Syn-COM: A Multi-Level Predictive Synergy Framework for Innovative Drug Combinations.

Drug prediction and treatment using bioinformatics and large-scale modeling have emerged as pivotal research areas. This study proposes a novel multi-level collaboration framework named Syn-COM for feature extraction and data integration of diseases and drugs. The framework aims to explore optimal drug combinations and interactions by integrating molecular virtuality, similarity clustering, overlap area, and network distance. It uniquely combines the characteristics of Chinese herbal medicine with clinical experience and innovatively assesses drug interaction and correlation through a synergy matrix. Gouty arthritis (GA) was used as a case study to validate the framework's reliability, leading to the identification of an effective drug combination for GA treatment, comprising Tamaricis Cacumen (Si = 0.73), Cuscutae Semen (Si = 0.68), Artemisiae Annuae Herba (Si = 0.62), Schizonepetae Herba (Si = 0.73), Gleditsiae Spina (Si = 0.89), Prunellae Spica (Si = 0.75), and Achyranthis Bidentatae Radix (Si = 0.62). The efficacy of the identified drug combination was confirmed through animal experiments and traditional Chinese medicine (TCM) component analysis. Results demonstrated significant reductions in the blood inflammatory factors IL1A, IL6, and uric acid, as well as downregulation of TGFB1, PTGS2, and MMP3 expression (p < 0.05), along with improvements in ankle joint swelling in GA mice. This drug combination notably enhances therapeutic outcomes in GA by targeting key genes, underscoring the potential of integrating traditional medicine with modern bioinformatics for effective disease treatment.

[Ecosystem Service Trade-off Synergy Strength and Spatial Pattern Optimization Based on Bayesian Network： A Case Study of the Fenhe River Basin].

Understanding the strength of trade-off and synergistic relationships among ecosystem services (ESs) is crucial for ecological management and restoration in the Fenhe River Basin. However, there is still a lack of sufficient research on the driving variables and spatial pattern optimization of the strength of ESs relationships in this area. Based on the quantitative assessment of six ESs in the Fenhe River Basin in 2000 and 2020, the ecosystem services trade-off synergy index (TSI) was introduced to quantitatively measure the strength of trade-off and synergistic relationships between each pair of ESs. A Bayesian network was constructed to identify the driving variables of trade-off and synergistic relationships, and sensitivity analysis was conducted to determine the degree of influence of key variables on the strength of these relationships. The optimization area of the strength of ESs trade-off and synergistic relationships was characterized in spatial patterns. The results showed that:① There were significant spatiotemporal differences in the six ESs in the Fenhe River Basin in 2000 and 2020. In terms of time scale, water yield, net primary productivity, crop productivity, soil conservation, and carbon storage all showed a trend of fluctuating increase. In terms of spatial scale, the spatial distribution changes in the six ESs were relatively small over the 20 years. ② The TSI of carbon storage was high in the surrounding area and low in the middle, showing a four-high and four-low pattern. The areas with the highest TSI between grain supply and other services were distributed from north to south. ③ Sensitivity analysis found that the strength of water yield, soil conservation, and habitat quality were significantly affected by precipitation, plant root depth restriction, and rainfall erosion. According to the conditional probability of different states of key variables, Wenshui County, Qingxu County, and Qi County in the central part of the Fenhe River Basin were identified as high-value areas for trade-off and synergistic relationships, which could be used as key areas for ecological restoration. These findings have important theoretical and practical significance for understanding the complex relationship between multiple ESs trade-off and synergistic relationships and their driving variables and for proposing sustainable ecological environment management policies.

The synergistic effect of obesity and dyslipidemia on hypertension: results from the STEPS survey.

BACKGROUND: Obesity and dyslipidemia are important risk factors for hypertension (HTN). When these two conditions coexist, they may interact in a synergistic manner and increase the risk of developing HTN and its associated complications. The aim of this study was to investigate the synergistic effect of general and central obesity with dyslipidemia on the risk of HTN. METHOD: Data from 40,387 individuals aged 25 to 64 years were obtained from a repeated cross-sectional study examining risk factors for non-communicable diseases (STEPS) in 2007, 2011 and 2016. Body mass index (BMI) was calculated as a measure of general obesity and waist circumference (WC) as a measure of central obesity. Dyslipidemia was defined as the presence of at least one of the lipid abnormalities. Hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or current use of antihypertensive medication. To analyze the synergistic effect between obesity and dyslipidemia and HTN, the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI) were calculated. A weighted logistic regression model was performed to estimate the odds ratios (ORs) for the risk of HTN. RESULTS: The results showed an association between obesity, dyslipidemia and hypertension. The interaction between obesity and dyslipidemia significantly influences the risk of hypertension. In hypertensive patients, the presence of general obesity increased from 14.55% without dyslipidemia to 64.36% with dyslipidemia, while central obesity increased from 13.27 to 58.88%. This interaction is quantified by RERI and AP values of 0.15 and 0.06 for general obesity and 0.24 and 0.09 for central obesity, respectively. The corresponding SI of 1.11 and 1.16 indicate a synergistic effect. The OR also show that the risk of hypertension is increased in the presence of obesity and dyslipidemia. CONCLUSION: Obesity and dyslipidemia are risk factors for HTN. In addition, dyslipidemia with central obesity increases the risk of HTN and has a synergistic interaction effect on HTN. Therefore, the coexistence of obesity and lipid abnormalities has many clinical implications and should be appropriately monitored and evaluated in the management of HTN.

Characterizing the water resource-environment-ecology system harmony in Chinese cities using integrated datasets: A Beautiful China perspective assessment.

Integrated management and synergistic improvement of the water system is a topic of widespread concern. This study innovatively integrates three functions of quality assessment, synergy evaluation, and driving influence determination to establish a systematic framework assessing water system harmony. A case study of 336 Chinese cities is further performed by combining multi-scale and multi-source datasets. The results show China's water system quality has improved from 2015 to 2022. Development in the water resource, environment, and ecology subsystems have been differentiated, with 0.05 %, 4.33 %, and -1.64 % changes, respectively. The degradation of water ecology and the weak synergy with the other two subsystems have limited China's water system harmony. Water environment improvement played a contributive role in improving the water system quality. The contribution structure of water resources, environment, and ecology has shifted towards equilibrium in recent years. We found and highlighted the north-south differentiation of water system harmony in Chinese cities. The Beijing-Tianjin-Hebei and its surroundings, the Yangtze River Delta, and the middle reaches of the Yangtze River are identified as priority regions for water system harmony improvement. The primary contribution of this study is to propose an assessing concept of water resource-environment-ecology system harmony, establish well-structured assessment methods, and integrate the multiple data sources. The novel methods and findings, including the indicator system, application of data mining and decomposing methods, and the city-level water system harmony map, deconstruct and quantify the complex and diverse water system, supporting clearer and more efficient water management policymaking.

Uncontrolled Manifold Analysis of the Effects of Different Fatigue Locations on Kinematic Coordination During a Repetitive Upper-Limb Task.

Fatigue at individual joints is known to affect interjoint coordination during repetitive multijoint tasks. However, how these coordination adjustments affect overall task stability is unknown. Twelve participants completed a repetitive pointing task at rest and after fatigue of the shoulder, elbow, and trunk. Upper-limb and trunk kinematics were collected. Uncontrolled manifold framework was applied to a kinematic model to link elemental variables to endpoint fingertip position. Mixed and one-way analysis of variances determined effects (phase and fatigue location) on variance components and synergy index, respectively. The shoulder fatigue condition had the greatest impact in causing increases in variance components and a decreased synergy index in the late phase of movement, suggesting more destabilization of the interjoint task caused by shoulder fatigue.

Distillery industrial wastewater(DIW) treatment by the combination of sono(US), photo(UV) and electrocoagulation(EC) process.

The color and Chemical Oxygen Demand (COD) reduction in distillery industrial effluent (DIW) was investigated utilizing photo (UV), sono (US), electrocoagulation (EC), UV + US, UV + EC, US + EC, and US + UV + EC technologies. The empirical study demonstrated that the UV + US + EC process removed almost 100% of color and 95.63% of COD from DIW while consuming around 6.97 kWh m-3 of electrical energy at the current density of 0.175 A dm-2, COD of 3600 mg L-1, UV power of 32 W, US power of 100 W, electrode pairings of Fe/Fe, inter-electrode distance of 0.75 cm, pH of 7, and reaction time of 4 h, respectively. The values found were much greater than those produced using UV, US, EC, UV + US, UV + EC, and US + EC methods. The influence of various control variables such as treatment time (1-5 h), current density (0.075-2.0 A dm-2), COD (1800-6000 mg L-1), inter-electrode distance (0.75-3.0 cm), electrode pairings (Fe/Fe, Fe/Al, Al/Fe, Al/Al), UV (8-32 W), and US (20-100 W) on the color and COD reduction were investigated to determine the optimum operating conditions. It was observed that, an increase in treatment time, current density, UV and US power, decrease in the COD, and inter-electrode distance with Fe/Fe electrode combination improved the COD removal efficiency. The UV and US + EC processes' synergy index was investigated and reported. The results showed that, the US + UV + EC treatment combination was effective in treating industrial effluent and wastewater.

Degradation of pefloxacin by hybrid hydrodynamic cavitation with H2O2 and O3.

The degradation of toxic chemicals, antibiotics and other residues in organic wastewater has attracted much attention. Among various degradation technologies, hydrodynamic cavitation (HC) reactors have the advantage of being simple to operate. Through the combination of HC and other oxidants, the removal efficiency and energy efficiency of organic matter can be greatly improved, and the consumption of chemicals and the processing costs can be reduced. In this work, HC technology combined with oxidants was used to degrade pefloxacin (PEF), and the effect of different operating conditions on PEF degradation was investigated. The results indicated that the removal efficiency of PEF treated with HC alone was 84.9% under the optimal HC conditions of pH 3.3 and 120 min, which is much higher than that (35.5%) of pH 5.3. When co-treating the PEF solution with HC and H2O2 at 0.3 MPa and pH 5.3, the optimal molar ratio of PEF to H2O2 was 1:5, the highest PEF removal efficiency was 69.7%, and the synergy index (SI) was 4.4. When combining HC with O3, the PEF removal efficiency gradually elevated with increasing ozone addition. When the addition amount of ozone was 0.675 g/h, the removal efficiency of PEF was the highest, which was 91.5% after treatment of 20 min. The intermediate products in the reaction process were analyzed based on UV-Vis spectroscopy and LC-MS, and the mechanism and reaction pathways of PEF were proposed.

Ferrihydrite/ultrasound activated peroxymonosulfate for humic acid removal.

In this study, ferrihydrite/ultrasound (US) system was used to activate peroxymonosulfate (PMS) to treat humic acid (HA) in artificial aqueous. The physical and chemical properties of ferrihydrite were characterized using SEM, zeta potential, BET, XRD, FTIR, and XPS analysis. A series of experiments were conducted to evaluate the effect of various factor on HA removal, including dosage of ferrihydrite, PMS concentration and pH value. The combination uses of US and ferrihydrite had obvious synergistic effect for HA removal. Under ferrihydrite/US/PMS system, nonthermal effect of US played the main role for HA removal. According to the result of radical quenching experiment, 1O2 was identified as the main reactive oxidative species (ROS) which contributed to HA removal. The study indicates ferrihydrite/US/PMS system is promising strategy for treatment of natural organic pollutant.

Selection of Optimal Palmer Predictors for Increasing the Predictability of the Danube Discharge: New Findings Based on Information Theory and Partial Wavelet Coherence Analysis.

The purpose of this study was to obtain synergistic information and details in the time-frequency domain of the relationships between the Palmer drought indices in the upper and middle Danube River basin and the discharge (Q) in the lower basin. Four indices were considered: the Palmer drought severity index (PDSI), Palmer hydrological drought index (PHDI), weighted PDSI (WPLM) and Palmer Z-index (ZIND). These indices were quantified through the first principal component (PC1) analysis of empirical orthogonal function (EOF) decomposition, which was obtained from hydro-meteorological parameters at 15 stations located along the Danube River basin. The influences of these indices on the Danube discharge were tested, both simultaneously and with certain lags, via linear and nonlinear methods applying the elements of information theory. Linear connections were generally obtained for synchronous links in the same season, and nonlinear ones for the predictors considered with certain lags (in advance) compared to the discharge predictand. The redundancy-synergy index was also considered to eliminate redundant predictors. Few cases were obtained in which all four predictors could be considered together to establish a significant information base for the discharge evolution. In the fall season, nonstationarity was tested through wavelet analysis applied for the multivariate case, using partial wavelet coherence (pwc). The results differed, depending on the predictor kept in pwc, and on those excluded.

Oxidative decomposition and mineralization of caffeine by advanced oxidation processes: The effect of hybridization.

The study consists of a detailed investigation of the degradability of the emerging water contaminant-caffeine by homogeneous and heterogeneous Advanced Oxidation Processes (AOP's), estimation of a synergy index for each hybrid operation thereof, and proposing the most plausible reaction mechanisms that are consistent with the experimental data. It also encompasses evaluation of the effect of the water matrix represented by carbonate species and humic acids, as strong scavengers of hydroxyl radicals. The results showed that single AOP's such as sonolysis (577 kHz) and photolysis with H2O2 provided complete caffeine elimination, but they were insufficient for the mineralization of the compound. Hybrid AOP's were considerably more effective, particularly when operated at a heterogeneous mode using commercial TiO2. The most effective hybrid process was UV-H2O2/TiO2, which provided more than 75% TOC decay at the minimum test doses of the reagent and catalyst. While the addition of ultrasound to the process significantly increased the rate of caffeine decomposition, it reduced the overall degradation of the compound to 64% in terms of TOC decay. The antagonistic effect was attributed to the formation of excess H2O2, and the presence of cavity clouds and/or high density layers that inhibited the transmission of UV light. The effect of natural water ingredients was found to reduce the reaction rates, signifying the major contribution of hydroxyl radicals to the destruction of caffeine. The proposed reaction mechanisms based on OH radical attack and the calculated energy barriers were in good agreement with the experimentally detected reaction byproducts.

Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma.

Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma.

Interaction Effects of Physical and Psychosocial Working Conditions on Risk for Sickness Absence: A Prospective Study of Nurses and Care Assistants in Sweden.

Employees in health and social care are often simultaneously exposed to both physical and psychosocial challenges that may increase their risk for sickness absence. The study examines interaction effects of physical and psychosocial work conditions on the future risk for sickness absence among nurses and care assistants in Sweden. The study was based on 14,372 participants in any of the Swedish Work Environment Surveys conducted during the years 1993-2013 with linked register information on background factors and compensated sickness absence. Adjusted hazard ratio (HR), stratified by occupation, and measures of additive interaction effects were estimated. The combinations of high psychosocial job demands and heavy physical work and strenuous postures, respectively, significantly increased the risks for sickness absence among nurses (HR 1.43; CI 1.09-1.88 and HR 1.42; CI 1.16-1.74, respectively), as well as among care assistants (HR 1.51; CI 1.36-1.67 and HR 1.49; CI 1.36-1.63, respectively). The combinations of low job control and both heavy physical work (HR 1.44; CI 1.30-1.60) and strenuous postures (HR 1.42; CI 1.30-1.56) were also associated with excess risk for sickness absence among care assistants. We also found interaction effects among care assistants but not among nurses. The results indicate that the high sickness absence rate among care workers in Sweden can be reduced if the simultaneous exposures of high psychosocial and high physical challenges are avoided. Management policies for reduced time pressure, improved lifting aids, and measures to avoid awkward work postures are recommended. For care assistants, increased influence over work arrangements is likely to lower their sickness absence risk.

Treatment of Cattle Manure by Anaerobic Co-Digestion with Food Waste and Pig Manure: Methane Yield and Synergistic Effect.

The management of cattle manure (CM) has become increasingly challenging because its production continues to rise, while the regulations on manure management have become increasingly stringent. In Korea, most farms produce CM as a dry mixture with lignocellulosic bedding materials (mainly sawdust), making it impractical to treat CM by anaerobic digestion. To address this problem, this study examined whether anaerobic co-digestion with food waste (FW) and pig manure (PM) could be an effective approach for the treatment of CM. The batch anaerobic digestion tests at different CM: FW: PM mixing ratios showed that more methane was produced as the FW fraction increased, and as the CM fraction decreased. The response surface models describing how the substrate mixing ratio affects the methane yield and synergistic effect (methane yield basis) were successfully generated. The models proved that the methane yield and synergistic effect respond differently to changes in the substrate mixing ratio. The maximum 30-day methane yield was predicted at 100% FW, whereas the maximum 30-day synergy index was estimated for the mixture of 47% CM, 6% FW, and 47% PM (total solids basis). The synergy index model showed that CM, FW, and PM could be co-digested without a substantial loss of their methane potential at any mixing ratio (30-day synergy index, 0.89-1.22), and that a possible antagonistic effect could be avoided by keeping the FW proportion less than 50%. The results suggest that co-digestion with PM and FW could be flexibly applied for the treatment and valorization of CM in existing anaerobic digestion plants treating FW and PM.

Interaction effects of physical and psychosocial working conditions on the risk of disability pension among nursing professionals and care assistants in Sweden: A prospective study.

BACKGROUND: Nursing professionals and care assistants are often subject to a combination of negative physical and psychosocial work environment factors, but most disability pension studies on such occupations have focused on one or the other of these factors. As they often coexist, there are reasons to assume that simultaneously being exposed to both types of exposures will increase the risk of disability more than being exposed to either. OBJECTIVES: The study examined combinations of physical and psychosocial work conditions as predictors of future disability pension among nursing professionals and care assistants in Sweden. PARTICIPANTS: The study was based on a random and representative sample of 79,004 participants in any of the Swedish Work Environment Surveys from 1993 to 2013. A total of 2576 nursing professionals, 10,175 care assistants, and 66,253 workers in other occupations were included. METHODS: Information on background factors and disability pension was obtained from population registers. Cox proportional hazard regressions with 95% confidence intervals (CI) were performed to study if pairs of combinations of physical and psychosocial factors were related to an increased risk of disability pension. Additionally, measures of synergistic effects were estimated. The analyses were stratified on occupation group, with adjustment for selected confounders. RESULTS: The results indicated increased hazard ratios (HR) for disability pension for most combinations of physical and psychosocial working conditions. The hazard ratios for joint exposure to high demands and heavy physical work were high among both nursing professionals (HR 1.91; CI 1.06-3.44) and care assistants (HR 2.09; CI 1.63-2.69). Also, the combination of high demands and strenuous postures resulted in significantly elevated risks of disability pension among nursing professionals (HR 1.95; CI 1.20-3.16) and care assistants (HR 2.18; CI 1.71-2.77). The HRs for joint exposure to low control and both heavy physical work and strenuous postures were significant among all other occupations (HR 2.30; CI 2.05-2.58 and HR 2.24; CI 2.01-2.51), and among care assistants (HR 1.52; CI 1.26-1.85 and HR 1.61; CI 1.34-1.93), but not significant among nursing professionals. The synergistic effects on disability pension from combined exposures were generally positive among all three occupational groups. CONCLUSION: Nursing professionals and care assistants exposed to both negative physical and psychosocial conditions had an increased risk of disability pension. A synergistic effect with respect to disability pension was found among care assistants who reported low control and strenuous postures at work.

Superior performance of FeVO4@CeO2 uniform core-shell nanostructures in heterogeneous Fenton-sonophotocatalytic degradation of 4-nitrophenol.

Porous FeVO4 nanorods decorated on CeO2 nanocubes (FeVO4@CeO2) were successfully prepared via a facile hydrothermal route and tested in the degradation of 4-nitrophenol (4-NP) for enhanced heterogeneous oxidation using ultrasonic (US), ultraviolet (UV), and binary irradiation US/UV, respectively. The nanostructure of the core-shell FeVO4@CeO2 was characterised using XRD, SEM, EDS elemental mapping, TEM, HRTEM, SAED, FTIR, Raman, BET, point of zero charge (PZC), XPS analysis and UV-vis DRS. The effect of various parameters, for examples, nanostructured core-shell amounts, hydrogen peroxide concentration, initial concentration, pH and irradiation time, on 4-NP degradation were investigated for the optimisation of the catalytic performance. The durability and stability of the core-shell nanostructured materials were also investigated and the obtained results revealed that the catalysts can endure the harsh sonophotocatalytic conditions even after six cycles. Mineralisation experiments were investigated using the optimised parameters. The core-shell nanostructured FeVO4@CeO2 has higher PZC than pure FeVO4 and CeO2, leading to excellent sonophotocatalytic activity even at high pH and stability for the degradation of 4-NP after six cycles. A possible mechanism over the FeVO4@CeO2 was proposed based on the special three-way Fenton-like mechanism and the dissociation of H2O2 with the experiments of active species trapping and calculated band gap energy.

Recommendation for the minimum number of steps to analyze when performing the uncontrolled manifold analysis on walking data.

The uncontrolled manifold (UCM) analysis quantifies the extent to which co-variation among a set of variables facilitates consistent performance by partitioning variance in those variables into two components then calculating their normalized difference (i.e., the synergy index). Although UCM-derived measures are thought to depend on the number of data points analyzed, the minimum number needed to reasonably approximate true values of these measures is unknown. For each of two performance variables related to mechanical stability of gait, we evaluated changes in UCM-derived measures when increasing the number of analyzed points, here steps. Fourteen older adults walked on a treadmill while motion capture tracked movement. For each subject, n steps (where n = 2-99) were randomly sampled from the first 100, then used to calculate UCM-derived variables. For each subject, variables were expressed as a percent of the subject-specific value with n = 100 and averaged across 50 simulations. For each n, 95% confidence intervals (CIs) were calculated from group data. The minimum number of steps to "reasonably approximate" a variables was defined as the value of n for which the lower CI was >90% of the value with n = 100. Regardless of performance variable, reasonable approximations of the synergy index were attained with n = 16 steps, whereas n = 50 steps were needed for each of the variance components However, the differences between using 16 steps and 50 steps were small. Collecting 15-20 steps is recommended for a reasonable approximation of the synergy indices considered herein, particularly when data collection is constrained to a limited number of steps.

Synergistic effect between ischaemic heart disease and common mental disorders and the risk of premature exit from the labour market: a nationwide register based study from Sweden.

Aims: Common mental disorders i.e. depressive and anxiety disorders (CMD) are frequent comorbid conditions in individuals with ischaemic heart disease (IHD). Still, their effect on preterm exit from the labour market [i.e. disability pension (DP)] in individuals with IHD has to date not been scrutinized. The aim of this study was to investigate the separate and joint effect of IHD and CMD on the risk of DP for women and men of working age. Material and methods: This population-based cohort study included all non-pensioned 4 823 069 individuals, registered as living in Sweden 31 December 2004 and then 16-64 years of age. Individuals with IHD or CMD were identified through using data on sickness absence, prescribed medication or in- or specialized outpatient care in 2005. Crude and adjusted hazard ratios (HR) and 95% confidence intervals (CI) for being granted DP in 2006-10 were estimated by means of Cox proportional hazard regression. Results: In the fully adjusted models, HRs for DP were 2.84 (95% CI; 2.57-3.13) and 2.83 (2.66-3.01) in women and men with IHD, respectively. Hazard ratios for DP in women and men with CMD were 5.13 (5.03-5.24) and 6.08 (5.93-6.24). In women and men with both conditions, crude HRs for DP were 18.38 (15.01-22.50) and 25.58 (22.27-29.37). There was a significant synergistic effect between IHD and CMD in both sexes in the crude models, which disappeared in women after adjusting for socio-demographic variables, and in men after additionally adjusting for comorbid somatic disorders. Conclusion: A comorbid CMD worsens the prognosis of IHD in terms of early exit from the labour market. Processes leading to DP in individuals with IHD are multifactorial and may involve the presence of CMD as well as comorbidity with other somatic diseases.

Interactions among different genetic loci in age-related macular degeneration.

PURPOSE: To evaluate the possible synergistic effect of at risk genotypes of ARMS2/LOC387715 (A69S), DNA repair SMUG1 rs3087404, CCL2-2518, C3 (R102G), CFH Y402H, complement factor B (L9H), and complement factor I (CFI) (G119R) in advanced age-related macular degeneration compared to those of healthy controls. Elucidation of synergistic effects between different genetic loci may clarify their pathogenetic pathways. METHODS: We calculated relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) to estimate the additive or supra-additive effects of the mentioned genotypes. RESULTS: ARMS2-CFH [RERI = 4.78 (95% CI 2.17-10.61), AP = 0.65 (95% CI 0.33-0.83), S = 4.11 (95% CI 1.40-12.06)], and CFH-C3 combinations [RERI = 2.71 (95% CI 0.04-7.01) AP = 0.47 (95% CI -0.03-0.7) S = 2.30 (95%CI 0.97-5.45)] have the most significant levels of synergism and C3-CFI combination [RERI = -1.65 (95%CI -4.34-0.06), AP = -0.92(95%CI -3.09 - -0.09), S = 0.32 (95%CI 0.09 = 1.20)] has the most significant level of antagonism. CONCLUSION: Among different genotype combinations ARMS2-CFH and CFH-C3 combinations have the most significant levels of synergism and C3-CFI combination has the most significant level of antagonism in AMD patients.

Independent and additive interaction between polymorphisms of tumor necrosis factor α-308 and lymphotoxin α+252 on risk of hepatocellular carcinoma related to hepatitis B.

This case-control study was aimed to assess the effect of genetic variants of tumor necrosis factor (TNF) α-308 and lymphotoxin (LT) α+252 on development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Their gene-gene interaction was also investigated. We enrolled 200 pairs of age- and sex-matched patients with cirrhotic HBV-HCC and unrelated patients with HBV-cirrhosis alone. Polymorphisms of TNFα-308 and LTα+252 were genotyped. Synergy index was used to calculate interaction between the variant genotypes. The results indicated that the frequency distribution of the variant genotypes (TNFα-308 G/A and LTα+252 G/G) in patients with HCC were significantly higher than those in patients with cirrhosis alone. Multivariate analysis indicated that TNFα-308 G/A (odds ratio [OR], 2.34) and LTα+252 G/G (OR, 2.04) were independent risk factors for HCC. By the clinical characteristics of study population, multivariate analysis demonstrated that independent factors associated with harboring the variant genotypes included cirrhosis with Child-Pugh C (OR = 6.47 in cases and OR = 11.56 in controls) and thrombocytopenia (OR = 8.86 in cases and OR = 7.74 in controls). Calculation of synergy index (SI) indicated that there are additive interaction between TNFα-308 G/A and LTα+252 G/G on risk of HCC (SI = 1.29). IN CONCLUSION: There are independent and additive interactions between TNFα-308 G/A and LTα+252 G/G on risk for HBV-HCC. They correlated with advanced hepatic fibrosis and severe liver damage, which might contribute to a higher risk for HCC.

Interactive effects between Lymphotoxin α +252 polymorphism and habits of substance use on risk of hepatocellular carcinoma.

This case-control study aimed to assess the interactive effect between polymorphisms of lymphotoxin (LT) α +252 and habitual substance use on risk of hepatocellular carcinoma (HCC). We enrolled 150 pairs of sex- and age-matched HCC patients and unrelated healthy controls. LTα genotypes were detected with polymerase-chain reaction and restrictive fragment length polymorphisms. Information about habits of substance use was obtained through personal interview. Multivariate analysis indicated that LTα +252 G/G genotypes [odds ratio (OR) = 3.36], Hepatitis B surface antigen (OR = 16.68), antibodies to hepatitis C virus (OR = 34.88) and having at least two habits of substance use (OR = 2.50) were independent risk factors for HCC. There were additive interactions among LTα +252 G/G genotype, chronic viral hepatitis, and habit of each substance use. IN CONCLUSION: There are independent and additive interactions between LTα +252 G/G genotype, chronic viral hepatitis, and habits of substance use on risk of HCC.