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Jun Zhang,1– 3,* Chun-Lin Mai,1,* Ying Xiong,1 Zhen-Jia Lin,1 Ying-Tao Jie,1 Jie-Zhen Mai,1 Chong Liu,1 Man-Xiu Xie,4 Xin Zhou,2,3 Xian-Guo Liu1,5,6 1Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 3Guangdong Cardiovascular Institute, Guangzhou, 510080, People’s Republic of China; 4Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 5Department of Anesthesiology, Guangdong Second Provincial Central Hospital, Guangzhou, 510317, People’s Republic of China; 6Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xian-Guo Liu; Xin Zhou Email liuxg@mail.sysu.edu.cn; zhoux89@mail2.sysu.edu.cnPurpose: Postmenopausal women often suffer from chronic pain, memory decline and mood depression. The mechanisms underlying the neuronal disorders are not fully understood, and effective treatment is still lacking.Methods: Oral administration of magnesium-L-threonate was tested to treat the neuronal disorders in ovariectomized and aged female mice. The pain hypersensitivity, memory function and depression-like behaviors were measured with a set of behavioral tests. Western blots, immunochemistry and in situ hybridization were used to assess molecular changes.Results: Chronic oral administration of magnesium-L-threonate substantially prevented or reversed the chronic pain and memory/emotional deficits in both ovariectomized and aged female mice. We found that phospho-p65, an active form of nuclear factor-kappaB, tumor necrosis factor-alpha and interleukin-1 beta were significantly upregulated in the neurons of dorsal root ganglion, spinal dorsal horn and hippocampus in ovariectomized and aged mice. The microglia and astrocytes were activated in spinal dorsal horn and hippocampus. Calcitonin gene–related peptide, a marker for peptidergic C-fibers, was upregulated in dorsal horn, which is associated with potentiation of C-fiber-mediated synaptic transmission in the model mice. In parallel with neuroinflammation and synaptic potentiation, free Mg2+ levels in plasma, cerebrospinal fluid and in dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg2+ deficiency, but did not affect the estrogen decline in ovariectomized and aged mice. Furthermore, in cultured dorsal root ganglion neurons, estrogen at physiological concentration elevated intracellular Mg2+, and downregulated phospho-p65, tumor necrosis factor-alpha and interleukin-1 beta exclusively in the presence of extracellular Mg2+.Conclusion: Estrogen decline in menopause may cause neuroinflammation by reducing intracellular Mg2+ in neurons, leading to chronic pain, memory/emotional deficits. Supplement Mg2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.Keywords: magnesium-L-threonate, postmenopause, neuroinflammation, chronic pain, memory, depression

Background: Ultraviolet radiation (UVR) exposure is the primary risk factor for melanoma although the relationship is complex. Compared to radiation from UVB wavelengths, UVA makes up a majority of the surface solar UVR, penetrates the skin more deeply, is the principal range emitted by tanning beds, and is less filtered by sunscreens and window glass. Few studies have examined the relationship between ambient UVA and UVB and melanoma risk., Methods: Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated for the association between satellite-based ambient (based on residential history) UVA, UVB and melanoma in non-Hispanic White participants using data from the United States Radiologic Technologists study, a large, nationwide prospective cohort. Associations of UVA and UVB quartile (Q) were examined in mutually adjusted and stratified models, additionally adjusted for demographic and sun sensitivity characteristics., Results: There were 837 incident melanoma cases among 62,785 participants. Incidence of melanoma was statistically significantly increased for the highest quartile of childhood UVA exposure after adjustment for UVB (IRR = 2.82; 95%CI:1.46,5.44), but not for higher childhood UVB after adjustment for UVA. Childhood UVA was associated with increased melanoma risk within strata of UVB. Childhood UVB was not associated with melanoma after adjustment for UVA, but there was some evidence of lower risk with increased lifetime ambient UVB after UVA adjustment., Conclusions: Melanoma risk was elevated among participants living in locations with high annual childhood and lifetime UVA after controlling for UVB. With confirmation, these findings support increased protection from solar UVA for melanoma prevention., (Published by Oxford University Press 2024.)

Background: Although childhood exposure to radioactive iodine-131 (I-131) is an established risk factor for thyroid cancer, evidence for an association with thyroid nodules is less clear. The objective of this study is to evaluate the association between childhood I-131 exposure and prevalence of ultrasound-detected thyroid nodules overall and by nodule histology/cytology (neoplastic/suspicious/non-neoplastic), size (<10 mm/≥10 mm), and number (single/multiple). Methods: This is a cross-sectional study of radiation dose (mean = 0.53 gray, range: 0.0003-31 gray) and screen-detected thyroid nodules conducted in 1998-2000 (median population age 21.5 years) in a cohort of 13,243 residents of Ukraine who were under 18 years at the time of the Chornobyl accident on April 26, 1986. Excess odds ratios per gray (excess odds ratio [EOR]/Gy) and confidence intervals (CIs) were estimated using logistic regression. Results: Among 13,078 eligible individuals, we identified 358 (2.7%) with at least one thyroid nodule. Significantly increased dose-response associations were found for all nodules and nodule groups with doses <5 Gy except individuals with non-neoplastic nodules. Among individuals with doses <5 Gy, the EOR/Gy for neoplastic nodules (5.35; CI: 2.19-15.5) was significantly higher than for non-neoplastic nodules (0.24; CI: 0.07-0.74), but the EOR/Gy did not vary by nodule size or number. Conclusions: Childhood exposure to I-131 is associated with an increased risk of thyroid nodules detected 12-14 years following exposure, and the risk for neoplastic nodules is higher than for non-neoplastic nodules. Analyses of incident thyroid nodules may help clarify dose-response patterns by nodule characteristics and provide insights into thyroid nodule etiology.

Background/objectives: Ocular melanoma is a rare, but deadly cancer. This large cancer registry study examines the associations between solar ultraviolet radiation (UVR) and incidence of different anatomical sites of ocular melanoma by sex, age, laterality, and race and ethnicity., Methods: Incidence data were derived from 21 cancer registries in the US for the years 2000-2019. Satellite-based UVR estimates were linked to county of residence at diagnosis. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quartiles using Poisson models., Results: UVR was not associated with total ocular melanoma (N = 18,089) comparing Q4 versus Q1 (IRR = 0.98; 95%CI:0.94,1.03; p-trend = 0.07) or conjunctival melanoma (IRR = 0.99; 95%CI:0.82,1.19; p-trend = 0.81). However, in analyses of continuous UVR (per 10 mW/m 2 ), risks were reduced for total ocular melanoma (IRR = 0.97; 95% CI: 0.96, 0.99). Incidence was increased for ciliary body/iris melanoma in the highest UVR quartile (IRR = 1.63; 95%CI:1.43,1.87; p-trend < 0.0001) and remained increased in non-Hispanic White individuals only. Incidence was reduced for choroidal melanoma in the highest UVR quartile (IRR = 0.86; 95%CI:0.82,0.91; p-trend < 0.0001)., Conclusions: UVR may be associated with increased risk of ciliary body/iris melanoma. Reduced risk of choroidal melanoma may be due to higher diffuse UVR exposure to posterior ocular sites in locations at higher latitudes. Our results support and expand previous findings of associations of UVR using various surrogates on ocular melanoma risk and serve as a starting point for understanding the differences in the relationship between UVR and specific anatomical sites., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced., Methods: We assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables., Results: There were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm 2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm 2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm 2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm 2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0-3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures., Conclusions: Our more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Although NSAIDs have been associated with both reduced and increased cutaneous melanoma risk, few studies have examined these associations by ultraviolet radiation (UVR) or personal sun-sensitivity. We examined the associations between NSAID use and first primary invasive cutaneous melanoma among 58,227 non-Hispanic white participants in the United States Radiologic Technologists cohort study. Poisson regression was used to calculate rate ratios (RR) and 95% likelihood-based confidence intervals (CI), adjusting for attained age, birth cohort, and ambient UVR. No significant association of melanoma was observed for any use of NSAIDs (RR, 0.87; 95% CI, 0.71-1.09). The relative risks of melanoma for the highest categories of aspirin and other NSAID use (≥5 times per month vs. none) were 0.93 (95% CI, 0.74-1.16) and 1.02 (95% CI, 0.83-1.25), respectively. Further analyses did not reveal dose-response for trends in frequency of NSAID use or interactions with sex, UVR, eye and hair color, and skin complexion. In this large nationwide study, NSAID use was not associated with melanoma risk., Prevention Relevance: NSAIDs have been associated with both reduced and increased melanoma risk. However, few studies have examined the role of UVR or personal sun-sensitivity on these associations. Our findings strengthen the evidence that NSAID use is not associated with melanoma risk, even in sun-sensitive subgroups., (©2022 American Association for Cancer Research.)

Study Question: Are reproductive factors and exogenous hormone use associated with incidence of cutaneous melanoma while accounting for ultraviolet radiation (UVR) exposure across different life periods and sun sensitivity factors?, Summary Answer: Earlier age at menarche and late age at first birth, but not other estrogen-related factors were associated with an increased incidence rate of melanoma, with higher risks observed for earlier age at menarche and light hair color at age 15 years., What Is Known Already: Although estrogens have been recognized as photosensitizing, previous studies have reported inconsistent findings for the association of melanoma with estrogen-related factors. Most have not collected detailed skin cancer risk factors and have not thoroughly investigated effect modification by ambient UVR and sun sensitivity., Study Design, Size, Duration: Participants in the US Radiologic Technologists study, an occupational cohort of 146 022 radiologic technologists (73% women), were included and followed during the four time periods (1983-1989, 1994-1998, 2003-2005 and 2012-2014)., Participants/materials, Setting, Methods: Non-Hispanic white female participants who completed both the second (baseline) and third questionnaires, and did not report having cancer (except keratinocyte carcinoma) at baseline, were included and followed from their age at completion of the second (baseline) questionnaire until the earlier of first primary cancer diagnosis, including invasive melanoma of the skin, or completion of either the third or fourth questionnaire. Reproductive and exogenous hormonal factors were ascertained from the second (baseline) questionnaire, which also collected information on demographic, lifestyle factors and sun sensitivity factors. Ambient UVR was assigned by linking geocoded residential locations, based on self-reported residential history information collected from the third questionnaire to satellite-based ambient UVR data from the National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer database. To examine the association of reproductive factors, exogenous hormone use, and first primary invasive melanoma of the skin, we used Poisson regression to calculate rate ratios (RRs) and 95% likelihood-based CIs, adjusting for attained age, birth cohort, lifetime average annual ambient UVR, contraceptives and menopausal hormone therapy use. To address the effect modification of ambient UVR exposure and sun sensitivities on melanoma risk, we conducted likelihood-ratio tests for multiplicative interaction., Main Results and the Role of Chance: Over a median follow-up time of 17.1 years, 0.95% of eligible participants had an incident first primary melanoma (n = 444). Higher melanoma incidence rates were observed in participants with older attained age, blue/green/gray eye color, blonde/red/auburn natural hair color at age 15, fair skin complexion, and higher UVR. We found an increased incidence rate of melanoma in women who experienced menarche at an earlier age (13, 12 and <12 years vs ≥14 years: RR = 1.48, 95% CI = 1.11-1.98; 1.19, 0.89-1.61; 1.26, 0.93-1.73), and in women with older age at first birth (25-29 and ≥30 years vs <25 years; 1.09, 0.86-1.39; 1.48, 1.12-1.95; P-value for trend = 0.006). However, no significant association was observed for other reproductive factors, and for all exogenous hormone use. The associations of melanoma incidence for most reproductive factors and exogenous hormone use were not modified by ambient UVR, eye color, natural hair color at age 15 and skin complexion. The exception was that natural hair color at age 15 modified the associations of melanoma for age at menarche (P-value for interaction = 0.004) and age at first birth among parous women (0.005). In participants with blonde/red/auburn natural hair color at age 15, we found increased risk of melanoma among women who experienced menarche at age 13, 12 and <12 years (vs ≥14 years: RR = 3.54, 95% CI = 1.98-6.90; 2.51, 1.37-4.98; 2.66, 1.41-5.36, respectively; P-value for trend = 0.10). However, the association between age at menarche and melanoma was null in participants with brown/black natural hair color at age 15., Limitations, Reasons for Caution: Information on reproductive history and exogenous hormone use was self-reported. We did not have information on specific doses or formulations of exogenous hormone medications or breastfeeding., Wider Implications of the Findings: Women residing in areas of high ambient UVR and those with blonde/red/auburn natural hair color may constitute an additional high-risk group in need of more frequent skin cancer screening. Identifying susceptible periods of exposure or factors that modify UVR susceptibility may aid in guiding more targeted guidelines for melanoma prevention., Study Funding/competing Interest(s): This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Authors declare no conflict of interest., Trial Registration Number: N/A., (Published by Oxford University Press 2022.)

Antineoplastic drugs such as oxaliplatin (OXA) often induce memory and emotional deficits. At present, the mechanisms underlying these side-effects are not fully understood, and no effective treatment is available. Here, we show that the short-term memory deficits and anxiety-like and depression-like behaviors induced by intraperitoneal injections of OXA (4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2B subunit of N-methyl-D-aspartate receptors in the hippocampus, which is critically involved in memory and emotion. The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate (L-TAMS, 604 mg/kg per day, from 2 days before until the end of experiments). We found that OXA injections significantly reduced the free Mg 2+ in serum and cerebrospinal fluid (from ~ 0.8 mmol/L to ~ 0.6 mmol/L). The Mg 2+ deficiency (0.6 mmol/L) upregulated tumor necrosis factor (TNF-α) and phospho-p65 (p-p65), an active form of nuclear factor-kappaB (NF-κB), and downregulated the NR2B subunit in cultured hippocampal slices. Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65, as well as microglial activation in the hippocampus and the medial prefrontal cortex. Finally, similar to oral L-TAMS, intracerebroventricular injection of PDTC, an NF-κB inhibitor, also prevented the OXA-induced memory/emotional deficits and the changes in TNF-α, p-p65, and microglia. Taken together, the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg 2+ is responsible for the memory/emotional deficits induced by OXA. Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.

Itch (pruritus), specifically chronic itch associated with disease conditions, significantly impairs the patient's quality of life. At present, the mechanisms underlying this aversive experience are still unclear, and the effective treatment of itch is largely unmet. Here, we report that intragastrical administration of bulleyaconitine A (BLA), which has been used for treating chronic pain for 30 years in China, inhibited itch-like behaviors induced by intradermal injection of histamine and chloroquine in mice and rats, dose-dependently. We found that a single application of the pruritic agents at the skin region innervated by the sural nerve induced long-term potentiation (LTP) of C-fiber field potentials evoked by the stimulation of the same nerve in the spinal dorsal horn of rats. The spinal LTP was remarkably reversed by the spinal application of either BLA or gastrin-releasing peptide receptor (GRPR) antagonist (PD176252). The effect of PD176252 was completely occluded by BLA, while the effect of BLA was only partially occluded by PD176252. Repetitive injection (daily, for four days) of either histamine or chloroquine in the back of the neck enhanced scratching behaviors progressively, and the itch sensitization persisted for at least one week after the discontinuation of the injections. The behavioral change was accompanied with the potentiation of C-fiber synaptic transmission in the dorsal horn. Both the itch sensitization and synaptic potentiation were substantially attenuated by intragastrical BLA. Together, BLA was effective in inhibiting histamine-dependent and histamine-independent itches, and the mechanisms underlying these effects were involved but not limited to the inhibition of gastrin-releasing peptide (GRP)-GRPR signaling in the spinal dorsal horn., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to explore the relationship between fasting glucose levels and all-cause and cause-specific mortality in Chinese population., Methods: The role of fasting blood glucose levels as a predictor of all-cause and cause-specific mortality was estimated in 9930 participants from four Chinese general populations with a 20-year follow-up. Multivariate Cox proportional hazard models were used to identify the relationship between fasting glucose and mortality., Results: There were 1471 deaths after a median follow-up of 20.2 years (a total of 187,374 person-years), including 310 cardiovascular deaths, 581 cancer deaths, and 580 other-cause deaths. After adjustment for age, sex, urban or rural, northern or southern of China, types of work, education level, physical exercise, smoking status, drinking status, body mass index, systolic blood pressure, and serum total cholesterol at baseline, the hazard ratios ( HR s) and 95% confidence intervals ( CI s) for all-cause mortality in the fasting blood glucose categories of <60, 60-69, 70-79, 90-99, 100-109, 110-125, and ≥126 mg/dl were 1.38 (1.04-1.84), 1.20 (1.01-1.43), 1.18 (1.03-1.36), 1.18 (0.99-1.41), 1.48 (1.16-1.88), 1.17 (0.84-1.62), and 2.23 (1.72-2.90), respectively, in contrast to the reference group (80-89 mg/dl). The HR s and 95% CI s for cardiovascular disease mortality in these groups were 2.58 (1.44-4.61), 1.41 (0.95-2.10), 1.56 (1.15-2.11), 1.29 (0.88-1.89), 1.36 (0.78-2.37), 1.05 (0.52-2.11), and 2.73 (1.64-4.56), respectively., Conclusions: Both low and high fasting glucose were significantly associated with increased risk of all-cause and cardiovascular mortality in Chinese general population.

N-type voltage-gated calcium (Cav2.2) channels are expressed in the central terminals of dorsal root ganglion (DRG) neurons, and are critical for neurotransmitter release. Cav2.2 channels are also expressed in the soma of DRG neurons, where their function remains largely unknown. Here, we showed that Cav2.2 was upregulated in the soma of uninjured L4 DRG neurons, but downregulated in those of injured L5 DRG neurons following L5 spinal nerve ligation (L5-SNL). Local application of specific Cav2.2 blockers (ω-conotoxin GVIA, 1-100 μM or ZC88, 10-1000 μM) onto L4 and 6 DRGs on the operated side, but not the contralateral side, dose-dependently reversed mechanical allodynia induced by L5-SNL. Patch clamp recordings revealed that both ω-conotoxin GVIA (1 μM) and ZC88 (10 μM) depressed hyperexcitability in L4 but not in L5 DRG neurons of L5-SNL rats. Consistent with this, knockdown of Cav2.2 in L4 DRG neurons with AAV-Cav2.2 shRNA substantially prevented L5-SNL-induced mechanical allodynia and hyperexcitability of L4 DRG neurons. Furthermore, in L5-SNL rats, interleukin-1 beta (IL-1β) and IL-10 were upregulated in L4 DRGs and L5 DRGs, respectively. Intrathecal injection of IL-1β induced mechanical allodynia and Cav2.2 upregulation in bilateral L4-6 DRGs of naïve rats, whereas injection of IL-10 substantially prevented mechanical allodynia and Cav2.2 upregulation in L4 DRGs in L5-SNL rats. Finally, in cultured DRG neurons, Cav2.2 was dose-dependently upregulated by IL-1β and downregulated by IL-10. These data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To explore the relationship between overnight urinary sodium to potassium ratio and the risk of cardiovascular disease (CVD). Methods: A subsample of 10 percent of the participants (35-59 years old) from the People's Republic of China-United States Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology (prospective survey) were used. Three consecutive overnight urine samples were collected in the autumn of 1983-1984 and the spring in 1985-1986, respectively. Urinary sodium and potassium were detected and calculated for 8 hours excretion. The occurrences of cardiovascular events were recorded in 2 years interval from 1987-1988 until December 31, 2005. Participants were divided into first ratio group, second ratio group, and third ratio group based on the tertiles of sodium to potassium ratio. Cox proportional hazard regression model was used to determine the relationship between sodium to potassium ratio and risk of CVD. In addition, participants were divided into 2 subgroups by the median of overnight urinary sodium and potassium, and then combined each other for 4 subgroups including low sodium-low potassium group, low sodium-high potassium group, high sodium-low potassium group, and high sodium-high potassium group, to explore the relationship between different sodium-potassium combinations and the risk of CVD. Results: A total of 954 participants were included in the final analysis, of whom 459 (48.1%) were males. There were 318 cases in the first, second and third ratio group, respectively. There were 347 cases in low sodium-low potassium group and high sodium-high potassium group, and 130 cases in low sodium-high potassium group and high sodium-low potassium group. After a median follow-up of 18.6 (18.3, 19.3) years, cardiovascular events occurred in 81 participants, including 64 stroke and 20 coronary heart disease events. Multivariate analysis showed that comparing with the first ratio group, the hazard ratios ( HR ) in the second and the third ratio groups were 2.04 (95% CI 1.06-3.95, P= 0.034) and 2.07 (95% CI 1.07-4.03, P= 0.032), respectively. The CVD risk in low sodium-low potassium group was 24% higher than the low sodium-high potassium group (reference), but this result did not reach statistical significant level ( P= 0.685). The risks in high sodium-high potassium group ( HR =3.32, 95% CI 1.26-8.76, P= 0.015) and high sodium-low potassium ( HR =3.04, 95% CI 1.05-8.83, P= 0.041) group were both significantly increased. Conclusions: Overnight urinary sodium to potassium ratio is positively correlated with the risk of cardiovascular events. High urinary sodium plays a more important role for the increased risk of cardiovascular events than low potassium.

Conditional logistic regression analysis and unconditional logistic regression analysis are commonly used in case control study, but Cox proportional hazard model is often used in survival data analysis. Most literature only refer to main effect model, however, generalized linear model differs from general linear model, and the interaction was composed of multiplicative interaction and additive interaction. The former is only statistical significant, but the latter has biological significance. In this paper, macros was written by using SAS 9.4 and the contrast ratio, attributable proportion due to interaction and synergy index were calculated while calculating the items of logistic and Cox regression interactions, and the confidence intervals of Wald, delta and profile likelihood were used to evaluate additive interaction for the reference in big data analysis in clinical epidemiology and in analysis of genetic multiplicative and additive interactions.

Objective: To explore the environmental risk factors of different categories of congenital heart defects (CHD) and provide evidence for further risk factors and prevention research of CHD phenotypes., Methods: Data of Guangdong CHD Register Study from 2004 to 2012 were used. In the study, 3 038 CHD cases and 3 038 paired controls from 34 hospitals distributed in 17 cities were registered and related information were collected using uniform, and structured questionnaires. All the CHD phenotypes were coded according to the International Classification of Diseases 10th Revision (ICD-10) and classified into 6 categories according to their pathological features. Univariate analyses were adopted to filter potential risk factors for each category of CHD. Then multivariate conditional Logistic regression was used to calculate the odds ratios of the risk factors for each category of CHD., Results: The risk factors for left-to-right shunt CHD included low (OR=2.63, 95%CI:2.04-3.39) or over birth weight (OR=2.21, 95%CI: 1.47-3.32), premature delivery (OR=1.95, 95%CI: 1.53-2.49), polyembryony (OR=1.99, 95%CI: 1.22-3.26), maternal low education, mother as factory worker (OR=1.62, 95%CI: 1.32-1.98), parity≥2 (OR=1.38, 95%CI: 1.13-1.69), maternal abnormal reproduction history (OR=2.29, 95%CI: 1.75-3.01), fever (OR=2.38, 95%CI: 1.26-4.48), virus infection (OR=1.80, 95%CI: 1.29-2.51), medicine usage (OR=1.73, 95%CI: 1.11-2.69), passive smoking (OR=1.69, 95%CI: 1.26-2.29), chemical agent contact (OR=8.71, 95%CI: 2.33-32.58), living in newly decorated houses (OR=2.56, 95%CI: 1.60-4.09) or room close to the main road (OR=1.40, 95%CI: 1.14-1.72) in the first 3 months of pregnancy and father as factory worker (OR=1.46, 95%CI: 1.23-1.73). The risk factors for pulmonary outflow tract obstruction CHD included low (OR=5.98, 95%CI: 2.88-12.44) or over birth weight (OR=6.56, 95%CI:1.19-36.26), maternal low education, parity≥2 (OR=2.08, 95%CI: 1.03-4.22), virus infection in the first 3 months of pregnancy (OR=4.30, 95%CI: 1.27-13.45). The risk factors for left ventricular outflow tract obstruction CHD included father as factory worker (OR=6.01, 95%CI:1.05-34.59). The risk factors for transposition of the great arteries included low birth weight (OR=12.93, 95%CI:1.14-146.26), maternal low education, mother as factory worker (OR=3.69, 95%CI:1.53-8.91). The risk factors for conditions with intra cardiac mixing of oxygenated and deoxygenated blood included parity=2 (OR=3.45, 95%CI: 1.42-8.38). The risk factors for other CHD included over birth weight (OR=4.87, 95%CI: 1.19-19.94), maternal abnormal reproduction history (OR=2.96, 95%CI: 1.14-7.68), virus infection (OR=4.92, 95%CI: 1.56-15.47), medicine usage (OR=4.90, 95%CI: 1.22-19.77) or passive smoking (OR=10.31, 95%CI: 1.25-85.05) in the first 3 months of pregnancy., Conclusion: The environmental risk factors were discrepant among different categories of CHD. Further risk factors study of CHD phenotypes should be performed specially. To prevent CHD, attention should be paid to the risk factors which are related to multi or complex categories of CHD.

Objective: To analyze the risk factors of congenital heart defects (CHD) in fetal and infants born from 2004 to 2011 in Guangdong province., Methods: Babies with CHD aged from 28th week of gestation to 1 year old postnatal from July 1 2004 to December 31 2011 were registered in Guangdong CHD monitoring network with 34 participating units. Totally 2568 CHD cases were included, and 1: 1 matched with a normal control cohort by gender, living district and birth date (time span within 3 months).Exposed information of mother and father at pre-pregnancy and early pregnancy was collected. Post collinearity diagnostics analysis, univariate analysis results were included in a multivariate analysis model with forward stepwise conditional logistic regression., Results: Multivariate conditional logistic regression analysis showed that high risk factors for CHD included low birth weight infant (OR = 5.34, P < 0.01), macrosomia (OR = 1.67, P < 0.05), low per capita income (0-1200 yuan, OR = 1.68, P < 0.01), exposure to chemical agent at early pregnancy (OR = 19.72, P < 0.01), floating population (OR = 2.13, P < 0.01), abnormal reproductive history (OR = 3.18, P < 0.01), exposure to passive smoking (OR = 2.59, P < 0.01), suffering from fever (OR = 3.74, P < 0.01), equal to or more than twice parity (OR = 1.45, P < 0.01), living in a newly (within six months)-decorated-apartment (OR = 2.74, P < 0.01), suffering from virus infection (OR = 2.08, P < 0.01), rural residence (OR = 1.33, P < 0.01), living in an apartment within 50 meters of major traffic road (OR = 1.52, P < 0.01), syphilis infection at early pregnancy (OR = 13.06, P < 0.05) and father's drinking habit at pre-pregnancy (OR = 1.57, P < 0.05)., Conclusion: Numerous risk factors for CHD in fetal and infants of Guangdong province are indicated by our results, comprehensive intervention should be considered in pre-pregnancy and early pregnancy to reduce the risk of CHD.

Objective: To analyze the differences of risk factors on congenital heart defect (CHD)between floating population and permanent residents in Guangdong., Methods: A multicenter case-control study was carried out to investigate the risk factors of CHD in floating population and in permanent residents. Data was from 34 Guangdong CHD Monitoring Network centers during the year of 2004 to 2011. Exposed information related to the parents at pre-pregnancy and early pregnancy periods, was collected, using the same questionnaire survey methodology in the two populations. Possible risk factors were analyzed by univariate analysis and multivariate non-conditional logistic regression(ENTER method)methods. Risk factors were compared between the two populations., Results: Totally, 855 CHD cases and their controls from the floating population, as well as 1673 cases and their controls from the permanent residents were included in this study. Age of the children under study was defined from 28th week of gestation to 1 year old postnatal. In the floating population, specific risk factor for CHD appeared as:maternal passive smoking in early pregnancy, while the specific protective factor as high family income. However, the specific risk factors would include: having diseases as maternal diabetes mellitus or syphilis, living in a newly (within half a year) decorated house or with fetal macrosomia in the permanent residents. High education level showed as a risk factor in floating population, however contrarily, as protective factor to the permanent residents. Except for the factors related to having fever of the mother and infant with low birth weight, factors as having history of deliveries more than two, with maternal virus infection, exposure to chemical agent and negative bearing history etc., have higher OR values in floating population than in the permanent residents., Conclusion: Significant differences of risk factors for CHD were noticed between floating population and the permanent residents, which have their individual specific risk factors. Most of the ORs appeared higher in floating population than in the permanent residents.

Objective: To summarize prevalence rate and region distribution of congenital heart disease (CHD) in 12-month-old and younger infants among four regions of Guangdong province, China., Methods: Data from Guangdong CHD monitoring network including 34 monitoring units covering different geographic regions were analyzed. Professional training on screening and diagnosing CHD was provided to each work group member to improve the diagnosis level. CHD infants under or aged 12 months detected in the monitoring unit were included. CHD was diagnosed by fetus and infants echocardiography., Results: From July 2004 to December 2010, 383 281 perinatal were registered and 3263 cases of CHD were detected in the 34 member units of Guangdong CHD monitoring network [total prevalence rate of CHD: 0.851% (3263/383 281), male prevalence rate: 0.868% (1799/207 347), female prevalence rate:0.828% (1456/175 843)].Stillbirth CHD prevalence rate was significantly higher than livebirth CHD prevalence rate [10.627% (676/6361) vs. 0.686% (2587/376 920), P < 0.01]. The total prevalence of CHD was significantly higher in Pearl River Delta region [0.906% (2826/311 823)] than in other regions [0.611% (437/71 458), P < 0.01]. Ventricular septal defect [39.93% (1033/2587) in livebirth] was the most dominant CHD, followed by patent ductus arteriosus [29.84% (772/2587)] and secundum atrial septal defect [13.76% (356/2587)]., Conclusions: The present data indicate that the prevalence of CHD in Guangdong is at the medium-upper level of the country associated with high stillbirth rate. The dominant type of CHD is ventricular septal defect. CHD prevalence is higher in the Pearl River Delta region than in other regions.

Objective: To evaluate the association between resting heart rate (HR) and all-cause death and coronary heart disease (CHD) events in the Chinese cohort., Methods: Data were obtained from the PRC-USA Cooperative Study on Cardiovascular and Cardiopulmonary Epidemiology. Baseline screen surveys were conducted in 1983 and 1984 from people aged 35 to 59 years living in urban or rural areas of Beijing and Guangzhou. Follow-up visits were performed for end point events of all-cause death and first CHD events every two years till 2005. Resting HR was determined from 5 consecutive intervals between R waves on the 12-lead electrocardiogram., Results: A total of 9856 (4805 males) people were included in the study and the mean follow up duration was 16.2 years. There were 1523 deaths, including 200 CHD events during the follow up period. Mean resting HR was 67.9 beat per minute (bpm) in men and 71.6 bpm in women respectively which had a trend to increase with aging. Cox Proportional Hazards model indicated the relative risk of all-cause death increased constantly with the increase of HR percentile after control of age, fasting glucose, serum cholesterol, serum triglyceride, body mass index, systolic blood pressure and diastolic blood pressure. With HR 60-89 bpm as control group, the relative risk and 95% confidence interval in group HR < 50 bpm, 50 - 59 bpm, 90 - 99 bpm and > or = 100 bpm were 0.76 (0.49 - 1.17), 0.87 (0.75 - 1.02), 1.33 (1.06 - 1.68), 1.48 (1.03 - 2.14) respectively. However there was no significant correlation between HR and CHD events in studied population., Conclusion: The risk of total death increased significantly in people with HR > or = 90 bpm suggesting higher resting heart rate might be an independent risk factor for all-cause death in the Chinese population.

Objective: To investigate gender-related differences in risk factors, clinical manifestation and outcomes in patients with aortic dissection (AD) from Guangzhou., Methods: Consecutive patients with AD admitted to our institute over the past 10 years were included in this retrospective analysis. Prevalence of hypertension, smoking, thickness of intraventricular septum and left ventricular posterior wall measured by echocardiography, and outcomes were compared between male and female AD patients., Results: There were more male AD patients than female AD patients (5.33:1) from the 418 patients. Prevalence of hypertension, thickness of intraventricular septum and left ventricular posterior wall were similar in male and female AD patients. Heavy smoking history was 56.5% in males and 13.6% in females (P = 0.000). Acute survival rate in female patients tended to be better than that in male patients., Conclusions: There were significantly more male AD patients than female AD patients in this cohort. Prevalence of heave smoking in male patients is 3 times higher than that in female population.

Objective: To discuss the clinical epidemiology features and change trend of aortic dissection (AD)., Methods: Retrospective analysis of consecutive 339 patients with AD over 10 years in Guangdong Cardiovascular Institution. Hospital records and prognosis were compared between two five-year periods., Results: 339 cases with AD were hospitalized during the past 10 years. The mean age was 55.7 +/- 11.2. The male/female ratio was 4.75 to 1. Hypertension was present in 71.7% of all patients. Heavy smoking history was elicited in 52.2% of all the patients. Type I dissection were identified in 32.3% of all the cases, type II in 5.1%, and type III in 62.6%. In-hospital mortality of acute type A dissection was 35.3%, acute type B dissection 8.0%. In two five-year periods, the total number of cases increased by 165%, among which type I was the fastest, increased by 270%. Changes of mean age and male/female ratio were not significant. For acute AD, changes of prognosis in one year improved, but did not reach statistical significance., Conclusions: This study provides insight into current regional profiles of AD. The number of hospitalized patients with AD is increasing dramatically. The mean age of the first-attack is much younger and the male ration is much higher than that reported by other regional researchers. Limited by sample size, one year prognosis of acute AD dissection improved, but did not reach statistical significance. These data support the urgent need for further improvement in prevention and treatment of AD.