Nonlinear Dose-response Curve Research Articles

The correlation between heavy metal ions in blood and metabolic dysfunction-associated steatotic liver disease from 1999 to 2018 based on NHANES data.

Metabolic-associated steatohepatitis and liver fibrosis (MASLD) is a growing public health concern, with environmental factors potentially playing a role in its development. This study aimed to investigate the associations between serum cadmium and mercury levels and the risk of MASLD in a nationally representative sample from the United States. Data from the National Health and Nutrition Examination Survey from 1999 to 2018 were analyzed. Serum cadmium and mercury concentrations were measured, and MASLD was defined based on established criteria. Logistic regression models were used to assess the associations between serum metal levels and MASLD, with adjustments for potential confounders. Stratified analyses and restricted cubic spline curves were employed to examine subgroup differences and nonlinear relationships. The study revealed significant inverse associations between serum cadmium and mercury levels and the likelihood of MASLD. Individuals in the highest quartiles of cadmium and mercury had lower odds of MASLD compared to those in the lowest quartiles (Model 3: Cadmium Q4 vs. Q1, Mercury Q4 vs. Q1). Stratified analyses showed stronger inverse associations in older adults, males, and never smokers for cadmium, and in females and individuals without diabetes for mercury. Nonlinear dose-response curves indicated critical thresholds beyond which the risk dynamics changed. Higher serum levels of cadmium and mercury were associated with a lower risk of MASLD, with notable variations across subgroups. These findings challenge the conventional understanding of these heavy metals as universally harmful and highlight the need for further research to unravel the complex interplay between environmental exposures and MASLD pathophysiology.

Selenium in cancer management: exploring the therapeutic potential.

Selenium (Se) is important and plays significant roles in many biological processes or physiological activities. Prolonged selenium deficiency has been conclusively linked to an elevated risk of various diseases, including but not limited to cancer, cardiovascular disease, inflammatory bowel disease, Keshan disease, and acquired immunodeficiency syndrome. The intricate relationship between selenium status and health outcomes is believed to be characterized by a non-linear U-shaped dose-response curve. This review delves into the significance of maintaining optimal selenium levels and the detrimental effects that can arise from selenium deficiency. Of particular interest is the important role that selenium plays in both prevention and treatment of cancer. Finally, this review also explores the diverse classes of selenium entities, encompassing selenoproteins, selenium compounds and selenium nanoparticles, while examining the mechanisms and molecular targets of their anticancer efficacy.

Gallic Acid-Encapsulated PAMAM Dendrimers as an Antioxidant Delivery System for Controlled Release and Reduced Cytotoxicity against ARPE-19 Cells.

Poly(amidoamine) (PAMAM) dendrimers have gained significant attention in various research fields, particularly in medicinal compound delivery. Their versatility lies in their ability to conjugate with functional molecules on their surfaces and encapsulate small molecules, making them suitable for diverse applications. Gallic acid is a potent antioxidant compound that has garnered considerable interest in recent years. Our research aims to investigate if the gallic acid-encapsulated PAMAM dendrimer generations 4 (G4(OH)-Ga) and 5 (G5(OH)-Ga) could enhance radical scavenging, which could potentially slow down the progression of age-related macular degeneration (AMD). Encapsulation of gallic acid in PAMAM dendrimers is a feasible alternative to prevent its degradation and toxicity. In vitro investigation of antioxidant activity was carried out using the DPPH and ABTS radical scavenging assays, as well as the FRAP assay. The IC50 values for DPPH and ABTS assays were determined through nonlinear dose-response curves, correlating the inhibition percentage with the concentration (μg/mL) of the sample and the concentration (μM) of gallic acid within each sample. G4(OH)-Ga and G5(OH)-Ga possess significant antioxidant activities as determined by the DPPH, ABTS, and FRAP assays. Moreover, gallic acid-encapsulated PAMAM dendrimers inhibit H2O2-induced reactive oxygen species (ROS) production in the human retinal pigment epithelium ARPE-19 cells, thereby improving antioxidant characteristics and potentially retarding AMD progression caused by ROS. In an evaluation of cell viability of ARPE-19 cells using the MTT assay, G4(OH)-Ga was found to reduce cytotoxic effects on ARPE-19 cells.

Phytochemicals Analysis, In vitro Anti-plasmodium Activity of Delonix regia Bark and Carica papaya Leaf Extracts in Combination with Chloroquine

Background: The effectiveness of treating malaria may be jeopardized by artemisinin-resistant parasites. Pharmaceutical companies have been using plants for a very long time to generate the prototype molecules needed to treat Plasmodium infections. Objective: To evaluate anti-plasmodial potency of extracts of Delonix regia and Carica papaya when used in combinations with chloroquine. Methods: The plants were collected from Homa-Bay County in Kenya, dried under shade to a consistent weight, and then milled into a fine powder. Organic solvents were then used for extraction. After phytochemical screening of the extracts was conducted, In vitro tests were done on the extracts against Plasmodium falciparum, with a starting concentration of 100µg/mL. To prepare the test concentration ranges, the extracts were serially diluted 2-fold in growth medium. In a sealed gas chamber, the assay plates were incubated at 370C for 72 hours with 3% O2 and 4% CO2 with N2 as the balance. By comparing each well's absorbance to that of a well that contained the drug-free control, the number of parasites still present at each concentration of the test substance were ascertained. Plotting survival against concentration enabled the determination of the IC50 values by a non-linear dose response curve fitting. Results: In this investigation, the extracts from Delonix regia showed significant synergism (based on IC50 shifts) with CQ for both the ethyl acetate and methanol extracts with the exception of the highest combination dosage. Carica papaya extracts were much improved by the presence of CQ; however, this was not consistently reflected in the corresponding CQ IC50. Conclusion: The results of this study which revealed synergism between the study plants extracts and chloroquine, support the reasons why some traditional healers have started combining medicinal herbs with chloroquine to boost its potency.

Dose-response relationship in cognitive behavioral therapy for depression: A nonlinear metaregression analysis.

Evidence on the optimal "dose" of cognitive behavioral therapy (CBT) for treating major depressive disorder is sparse. This analysis aimed to evaluate the dose-response curve in CBT using a nonlinear approach, whereby "dose" was defined as number of treatment sessions. The dose-response curve of CBT was compared to other psychotherapies and pharmacological treatments for depression. A systematic review and metaregression analysis of randomized controlled trials (RCTs) examining the efficacy of CBT in adults with acute depression was conducted. Treatment arms examining other psychosocial or pharmacological interventions were also analyzed. Cubic spline metaregression techniques were used to model nonlinear dose-response curves. Seventy-two studies and 7,377 participants were included. Modeling the dose-response curve between change of depression symptom severity and the number of CBT sessions resulted in a nonlinear curve characterized by a strong improvement in symptom severity from baseline within the first eight sessions. Symptom reduction continues in the further course of the treatment, but at a slower pace. A similar pattern of symptom development was found for other therapies as well, although the prominence of early improvement and overall effect sizes vary across treatment arms. Results imply a general tendency for the strongest alleviation of depressive symptom severity in early stages of CBT treatment, thus, if aiming at symptom alleviation, speak for short CBT interventions. However, these findings have to be discussed in the light of the limited data regarding the sustainability of treatment effects in short-term therapies and effects beyond symptomatic changes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Impact on the Transcriptome of Proton Beam Irradiation Targeted at Healthy Cardiac Tissue of Mice.

Proton beam therapy is considered a step forward with respect to electromagnetic radiation, thanks to the reduction in the dose delivered. Among unwanted effects to healthy tissue, cardiovascular complications are a known long-term radiotherapy complication. The transcriptional response of cardiac tissue from xenografted BALB/c nude mice obtained at 3 and 10 days after proton irradiation covering both the tumor region and the underlying healthy tissue was analyzed as a function of dose and time. Three doses were used: 2 Gy, 6 Gy, and 9 Gy. The intermediate dose had caused the greatest impact at 3 days after irradiation: at 2 Gy, 219 genes were differently expressed, many of them represented by zinc finger proteins; at 6 Gy, there were 1109, with a predominance of genes involved in energy metabolism and responses to stimuli; and at 9 Gy, there were 105, mainly represented by zinc finger proteins and molecules involved in the regulation of cardiac function. After 10 days, no significant effects were detected, suggesting that cellular repair mechanisms had defused the potential alterations in gene expression. The nonlinear dose-response curve indicates a need to update the models built on photons to improve accuracy in health risk prediction. Our data also suggest a possible role for zinc finger protein genes as markers of proton therapy efficacy.

Maternal Iodine Status and Birth Outcomes: A Systematic Literature Review and Meta-Analysis.

Background & aims: Iodine is important for thyroid function during pregnancy to support fetal growth, but studies of maternal iodine status and birth outcomes are conflicting. We aimed to quantify the association between iodine status and birth outcomes, including potential threshold effects using nonlinear dose−response curves. Methods: We systematically searched Medline and Embase to 10 October 2022 for relevant cohort studies. We conducted random-effects meta-analyses of urinary iodine concentration (UIC), iodine:creatinine ratio (I:Cr), and iodide intake for associations with birth weight, birth weight centile, small for gestational age (SGA), preterm delivery, and other birth outcomes. Study quality was assessed using the Newcastle-Ottawa scale. Results: Meta-analyses were conducted on 23 cohorts with 42269 participants. Birth weight was similar between UIC ≥ 150 μg/L and <150 μg/L (difference = 30 g, 95% CI −22 to 83, p = 0.3, n = 13, I2 = 89%) with no evidence of linear trend (4 g per 50 μg/L, −3 to 10, p = 0.2, n = 12, I2 = 80%). I:Cr was similar, but with nonlinear trend suggesting I:Cr up to 200 μg/g associated with increasing birthweight (p = 0.02, n = 5). Birthweight was 2.0 centiles (0.3 to 3.7, p = 0.02, n = 4, I2 = 0%) higher with UIC ≥ 150 μg/g, but not for I:Cr. UIC ≥ 150 μg/L was associated with lower risk of SGA (RR = 0.85, 0.75 to 0.96, p = 0.01, n = 13, I2 = 0%), but not with I:Cr. Conclusions: The main risk of bias was adjustment for confounding, with variation in urine sample collection and exposure definition. There were modest-sized associations between some measures of iodine status, birth weight, birth weight centile, and SGA. In pregnancy, we recommend that future studies report standardised measures of birth weight that take account of gestational age, such as birth weight centile and SGA. Whilst associations were modest-sized, we recommend maintaining iodine sufficiency in the population, especially for women of childbearing age on restricted diets low in iodide.

Abstract 4159: Lower doses of self-amplifying mRNA drive superior neoantigen-specific CD8 T cell responses in cancer patients versus high doses

Abstract The immunogenicity and efficacy of RNA-based vaccine platforms has been abundantly shown through their application in prophylactic SARS-CoV2 vaccines. Contrasting to mRNA based vectors, self amplifying mRNA platforms may offer dose-sparing and superior induction of T cell responses, and may also trigger distinct innate immune pathways, which may exert adjuvanting or inhibiting effects on vaccine-induced immunity. Optimal dosing for a novel self-amplifying mRNA (SAM) in a heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and SAM boosts was evaluated in two first-in-human phase 1/2 clinical trials assessing personalized neoantigen vaccines in patients with metastatic cancer (NCT03639714, NCT03953235). SAM vaccine dose escalation was performed to assess safety, tolerability, and immunogenicity, including administration of up to 8 SAM doses at 30, 100, or 300µg following a fixed dose of ChAd (1012 vp) over the course of a year. SAM was safe and well tolerated at all 3 dose levels, with no evidence of increasing reactogenicity with sequential doses. However, while immune monitoring via IFNγ ELISpot revealed that the 30µg SAM dose boosted T cell responses induced by the ChAd prime, the 100µg and 300µg SAM doses resulted in maintenance of T cell levels, without a clear T cell boost, suggesting a non-linear and likely bell-shaped dose-response curve to SAM in humans. Follow-up studies in non-human primates (NHPs) using a model antigen revealed dose-dependent increases in serum IFNa levels following administration of increasing SAM doses. Similarly, while multiple inflammatory cytokines were transiently increased following both ChAd and SAM administration in patients, serum IFNa levels were only increased 24h post SAM administration and correlated positively with SAM dose. Increased IFNa levels post SAM dosing suggested activation of mRNA-sensing innate immune pathways that may reduce the amplification of, and/or antigen expression by, the SAM vector and thus blunt T cell boosting at higher SAM doses. In addition, analysis of T cell responses in patients and NHPs showed increased boosting of T cell responses with longer intervals. These data lead to a reduction of the SAM dose to 30µg and adjusting SAM dosing intervals to 8 weeks in the Phase 2 portion of these clinical studies. Multiple patients have been dosed with the adjusted vaccine regimen, and preliminary data suggest robust boosting of ChAd-induced neoantigen-specific T cell responses with the selected SAM dosing regimen and the 30µg dose. We anticipate that this translational approach of adjusting clinical vaccine regimens based on strong translational immune data will increase the potency of our heterologous neoantigen vaccine, and subsequently provide more durable clinical benefit to patients with cancer. Citation Format: Christine D. Palmer, Amy R. Rappaport, Meghan G. Hart, Lauren D. Kraemer, Sonia Kounlavouth, Martina Marrali, Jason R. Jaroslavsky, Charmaine N. Nganje, Annie Shen, Gregory R. Boucher, Melissa A. Kachura, Ciaran D. Scallan, Sue-Jean Hong, Leonid Gitlin, Alexander I. Spira, Chrisann Kyi, Daniel V. Catenacci, Raphael Rousseau, Andrew Ferguson, Karin Jooss. Lower doses of self-amplifying mRNA drive superior neoantigen-specific CD8 T cell responses in cancer patients versus high doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4159.

Abstract B025: Antifragile therapy

Abstract We present a novel paradigm of evolutionary cancer therapy based on the “antifragility” of the drug dose-response function. Antifragility is the word originally coined to describe the opposite of fragility. Systems or organisms can be described as antifragile if they derive a benefit from systemic variability, volatility, randomness, or disorder. In this work, we quantify the evolutionary and ecological benefit (or harm) derived from increasing dose volatility in treatment scheduling. Nonlinear sigmoidal dose-response curves are ubiquitous in medicine and have both convex and concave regions. Despite the ubiquity of dose response assays in biological sciences, these curves are typically used to measure differential response in first-order effects (mean value of drug dose delivered), while second-order effects (variance of drug dose) are generally ignored. Analysis of the convexity of dose response curves provides a direct prediction of response to continuous treatment (“even” schedules with zero volatility) in comparison to high-dose/low-dose treatment (“uneven” schedules with high volatility). For example, if the dose response function is antifragile (concave) near a dose of ‘x’, continuous administration of x may have a less efficacious response compared to a regimen that switches equally between 120% of x and 80% of x, even though both regimens use the same total drug. Mathematical analysis of dose response curves in vitro for a H3122 ALK-positive non-small cell lung cancer (NSCLC) cell line predicts that evolved-resistance cell lines can be more effectively treated using volatile treatment scheduling regimens, while treatment-naïve cell lines are most effectively treated by continuous treatment. However, selection pressure due to treatment selects for resistant phenotypes over time. We construct a mathematical model of gradual resistance, parameterized to data, and predict time-dependent antifragility in continuous (8 weeks), volatile (8 weeks) ALK inhibition in vivo. The key insight is that dose-response concavity (“anti-fragility”) increases in proportion to the amount of resistance in the tumor population. Antifragility provides a time-dependent metric which 1) predicts the emergence of resistance and 2) determines the optimal subsequent dosing strategy. Previous work indicates that resistance to ALK inhibitors occurs gradually, through the acquisition of multiple cooperating genetic and epigenetic adaptive changes. This observation led us to hypothesize that there is a critical point in the evolution of ALK-positive tumors where it is optimal to switch from continuous treatment to volatile dosing to optimally control the onset of gradual resistance. This hypothesis is also tested in vivo, comparing continuous and volatile treatment schedules of ALK inhibitors to a switching schedule of continuous-volatile (4 weeks each). We end by discussing the implications for adaptive therapy. Citation Format: Jeffrey West, Bina Desai, Maximilian Strobl, Luke Pierik, Richard Miles, Cole Armagost, Mark Robertson-Tessi, Andriy Marusyk, Alexander R. A. Anderson. Antifragile therapy [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B025.

Cumulative noise exposure and the risk of high-frequency hearing loss relationships

Objective: To explore the dose-response relationship between cumulative noise exposure and high-frequency hearing loss, and further to provide a basis for the control of occupational hazards of noise. Methods: A Meta-analysis of dose-response relationships was performed on the data of eligible literatures published in China from January 2000.1 to December 2019.12. Results: The initial combined Odds Ratio (OR) and its 95%CI in the Meta-analysis were 1.10 (1.08-1.12) . As the Begg's funnel plot and Egger's test indicated publication bias (t=5.97, P<0.01) , the Trim-and-Fill Method was used for OR value adjustment. The adjusted-OR was 1.09 (1.07-1.12) ; sensitivity analysis showed that the results of this Meta-analysis have high stability; subgroup analysis indicated that the ORs of the steady-state noise group and the non-steady-state noise group were 1.10 (1.08-1.12) and 1.14 (1.07-1.21) , the ORs of the old standard group and the new standard group were 1.10 (1.08-1.12) and 1.11 (1.00-1.24) , respectively. The nonlinear dose-response relationship curve demonstrated that the risk of high-frequency hearing loss increases rapidly after CNE reaches 95 dB (A) ·years. Conclusion: There is a definite dose-response relationship between CNE and high-frequency hearing loss, which can be used to predict the risk of high-frequency hearing loss in noisy workers.

Association Between Stress Hyperglycemia Ratio and In-hospital Outcomes in Elderly Patients With Acute Myocardial Infarction.

Backgrounds: Emerging evidence suggests that stress hyperglycemia ratio (SHR), an index of relative stress hyperglycemia, is of great prognostic value in acute myocardial infarction (AMI), but current evidence is limited in elderly patients. In this study, we aimed to assess whether SHR is associated with in-hospital outcomes in elderly patients with AMI.Methods: In this retrospective study, patients who were aged over 75 years and diagnosed with AMI were consecutively enrolled from 2015, January 1st to 2019, December 31th. Admission blood glucose and glycosylated hemoglobin (HbA1C) during the index hospitalization were used to calculate SHR. Restricted quadratic splines, receiver-operating curves, and logistic regression were performed to evaluate the association between SHR and in-hospital outcomes, including in-hospital all-cause death and in-hospital major adverse cardiac and cerebrovascular events (MACCEs) defined as a composite of all-cause death, cardiogenic shock, reinfarction, mechanical complications of MI, stroke, and major bleeding.Results: A total of 341 subjects were included in this study. Higher SHR levels were observed in patients who had MACCEs (n = 69) or death (n = 44) during hospitalization. Compared with a SHR value below 1.25, a high SHR was independently associated with in-hospital MACCEs (odds ratio [OR]: 2.945, 95% confidence interval [CI]: 1.626–5.334, P < 0.001) and all-cause death (OR: 2.871 95% CI: 1.428–5.772, P = 0.003) in univariate and multivariate logisitic analysis. This relationship increased with SHR levels based on a non-linear dose-response curve. In contrast, admission glucose was only associated with clinical outcomes in univariate analysis. In subgroup analysis, high SHR was significantly predictive of worse in-hospital clinical outcomes in non-diabetic patients (MACCEs: 2.716 [1.281–5.762], P = 0.009; all-cause death: 2.394 [1.040–5.507], P = 0.040), but the association was not significant in diabetic patients.Conclusion: SHR might serve as a simple and independent indicator of adverse in-hospital outcomes in elderly patients with AMI, especially in non-diabetic population.

Ethnic Differences in the Association Between Body Mass Index and Type 2 Diabetes Risk: A Meta-Analysis of Prospective Cohort Studies

ObjectivesThe association between body mass index (BMI) and total body adiposity differs across ethnic groups. For instance, South Asians (SA) and East Asians (EA) have lower body fat for a given BMI level than Europeans, while the opposite is true for African-Caribbeans (AC). This suggests that the relationship between BMI and type 2 diabetes (T2D) risk may also vary depending on ethnicity. We conducted a meta-analysis to investigate whether the association between BMI and the risk of T2D differs across ethnic groups. MethodsMEDLINE, EMBASE and Web of Science were searched up to July 2020. We included prospective cohort studies of >2 years, which investigated the association between BMI and T2D incidence among adults of a specified ethnicity. Linear and non-linear dose-response meta-analyses were performed using random effects models, with subgroup analyses by ethnicity. The heterogeneity among studies was estimated using the Cochran Q test and I2 statistic. Study quality was assessed with the Newcastle-Ottawa Scale. Results54 studies were included. Cohorts were stratified into the following ethnic subgroups: AC (N = 67,453), EA (N = 1,012,135), European (N = 206,424), Indigenous (N = 10,533), Latin American (LA) (N = 4,669), SA (N = 9,395), and Southeast Asian (SEA) (N = 51,129). Linear dose-response associations between 1 kg/m2 increase in BMI and T2D were observed for the SEA (RR = 1.26; 95% CI, 1.10, 1.30) and SA (RR = 1.11; 95% CI: 1.04, 1.19) subgroups with no evidence of departure from linearity. Associations departed from linearity for all other subgroups. At a BMI level of 30 kg/m2, the non-linear dose-response curves for each of the other subgroups displayed the following risk ratios; AC: RR = 3.13 (95% CI, 1.95, 5.02), EA: RR = 2.39 (95% CI, 1.96, 2.92), European: RR = 7.41 (95% CI, 3.88, 14.18), Indigenous: RR = 8.15 (95% CI, 6.07; 10.95), and LA: RR = 12.82 (95% CI, 5.50, 29.92). For all subgroups, there was a high degree of interstudy heterogeneity (I2 > 75%). ConclusionsOur findings indicated that the association between BMI and the risk of T2D differs across ethnic groups, suggesting that ethnic-specific BMI cut-offs could be helpful in identifying cardiometabolic risk profiles across different populations. Funding SourcesCanadian Institutes for Health Research.

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019

SummaryBackgroundEnding the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally.MethodsWe estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available.FindingsGlobally in 2019, 1·14 billion (95% uncertainty interval 1·13–1·16) individuals were current smokers, who consumed 7·41 trillion (7·11–7·74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27·5% [26·5–28·5] reduction) and females (37·7% [35·4–39·9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0·99 billion (0·98–1·00) in 1990. Globally in 2019, smoking tobacco use accounted for 7·69 million (7·16–8·20) deaths and 200 million (185–214) disability-adjusted life-years, and was the leading risk factor for death among males (20·2% [19·3–21·1] of male deaths). 6·68 million [86·9%] of 7·69 million deaths attributable to smoking tobacco use were among current smokers.InterpretationIn the absence of intervention, the annual toll of 7·69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a clear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens.FundingBloomberg Philanthropies and the Bill & Melinda Gates Foundation.

Self-rated health in relation to fruit and vegetable consumption and physical activity among older cancer survivors.

We aimed to investigate associations of self-rated health with fruit and vegetable consumption (FVC) and physical activity (PA) among older cancer survivors. We used the 2017 Behavioral Risk Factor Surveillance System to identify cancer survivors ≥ 65 years (N = 2663). Self-reported FVC and PA were categorized as ordinal variables to approximate quartiles. Low general health (LGH) was defined as fair or poor self-rated health. A multivariable logistic regression treating LGH as the outcome was used to calculate adjusted odd ratios (aORs) and 95% confidence intervals (CIs) for FVC and PA. Restricted cubic spline depicted non-linear dose-response curves for FVC and PA. In comparative analysis, we used the same logistic regression and dose-response model to calculate ORs of FVC and PA in 73,134 people ≥ 65 years without cancer history. Overall, 470 (17.7%) survivors had LGH. Survivors' mean age was 73.3 years (SD = 5.2), 55.1% of them were female, and 95.4% self-reported as white. In cancer survivors, FVC was not associated with LGH (≥ 28 vs. < 14 times/week: aOR = 1.02, 95% CI = 0.75-1.39, p-trend = 0.50), whereas PA was inversely associated with LGH (≥ 30 vs. < 7 MET-hours/week: aOR = 0.55, 95% CI = 0.41-0.75, p-trend < 0.01). Dose-response curves demonstrated consistent association patterns. In comparative analysis, ORs of PA did not change substantially but we observed inverse association for FVC. An inverse association between PA and LGH was observed among older cancer survivors, but no significant association was obtained for FVC among them. Regular PA may maintain or indicate a favorable health in older cancer survivors, whereas impacts of FVC deserve further investigations.

Body mass index and all-cause mortality in patients with percutaneous coronary intervention: A dose-response meta-analysis of obesity paradox.

The association between body mass index (BMI) and mortality of patients with percutaneous coronary intervention (PCI) is still controversial. We hope to explore whether the 'obesity paradox' really exists through this dose-response meta-analysis. PubMed, Embase and Cochrane databases were systematically searched for eligible studies up to April 2020. The random-effects restricted cubic spline models were used to evaluate the potential non-linear relationship between BMI and all-cause mortality of patients undergoing PCI. Fifteen studies were identified and included total 138 592 participants. The pooled hazard ratio of all-cause mortality was 0.60 (95% confidence interval: 0.45-0.82) when compared the highest category (mean = 33.32 kg m-2 ) of BMI with the lowest category (mean = 18.89 kg m-2 ). A non-linear U-shaped dose-response curve between BMI and the risk of all-cause mortality was found, with higher mortality rate at BMI lower than 27 kg m-2 and higher than 32 kg m-2 . The 'obesity paradox' does exist after PCI. The association between BMI and the risk of all-cause mortality for patients undergoing PCI is U shaped, with a nadir of risk at a BMI of 27 to 32 kg m-2 and the highest risk at patients with underweight. The relationship between other prognostic indicators and BMI is worthy of further research.

The effects of Canola oil on cardiovascular risk factors: A systematic review and meta-analysis with dose-response analysis of controlled clinical trials

Background and aimsCanola oil (CO) is a plant-based oil with the potential to improve several cardiometabolic risk factors. We systematically reviewed controlled clinical trials investigating the effects of CO on lipid profiles, apo-lipoproteins, glycemic indices, inflammation, and blood pressure compared to other edible oils in adults. Methods and resultsOnline databases were searched for articles up to January 2020. Forty-two articles met the inclusion criteria. CO significantly reduced total cholesterol (TC, −0.27 mmol/l, n = 37), low-density lipoprotein cholesterol (LDL-C, −0.23 mmol/l, n = 35), LDL-C to high-density lipoprotein cholesterol ratio (LDL/HDL, −0.21, n = 10), TC/HDL (−0.13, n = 15), apolipoprotein B (Apo B, −0.03 g/l, n = 14), and Apo B/Apo A-1 (−0.02, n = 6) compared to other edible oils (P < 0.05). Compared to olive oil, CO decreased TC (−0.23 mmol/l, n = 9), LDL-C (−0.17 mmol/l, n = 9), LDL/HDL (−0.39, n = 2), and triglycerides in VLDL (VLDL-TG, −0.10 mmol/l, n = 2) (P < 0.05). Compared to sunflower oil, CO improved LDL-C (−0.14 mmol/l, n = 11), and LDL/HDL (−0.30, n = 3) (P < 0.05). In comparison with saturated fats, CO improved TC (−0.59 mmol/l, n = 11), TG (−0.08 mmol/l, n = 11), LDL-C (−0.49 mmol/l, n = 10), TC/HDL (−0.29, n = 5), and Apo B (−0.09 g/l, n = 4) (P < 0.05). Based on the nonlinear dose–response curve, replacing CO with ~15% of total caloric intake provided the greatest benefits. ConclusionCO significantly improved different cardiometabolic risk factors compared to other edible oils. Further well-designed clinical trials are warranted to confirm the dose–response associations.

Bayesian Meta-analysis of Multiple Continuous Treatments with Individual Participant-Level Data: An Application to Antipsychotic Drugs.

Modeling dose-response relationships of drugs is essential to understanding their safety effects on patients under realistic circumstances. While intention-to-treat analyses of clinical trials provide the effect of assignment to a particular drug and dose, they do not capture observed exposure after factoring in nonadherence and dropout. We develop a Bayesian method to flexibly model the dose-response relationships of binary outcomes with continuous treatment, permitting multiple evidence sources, treatment effect heterogeneity, and nonlinear dose-response curves. In an application, we examine the risk of excessive weight gain for patients with schizophrenia treated with the second-generation antipsychotics paliperidone, risperidone, or olanzapine in 14 clinical trials. We define exposure as total cumulative dose (daily dose × duration) and convert to units equivalent to 100 mg of olanzapine (OLZ doses). Averaging over the sample population of 5891 subjects, the median dose ranged from 0 (placebo randomized participants) to 6.4 OLZ doses (paliperidone randomized participants). We found paliperidone to be least likely to cause excessive weight gain across a range of doses. Compared with 0 OLZ doses, at 5.0 OLZ doses, olanzapine subjects had a 15.6% (95% credible interval: 6.7, 27.1) excess risk of weight gain; corresponding estimates for paliperidone and risperidone were 3.2% (1.5, 5.2) and 14.9% (0.0, 38.7), respectively. Moreover, compared with nonblack participants, black participants had a 6.8% (1.0, 12.4) greater risk of excessive weight gain at 10.0 OLZ doses of paliperidone. Nevertheless, our findings suggest that paliperidone is safer in terms of weight gain risk than risperidone or olanzapine for all participants at low to moderate cumulative OLZ doses.

CT dosimetry at the Australian Synchrotron for 25-100 keV photons and 35-160 mm-diameter biological specimens.

The dose length product (DLP) method for medical computed tomography (CT) dosimetry is applied on the Australian Synchrotron Imaging and Medical Beamline (IMBL). Beam quality is assessed from copper transmission measurements using image receptors, finding near 100% (20 keV), 3.3% (25 keV) and 0.5% (30-40 keV) relative contributions from third-harmonic radiation. The flat-panel-array medical image receptor is found to have a non-linear dose response curve. The amount of radiation delivered during an axial CT scan is measured as the dose in air alone, and inside cylindrical PMMA phantoms with diameters 35-160 mm for mono-energetic radiation 25-100 keV. The radiation output rate for the IMBL is comparable with that used for medical CT. Results are presented as the ratios of CT dose indices (CTDI) inside phantoms to in air with no phantom. Ratios are compared for the IMBL against medical CT where bow-tie filters shape the beam profile to reduce the absorbed dose to surface organs. CTDI ratios scale measurements in air to estimate the volumetric CTDI representing the average dose per unit length, and the dose length product representing the absorbed dose to the scanned volume. Medical CT dose calculators use the DLP, beam quality, axial collimation and helical pitch to estimate organ doses and the effective dose. The effective dose per unit DLP for medical CT is presented as a function of body region, beam energy and sample sizes from neonate to adult.

One-stage dose-response meta-analysis for aggregated data.

The standard two-stage approach for estimating non-linear dose-response curves based on aggregated data typically excludes those studies with less than three exposure groups. We develop the one-stage method as a linear mixed model and present the main aspects of the methodology, including model specification, estimation, testing, prediction, goodness-of-fit, model comparison, and quantification of between-studies heterogeneity. Using both fictitious and real data from a published meta-analysis, we illustrated the main features of the proposed methodology and compared it to a traditional two-stage analysis. In a one-stage approach, the pooled curve and estimates of the between-studies heterogeneity are based on the whole set of studies without any exclusion. Thus, even complex curves (splines, spike at zero exposure) defined by several parameters can be estimated. We showed how the one-stage method may facilitate several applications, in particular quantification of heterogeneity over the exposure range, prediction of marginal and conditional curves, and comparison of alternative models. The one-stage method for meta-analysis of non-linear curves is implemented in the dosresmeta R package. It is particularly suited for dose-response meta-analyses of aggregated where the complexity of the research question is better addressed by including all the studies.

Prediction of hemoglobin levels in individual hemodialysis patients by means of a mathematical model of erythropoiesis.

Anemia commonly occurs in people with chronic kidney disease (CKD) and is associated with poor clinical outcomes. The management of patients with anemia in CKD is challenging, due to its severity, frequent hypo-responsiveness to treatment with erythropoiesis stimulating agents (ESA) and common hemoglobin cycling. Nonlinear dose-response curves and long delays in the effect of treatment on red blood cell population size complicate predictions of hemoglobin (Hgb) levels in individual patients. A comprehensive physiology based mathematical model for erythropoiesis was adapted individually to 60 hemodialysis patients treated with ESAs by identifying physiologically meaningful key model parameters from temporal Hgb data. Crit-Line® III monitors provided non-invasive Hgb measurements for every hemodialysis treatment. We used Hgb data during a 150-day baseline period together to estimate a patient’s individual red blood cell lifespan, effects of the ESA on proliferation of red cell progenitor cells, endogenous erythropoietin production and ESA half-life. Estimated patient specific parameters showed excellent alignment with previously conducted clinical studies in hemodialysis patients. Further, the model qualitatively and quantitatively reflected empirical hemoglobin dynamics in demographically, anthropometrically and clinically diverse patients and accurately predicted the Hgb response to ESA therapy in individual patients for up to 21 weeks. The findings suggest that estimated model parameters can be used as a proxy for parameters that are clinically very difficult to quantify. The presented method has the potential to provide new insights into the individual pathophysiology of renal anemia and its association with clinical outcomes and can potentially be used to guide personalized anemia treatment.