RESULTS: We found a positive additive interaction between physical abuse and pandemic exposure in relation to suicidality (combined effect was greater than additive effect (risk difference 0.54 vs. 0.36)). Conversely, less than additive interactions between peer bullying and pandemic regarding depression and anxiety were observed. CONCLUSIONS: Childhood adversities have diverse reactions to adult stressor depending on the nature of the childhood adversity and the mental health outcomes.

Smoking Timing, Healthy Diet, and Risk of Incident CKD Among Smokers: Findings From UK Biobank.

RATIONALE & OBJECTIVE: Although smoking is a recognized risk factor for chronic kidney disease (CKD), the relationship between the time smoking is initiated after awakening each day and CKD remains largely unstudied. This study examined the association between this timing and the risk of CKD, and the potential interactions of smoking timing with other risk factors for the occurrence of CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A total of 32,776 participants in the UK Biobank with complete data on the time from waking to the first cigarette and free of prevalent CKD were included. EXPOSURE: Time from waking to the first cigarette. OUTCOME: Incident CKD cases. ANALYTICAL APPROACH: Cox proportional hazards regression was used to investigate the associations between the time smoking is initiated each day and the risk of CKD. The potential interactions of smoking timing with risk factors in relationship to CKD risk were assessed on both multiplicative and additive scales. RESULTS: During a median follow-up period of 12 years, 940 incident CKD cases occurred. Shorter durations of time from waking to the first cigarette were associated with a higher risk of incident CKD (P trend=0.01). Compared with>120 minutes, the adjusted hazard ratio (HR) associated with smoking timing was 1.28 (95% CI, 0.92-1.80) for 61-120 minutes, 1.48 (95% CI, 1.11-1.96) for 30-60 minutes, 1.36 (95% CI, 1.01-1.88) for 5-15 minutes, and 1.70 (95% CI, 1.22-2.37) for<5 minutes, respectively. Furthermore, there was a significant additive interaction and multiplicative interactions between the timing of smoking and a healthy diet score (P for additive interaction=0.01; P for multiplicative interaction = 0.004). LIMITATIONS: Generalizability, possible residual confounding, limiting causal inference. CONCLUSIONS: These findings reveal a significant association between the shorter time from waking to the first cigarette and a higher CKD risk. The magnitude of these associations was greater in the setting of an unhealthy diet. PLAIN-LANGUAGE SUMMARY: This study explored the association of the daily timing of first cigarette smoking and the occurrence of kidney disease. Further, we addressed whether this association was influenced by the quality of the diet. The study found that smoking very soon after waking, especially when combined with a poorer quality diet, was associated with a significantly increased risk of developing chronic kidney disease. This research emphasizes the value of healthier lifestyle choices for kidney health.

Joint effects of air pollution and genetic susceptibility on incident primary open-angle glaucoma.

BACKGROUND: Air pollutants are important exogenous stimulants to eye diseases, but knowledge of associations between long-term exposure to air pollutants and the risk of primary open-angle glaucoma (POAG) is limited. This study aimed to determine whether long-term exposure to air pollutants, genetic susceptibility, and their joint effects lead to an elevated risk of incident POAG. METHODS: This is a population-based prospective cohort study from UK Biobank participants with complete measures of air pollution exposure and polygenetic risk scores. Cox proportional hazard models were fitted to assess the individual and joint effects of long-term exposure to air pollutants and genetics on the risk of POAG. In addition, the effect modification of genetic susceptibility was examined on an additive or multiplicative scale. RESULTS: Among 434,290 participants with a mean (SD) age of 56.5 (8.1) years, 6651 (1.53 %) were diagnosed with POAG during a median follow-up of 13.7 years. Long-term exposure to air pollutants was associated with an increased risk of POAG. The hazard ratios associated with per interquartile range increase in PM2.5, PM2.5 absorbance, PM10, NO2, and NOX individually ranged from 1.027 (95 % CI: 1.001-1.054) to 1.067 (95 % CI: 1.035-1.099). Compared with individuals residing in low-pollution areas and having low polygenic risk scores, the risk of incident POAG increased by 105.5 % (95 % CI: 78.3 %-136.9 %), 79.7 % (95 % CI: 56.5 %-106.5 %), 103.2 % (95 % CI: 76.9 %-133.4 %), 89.4 % (95 % CI: 63.9 %-118.9 %), and 90.2 % (95 % CI: 64.8 %-119.5 %) among those simultaneously exposed to high air pollutants levels and high genetic risk, respectively. Genetic susceptibility interacted with PM2.5 absorbance and NO2 in an additive manner, while no evidence of multiplicative interaction was found in this study. Stratification analyses revealed stronger effects in Black people and the elderly. CONCLUSION: Long-term air pollutant exposure was associated with an increased risk of POAG incidence, particularly in the population with high genetic predisposition.

Additive Interaction Between Insulin Resistance, Chronic Low-Grade Inflammation and Vitamin D Deficiency on the Risk of Type 2 Diabetes Mellitus: A Cohort Study.

OBJECTIVES: The aim of this study was to explore, on an additive scale, the combined effect of the association between insulin resistance (IR), chronic low-grade inflammation (CLGI) and vitamin D deficiency (VDD) on the risk of type 2 Diabetes Mellitus (T2DM). METHODS: This is a cohort study, including 1484 non-diabetic subjects, followed for a period of four years. 25 hydroxy-vitamin D (25OHD), hypersensitive C-reactive protein (HsCRP) and triglyceride-glucose index were assessed. Based on VDD and CLGI, the population was subdivided into 4 exposure groups. Analysis was performed both in the case of IR and without IR. Cox proportional regression and additive interaction were applied to explore cumulative effects of exposure. RESULTS: At follow-up, 162 newly diagnosed cases of T2DM were identified. TYG index (RR = 4.0[2.8-5.6]), HsCRP (RR = 1.6 [1.4-1.7]) and 25OHD (RR = 0.96 [0.39-0.98]) were all significantly associated with the risk of T2DM (p < 0.01). The highest excess risk was recorded in patients cumulating simultaneously IR, CLGI and VDD (RR= 8.4[3.6-19.8], p < 0.0001). The additive interaction was significant, the excess risk linked to the interaction RERI = 10.5[1.43-19.7], the proportion attributable to the combined effect: AP = 0.61[0.37-0.85], and the interaction was synergistic: synergy index: 2.8[1.42-5.69]. CONCLUSION: Baseline levels of TYG index, 25OHD and HsCRP are strongly predictive of future T2DM, and their joint effects are additive and synergistic. Interventional studies are therefore warranted in order to evaluate whether vitamin D supplementation, combined with appropriate anti-inflammatory therapies, is effective as a preventive strategy to reduce the risk of T2DM.

Additive interaction of family medical history of diabetes with hypertension on the diagnosis of diabetes among older adults in India: longitudinal ageing study in India.

BACKGROUND: The present study aimed to estimate the additive interaction of family history of diabetes and hypertension on the diagnosis of diabetes among individuals aged 45 years and above in India. The coexistence of these two exposures may act synergistically on the risk of diabetes, leading to adverse health outcomes. METHODS: The study utilized the data from the Longitudinal Ageing Study in India (LASI) Wave 1 (2017-2018). The total sample size for the current study was 58,612 individuals aged 45 years and above. Multivariable logistic regression models were employed to determine the individual and joint effect of a family history of diabetes with hypertension on diabetes. An additive model was applied to assess the interaction effect of the family medical history of diabetes with hypertension on the diagnosis of diabetes by calculating three different measures of additive interaction such as the relative excess risk ratio (RERI), attribution proportion due to interaction (AP), and synergy index (S). RESULTS: The prevalence of diabetes was three times higher among individuals with family history of diabetes (27.8% vs. 9.2%) than those without family history. Individuals with family history of diabetes (AOR: 2.47, CI: 2.11 2.89) had 2.47 times higher odds of having diabetes than those without family history. The prevalence of diabetes was significantly higher among individuals with hypertension and family history of diabetes (46.6%, 95% CI: 39.7-53.6) than those without the coexistence of family history of diabetes and hypertension (9.9%, 95% CI: 9.5-10.4), individuals with hypertension and without a family history of diabetes (22.7%, 95% CI: 21.2-24.2), and individuals with family history of diabetes and without hypertension (16.5%, 95% CI: 14.5-18.7). Moreover, the adjusted odds ratio (AOR) of the joint effect between family medical history of diabetes and hypertension on diabetes was 9.28 (95% CI: 7.51-11.46). In the adjusted model, the RERI, AP, and S for diabetes were 3.5 (95% CI: 1.52-5.47), 37% (0.37; 95% CI: 0.22-0.51), and 1.69 (95% CI: 1.31-2.18) respectively, which indicates that there is a significant positive interaction between family history of diabetes and hypertension on the diagnosis of diabetes. The study findings on interaction effects further demonstrate consistent results for two models of hypertension (self-reported hypertension and hypertensive individuals receiving medication) even after adjustment with potential confounding factors on diabetes (self-reported diabetes and individuals with diabetes receiving medication). CONCLUSIONS: The study findings strongly suggest that the interaction of family history of diabetes with hypertension has a positive and significant effect on the risk of diabetes even after adjustment with potential confounding factors. Furthermore, the findings indicate a synergistic effect, emphasizing the importance of considering both family medical history of diabetes and hypertension when assessing diabetes risk and designing preventive strategies or interventions.

Associations of evening-type and insomnia symptoms with depressive symptoms among youths.

BACKGROUND: Evening-type and insomnia symptoms are significantly related to each other and independently associated with depressive symptoms, yet few studies have examined the potential interaction between these two conditions. Therefore, we aimed to examine the associations of evening-type and insomnia symptoms with depressive symptoms among Chinese youths, with a specific focus on the joint effects of the two conditions on depressive symptoms. METHODS: Participants aged between 12 and 25 were invited to participate in an online survey from December 15, 2022, to May 26, 2023. Multivariate logistic regression models and additive interaction models were used to examine the independent and joint effects of chronotypes and insomnia symptoms on depressive symptoms, respectively. RESULTS: Of the 6145 eligible youths, the prevalence of evening-type and insomnia symptoms were 24.9 % and 29.6 %, respectively. Both evening-type (adjusted OR, [AdjOR]: 3.21, 95 % CI: 2.80-3.67) and insomnia symptoms (AdjOR: 10.53, 95 % CI: 9.14-12.12) were associated with an increased risk of depressive symptoms. In addition, the additive interaction models showed that there is an enhanced risk of depression related to interaction between evening-type and insomnia symptoms (relative excess risk due to interaction, [RERI]: 11.66, 95 % CI: 7.21-16.11). CONCLUSIONS: The present study provided additional evidence demonstrating the presence of interaction between evening-type and insomnia symptoms, which can lead to a higher risk of depressive symptoms. Our findings argue the need for addressing both sleep and circadian factors in the management of depressive symptoms in young people.

The association between physical activities combined with dietary habits and cardiovascular risk factors.

Objectives: The aim of this study was to investigate the association between physical activities combined with dietary habits and cardiovascular risk factors in adults from Nanjing, China. Methods: The cross-sectional survey conducted in 2017 involved a sample of 60 283 individuals aged ≥18 years in Nanjing municipality, China. The sampling method used was multistage stratified cluster sampling. The primary outcomes from multivariate logistic regression analysis with adjusted potential confounders were the relationships between physical activities combined with dietary habits and cardiovascular risk variables. Relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) were used to assess an additive interaction between dietary habits and physical activities. Results: After adjusting potential confounders, cardiovascular risk factors were significantly associated with the association of physical inactivity and unhealthy diet, with the highest odds ratios (ORs) for low density lipoprotein-cholesterol (HLDL-c) (1.64, 95% CI [1.47, 1.84]) and hypertension (1.55, 95% CI [1.46, 1.64]). Additive interactions between physical inactivity and unhealthy diet were found in on cardiovascular risk factors of higher low-density lipoprotein-cholesterol (HLDL-c) (S, 2.57; 95% CI [1.27, 5.21]), type 2 diabetes (T2D) (S, 1.96; 95% CI [1.23, 3.13]), dyslipidemia (S, 1.69; 95% CI [1.08, 2.66]) and hypertension (S, 1.46; 95% CI [1.12, 1.89]). Their RERI was 0.39 (95% CI [0.18, 0.60]), 0.22 (95% CI [0.09, 0.35]), 0.11 (95% CI [0.03, 0.19]) and 0.17 (95% CI [0.06, 0.28]), respectively. OR of being HLDL-c, T2D, hypertension and dyslipidemia in participants of physical inactivity and unhealthy diet was 24%, 15%, 11% and 8.3%, respectively. Multiplicative interaction was detected in obesity, hypertension, T2D and HLDL-c. Conclusion: An unhealthy diet and physical inactivity were strongly linked to cardiovascular risk factors. This study also showed that an unhealthy diet and physical inactivity combined to produce an additive effect on T2D, hypertension, HLDL-c, and dyslipidemia, suggesting a higher risk than the total of these factors, especially HLDL-c. Preventive strategies aimed at reducing cardiometabolic risks such as hypertension, T2D, HLDL-c, and dyslipidemia are necessary for targeting physical inactivity and unhealthy diet.

Beyond task response-Pre-stimulus activity modulates contents of consciousness.

The current discussion on the neural correlates of the contents of consciousness (NCCc) focuses mainly on the post-stimulus period of task-related activity. This neglects the substantial impact of the spontaneous or ongoing activity of the brain as manifest in pre-stimulus activity. Does the interaction of pre- and post-stimulus activity shape the contents of consciousness? Addressing this gap in our knowledge, we review and converge two recent lines of findings, that is, pre-stimulus alpha power and pre- and post-stimulus alpha trial-to-trial variability (TTV). The data show that pre-stimulus alpha power modulates post-stimulus activity including specifically the subjective features of conscious contents like confidence and vividness. At the same time, alpha pre-stimulus variability shapes post-stimulus TTV reduction including the associated contents of consciousness. We propose that non-additive rather than merely additive interaction of the internal pre-stimulus activity with the external stimulus in the alpha band is key for contents to become conscious. This is mediated by mechanisms on different levels including neurophysiological, neurocomputational, neurodynamic, neuropsychological and neurophenomenal levels. Overall, considering the interplay of pre-stimulus intrinsic and post-stimulus extrinsic activity across wider timescales, not just evoked responses in the post-stimulus period, is critical for identifying neural correlates of consciousness. This is well in line with both processing and especially the Temporo-spatial theory of consciousness (TTC).

Combined association of abdominal obesity and depressive symptoms with risk of type 2 diabetes: A cohort study.

OBJECTIVE: To explore the combined effect of abdominal obesity and depressive symptoms on the risk to type 2 diabetes, while also assessing the potential influence of various glycemic states and gender on this combined relationship. METHODS: Data is acquired from the China Health and Retirement Longitudinal Study, and 5949 participants were included for analysis. Participants were divided into four groups: neither have abdominal obesity nor depressive symptoms (AO-/DS-), only have depressive symptoms (AO-/DS+), only have abdominal obesity (AO+/DS-), and have both abdominal obesity and depressive symptoms (AO+/DS+). Stratified analyses differentiating the glycemic statuses and sex of the participants were also carried out. RESULTS: After adjusting for the confounders, the AO-/DS+, AO+/DS- and AO+/DS+ phenotypes were all discovered to be risk factors for type 2 diabetes (OR = 1.38, 95%CI: 1.06-1.79; OR = 2.07, 95%CI: 1.63-2.63; OR = 2.38, 95%CI: 1.83-3.11, respectively) compared with the AO-/DS- phenotype in the overall population. In further stratified analyses, we arrived at the same conclusion for normoglycemic individuals, especially in females. For prediabetes and males, the AO+/DS- and AO+/DS+ phenotypes are risk factors for type 2 diabetes compared with the AO-/DS- phenotype, but not with AO-/DS+. CONCLUSION: Regardless of glycemic status and sex, the coexistence of abdominal obesity and depressive symptoms were associated with an increased risk of type 2 diabetes. Depressive symptoms were independent risk factors for type 2 diabetes only in normoglycemic individuals and females.

Association of cognitive reserve with the risk of dementia in the UK Biobank: role of polygenic factors.

BACKGROUND: It remains unclear whether cognitive reserve can attenuate dementia risk among people with different genetic predispositions. AIMS: We aimed to examine the association between cognitive reserve and dementia, and further to explore whether and to what extent cognitive reserve may modify the risk effect of genetic factors on dementia. METHOD: Within the UK Biobank, 210 631 dementia-free participants aged ≥60 years were followed to detect incident dementia. Dementia was ascertained through medical and death records. A composite cognitive reserve indicator encompassing education, occupation and multiple cognitively loaded activities was created using latent class analysis, categorised as low, moderate and high level. Polygenic risk scores for Alzheimer's disease were constructed to evaluate genetic risk for dementia, categorised by tertiles (high, moderate and low). Data were analysed using Cox models and Laplace regression. RESULTS: In multi-adjusted Cox models, the hazard ratio (HR) of dementia was 0.66 (95% confidence interval (CI) 0.61-0.70) for high cognitive reserve compared with low cognitive reserve. In Laplace regression, participants with high cognitive reserve developed dementia 1.62 (95% CI 1.35-1.88) years later than those with low cognitive reserve. In stratified analysis by genetic risk, high cognitive reserve was related to more than 30% lower dementia risk compared with low cognitive reserve in each stratum. There was an additive interaction between low cognitive reserve and high genetic risk on dementia (attributable proportion 0.24, 95% CI 0.17-0.31). CONCLUSIONS: High cognitive reserve is associated with reduced risk of dementia and may delay dementia onset. Genetic risk for dementia may be mitigated by high cognitive reserve. Our findings underscore the importance of enhancing cognitive reserve in dementia prevention.

Sulfur-containing amino acids and risk of schizophrenia.

BACKGROUND: Schizophrenia is a chronic and complex severe psychiatric disorder. Male and female are different in their risks for schizophrenia for the biologic and sociocultural reasons. Homocysteine (Hcy), Cysteine (Cys), and methionine (Met) play important roles in metabolism, and the three amino acids may also be involved in pathogenesis of schizophrenia. OBJECTIVE: This study aimed to test the associations between sulfur-containing amino acid blood levels and risk of schizophrenia, evaluating the different risk in male and female. METHODS: We organized a case-control study on 876 individuals with schizophrenia and 913 age- and sex-matched healthy subjects as control group. The concentrations of Hcy, Cys and Met were measured by liquid chromatography-tandem mass spectrometry technology. Subsequently, restricted cubic spline was applied to explore full-range associations of these amino acids with schizophrenia. Interactions between levels of the three amino acids and sex on additive scale were also tested. RESULTS: Hcy levels at ≤29 µmol/L were associated with sharply increased risk of schizophrenia, inversely, Met was associated with sharply decreased risk of schizophrenia at levels ≤22 µmol/L. Increased Cys levels were associated with decreased risk of schizophrenia. Almost inverse associations were observed between Cys/Hcy and Met/Hcy ratios and schizophrenia. Significant synergistic interactions between levels of all the three amino acids and sex were discovered on an additive scale. CONCLUSIONS: Our study suggests a close association between sulfur-containing amino acids and schizophrenia with different risk in male and female. Future studies are demanded to clarify the pathogenic role of Hcy, Cys and Met in schizophrenia.

Familial Risk and Interaction With Smoking and Alcohol Consumption in Bladder Cancer: A Population-Based Cohort Study.

Background: Although genetic factors are known to play a role in the pathogenesis of bladder cancer, population-level familial risk estimates are scarce. We aimed to quantify the familial risk of bladder cancer and analyze interactions between family history and smoking or alcohol consumption. Methods: Using the National Health Insurance database, we constructed a cohort of 5,524,403 study subjects with first-degree relatives (FDRs) and their lifestyle risk factors from 2002 to 2019. Familial risk was calculated using hazard ratios (HRs) with 95% confidence intervals (CIs) that compare the risk of individuals with and without affected FDRs. Interactions between family history and smoking or alcohol intake were assessed on an additive scale using the relative excess risk due to interaction (RERI). Results: Offspring with an affected parent had a 2.09-fold (95% CI: 1.41 - 3.08) increased risk of disease compared to those with unaffected parents. Familial risks of those with affected father and mother were 2.26 (95% CI: 1.51 - 3.39) and 1.10 (95% CI: 0.27 - 4.41), respectively. When adjusted for lifestyle factors, HR reduced slightly to 2.04 (95% CI: 1.38 - 3.01), suggesting that a genetic predisposition is the main driver in the familial aggregation. Smokers with a positive family history had a markedly increased risk of disease (HR: 3.60, 95% CI: 2.27 - 5.71), which exceeded the sum of their individual risks, with statistically significant interaction (RERI: 0.72, 95% CI: 0.31 - 1.13). For alcohol consumption, drinkers with a positive family history also had an increased risk of disease, although the interaction was not statistically significant (RERI: 0.05, 95% CI: -3.39 - 3.48). Conclusion: Smokers and alcohol consumers with a positive family history of bladder cancer should be considered a high-risk group and be advised to undergo genetic counseling.

Ethnic differences of genetic risk and smoking in lung cancer: two prospective cohort studies.

BACKGROUND: The role of genetic background underlying the disparity of relative risk of smoking and lung cancer between European populations and East Asians remains unclear. METHODS: To assess the role of ethnic differences in genetic factors associated with smoking-related risk of lung cancer, we first constructed ethnic-specific polygenic risk scores (PRSs) to quantify individual genetic risk of lung cancer in Chinese and European populations. Then, we compared genetic risk and smoking as well as their interactions on lung cancer between two cohorts, including the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). We also evaluated the absolute risk reduction over a 5-year period. RESULTS: Differences in compositions and association effects were observed between the Chinese-specific PRSs and European-specific PRSs, especially for smoking-related loci. The PRSs were consistently associated with lung cancer risk, but stronger associations were observed in smokers of the UKB [hazard ratio (HR) 1.26 vs 1.15, P = 0.028]. A significant interaction between genetic risk and smoking on lung cancer was observed in the UKB (RERI, 11.39 (95% CI, 7.01-17.94)], but not in the CKB. Obvious higher absolute risk was observed in nonsmokers of the CKB, and a greater absolute risk reduction was found in the UKB (10.95 vs 7.12 per 1000 person-years, P <0.001) by comparing heavy smokers with nonsmokers, especially for those at high genetic risk. CONCLUSIONS: Ethnic differences in genetic factors and the high incidence of lung cancer in nonsmokers of East Asian ethnicity were involved in the disparity of smoking-related risk of lung cancer.