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.

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.

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.

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.

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.

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.

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.

Household air pollution and risk of incident lung cancer in urban China: A prospective cohort study.

Household air pollution (HAP) is associated with the development of lung cancer, yet few studies investigated the exposure patterns and joint associations with tobacco smoking. In our study, we included 224 189 urban participants from China Kadoorie Biobank (CKB), 3288 of which diagnosed with lung cancer during the follow-up. Exposure to four HAP sources (solid fuels for cooking/heating/stove and environmental tobacco smoke exposure) was assessed at baseline. Distinct HAP patterns and their associations with lung cancer were examined through latent class analysis (LCA) and multivariable Cox regression. A total of 76.1% of the participants reported regular cooking and 52.2% reported winter heating, of which 9% and 24.7% used solid fuels, respectively. Solid fuel heating increased lung cancer risk (Hazards ratio [HR]: 1.25, 95% confidence interval [CI]: 1.08-1.46). LCA identified three HAP patterns; the "clean fuel cooking and solid fuel heating" pattern significantly increased lung cancer risk (HR: 1.25, 95% CI: 1.10-1.41), compared to low HAP pattern. An additive interaction was observed between heavy smoking and "clean fuel cooking and solid fuel heating" (relative excess risk [RERI]: 1.32, 95% CI: 0.29-2.47, attributable proportion [AP]: 0.23, 95% CI: 0.06-0.36). Cases resulting from solid fuel account for ~4% of total cases (population attribute fraction [PAF]overall : 4.31%, 95% CI: 2.16%-6.47%, PAFever smokers : 4.38%, 95% CI: 1.54%-7.23%). Our results suggest that in urban China, solid fuel heating increased the risk of lung cancer, particularly among heavy smokers. The whole population could benefit from cleaner indoor air quality by reducing using solid fuels, especially smokers.

Familial risk of seropositive rheumatoid arthritis and interaction with smoking: a population-based cohort study.

OBJECTIVES: We evaluated the familial risk of seropositive rheumatoid arthritis (RA) and examined interactions between family history and smoking. METHODS: Using the National Health Insurance and Health Screening Program databases, which include information on familial relationships and lifestyle factors, we identified 5 524 403 individuals with first-degree relatives (FDRs) from 2002-2018. We calculated familial risk using hazard ratios (HRs) with 95% CIs which compare the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using the relative excess risk due to interaction (RERI). RESULTS: Individuals with affected FDR had 4.52-fold (95% CI 3.98, 5.12) increased risk of disease compared with those with unaffected FDR. Familial risk adjusted for lifestyle factors decreased slightly (HR 4.49), suggesting that a genetic contribution is the predominant driver in the familial aggregation of RA. Smoking was associated with an increased risk of disease that was more pronounced among heavy (HR 1.92 95% CI 1.70, 2.18) compared with moderate (HR 1.15 95% CI 1.04, 1.28) smoking. In the interaction analysis, the risk associated with the combined effect of smoking and family history was higher than the sum of their individual effects, though statistically non-significant (RERI 1.30 95% CI ‒0.92, 3.51). Heavy smokers with a positive family history showed a prominent interaction (RERI 4.13 95% CI ‒0.88, 9.13) which exceeded moderate smokers (RERI 0.61 95% CI ‒1.90, 3.13), suggesting a dose-response interaction pattern. CONCLUSION: Our findings indicate the possibility of an interaction between RA-associated genes and smoking.

Behavioural activity pattern, genetic factors, and the risk of nonalcoholic fatty liver disease: A prospective study in the UK Biobank.

BACKGROUND & AIMS: Physical activity, sedentary behaviour, and genetic variants have been associated with the nonalcoholic fatty liver disease (NAFLD). However, whether and how the degree of healthy activity patterns may modify the impact of genetic susceptibility on NAFLD remains unknown. METHODS: Behaviour activity factors were determined according to total physical activity (TPA) and sedentary time. The polygenic risk score (PRS) was calculated by variants in PNPLA3, TM6SF2, MBOAT7, and GCKR. Cox regression was used to analyse the associations of genetic and behaviour activity factors with incident NAFLD in the UK Biobank (N = 338 087). RESULTS: During a median follow-up of 12.4 years, 3201 incident NAFLD cases were ascertained. Analyses of TPA and sedentary time simultaneously showed a dose-response association with the risk of NAFLD (ptrend < .001). The association of behaviour activity patterns with NAFLD varied by genetic variants. Of the subjects with high genetic risk, we observed a null protective effect of moderate or high TPA on NAFLD risk, while sitting less than three hours a day significantly decreased the risk of NAFLD (p = 3.50 × 10-4 ). The high genetic risk of NAFLD can also be offset by the combination of moderate physical activity and shorter sedentary time. Moreover, the high genetic risk group has the greatest reduction of 10-year absolute risk (6.95 per 1000 person-years) if reaching both healthy activities. CONCLUSIONS: Moderate-to-high physical activity and favourable sedentary behaviour may be lifestyle modifications in preventing NAFLD, which could offset the harmful effect of predisposing genetic factors.

Additive interaction between dietary inflammatory index and some key risk factors of multiple sclerosis: a population-based incident case-control study.

BACKGROUND: Recently, dietary inflammatory index (DII) has been introduced as a significant risk factor for MS. We examined the interaction between dietary inflammatory index and some formerly demonstrated key risk factors of multiple sclerosis (MS). MATERIAL AND METHODS: We conducted a population-based incident case-control study of 547 MS cases and 1057 controls. Multiplicative and additive interaction were assessed using interaction term in the logistic regression model and synergy index (SI), respectively. RESULTS: Additive interaction was detected between DII and drug abuse (SI = 2.58; 95% CI: 1.14-5.82), gender (SI = 2.00; 95% CI: 1.39-2.87) and history of depression (SI = 1.68; 95% CI: 1.04-2.72) on the risk scale. The risk of MS in drug abusers with DII ≥ 0 was 10.4-times higher than that in non-drug abusers with DII < 0 (OR = 10.4, 95% CI: 5.12-21.02, P < 0.001). We also found that women with DII ≥ 0 had a 9.2 times larger risk compared with the men with DII < 0(OR = 9.2, 95% CI: 6.3-13.5, P < 0.001). Similarly, the risk of MS was remarkably higher in those with a history of depression and DII >0 (OR = 7.6, 95% CI: 5.1-11.5, P < 0.001). There was no evidence of multiplicative interaction between DII and the other risk factors of MS on the risk scale. CONCLUSIONS: We identified additive interaction between DII and drug abuse, gender and history of depression on MS. Further studies are needed to understand the underlying mechanisms of these detected interactions.

Associations of socioeconomic status and obesity with hypertension in tibetan adults in a Chinese plateau area.

BACKGROUND: Previous studies have identified that socioeconomic status (SES) and obesity are associated with hypertension. However, their interaction on hypertension risk has not yet been assessed. METHODS: The study used data from 6,069 Tibetan residents in Chengguan District in Lhasa, the Chinese Tibetan autonomous region's capital, based on a cohort study conducted from May 2018 to September 2019 in five provinces in southwest China. We used logistic regression models to assess the complex relations of SES and obesity with hypertension. RESULTS: Compared with individuals of high SES, low and moderate SES were positively associated with high risk of hypertension. SES and obesity have significant additive interaction on hypertension (general obesity by BMI: RERI = 1.33, P < 0.001; abdominal obesity by WC: RERI = 0.76, P < 0.001; abdominal obesity by WHtR: RERI = 0.96, P < 0.001). In people from the low and moderate SES segments, obesity was linked to an increased risk of hypertension, but the correlations were stronger in people from the moderate SES category. Compared with people of high SES and non obese, those with moderate SES and obesity had a higher risk of hypertension, and ORs were 4.38 (2.80, 6.84) for general obesity by BMI, 3.38 (2.05, 5.57) for abdominal obesity by WC, and 3.18 (1.57, 6.42) for abdominal obesity by WHtR. CONCLUSION: There is an independent and additive interaction effect of obesity and SES on the risk of hypertension. People with obesity, especially those of moderate and low SES, should reduce weight and waist circumference, and pay more attention to blood pressure. Moreover, the government, health administration departments, and society should prioritize improving the socioeconomic status of the Tibetan population and addressing risk factors like obesity.

Uncovering Aging Chemistry of Perovskite Precursor Solutions and Anti-aging Mechanism of Additives.

The aging of precursor solutions is the major stumbling block for the commercialization of perovskite solar cells (PSCs). Herein, for the first time we used the state-of-the-art in situ liquid time-of-flight secondary ion mass spectrometry to molecularly explore the perovskite precursor solution chemistry. We identified that the methylammonium and formamidinium cations and the I- anion are the motivators of the aging chemistry. Further, we introduced two kinds of Lewis bases, triethyl phosphate (TP) and ethyl ethanesulfonate (EE), as new additives in the solution and unraveled that both of them can protect the reactive cations from aging through weak interactions. Significantly, TP is superior to EE in enhancing long-term solution stability as it can well-maintain the internal interaction structures within the solution phase. The PSC derived from a fresh TP-doped solution delivered a high power conversion efficiency of 23.06 %, 92.23 % of which remained in that from a 21-day-old solution.

The Mediterranean diet and physical activity: better together than apart for the prevention of premature mortality.

Diet and physical activity (PA) have been studied extensively in epidemiology as single or combined lifestyle factors; however, their interaction has not been studied thoroughly. Studying potential synergisms between lifestyle components with a comprehensive interaction analysis, including additive measures of interaction, provides key insights into the nature of their joint effect and helps target interventions more effectively. First, a comprehensive review was conducted to assess the potential research gap regarding reported interaction analyses conducted in studies assessing the Mediterranean diet (MedDiet) in combination with PA on all-cause mortality. Thereafter, we prospectively assessed the joint association of the MedDiet with PA on all-cause mortality in the Seguimiento Universidad de Navarra (SUN) cohort, followed by both multiplicative and additive interaction analyses. The conjoint effect of low adherence to the MedDiet and low PA observed an increased risk greater than the individual risk factors, suggesting a potential additive interaction or synergism between both exposures, with relative risk due to interaction (RERI) and (95 % confidence interval (95 % CI)) = 0·46 (­0·83 to 1·75) and attributable proportion (95 % CI) due to interaction of 36 % (­0·62, 1·34). No multiplicative interaction was detected. Studying interactions between lifestyle factors, such as the MedDiet and PA, is particularly relevant given the current research gaps in studying the complexities of combined aspects of lifestyle in comparison with isolated behaviours. Our findings underline the important public health message of adhering to both the MedDiet and PA for the prevention of premature mortality.

Maternal periconceptional alcohol consumption and gastroschisis in the National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Gastroschisis is particularly prevalent among offspring of young women and has increased over recent decades. Although previous studies suggest that maternal alcohol consumption is associated with increased gastroschisis risk, none have explored whether maternal age modifies that association. OBJECTIVE: The objective of the study was to evaluate associations between self-reported maternal periconceptional alcohol consumption (1 month prior through the third month after conception) and risk of gastroschisis among offspring, by maternal age. METHODS: We used data from the National Birth Defects Prevention Study (NBDPS), a multi-site population-based case-control study. The analysis included 1450 gastroschisis cases and 11,829 unaffected liveborn controls delivered during 1997-2011 in ten US states. We estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the individual and joint effects of alcohol consumption and young maternal age at delivery (<25 years vs ≥25 years) on gastroschisis risk. We estimated the relative excess risk due to interaction (RERI) to quantify additive interaction. RESULTS: Periconceptional alcohol consumption was common regardless of maternal age (women <25 years: cases 38.8%, controls 29.3%; women ≥25: cases 43.5%, controls 39.5%). Compared with women ≥25 years who did not consume alcohol, we observed increased risk of gastroschisis among women <25 years, with higher estimates among those who consumed alcohol (women <25 years who did not consume alcohol. aOR 5.90, 95% CI 4.89, 7.11; women <25 years who did consume alcohol: aOR 8.21, 95% CI 6.69, 10.07). Alcohol consumption among women ≥25 years was not associated with gastroschisis (aOR 1.12, 95% CI 0.88, 1.42). This suggests super-additive interaction between alcohol consumption and maternal age (RERI -2.19, 95% CI 1.02, 3.36). CONCLUSIONS: Periconceptional alcohol consumption may disproportionately increase risk of gastroschisis among young mothers. Our findings support public health recommendations to abstain from alcohol consumption during pregnancy.

Joint effect of cognitive decline and walking ability on incidence of wandering behavior in older adults with dementia: A cohort study.

OBJECTIVES: Wandering behavior is one of the most troublesome behavioral disturbances in dementia. Inconsistent associations between physical function and wandering behavior were reported, and the effect of cognitive decline may be different according to walking ability. The purposes of this study are to investigate whether high walking ability is a risk factor for wandering behavior and to investigate the interaction of walking ability and cognitive function with wandering behavior in older adults with dementia. METHODS: This retrospective cohort study included 3979 elderly adults with dementia. The association of cognitive function and walking ability with incidence of wandering behavior during a 5-year follow-up period were examined using a generalized linear model, and relative excess risk due to interaction (RERI) was calculated. RESULTS: Severe cognitive decline and high walking ability were associated with a higher risk for wandering behavior. Additionally, some joint effects of cognitive decline and walking ability decline were higher than the sum of its individual effects (RERI [95% confidence interval], severe cognitive decline × 'walk with help': 1.58 [0.35, 2.81]; severe cognitive decline × 'independent': 3.09 [1.05, 5.14]). CONCLUSIONS: Effects of cognitive decline and walking ability on incidence of wandering behavior were observed, and the effects varied depending on their combination.

Air Pollution, Genetic Factors, and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Rationale: Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. Objectives: To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. Methods: We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM) (PM ⩽2.5 µm in aerodynamic diameter [PM2.5], coarse PM between 2.5 µm and 10 µm in aerodynamic diameter [PMcoarse], and PM ⩽10 µm in aerodynamic diameter [PM10]), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated by using land-use regression models, and the association between air pollutants and incident lung cancer was investigated by using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. Measurements and Main Results: The results showed significant associations between the risk of lung cancer and PM2.5 (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.33-2.01; per 5 µg/m3), PM10 (HR, 1.53; 95% CI, 1.20-1.96; per 10 µg/m3), NO2 (HR, 1.10; 95% CI, 1.05-1.15; per 10 µg/m3), and NOx (HR, 1.13; 95% CI, 1.07-1.18; per 20 µg/m3). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution exposure, those with high air pollution exposure and high genetic risk had the highest risk of lung cancer (PM2.5: HR, 1.71; 95% CI, 1.45-2.02; PM10: HR, 1.77; 95% CI, 1.50-2.10; NO2: HR, 1.77; 95% CI, 1.42-2.22; NOx: HR, 1.67; 95% CI, 1.43-1.95). Conclusions: Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.

Identification of individuals benefiting from the kakaritsuke-yakuzaishi (family pharmacist) system in Japan: a retrospective cohort study using an employment-based health insurance claims database.

BACKGROUND: The kakaritsuke-yakuzaishi system (henceforth, the family pharmacist system) which provides more health services than those by general pharmaceutical practice, was implemented in Japan in April 2016. To distribute medical resources and medical care expenditures appropriately, identifying the possible major beneficiaries of this system is essential. By analyzing administrative claims data through this retrospective cohort study, we identified modifiers of the potential benefits of the system. Further, we integrated the identified modifiers into a scoring system that indicates the possible benefitting subpopulations. METHODS: We obtained data about individuals under 75 years old routinely using community pharmacies in Japan from the JMDC database. We classified the individuals as users or non-users. We used claims related to "choufukutouyaku-sougosayoutou-boushi-kasan (additional therapeutic duplication and drug interaction [TDDI] prevention fees)" filed between April 2018 and March 2020, which indicate that individuals' prescriptions were modified to adjust leftover drugs or to avoid TDDI as indicators of potential benefit. We estimated adjusted absolute risk differences and 95% confidence intervals for product terms using multiple generalized linear regression models. We included the factors whose 95% confidence interval lower limits did not reach 0 in the multiple logistic regression models for developing a scoring system. RESULTS: The eligible cohort included 162,340 individuals (1,214 users and 161,126 non-users). The leftover drugs adjustment significantly increased for individuals prescribed antidepressants. However, as only one modifier was identified, we did not develop a scoring system for the leftover drugs adjustment. For TDDI prevention, the following factors were included in the scoring system: being female, being prescribed ≥ 6 drug types, using ≥ 2 medical institutions, and being prescribed proton pump inhibitors, antibiotics, probiotics, or traditional Japanese herbal medicines. The developed scoring system for TDDI prevention scored "female" and "traditional Japanese herbal medicines prescription" factors higher than other factors. CONCLUSIONS: Individuals who are female or prescribed traditional Japanese herbal medicines, or antidepressants may benefit significantly from the family pharmacist system.

Rapid characterisation of xanthine oxidase inhibitors from the flowers of Chrysanthemum morifolium Ramat. Using metabolomics approach.

INTRODUCTION: Hyperuricemia is the key risk factor for gout, in which the elevated uric acid is attributed to the oxidation of hypoxanthine and xanthine to uric acid by xanthine oxidase (XO). Adverse effects of the current treatments lead to an urgent need for safer and more effective alternative from natural resources. OBJECTIVE: To compare the metabolite profile of Chrysanthemum morifolium flower fraction with that of its detannified fraction in relation to XO inhibitory activity using a rapid and effective metabolomics approach. METHODS: Proton nuclear magnetic resonance (1 H-NMR)-based metabolomics approach coupled with multivariate data analysis was utilised to characterise the XO inhibitors related to the antioxidant properties, total phenolic, and total flavonoid contents of the C. morifolium dried flowers. RESULTS: The highest XO inhibitory activity, 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity, total phenolic and flavonoid content with strong positive correlation between them were observed in the ethyl acetate (EtOAc) fraction. Detannified EtOAc showed higher XO inhibitory activity than non-detannified EtOAc fraction. A total of 17 metabolites were tentatively identified, of which three namely kaempferol, 4-hydroxybenzoic acid and apigenin, could be suggested to be responsible for the strong XO inhibitory activity. Additive interaction between 4-hydroxybenzoic acid and apigenin (or kaempferol) in XO inhibition was demonstrated in the interaction assay conducted. CONCLUSION: Chrysanthemum morifolium dried flower-part could be further explored as a natural XO inhibitor for its anti-hyperuricemic potential. Metabolomics approach served as an effective classification of plant metabolites responsible for XO inhibitory activity, and demonstrated that multiple active compounds can work additively in giving combined inhibitory effects.

Association of Body Mass Index and Abdominal Obesity with the Risk of Airflow Obstruction: National Health and Nutrition Examination Survey (NHANES) 2007-2012.

This study aimed to explore the relationship between body mass index (BMI) and abdominal obesity and the risk of airflow obstruction, based on the data from the 2007-2012 National Health and Nutrition Survey (NHANES). Logistic regression was applied to assess the relationships between BMI or abdominal obesity and the risk of airflow obstruction by the fixed ratio method and the lower limit of normal (LLN) method. We further used the restricted cubic splines with 3 knots located at the 5th, 50th, and 95th percentiles of the distribution to evaluate the dose-response relationship. A total of 12,865 individuals aged 20-80 years old were included. In the fixed ratio method, underweight was positively correlated with the risk of airflow obstruction, and overweight and obesity were negatively correlated with the risk of airflow obstruction. In the LLN method, the results were consistent with the fixed ratio method. Abdominal obesity was positively associated with the risk of airflow obstruction only in the fixed ratio method (OR: 1.41, 95% CI: 1.04-1.90). There was an additive interaction between underweight and smoking on airflow obstruction in both methods. Abdominal obesity and smoking had additive interactions in the LLN method. Dose-response analysis indicated that there was a non-linear trend between BMI and the risk of airflow obstruction (Pfor nonlinearity < 0.01). Our study suggested that underweight and abdominal obesity were associated with the increased risk of airflow obstruction, and overweight and general obesity were associated with the decreased risk of airflow obstruction.