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Background: The dose-response association between serum albumin and atrial fibrillation is not well known. This study aims to assess the relationship between albumin and atrial fibrillation and the potential dose-response effect. Methods: Studies reported that the serum albumin and AF were identified by searching the EMBASE, PubMed, and Cochrane Library databases. The potential dose-response effect was performed by using a stage robust error meta-regression. Results: Nine studies were included with a total of 32,130 individuals. Patients with high albumin level were associated with a decreased risk of atrial fibrillation compared with patients with low serum albumin (OR[odds ratio]: 0.62, 95% CI [0.44, 0.89]; I 2 = 76%; P = 0.009). In the dose-response analysis, for each 10 g/L increase in serum albumin level, the risk of atrial fibrillation decreased by 36% (95% CI: 0.51-0.81, I 2 = 87%, P < 0.001). Furthermore, a significant negative linear relationship between serum albumin and the risk of atrial fibrillation (P nonlinearity = 0.33) was found. Conclusion: Our dose-response meta-analysis suggests that low serum albumin level is associated with an increased risk of atrial fibrillation. Further studies are needed to explore the effect of induction of elevated serum albumin levels on the prevention of atrial fibrillation.
Objective: Both tooth loss and dementia are age-related and frequently-occurring diseases. Increasing attention has been given to explore the pathogenesis related to oral-brain function disorders. The present study was performed to evaluate the association between tooth loss and dementia through a dose-response meta-analysis. Methods: Relevant cohort studies were searched from online databases up until June 20, 2018, which examined the association between tooth loss and the risk of dementia. Literature selection according to inclusion and exclusion criteria, as well as data extraction from included studies were completed independently by two reviewers. Data syntheses in this meta-analysis were performed using Stata 12.0 software. Results: A total of 8 cohort studies were included, containing a total of 14,362 samples and 2,072 dementia patients. The result of the meta-analysis indicated that patients with tooth loss faced a 1.34 times greater risk of developing dementia (RR = 1.34,95% CI = 1.19-1.51). The result from this dose-response meta-analysis in a linear model, suggested that every missed tooth might increase the risk of dementia by 1.01 times (RR = 1.01, 95%CI = 1.00-1.02). Further subgroup analyses pointed out that tooth loss patients without dentures may have a higher risk of dementia than those with dentures (with denture: RR = 0.98, 95% CI = 0.87-1.10; without denture: RR = 1.53, 95% CI = 1.19-1.97); at the same time, the study design, study area and education level of the study participants, might also have some effect on the results. Conclusions: Tooth loss may be a risk factor for the development of dementia. In addition, there is a dose-response relationship with the increase of missing teeth.
Previous studies have suggested an association between secondhand smoke (SHS) exposure and risk of depressive symptoms. However, it remains unclear whether there is a dose-response relationship. The effect estimates were pooled using fixed-effect or random-effect models based on homogeneity analysis. The dose-response meta-analysis was performed by linear and non-linear regression. Subgroup analyses were conducted to explore the possible sources of heterogeneity. Twenty-four studies were included in this meta-analysis. SHS exposure was significantly associated with increased odds of depressive symptoms (odds ratio (OR) = 1.32, 95% confidence interval (CI) 1.25-1.39). For SHS exposure expressed as an ordinal variable, the dose-response meta-analysis revealed a monotonically increasing relationship between SHS exposure and depressive symptoms. A similar dose-response relationship was observed for SHS exposure expressed as a continuous variable (OR = 1.57, 95% CI = 1.26-1.87). Our findings suggest that SHS exposure is associated with increasing odds of depressive symptoms in a dose-response manner.
Several epidemiological studies have found an association between shoulder-loaded work activities and specific shoulder diseases. No study has derived the dose-response relationship and resulting doubling dose, important for the recognition of occupational diseases. This systematic review is an update of the van der Molen et al. (2017) review. Based on its methodologies, we identified new studies published up to November 2018. The dose-response relationship between physical occupational demands (hands at/above shoulder level, repetitive movements, forceful work, hand-arm vibrations) and specific shoulder diseases (defined as ICD-10 M 75.1-5: rotator cuff syndrome, bicipital tendinitis, calcific tendinitis, impingement, and bursitis) was derived. No evidence for sex-specific differences in the dose-response relationship was found. If there were at least two studies with comparable exposures, a meta-analysis was carried out. The pooled analysis resulted in a 21% risk increase (95% CI 4-41%) per 1000 h of work with hands above shoulder level. A meta-analysis was not possible for other occupational burdens due to the low number of studies and differing exposure measurements; an estimate of the doubling dose was made based on the cohort study of Dalbøge et al. (2014). To conclude, the present systematic review with meta-analysis contributes to knowledge of the level of exposure at which specific shoulder diseases-particularly rotator cuff lesions-should be recognized as an occupational disease.
The gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) has recently been recognized to be one of the risk factors for cardiovascular disease (CVD). However, there is a scarcity of data on the relationship between circulating TMAO levels and hypertension in patients with CVD. Meta analysis and a dose-response relationship were used in this study to assess the relationship between circulating trimethylamine N-oxide levels and the risk of hypertension in patients with CVD.
The relationship between serum vitamin D and atrial fibrillation (AF) or postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass graft (CABG) is still debated. It is also unclear whether there is a dose-response relationship between circulating vitamin D and the risk of AF or POAF.
Objective: Diet lifestyle can influence the risk of endometriosis. Therefore, we conducted a systematic meta-analysis to investigate the association between dairy products and the risk of endometriosis. Besides, we performed a dose-response meta-analysis to evaluate the amount of dairy intake affecting the risk of endometriosis. Methods: Relevant studies were searched from Pubmed, Embase databases, Cochrane Library, and Web of Science from the inception to November 6th, 2020. Also, the dose-response meta-analysis was conducted. All the pooled results were performed by risk ratios (RRs). Results: Finally, seven high-quality studies were included in the present meta-analysis. Total dairy intake was inversely associated with the risk of endometriosis, and the risk of endometriosis tended to decrease with a decrease in the risk of endometriosis when dairy products intake was over 21 servings/week (RR 0.87, 95% CI 0.76-1.00; p non-linearity = 0.04). Similarly, people who consumed more than 18 servings of high-fat dairy products per week had a reduced risk of endometriosis (RR 0.86, 95% CI 0.76-0.96). When stratified-analyses were conducted based on specific dairy product categories, it indicated that people with high cheese intake might have a reduced risk of endometriosis (RR 0.86, 95% CI 0.74-1.00). Other specific dairy products such as whole milk (RR 0.90, 95% CI 0.72-1.12), reduced-fat/skim milk (RR 0.83, 95% CI 0.50-1.73), ice cream (RR 0.83, 95% CI 0.50-1.73), and yogurt (RR 0.83, 95% CI 0.62-1.11) have not shown significant evidence of an association with the risk of endometriosis. However, there is a higher risk of endometriosis in the females with high butter intake compared to females with low butter intake (1.27, 95% CI 1.03-1.55). Conclusions: Overall, dairy products intake was associated with a reduction in endometriosis, with significant effects when the average daily intake ≥3 servings. When analyzed according to the specific type of dairy product, it was shown that females with higher high-fat dairy and cheese intake might have a reduced risk of endometriosis. However, high butter intake might be associated to the increased risk of endometriosis. More future studies are needed to validate and add to this finding.
The optimal dose of tranexamic acid to inhibit hyperfibrinolysis in postpartum haemorrhage is unclear. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Cesarean Delivery (TRACES) was a double-blind, placebo-controlled, randomised, multicentre dose-ranging study to determine the dose-effect relationship for two regimens of intravenous tranexamic acid vs placebo.
Conflicting results identifying the relationship between benzodiazepine drug use and cancer risk. Therefore, we conducted a dose-response meta-analysis of prospective cohort studies to clarify and quantitative assessed the relationship between benzodiazepine drug use and cancer risk. Up to July 2017, 22 original publications were included in current meta-analysis. Our results showed statistically significant association between benzodiazepine drug use and cancer risk (RR:1.25; 95% CI, 1.15-1.36). Subgroup analysis showed benzodiazepine using was associated with significantly a higher risk of breast cancer (RR:1.15; 95% CI, 1.05-1.26), ovarian cancer (RR:1.17; 95% CI, 1.09-1.25), colon cancer (RR:1.07; 95% CI, 1.02-1.13), renal cancer (RR:1.31; 95% CI, 1.15-1.49), malignant melanoma (RR:1.10; 95% CI, 1.03-1.17), brain cancer (RR:2.06; 95% CI, 1.76-2.43), esophagus cancer (RR:1.55; 95% CI, 1.30-1.85), prostate cancer (RR:1.26; 95% CI, 1.16-1.37), liver cancer (RR:1.22; 95% CI, 1.13-1.31), stomach cancer (RR:1.17; 95% CI, 1.03-1.32), pancreatic cancer (RR:1.39; 95% CI, 1.17-1.64) and lung cancer (RR:1.20; 95% CI, 1.12-1.28). Furthermore, a significant dose-response relationship was observed between benzodiazepine drug use and cancer risk (likelihood ratio test, P < 0.001). Our results showed per 500 mg/year, per 5 year of time since first using, per 3 prescriptions and per 3 year of duration incremental increase in benzodiazepine drug use was associated with a 17%, 4%, 16% and 5% in cancer risk increment. Considering these promising results, increasing benzodiazepine using might be harmful for health.
1. Standard renal clearance techniques were used to assess the dose-response relationship between acute gentamicin infusion and the magnitude of hypercalciuria and hypermagnesiuria in the anaesthetized Sprague-Dawley rat. Also investigated were whether these effects occurred independently of renal tubular cell injury. 2. Acute gentamicin infusion was associated with a significant hypercalciuria and hypermagnesiuria evident within 30 min of drug infusion. The magnitude of these responses was related to the dose of drug infused (0.14-1.12 mg kg(-1) min[-1]). Increased urinary electrolyte losses resulted from a decreased tubular reabsorption of calcium and magnesium. 3. A rapid dose-related increase in urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion was also observed in response to gentamicin infusion. However, there was no evidence of renal tubular cell injury and no myeloid bodies were observed within the lysosomes of the proximal tubular cells. Gentamicin may thus interfere with the mechanisms for cellular uptake and intracellular processing of NAG causing increased NAG release into the tubular lumen. 4. The absence of changes in renal cellular morphology indicates that the excessive renal losses of calcium and magnesium were an effect of gentamicin per se and not the result of underlying renal tubular injury. The renal effects described in this paper were apparent after administration of relatively low total drug doses, and with plasma concentrations calculated to be within the clinical range. These findings suggest that disturbances of plasma electrolyte homeostasis could occur in the absence of overt renal injury in patients receiving aminoglycoside antibiotics.
Individuals with low socioeconomic status (SES) experience a higher risk of mortality, in general, and alcohol-attributable mortality in particular. However, a knowledge gap exists concerning the dose-response relationships between the level of socioeconomic deprivation and the alcohol-attributable mortality risk.
Presence of individual fatty acid ethyl esters (FAEEs) in meconium is considered to be a reliable biomarker of prenatal alcohol exposure, and their concentration has been found to be linearly associated with poor postnatal development, supporting the widely extended idea that ethanol is a non-threshold teratogen. However, a growing number of epidemiological studies have consistently found a lack of adverse short- and long-term fetal outcomes at low exposure levels. We therefore aimed to investigate the relationship between the concentration of individual FAEEs and prenatal alcohol exposure in meconium samples collected within the first 6 to 12?h after birth from 182 babies born to abstainer mothers and from 54 babies born to women who self-reported either light or moderate alcohol ingestion in the second or third trimester of pregnancy. In most cases, the individual FAEE concentrations were negligible and not significantly different (P >0.05) between exposed and control babies. The concentrations appeared to increase linearly with the dose only in the few babies born to mothers who reported >3 drinks/week. These results provide evidence that the correlation between prenatal alcohol exposure and individual FAEE concentrations in meconium is non-linear shape, with a threshold probably at 3 drinks/week.
Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC50). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC50-based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.
Background: Uric acid (UA) is proposed as a potential risk factor for stroke in adult, yet the results from published studies are not generally accordant. Method: We included prospective studies that explored the relationship between serum UA (SUA) and strokes. In this study, strokes include ischemic stroke and hemorrhagic stroke, which consists of intracerebral hemorrhage and subarachnoid hemorrhage. The effect-size estimates were expressed as hazard ratio (HR) and 95% confidence interval (CI). Sensitivity and subgroup analyses were performed to assess the robustness of the pooled estimation and potential sources of heterogeneity between studies. Results: We meta-analyzed 19 prospective cohort articles, which involve 37,386 males and 31,163 females. Overall analyses results showed a significant association between a 1 mg/dl increase in high levels of SUA and the risk of total stroke (HR = 1.13; 95% CI: 1.09-1.18; P < 0.001), ischemic stroke (HR = 1.15; 95% CI: 1.10-1.21; P < 0.001), and hemorrhagic stroke (HR = 1.07; 95% CI: 1.00 to 1.15; P = 0.046). No significant difference was found between ischemic stroke and hemorrhagic stroke. In the subgroup analyses, the association of high SUA levels and the risk of total stroke was statistically significant in females (HR = 1.19; 95% CI: 1.12-1.26; P < 0.001) and males (HR = 1.11; 95% CI: 1.05-1.17; P < 0.001). Coincidentally, the association was also statistically significant for ischemic stroke, both in females (HR = 1.26; 95% CI: 1.17-1.36; P < 0.001) and in males (HR = 1.12; 95% CI: 1.06-1.19; P < 0.001). However, for hemorrhagic stroke, it was only statistically significant in females (HR = 1.19; 95% CI: 1.04-1.35; P = 0.01). Our dose-response research indicated the J-shaped trend between the ascending SUA levels and the higher risk of suffering from a stroke. Conclusions: Our findings indicate that elevated SUA is a significant risk factor for adult stroke, both for ischemic stroke and hemorrhagic stroke, and especially in females.
In relapsed and refractory multiple myeloma (RRMM), there are few treatment options once patients progress from the established standard of care. Several bispecific T-cell engagers (TCE) are in clinical development for multiple myeloma (MM), designed to promote T-cell activation and tumor killing by binding a T-cell receptor and a myeloma target. In this study we employ both computational and experimental tools to investigate how a novel trispecific TCE improves activation, proliferation, and cytolytic activity of T-cells against MM cells. In addition to binding CD3 on T-cells and CD38 on tumor cells, the trispecific binds CD28, which serves as both co-stimulation for T-cell activation and an additional tumor target. We have established a robust rule-based quantitative systems pharmacology (QSP) model trained against T-cell activation, cytotoxicity, and cytokine data, and used it to gain insight into the complex dose response of this drug. We predict that CD3-CD28-CD38 killing capacity increases rapidly in low dose levels, and with higher doses, killing plateaus rather than following the bell-shaped curve typical of bispecific TCEs. We further predict that dose-response curves are driven by the ability of tumor cells to form synapses with activated T-cells. When competition between cells limits tumor engagement with active T-cells, response to therapy may be diminished. We finally suggest a metric related to drug efficacy in our analysis-"effective" receptor occupancy, or the proportion of receptors engaged in synapses. Overall, this study predicts that the CD28 arm on the trispecific antibody improves efficacy, and identifies metrics to inform potency of novel TCEs.
Knee osteoarthritis is a common, chronic condition and main contributor to global disability. Total knee arthroplasty (TKA) is the most successful treatment for end-stage knee osteoarthritis. It is assumed that in the field of surgery, there is a relationship between hospital volume and health outcomes and that higher hospital volume results in better health outcomes. As a consequence, minimum volume thresholds have been implemented in Germany for various procedures, including TKA (50 procedures per year). To date, it is unclear whether minimum volume thresholds truly result in better outcomes. The objective of this study will be to quantify the relationship between hospital volume and patient-relevant outcomes in patients undergoing TKA.
Gluten proteins are known as immunological triggers for inflammation resulting in mucosal lesions in patients with coeliac disease (CD). Adherence to a strict gluten-free diet (GFD) is currently known as the only effective treatment for CD. In this study, we performed a systematic review and dose-response meta-analysis on data from previous studies to investigate the association between different gluten doses administered and the risk of CD relapse. Electronic databases were systematically searched to retrieve studies that investigated the response of CD patients to different amounts of gluten intake and evaluated the clinical, serologic, and/or histologic evidence to recognize disease relapse. Study-specific relative risks (RRs) were combined using a random effects model. A total of 440 identified published papers were screened, of which 7 records were selected following full-text reviewing and eligibility assessment for dose-response meta-analysis. According to our analysis, the risk of CD relapse is estimated to be 0.2% (RR: 1.002; 95% CI: 1.001 to 1.004) following the consumption of 6 mg gluten/day, which was increased to 7% (RR: 1.07; 95% CI: 1.03 to 1.10), 50% (RR: 1.50; 95% CI: 1.23 to 1.82), 80% (RR: 1.80; 95% CI: 1.36 to 2.38), and 100% (RR: 2.00; 95% CI: 1.43 to 2.78) by the daily intake of 150, 881, 1276, and 1505 mg gluten, respectively. Although good adherence to a GFD can adequately control CD-related symptoms, disease relapse might happen even with a very low dose of gluten, and the duration of exposure to gluten is also an important matter. The current literature has substantial limitations, such as relying on the data from just a few countries that were different in terms of the amount of gluten administered, the duration of the challenge, etc. Therefore, more randomized clinical trials using a standardized gluten challenge protocol are needed to confirm the findings of the present study.
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