J-shaped Dose-response Relationship Research Articles

Dose-Response Relationship Between Alcohol Consumption and Gout Risk: Do Subtypes of Alcoholic Beverages Make a Difference?

Although previous studies have explored the association of drinking with gout risk, we sought to explore the dose-response relationship and the evidence between subtypes of alcoholic beverages and gout risk. The weekly alcoholic beverage consumption of patients in the UK Biobank was collected and calculated. The Cox regression model was applied to assess the effects of drinking alcohol in general and its subtypes on gout risk by calculating the hazard ratio (HR) and 95% CIs. Additionally, the restricted cubic splines were used to estimate the dose-response relationship between alcohol consumption and gout risk. To evaluate the robustness, we performed subgroup analysis across various demographic characteristics. During a mean follow-up period of 11.7 years, a total of 5728 new incident gout cases were diagnosed among 331,865 participants. We found that light alcohol consumption was linked to a slight decrease in gout incidence among female individuals (HR 0.78, 95% CI 0.65-0.94, P = 0.01), whereas there was no significant association in male individuals. Moreover, the dose-response relationship showed that drinking light red wine and fortified wine could reduce the gout risk, whereas beer or cider, champagne or white wine, and spirits increased the gout risk at any dose. Our study suggested a J-shaped dose-response relationship between drinking and gout risk in female individuals, but not in male individuals. For specific alcoholic beverages, light consumption of red wine and fortified wine was associated with reduced gout risk. These findings offer new insights into the roles of alcoholic beverages in gout incidence risk, although further validation is warranted.

The effects of daily dose of intense exercise on cardiac responses and atrial fibrillation.

Atrial fibrillation (AF) is a supraventricular tachyarrhythmia that is strongly associated with cardiovascular (CV) disease and sedentary lifestyles. Despite the benefits of exercise on overall health, AF incidence in high-level endurance athletes rivals that of CV disease patients, suggesting a J-shaped relationship with AF. To investigate the dependence of AF vulnerability on exercise, we varied daily swim durations (120, 180 or 240minday-1 ) in 7-week-old male CD1mice. We assessed mice after performing equivalent amounts of cumulative work during swimming (i.e. ∼700L O2 kg-1 ), as determined from O2 consumption rates ( ). The mean during exercise increased progressively throughout the training period and was indistinguishable between the swim groups. Consistent with similar improvements in aerobic conditioning induced by swimming, skeletal muscle mitochondria content increased (P=0.027) indistinguishably between exercise groups. Physiological ventricular remodelling, characterized by mild hypertrophy and left ventricular dilatation, was also similar between exercised mice without evidence of ventricular arrhythmia inducibility. By contrast, prolongation of daily swim durations caused progressive and vagal-dependent heart rate reductions (P=0.008), as well as increased (P=0.005) AF vulnerability. As expected, vagal inhibition prolonged (P=0.013) atrial refractoriness, leading to reduced AF vulnerability, although still inducible in the 180 and 240min swim groups. Accordingly, daily swim dose progressively increased atrial hypertrophy (P=0.003), fibrosis (P<0.001) and macrophage accumulation (P=0.006) without differentially affecting the ventricular tissue properties. Thus, increasing daily exercise duration drives progressively adverse atrial-specific remodelling and vagal-dependent AF vulnerability despite robust and beneficial aerobic conditioning and physiological remodelling of ventricles and skeletal muscle. KEY POINTS: Previous studies have suggested that a J-shaped dose-response relationship exists between physical activity and cardiovascular health outcomes, with moderate exercise providing protection against many cardiovascular disease conditions, whereas chronic endurance exercise can promote atrial fibrillation (AF). We found that AF vulnerability increased alongside elevated atrial hypertrophy, fibrosis and inflammation as daily swim exercise durations in mice were prolonged (i.e. ≥180minday-1 for 6weeks). The MET-hweek-1 (based on O2 measurements during swimming) needed to induce increased AF vulnerability mirrored the levels linked to AF in athletes. These adverse atria effects associated with excessive daily exercise occurred despite improved aerobic conditioning, skeletal muscle adaptation and physiological ventricular remodelling. We suggest that atrial-specific changes observed with exercise arise from excessive elevations in venous filling pressures during prolonged exercise bouts, which we argue has implications for all AF patients because elevated atrial pressures occur in most cardiovascular disease conditions as well as ageing which are linked to AF.

Triglyceride–glucose index associates with incident heart failure: A cohort study

AimsTriglyceride–glucose (TyG) index has been proposed as a simple surrogate marker of insulin resistance. However, few studies have investigated the association of TyG index with heart failure (HF). We aimed to explore the relationship between TyG index and incident HF. MethodsA total of 138,620 participants from the Kailuan study were included for analysis. TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL) / 2]. Cox proportional hazard models were used to investigate the association between TyG index and the risk of HF. Restricted cubic spline analysis was applied to evaluate the dose-response relationship between TyG index and the risk of HF. ResultsThere were 1602 incident HF cases among the 138,620 participants during a median follow-up of 8.78 years. Compared with those in the lowest quartile group of TyG index, participants with the highest quartile of TyG index had a 24% higher risk of HF (HR=1.24, 95%CI=1.07-1.44) after adjusting for other risk factors. Restricted cubic spline analysis showed a significant J-shaped dose-response relationship between TyG index and risk of HF (P for non-linearity < 0.001). The significant association was still observed among the men and participants with or without abdominal obesity in subgroup analyses. ConclusionThe TyG index was positively associated with the risk of HF, which indicates that the TyG index might be useful to identify people at high-risk for developing HF.

Continuous metabolic syndrome severity score and the risk of CVD and all-cause mortality.

The dualistic diagnostic criteria for metabolic syndrome overlooked the severity of metabolic syndrome, and the relationships between the severity of metabolic syndrome and adverse health conditions are poorly characterized. We therefore aimed to investigate the associations of metabolic syndrome severity with incident cardiovascular disease (CVD)/all-cause mortality. A total of 116,772 participants from the Kailuan study were followed up biennially between 2006 and 2018. The severity of metabolic syndrome was evaluated using a continuous metabolic syndrome severity score (MetS score). Cox proportional hazards model was used to examine the association between MetS score and the risk of CVD and all-cause mortality. Restricted cubic spline analyses were performed to explore the dose-response associations. We found that the risk of CVD and all-cause mortality increased consistently with the MetS score. In the multivariable-adjusted model, the hazard ratios of CVD and all-cause mortality were 2.05 (95% CI 1.86-2.25) and 1.45 (95% CI 1.35-1.56), respectively, in those subjects>75th percentile compared with those <25th percentile. Additionally, a J-shaped dose-response relationship was found between MetS score and the risk of all-cause mortality (pnonlinearity <.001), while a linear relationship between MetS score and the risk of CVD was observed in this study (pnonlinearity =.737). This study suggests significant dose-response relationships between MetS score and the risk of CVD/mortality. Subjects without metabolic syndrome but with a relatively high MetS score should raise their awareness and pay more attention to the possible increased risk of CVD events.

Noise exposure and risk of myocardial infarction incidence and mortality: a dose-response meta-analysis.

The strength and shape of the dose-response relationship between different types of noise and myocardial infarction (MI) remain unclear. Therefore, we aimed to summarize the evidence of the association between various types of noise and MI incidence and mortality through a dose-response meta-analysis. We performed a systematic search of the PubMed, Embase, and Web of Science databases up to December 19, 2021. The generalized least-squares method and restricted cubic splines were used to assess the potential linear and nonlinear dose-response relationships between noise exposure and the risk of MI events. Twenty observational studies with 34 reports met the eligibility criteria. In the linear models, the pooled relative risk and corresponding 95% confidence interval (CI) for MI incidence was 1.04 (95% CI: 1.02 - 1.05), and the MI mortality was 1.02 (95% CI: 1.02 - 1.03) for each 10dB(A) increase in noise exposure. In addition, we observed an approximately J-shaped dose-response relationship between noise and MI mortality (Pnonlinearity = 0.0037), whereas the threshold for the statistical impact of noise on MI mortality may be 42dB(A). Our findings support the notion that various types of noise exposure have a positive dose-response relationship with the risk of MI incidence and mortality.

The protective effect of alcohol consumption on the incidence of cardiovascular diseases: is it real? A systematic review and meta-analysis of studies conducted in community settings

BackgroundThis study investigated the dose-response relationship between alcohol consumption and CVD incidence, conducting a meta-analysis of studies focusing on residents from local communities. Further, we examined whether light to moderate alcohol consumption had a protective effect on CVD incidence through a sub-group analysis.MethodsThis study conducted a meta-analysis of the relationship between alcohol consumption and CVD incidence, selecting journals published up to December 2017. The alcohol consumption level was classified into non-consumers, light (0.01–10.0 g/day), light to moderate (10.1–20.0 g/day), moderate (20.1–40.0 g/day), moderate to high (40.1–60.0 g/day), and high (> 60.0 g/day) groups. The sub-group analysis was conducted according to the number of comorbidities and age.ResultsSeven articles were selected in total for the meta-analysis. The mean Newcastle-Ottawa scale score was 8.14 points, suggesting studies were of high quality. There was a J-shaped dose-response relationship between alcohol consumption level and CVD incidence only in men. In general, light to moderate and moderate consumption lowered CVD incidence (Relative risk (RR) [95% confidence interval (CI)] was 0.68 [0.57–0.81] and 0.72 [0.58–0.90], respectively). In men with 3–4 comorbidities, there were no protective effects of light to moderate and moderate consumption on CVD incidence. In either groups of only men or men and women there were protective effects of light to moderate and moderate consumption on CVD incidence only in those aged between 41 and 65.DiscussionWe found that light to moderate and moderate alcohol consumption had a protective effect on CVD incidence, there was no protective effect either in those with at least three comorbidities or people aged 40 or younger.ConclusionsWe conclude that not all local community residents experience a protective effect of light to moderate consumption on CVD incidence. As such, it is necessary to recommend a moderate amount of drinking or less for each individual.

Parity and risk of maternal cardiovascular disease: A dose-response meta-analysis of cohort studies.

Parity has been reported to play an important role in the development of cardiovascular disease; however, the results are still controversial. We aimed to conduct a meta-analysis of cohort studies to assess quantitatively the association between parity and cardiovascular disease risk. PubMed and Web of Science databases were searched to 1 June 2018, supplemented by manual searches of the bibliographies of retrieved articles. And multivariate-adjusted relative risks were pooled by using random-effects models. Restricted cubic spline analysis with four knots was used to explore the relationship of parity and the risk of cardiovascular disease. Ten cohort studies involving 150,512 incident cases of cardiovascular disease among 3,089,929 participants were included in the meta-analysis. A significant association between parity and cardiovascular disease risk was observed while comparing parity with nulliparity, with a summarised relative risk of 1.14 (95% confidence interval (CI) 1.09-1.18; I2 = 62.0%, P = 0.002). In the dose-response analysis, we observed a potential non-linear J-shaped dose-response relationship between the number of parity and cardiovascular disease risk, the summary risk estimates for an increase of one live birth was 1.04 (95% CI 1.02-1.05), with significant heterogeneity ( I2 = 89.6%). In addition, the similar J-shaped associations between parturition number and cardiovascular disease, ischaemic heart disease or stroke risk were also observed. Our findings suggest that ever parity is related to cardiovascular disease risk and there is an association between the number of pregnancies and the risk of cardiovascular disease. Since the number of included studies was limited, further studies are warranted to confirm our findings.

Evaluation of the Validity of a Nonlinear J-Shaped Dose-Response Relationship in Cancers Induced by Exposure to Radiofrequency Electromagnetic Fields.

The radiofrequency electromagnetic fields (RF-EMFs) produced by widely used mobile phones are classified as possibly carcinogenic to humans by International Agency for Research on Cancer (IARC). Current data on the relationship between exposure to RF-EMFs generated by commercial mobile phones and brain cancer are controversial. Our studies show that this controversy may be caused by several parameters. However, it seems that the magnitude of exposure to RF-EMFs plays a basic role in RF-induced carcinogenesis. There is some evidence indicating that, in a similar pattern with ionizing radiation, the carcinogenesis of non-ionizing RF-EMF may have a nonlinear dose-response relationship. In this paper, the evidence which supports a nonlinear J-shaped dose-response relationship is discussed.

Abstract P209: Dose-Response Relationship Between Dietary Intake of Alpha-linolenic Acid and Risk of Coronary Heart Disease: A Meta-analysis of Prospective Studies

Introduction: Previous studies show that alpha-linolenic acid (ALA) is associated with reduced risk of coronary heart disease (CHD). However, it remains unclear whether and how dietary ALA doses are related to CHD. Hypothesis: We hypothesized that higher dietary ALA intake is associated with a greater reduction in risk of CHD. Methods: We searched PubMed, EMBASE, and Web of Science for prospective studies examining the association between dietary ALA intake and CHD risk. Dietary ALA intake was assigned or measured by self-report. Outcomes were reported as total and fatal CHD and/or myocardial infarction, which were obtained from blinded endpoint assessments or medical records. Two-stage fixed-effects dose-response meta-analyses were conducted to estimate the association between increasing ALA intake (relative to study-specific referents) and CHD. Results: Fifteen published articles were identified and included in the meta-analysis (13 cohort studies and 2 randomized controlled trials). The pooled analysis was based on 310,768 individuals with 12,049 events with a mean length of follow-up of 9.6 years. The analysis showed a J-shaped curve between ALA intake and relative risk of total CHD (Chi-square=21.08, p&lt;0.001). ALA intake from 0.3-1.4g/day showed reduced risk of total CHD, while intake ≥2.5g/day was associated with increased risk of CHD, compared to people without ALA intake (Figure 1A). Approximately 1g/day of ALA intake was associated with the lowest risk of total CHD. ALA intake was linearly associated with fatal CHD - every 1g/day increase in ALA intake was associated with an 11% decrease in fatal CHD risk (95% CI: -0.16, -0.05) (Figure 1B). Conclusion: The J-shaped dose-response relationship based on our pooled analysis suggests that 1g/day of dietary ALA may be optimal for total CHD prevention. Though a higher dietary ALA intake was associated with reduced risk of fatal CHD, the excess total CHD risk at higher ALA intakes warrants further investigation, especially through randomized controlled trials.

Mobile phone use and cancer: Does dose really matter?

The past decades have witnessed rapid evolution of telecommunication technology and wireless devices. Due to these rapid advances, cell phone usage has remarkably increased the level of human exposure to radiofrequency-electromagnetic fields (RF-EMFs). In the past, it was widely believed that, RF-EMF, in contrast to ionizing radiation, does not have enough energy for ionizing atoms and hence does not cause DNA damage which can lead to cancer. However, substantial evidence now indicates that RF-EMFs increase the reactive oxygen species production and DNA damages which play an important role in the initiation and progression of cancer. Currently, there is no widely accepted answer to this question whether there is a relationship between exposure to RF-EMFs from cell phones and cancer incidence and mortality. Although it seems that this issue is a long-term unsolved problem, new studies have raised new concerns over the safety of mobile phones. Mortazavi have previously studied the health effects of cellular phones, mobile base stations, and Wi-Fi. They have also reviewed reports claiming no link between exposure to RF and brain cancer. They found that in many cases there were large errors and/or major shortcomings in these articles. They have also reported that current controversies may be caused by the key parameter of the large difference in the magnitude of exposures to RF-EMFs in different studies. In this light, in a similar pattern with ionizing radiation, a nonlinear J-shaped dose–response relationship for the carcinogenesis of nonionizing RF-EMF is introduced.

Inference for the existence of hormetic dose-response relationships in toxicology studies.

In toxicology studies hormesis refers to a dose-response relationship with a stimulatory response at low doses and an inhibitory response at high doses. In this manuscript, we particularly focus on a J-shaped dose-response relationship for binary cancer responses. We propose and examine two new flexible models for testing the hypothesis of hormesis in a Bayesian framework. The first model is parametric and enhances the flexibility of modeling a hormetic zone by using a non-linear predictor in a multistage model. The second model is non-parametric and allows multiple model specifications, weighting the contribution of each model via Bayesian model averaging (BMA). Simulation studies show that the non-parametric modeling approach with BMA provides robust sensitivity and specificity for detecting hormesis relative to the parametric approach, regardless of the shape of a hormetic zone.

Positive linear dose-response relationships, but no J-shaped relationship, between drinking habits and estimated glomerular filtration rate in middle-aged Japanese men.

The relationship between drinking frequency and amount of alcohol consumption (i.e., drinking habits) and the risk of chronic kidney disease (CKD) remains unclear. We aimed to clarify either a linear or J-shaped dose-response relationship between drinking habits and estimated glomerular filtration rate (eGFR) as a biomarker for identifying individuals at high risk of CKD. In a large-scale cross-sectional study, 403 men and 121 women with an eGFR of 30-60mL/min per 1.73m(2) were defined as cases, and 1209 men and 363 women with ≥60mL/min/1.73m(2) were randomly extracted as controls (one case subject was matched with three control subjects, matched according to age and season of data collection). We calculated multivariate-adjusted CKD risk and the corresponding mean eGFR according to drinking habits. In men, negative and positive linear relationships with drinking habits were found for CKD risk and mean eGFR (p<0.001 for all linear terms), respectively, but there were no corresponding J-shaped relationships (not significant for all quadratic terms). In regard to the mean eGFR, however, positive linear relationships were only shown in men in the highest eGFR quartile (p<0.05 and p<0.01 for drinking frequency and amount of alcohol consumption, respectively). In women, no association was found. Regarding each drinking habit, we found a positive linear dose-response relationship to eGFR in middle-aged men with an eGFR ≥30mL/min/1.73m(2).

Effect of Drinking on All-Cause Mortality in Women Compared with Men: A Meta-Analysis

Alcoholic beverages are consumed by humans for a variety of dietary, recreational, and other reasons. It is uncertain whether the drinking effect on risk of all-cause mortality is different between women and men. We conducted a meta-analysis to evaluate the effect of drinking on the risk of all-cause mortality in women compared with men. We selected cohort studies with measures of relative risk (RR) and 95% confidence interval (CI) for all-cause mortality for drinkers versus nondrinkers by sex. Sex-specific RR and 95% CI were used to estimate the female-to-male ratio of RR (RRR) and 95% CI. Pooled estimates of RRR across studies were obtained by the fixed-effects model or the random-effects model (if heterogeneity was detected). Second-order fractional polynomials and random effects meta-regression models were used for modeling the dose-risk relationship. Twenty-four studies were considered eligible. A total of 2,424,964 participants (male: 1,473,899; female: 951,065) were enrolled and 123,878 deaths (male: 76,362; female: 47,516) were observed. Compared with nondrinkers, the pooled female-to-male RRR for drinkers was 1.07 (95% CI: 1.02, 1.12). Subgroup analyses showed that the increased risk among female drinkers appeared to be consistent. J-shaped dose-response relationship was confirmed between alcohol and all-cause mortality in men and women, respectively. Moreover, the female-to-male RRR of all-cause mortality were 1.52 (95% CI: 1.01, 2.29), 1.95 (95% CI: 1.08, 3.49), and 2.36 (95% CI: 1.15, 4.88), respectively, for those who consumed 75, 90, and 100 g/day of alcohol. Females had an increased risk for all-cause mortality conferred by drinking compared with males, especially in heavy drinkers. The present study suggested that female drinkers, particularly heavy drinkers, should moderate or completely reduce their level of consumption to have a health benefit.

Reduction in Mutation Frequency by Very Low-Dose Gamma Irradiation of Drosophila melanogaster Germ Cells

To determine whether the linear no-threshold (LNT) model for stochastic effects of ionizing radiation is applicable to very low-dose radiation at a low dose rate, we irradiated immature male germ cells of the fruit fly, Drosophila melanogaster, with several doses of (60)Co gamma rays at a dose rate of 22.4 mGy/h. Thereafter, we performed the sex-linked recessive lethal mutation assay by mating the irradiated males with nonirradiated females. The mutation frequency in the group irradiated with 500 microGy was found to be significantly lower than that in the control group (P < 0.01), whereas in the group subjected to 10 Gy irradiation, the mutation frequency was significantly higher than that in the control group (P < 0.03). A J-shaped dose-response relationship was evident. Molecular experiments using DNA microarray and quantitative reverse transcription PCR indicated that several genes known to be expressed in response to heat or chemical stress and grim, a positive regulator of apoptosis, were up-regulated immediately after irradiation with 500 microGy. The involvement of an apoptosis function in the non-linear dose-response relationship was suggested.

Effects of sub-chronic exposure to palladium (as potassium hexachloro-palladate) on cytokines in male Wistar rats

Palladium (Pd) is a heavy metal belonging to the platinum group elements. It has been shown that Pd and its compounds can cause sensitization, asthma and dermatologic disorders. In this study, Wistar rats were exposed for 3 months to 0, 1, 10, 100, and 250 ng/ml of Pd (as potassium hexachloro-palladate) in drinking water. At the end of exposure, possible changes in two type-1 cytokines [interleukin (IL)-2, interferon (INF)-gamma] and one type-2 cytokine (IL-4) in the serum were measured. After the sub-chronic exposure, analysis of variance of IL-2 and INF-gamma response shows that the difference between mean values in the groups of animals exposed reaches statistical significance for IL-2 (P = 0.001), showing a J-shaped dose-response relationship. At the higher dose of 250 ng/ml Pd, it was observed a significant increase in IL-2 production when compared with the controls. Furthermore at 1 and 10 ng/ml of Pd we observed an increase of INF-gamma production that was significant at 100 ng/ml of Pd, while at the higher dose of 250 ng/ml of Pd the response was indistinguishable from the control. At the doses investigated, Pd has been shown not to determine a modification of IL-4 response (P = 0.10). These preliminary findings indicate the need to carry out further investigations regarding the effect of other Pd compounds and the measurement of other types of cytokines both in the animal model used in our study and other models.

Consumption of Soft Drinks and Hyperactivity, Mental Distress, and Conduct Problems Among Adolescents in Oslo, Norway

We examined whether high levels of consumption of sugar-containing soft drinks were associated with mental distress, hyperactivity, and conduct problems among adolescents. A cross-sectional population-based survey was conducted with 10th-grade students in Oslo, Norway (n = 5498). We used the Hopkins Symptom Checklist and the Strengths and Difficulties Questionnaire to assess mental health outcomes. There was a J-shaped dose-response relationship between soft drink consumption and mental distress, conduct problems, and total mental health difficulties score; that is, adolescents who did not consume soft drinks had higher scores (indicating worse symptoms) than those who consumed soft drinks at moderate levels but lower scores than those with high consumption levels. The relationship was linear for hyperactivity. In a logistic regression model, the association between soft drink consumption and mental health problems remained significant after adjustment for behavioral, social, and food-related variables. The highest adjusted odds ratios were observed for conduct problems among boys and girls who consumed 4 or more glasses of sugar-containing soft drinks per day. High consumption levels of sugar-containing soft drinks were associated with mental health problems among adolescents even after adjustment for possible confounders.

J-Shaped Dose-Response Relationship for Tumor Induction by Caffeic Acid in the Rat Forestomach, Modeled by Non-Monotonic Dose Response for DNA Damage and Cell Proliferation

Dose-response relationships for chemical tumor induction can be described with stochastic carcinogenesis models by incorporation of dose-dependent parameters. We used a two-stage mutational model with clonal expansion of intermediate cells to mimic the observed U-shaped (more precisely: J-shaped) dose response for cell division in the forestomach of rats treated with caffeic acid. The question was whether biologically acceptable model parameters for the rates of mutation and cell turnover could be found to fit the experimental data, including tumor incidence in controls and at high dose. Using rates of cell turnover in proportion to the experimental labeling indices for DNA replication, model parameters could fit the tumor incidences within the 95% confidence limits of the experimental data, and the J-shape was retained quantitatively. However, when the smaller confidence limits derived from historical data on the spontaneous forestomach tumor incidence were taken into account, the original model could no longer accommodate all data and had to be expanded. For that, mutation rates were considered to be proportional to both the level of DNA damage and the rate of cell division, and both factors were allowed to be dose dependent. For the DNA damage, an increment over background was used at the higher, cytotoxic dose levels. This model improvement resulted in biologically acceptable parameters to fit all available data, demonstrating its usefulness for further analyses of hormetic dose response.

Exercise, Immunity, and Susceptibility to Infection

Regular, moderate exercise enhances immune function and attenuates immune disturbances associated with acute exercise (ie, a single bout of vigorous exercise). Epidemiologic data suggest that vigorous exercise may temporarily reduce resistance to viral infection. However, objective data do not clearly show a J-shaped dose-response relationship between exercise and immune function. Nutritional, hygienic, exercise, environmental, and pharmacologic strategies can minimize the risk of infection. Persons who have systemic symptoms should avoid competition and heavy training.