Search

Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients. [ABSTRACT FROM AUTHOR]

The International Nuclear Workers Study (INWORKS) contributes knowledge on the dose-response association between predominantly low dose, low dose rate occupational exposures to penetrating forms of ionizing radiation and cause-specific mortality. By extending follow-up of 309,932 radiation workers from France (1968–2014), the United Kingdom (1955–2012), and the United States (1944–2016) we increased support for analyses of temporal variation in radiation-cancer mortality associations. Here, we examine whether age at exposure, time since exposure, or attained age separately modify associations between radiation and mortality from all solid cancers, solid cancers excluding lung cancer, lung cancer, and lymphohematopoietic cancers. Multivariable Poisson regression was used to fit general relative rate models that describe modification of the linear excess relative rate per unit organ absorbed dose. Given indication of greater risk per unit dose for solid cancer mortality among workers hired in more recent calendar years, sensitivity analyses considering the impact of year of hire on results were performed. Findings were reasonably compatible with those from previous pooled and country-specific analyses within INWORKS showing temporal patterns of effect measure modification that varied among cancers, with evidence of persistent radiation-associated excess cancer risk decades after exposure, although statistically significant temporal modification of the radiation effect was not observed. Analyses stratified by hire period (< 1958, 1958+) showed temporal patterns that varied; however, these analyses did not suggest that this was due to differences in distribution of these effect measure modifiers by hire year. [ABSTRACT FROM AUTHOR]

Athletes in contact and collision sports can sustain frequent subconcussive head impacts. Although most impacts exhibit low kinematics around or below 10 g of head linear acceleration, there is growing concern regarding the cumulative effects of repetitive sports head impacts. Even mild impacts can lead to brain deformations as shown through neuroimaging and finite element modeling, and thus may result in mild and transient effects on the brain, prompting further investigations of the biomechanical dose—brain response relationship. Here we report findings from a novel laboratory study with continuous monitoring of brain activity through electroencephalography (EEG) during controlled soccer head impacts. Eight healthy participants performed simulated soccer headers at 2 mild levels (6 g, 4 rad/s and 10 g, 8 rad/s) and three directions (frontal, oblique left, oblique right). Participants were instrumented with an inertial measurement unit (IMU) bite bar and EEG electrodes for synchronized head kinematics and brain activity measurements throughout the experiment. After an impact, EEG exhibited statistically significant elevation of relative and absolute delta power that recovered within two seconds from the impact moment. These changes were statistically significantly higher for 10 g impacts compared with 6 g impacts in some topographical regions, and oblique impacts resulted in contralateral delta power increases. Post-session resting state measurements did not indicate any cumulative effects. Our findings suggest that even mild soccer head impacts could lead to immediate, transient neurophysiological changes. This study paves the way for further dose-response studies to investigate the cumulative effects of mild sports head impacts, with implications for long-term athlete brain health. [ABSTRACT FROM AUTHOR]

The impact of vitamin B2 (riboflavin) intake on cognitive performance among older adults in the United States (US) remains inadequately understood. This study aimed to explore the association between vitamin B2 intake and cognitive performance among non-institutionalized elderly people in the US. Weighted logistic regression was used to evaluate the association between vitamin B2 intake and cognitive performance. Vitamin B2 intake was determined from the mean of two 24-hour dietary recall interviews. Three cognitive ability assessment tests, namely the Immediate Recall Test (IRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST), were performed. Participants included all older adults over 60 who underwent cognitive scoring, with cut-offs defined based on the lowest quartile (25th percentile) for each test (the cut-offs for the three scores were 15.625, 12, and 33, respectively). Sensitivity analysis, including dose-response curves, subgroup analyses, interaction effects, per 1 standard deviation (SD), recommended dietary allowance (RDA), and residual energy model analysis, were performed to solidify the solid association between vitamin B2 and cognitive performance. A total of 2893 individuals aged over 60 were included, with a mean age of 69 (7) years, and 46% were men. There was a significant association between vitamin B2 intake and all three cognitive scores (IRT, Odds Ratio = 0.77, 95% confidence interval: [0.65,0.92]; AFT, 0.75, [0.64,0.88]; DSST, 0.72, [0.59,0.88]). Moreover, vitamin B2 intake above the RDA reduced the risk of low cognitive performance (IRT, 0.66, [0.46,0.93]; AFT, 0.83, [0.62,1.11]; DSST, 0.65, [0.45,0.92]) compared to intake below the RDA. Dose-response curves indicated that higher vitamin B2 intake was negatively associated with the risk of low cognitive performance. Physical activity may modify the association between vitamin B2 and cognitive performance. Vitamin B2 intake was positively associated with cognitive performance among older adults. Adequate vitamin B2 intake could help protect cognitive function. [ABSTRACT FROM AUTHOR]

This study is the first to report 50% and 95% effect-site concentrations (EC50 and EC95, respectively) of the new short-acting benzodiazepine, remimazolam, for the successful insertion of i-gels with co-administration of fentanyl. Thirty patients (38 ± 5 years old, male/female = 4/26) were randomly assigned into five groups to receive one of five different remimazolam doses (0.1, 0.15, 0.2, 0.25, and 0.3 mg/kg bolus followed by infusion of 1, 1.5, 2, 2.5, and 3 mg/kg/h, respectively, for 10 min), which were designed to maintain a constant effect-site concentration of remimazolam at the time of i-gel insertion. At 6 min after the start of remimazolam infusion, all patients received 2 µg/kg fentanyl. i-gel insertion was attempted at 10 min and the success or failure of insertion were assessed by the patient response. Probit analysis was used to estimate the EC50 and EC95 values of remimazolam with 95% confidence intervals (CIs). In the five remimazolam dose groups, two, two, four, five, and six of the six patients in each group had an i-gel successfully inserted. Two patients in the lowest remimazolam dose group were conscious at the time of i-gel insertion and were counted as failures. The EC50 and EC95 values of remimazolam were 0.88 (95% CI, 0.65–1.11) and 1.57 (95% CI, 1.09–2.05) µg/ml, respectively. An effect-site concentration of ≥ 1.57 µg/ml was needed to insert an i-gel using remimazolam anesthesia, even with 2 µg/kg fentanyl. Trial registration: The study was registered in Japan Registry of Clinical Trials on 19 April 2021, Code jRCTs041210009. [ABSTRACT FROM AUTHOR]

How viral infections develop can change based on the number of viruses initially entering the body. The understanding of the impacts of infection doses remains incomplete, in part due to challenging constraints, and a lack of research. Gaining more insights is crucial regarding the measles virus (MV). The higher the MV infection dose, the earlier the peak of acute viremia, but the magnitude of the peak viremia remains almost constant. Measles is highly contagious, causes immunosuppression such as lymphopenia, and contributes substantially to childhood morbidity and mortality. This work investigated mechanisms underlying the observed wild-type measles infection dose responses in cynomolgus monkeys. We fitted longitudinal data on viremia using maximum likelihood estimation, and used the Akaike Information Criterion (AIC) to evaluate relevant biological hypotheses and their respective model parameterizations. The lowest AIC indicates a linear relationship between the infection dose, the initial viral load, and the initial number of activated MV-specific T cells. Early peak viremia is associated with high initial number of activated MV-specific T cells. Thus, when MV infection dose increases, the initial viremia and associated immune cell stimulation increase, and reduce the time it takes for T cell killing to be sufficient, thereby allowing dose-independent peaks for viremia, MV-specific T cells, and lymphocyte depletion. Together, these results suggest that the development of measles depends on virus-host interactions at the start and the efficiency of viral control by cellular immunity. These relationships are additional motivations for prevention, vaccination, and early treatment for measles. Measles infection dose responses: insights from mathematical modeling. Top: Model-data fits for acute viremia in response to changes in measles infection doses. 10 4 , 10 3 , 10 2 , 10 and 1 TCID 50 correspond to red diamonds, blue stars, orange triangles, magenta dots, and green squares respectively. The solid lines represent the trajectories generated by the proposed model parameterization. The shapes represent data. The dark grey dotted dashed line represents the limit of detection < 0.3. Bottom: Cartoon illustrating that when the measles infection dose increases, the stimulation of the measles-specific cellular immune responses increases early on post-infection. This enhanced immune response reduces the time required to clear the infectious viral load and helps maintain similar levels of viral loads and lymphocyte depletion irrespective of the initial dose. [ABSTRACT FROM AUTHOR]

Microplastics are emerging contaminants that have been detected recently in most environmental and biological systems, yet their health risk for humans has not been clearly summarized. Here we review human health risk associated with exposure to microplastics with focus on methods of exposure assessment, hazard identification, dose–response assessment, exposure assessment, and risk characterization. Hazards include direct hazards, hazards from contaminants released by microplastics, and hazards from microplastic interactions with surrounding contaminants. Microplastics trigger oxidative stress, disrupt metabolism, interfere with gut microflora and gastrointestinal functions, disrupt hepatic, cardiopulmonary and immune systems, and degrade reproductive health. Some additives leached from microplastics such as phthalates are endocrine disruptors and thus impact reproductive health. The interaction of microplastics with other pollutants in the environment induces varied hazards following synergistic or antagonistic effects. [ABSTRACT FROM AUTHOR]

A recently acquired letter between Hermann Muller and his wife (March 21, 1933) reveals that Muller had learned that he had been nominated for the Nobel Prize in 1932 with about 1/3 of the total votes being supportive. Muller was hopeful that over time sufficient votes would lead to receiving the award. The knowledge of Muller on this matter and its timing provide a likely explanation why Muller never cited the negative mouse mutation findings of George Snell, performed under Muller's direction during that time period. This action of Muller, along with the failure of Snell to promote his discovery, greatly reduced the chances that those findings would complicate his attempt to garner support for his LNT single-hit model and its application to hereditary and cancer risk assessment. It also helped Muller achieve the Nobel Prize, allowing him the necessary international visibility to promote his ideologically driven ionizing radiation-related LNT-based paradigm. [ABSTRACT FROM AUTHOR]

The present study aimed to establish whether habitual alcohol consumption benefits verbal and spatial working memory performance after addressing the main criticisms that have been raised against the finding that alcohol benefits cognition. An adult lifespan sample of 1,652 healthy adults between 21 and 80 years of age participated in the study. Participants were classified as lifetime nondrinkers or drinkers, and several demographic and biological variables were controlled. Alcohol consumption was assessed through a lifestyle questionnaire created for the study. Working memory was measured through a 2-back computerized task. Discrimination and speed in verbal and spatial working memory among drinkers were superior to those among nondrinkers. Total alcohol intake across life and the amount of alcohol intake per week predicted higher verbal and spatial working memory discrimination. Beer drinkers showed more accurate and faster responses in verbal and spatial working memory than nondrinkers, wine drinkers and spirit drinkers. The optimal amount of alcohol intake to benefit working memory for women and men was 100 g per week, which is equivalent to one drink per day. After consuming 350 g of alcohol per week, equivalent to 25 drinks per week, the effects of alcohol on working memory become more negative than the effects of alcohol abstinence. While alcohol consumption is considered a risk factor for several diseases, we found that moderate alcohol intake benefits working memory performance throughout the adult lifespan to a greater extent than whole-life abstinence. [ABSTRACT FROM AUTHOR]

Use of nonlinear statistical methods and models are ubiquitous in scientific research. However, these methods may not be fully understood, and as demonstrated here, commonly-reported parameter p-values and confidence intervals may be inaccurate. The gentle introduction to nonlinear regression modelling and comprehensive illustrations given here provides applied researchers with the needed overview and tools to appreciate the nuances and breadth of these important methods. Since these methods build upon topics covered in first and second courses in applied statistics and predictive modelling, the target audience includes practitioners and students alike. To guide practitioners, we summarize, illustrate, develop, and extend nonlinear modelling methods, and underscore caveats of Wald statistics using basic illustrations and give key reasons for preferring likelihood methods. Parameter profiling in multiparameter models and exact or near-exact versus approximate likelihood methods are discussed and curvature measures are connected with the failure of the Wald approximations regularly used in statistical software. The discussion in the main paper has been kept at an introductory level and it can be covered on a first reading; additional details given in the Appendices can be worked through upon further study. The associated online Supplementary Information also provides the data and R computer code which can be easily adapted to aid researchers to fit nonlinear models to their data. [ABSTRACT FROM AUTHOR]

The application of nanomaterials in various fields has both benefits and risks. While the unique physico-chemical properties of nanomaterials are valuable for diverse applications, they may also alter how nanomaterials are taken up in the body, thus affecting their potential toxicity to humans. To ensure their safety, the potential risk of nanomaterials needs to be assessed. The risk of a given nanomaterial is typically evaluated through in vitro and in vivo studies. The H2020 NanoInformaTIX project, that is conducted under the European Union's Horizon 2020 research and innovation programme is focusing on the study of nanomaterials. One of its objectives includes the identification of nanomaterial toxicity, of which the first step consists of the detection of a nanomaterial dose-response relationship. In this paper, we focus on this step, which can be done for a given nanomaterial toxicity endpoint of interest, using statistical tests for a monotone dose-response trend, i.e., monotone relationship between the increasing concentration of the nanomaterial and the toxicity endpoint. The significance of the monotone trend is tested using a likelihood ratio test and t-tests. An R package and a Shiny App were developed to perform the analysis. As an illustration, data extracted from the H2020 NanoInformaTIX platform is presented as a case study. This data consists of genetic toxicity studies with DNA strand breaks as the toxicity endpoint of interest. Significant trends were found for 12 out of 26 nanomaterials after adjusting for multiplicity by applying the False discovery rate (FDR) method. [ABSTRACT FROM AUTHOR]

Silica fibre thermoluminescence (TL) dosimeters have demonstrated versatility in medical and industrial, offering high spatial resolution, sensitivity, water resistance, and insensitivity to electromagnetic fields. A systematic review focusing on the medical applications of silica fibre TLDs is conducted, highlighting the potential of these materials in medical radiation dosimetry. Despite some limitations, such as non-linearity at low energies and relatively high signal fading, silica fibre TL dosimeters have shown excellent TL performance. However, their application in clinical practice is yet to be established since the TL responses for a wide range of doses and energies are not accurately certified yet. [ABSTRACT FROM AUTHOR]

Biosafety laboratories are specialized in handling dangerous microorganisms, but there are cases where contaminants are leaked due to improper handling and other reasons. Therefore, an in-depth understanding of the pattern of infection after a laboratory spill can help laboratory personnel get out of danger as soon as possible and avoid the occurrence of infection events. In this paper, we take the COVID-19 virus outbreak in recent years as an example to explore the probability of infection of laboratory personnel under different circumstances. The study used computational fluid dynamics (CFD) to predict the change of contaminant concentration over time in a typical laboratory, and then analyzed the relationship between contaminant concentration and infection probability by using a metrological response model, and calculated the infection probability of indoor personnel over time in the presence or absence of obstacles in the laboratory and the different locations of contaminant leakage, respectively. The results showed that the probability of personnel infection remained basically stable after 8 min of contaminant leakage; at the same time, the probability of infection was higher when the contaminant source was located below the exhaust vent than in other locations; and the probability of illness was lower in laboratories with obstacles than in laboratories without obstacles under the same conditions. This finding is helpful for laboratory layout design. [ABSTRACT FROM AUTHOR]

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose–response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5–13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose–response curves were examined. Mixed model analysis showed positive linear dose–response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73–88%) children, but not all, showed positive linear dose–response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose–response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose–response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121). [ABSTRACT FROM AUTHOR]

Background: Alcohol consumption is the most important risk factor responsible for the disease burden of liver cirrhosis (LC). Estimates of risk relationships available usually neither distinguish between different causes such as alcohol-related LC or hepatitis-related LC, nor differentiate between morbidity and mortality as outcome. We aimed to address this research gap and identify dose–response relationships between alcohol consumption and LC, by cause and outcome. Methods: A systematic review using PubMed/Medline and Embase was conducted, identifying studies that reported an association between level of alcohol use and LC. Meta-regression models were used to estimate the dose–response relationships and control for heterogeneity. Results: Totally, 44 studies, and 1 secondary data source, with a total of 5,122,534 participants and 15,150 cases were included. Non-linear dose–response relationships were identified, attenuated for higher levels of consumption. For morbidity, drinking 25 g/day was associated with a RR of 1.81 (95% CI 1.68–1.94) compared to lifetime abstention; 50 g/day and 100 g/day corresponded to 3.54 (95% CI 3.29–3.81) and 8.15 (95% CI 7.46–8.91), respectively. For mortality, for 25 g/day, a RR of 2.65 (95% CI 2.22–3.16); for 50 g/day, a RR of 6.83 (95% CI 5.84–7.97); for 100 g/day, a RR of 16.38 (95% CI 13.81–19.42) were identified. A higher risk for alcohol-related and all-cause LC as compared to hepatitis C-related LC was found. Conclusion: Our results demonstrated higher acceleration for mortality compared to morbidity. The current findings will inform the way we quantify the burden due to LC attributable to alcohol use. [ABSTRACT FROM AUTHOR]

This study aimed to determine salinity tolerances in Coxiella gastropods from Australian salt lakes and whether different species exhibit characteristically different tolerances. Controlled gradual accumulation experiments were conducted to estimate both the maximum and minimum salinity levels at which 50% of individuals (IC50) remained active for 25 populations representing six species. All studied species showed remarkable euryhalinity and were tolerant of very high levels of salinity, some more than others, while minimum salinity tolerance varied little among populations and species. The experimental trends in salinity tolerances were consistent with the salinity distributions of species in the field, although the former were typically broader than latter. The findings suggest that Coxiella comprises some of the most salt tolerant gastropods globally. [ABSTRACT FROM AUTHOR]

Purpose: Fluid use could modulate the effect of balanced solutions (BS) on outcome of intensive care unit (ICU) patients. It is uncertain whether fluid use practices are driven more by patient features or local practices. It is also unclear whether a "dose–response" for the potential benefits of balanced solutions exists. Methods: The secondary analysis of the Balanced Solution in Intensive Care Study (BaSICS) compared 0.9% saline versus Plasma-Lyte 148® (BS) for fluid therapy in the ICU. The relative contribution of patient features and enrolling site (the random effect) on the volume of fluid used up to day 3 after admission was assessed using different methods, including a Bayesian regression, a frequentist mixed model, and a random forest, all adjusted for relevant patient confounders. Subsequently, a variety of methods were used to assess whether volume of fluid used modulated the effect of BS on 90-day mortality, including a traditional subgroup analysis for patients that remained alive and in the ICU up to 3 days, a Bayesian network accounting for competing risks, and an analysis based on site practices. Results: 10,505 patients were analyzed. Median fluid use in the BS arm and in the 0.9% saline arm were 2500 mL and 2488 mL, respectively. The random effect in the Bayesian regression explained 0.32 (95% credible intervals (CrI) 0.24–0.41) of all model variance (0.33, 95% credible intervals from 0.32–0.35). Frequentist and random forest models produced similar results. In the analysis including only patients alive and in the ICU at 3 days, there was a strong suggestion of interaction between fluid use and the effect of BS, driven mostly by a lower mortality with BS compared to 0.9% saline as fluid use increased for patients with sepsis. These results were consistent in the Bayesian network analysis and in an analysis based on site practices, where septic patients enrolled to BS at high fluid use sites had a lower mortality (absolute risk reduction of − 0.13 [95% credible interval − 0.27 to − 0.01]; 0.98 probability of benefit). Conclusion: Baseline patient characteristics collected in the BaSICS trial explain less of the variance of fluid use during the first 3 days than the enrolling site. Volume of fluid used and the effects of BS appear to interact, mostly in the sepsis subgroup where there was a strong association between fluid use after enrollment and the effect of BS on 90-day mortality. [ABSTRACT FROM AUTHOR]

Observational research can be strengthened by examining potential dose–response relationships that correlate a clinical intervention with a patient outcome. Despite being a classic criterion for establishing causality, dose–response testing can be difficult to interpret in clinical medicine due to multiple diverse pitfalls. This review introduces a cautionary framework for investigators considering dose–response relationships in observational research to support evidence-based medicine. Each pitfall is illustrated with a specific example relevant when analyzing a dose–response relationship. Several pitfalls stem from faulty interpretation including confounding by indication and fallible range selection. Additional pitfalls relate to improper analysis including fitting a nonlinear model and misclassification error. Further pitfalls arise in special situations including subjective self-report and artifacts from survival bias. These caveats are common sources of misunderstanding in analyses that examine the link between varying exposures and the intensity of clinical outcomes. Awareness of specific pitfalls, we suggest, might help advance the conduct, application, and translation of dose–response relationships in observational research to inform evidence-based medical care. [ABSTRACT FROM AUTHOR]

This study evaluates the impact of a sector-specific industrial policy program on the performance of Ethiopian chemical manufacturing firms using a quasi-experimental design. The data for the study come from firm-level field surveys and administrative sources. To account for heterogeneity and selection bias due to observable and unobservable factors, we employ a range of empirical strategies, including quantile regression, propensity score matching (PSM), endogenous switching regression (ESR), and generalized propensity score (GPS) models. We also used alternative estimation methods that fit our data and sample size. Our findings show that the program has a positive and significant effect on productive capacity utilization of beneficiary firms, while there is no evidence of any impact on employment generation. The results show that the program's beneficiary firms utilized an actual productive capacity of 4.5–7.6% more than non-beneficiaries. We conclude that the program has mixed effects on the performance of the domestic chemical manufacturing firms. This study contributes to the scant literature that provides empirical evidence that informs public policy decisions in the context of developing countries. [ABSTRACT FROM AUTHOR]

Purpose of Review: Although there is extensive research on how much aerobic exercise to prescribe in order to reduce the risks of cardiovascular disease (CVD) and premature mortality, there is limited research on how much resistance exercise to prescribe. This review is to help fill important gaps in knowledge on effective minimum dose, beneficial optimum dose, and safe maximum dose of resistance exercise for CVD prevention and longevity. Recent Findings: In contrast to aerobic exercise where "some is good, more is better," recent observational studies suggested a J-shaped relation where more time in resistance exercise was associated with lower CVD risk and mortality only up to 40–60 min/week, beyond which risk reductions attenuated or even disappeared. While it remains unclear, postulated mechanisms that may underlie the higher CVD risk and mortality with higher resistance exercise doses include increased arterial stiffness and chronic inflammation. Summary: Current observational data suggest that "more may not be better" for dose-response relations of resistance exercise with CVD and mortality; however, this requires confirmation, especially from randomized controlled trials that directly test and compare multiple doses of resistance exercise. Until these data exist, it is prudent to recommend small doses of resistance exercise for cardiovascular health and longevity. [ABSTRACT FROM AUTHOR]

The analysis of dose–response, concentration–response, and time–response relationships is a central component of toxicological research. A major decision with respect to the statistical analysis is whether to consider only the actually measured concentrations or to assume an underlying (parametric) model that allows extrapolation. Recent research suggests the application of modelling approaches for various types of toxicological assays. However, there is a discrepancy between the state of the art in statistical methodological research and published analyses in the toxicological literature. The extent of this gap is quantified in this work using an extensive literature review that considered all dose–response analyses published in three major toxicological journals in 2021. The aspects of the review include biological considerations (type of assay and of exposure), statistical design considerations (number of measured conditions, design, and sample sizes), and statistical analysis considerations (display, analysis goal, statistical testing or modelling method, and alert concentration). Based on the results of this review and the critical assessment of three selected issues in the context of statistical research, concrete guidance for planning, execution, and analysis of dose–response studies from a statistical viewpoint is proposed. [ABSTRACT FROM AUTHOR]

The results of environmental epidemiological studies regarding the relationship between human exposure to nickel and the risk of diabetes remain controversial. Therefore, we performed a meta-analysis to investigate the relationship between nickel exposure and diabetes. PubMed, Web of Science, and Embase electronic databases were thoroughly searched from their inception to May 2023 to obtain relevant studies. The random-effects model was employed to determine pooled odds ratios (ORs) and 95% confidence intervals (CIs). Stratified and sensitivity analyses were also performed. Cochran Q test and I2 statistic were employed to assess heterogeneity between studies. Begg's and Egger's tests were employed to evaluate publication bias. The indicated studies were evaluated using the ROBINS-E risk of bias tool. The dose–response relationship between nickel in urine and diabetes risk was estimated by restricted cubic spline. A total of 12 studies with 30,018 participants were included in this study. In this meta-analysis, comparing the highest vs. lowest levels of nickel exposure, the pooled ORs for diabetes were 1.42 (95% confidence interval 1.14–1.78) for urine and 1.03 (0.57–1.86) for blood, respectively. A linear relationship between urinary nickel and diabetes risk was discovered in the dose–response analysis (P nonlinearity = 0.6198). Each 1 µg/L increase of urinary nickel, the risk of diabetes increased by 7% (OR = 1.07, 95% CI 1.04–1.10). The risk of diabetes was positively correlated with urine nickel exposure, whereas the risk was not significantly correlated with blood nickel. In the future, more high-quality prospective studies are needed to validate this conclusion. [ABSTRACT FROM AUTHOR]

Background: Current regulatory discussions about microplastics are often questioned based on a lack of data indicating high ecotoxic hazards of these particles within standard and recognized definitions. Moreover, there is scientific debate on what metrics to report the micro-nanoplastics toxicity (i.e. mass or particle counts-based exposure). We present here the high potential sensitivity of three genotypically different clones of the European Daphnia longispina species complex exposed to non-functionalized polystyrene nanobeads of 50 nm and 100 nm in diameter according to adapted OECD 202 test protocol. Results: EC50s 48 h varied from 0.2 to 8.9 mg L−1 (mean 2.49 mg L−1) for 50 nm beads, and from 32.7 to 90.3 mg L−1 (mean 59.39 mg L−1) for the 100 nm. EC10s 48 h varied from 0.0007 to 7.5 mg L−1 (mean 0.28 mg L−1) for 50 nm beads, and from 25.5 to 69.1 mg L−1 (mean 47.51 mg L−1) for the 100 nm. Inter-clonal variability was about tenfold. Therefore, several 1000 s-fold variations in mass-based ecotoxicity for these polystyrene beads was observed if particle size and Daphnia genotype are considered jointly. Conclusions: Such ecotoxicity potential is comparable to highly toxic chemicals in global and EU-based regulatory classification and labelling. Ecotoxicity based on particle counts suggested convergence of EC50s, with effects generally observed around 1011 to1015 particles L−1. The present results highlight the potential high hazard of these particles and the relevance of particle size and exposure metrics on hazard conclusion. [ABSTRACT FROM AUTHOR]

FMRFamide-gated Na + channel (FaNaC) is a member of the DEG/ENaC family and activated by a neuropeptide, FMRFamide. Structural information about the FMRFamide-dependent gating is, however, still elusive. Because two phenylalanines of FMRFamide are essential for the activation of FaNaC, we hypothesized that aromatic-aromatic interaction between FaNaC and FMRFamide is critical for FMRFamide recognition and/or the activation gating. Here, we focused on eight conserved aromatic residues in the finger domain of FaNaCs and tested our hypothesis by mutagenic analysis and in silico docking simulations. The mutation of conserved aromatic residues in the finger domain reduced the FMRFamide potency, suggesting that the conserved aromatic residues are involved in the FMRFamide-dependent activation. The kinetics of the FMRFamide-gated currents were also modified substantially in some mutants. Some results of docking simulations were consistent with a hypothesis that the aromatic-aromatic interaction between the aromatic residues in FaNaC and FMRFamide is involved in the FMRFamide recognition. Collectively, our results suggest that the conserved aromatic residues in the finger domain of FaNaC are important determinants of the ligand recognition and/or the activation gating in FaNaC. [ABSTRACT FROM AUTHOR]

While noise pollution from transportation has become an important public health problem, the relationships between different sources of traffic noise and cardiovascular diseases (CVDs) remain inconclusive. A comprehensive meta-analysis was therefore conducted to quantitatively assess the effects of long-term exposure to road traffic, railway, and aircraft noise on CVDs and relevant subtypes. We systematically retrieved PubMed, Embase, and Web of Science for articles published before April 4, 2022. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated by the fixed- or random-effects models. In total, 23 articles were included in our meta-analysis. The risk of CVDs increased by 2% (RR 1.020, 95% CI 1.006–1.035) and 1.6% (RR 1.016, 95% CI 1.000–1.032) for every 10 dB increment of road traffic and aircraft noise. For CVD subtypes, the risk increased by 3.4% (1.034, 1.026–1.043) for stroke and 5% (1.050, 1.006–1.096) for heart failure with each 10 dB increment of road traffic noise; the risk of atrial fibrillation increased by 1.1% (1.011, 1.002–1.021) with each 10 dB increment of railway noise; and the risk increased by 1% (1.010, 1.003–1.017) for myocardial infarction, 2.7% (1.027, 1.004–1.050) for atrial fibrillation, and 2.3% (1.023, 1.016–1.030) for heart failure with each 10 dB increment in aircraft noise. Further, effects from road traffic, railway, and aircraft noise all followed positive linear trends with CVDs. Long-term exposure to traffic noise is positively related to the incidence risk of cardiovascular events, especially road traffic noise which significantly increases the risk of CVDs, stroke, and heart failure. [ABSTRACT FROM AUTHOR]

Purpose: Diabetic foot ulcers are reported to be the most expensive complications of diabetes, with high morbidity and mortality rates. If the necessary care is not provided for the wound to heal, the individual may end up amputating the affected feet. Photobiomodulation therapy is a promising non-pharmacological treatment option for wound healing. The objective of the present study is to establish a dose-response relationship between photobiomodulation therapy and oxidative stress markers in the healing dynamics of diabetic neuropathic ulcers in Wistar rats. Methodology: Diabetic neuropathy was induced in 126 Albino Wistar rats. An excisional wound of an area of 2cm2 was made on the neuropathy-induced leg. Photobiomodulation therapy of dosages 4, 6, 8, 10, 12, and 15 J/cm2 of wavelengths 655 and 808 nm was irradiated. The control group animals were kept un-irradiated. The outcome measures were assessed during wound healing's inflammatory, proliferative and remodelling phases. Results: In the experimental group, animals treated with photobiomodulation therapy at doses of 4, 6, and 8 J/cm2 showed better wound healing dynamics. Photobiomodulation therapy modulated the reactive oxygen species and antioxidant levels, thereby improving the oxidative status of the wound. Conclusion: Photobiomodulation therapy of dosages 4, 6, and 8 J/cm2 is effective and is a promising adjuvant modality in treating diabetic neuropathic ulcers. There was a strong dose-response relationship in the experimental groups treated with 4, 6 and 8 J/ cm2. [ABSTRACT FROM AUTHOR]

Modelling the inter-relationships between litter accumulation and plant–soil feedback is a major challenge to predict natural and agricultural ecosystem dynamics. At increasing levels of undecomposed plant litter, seedling growth tends to show a multi-faceted response trend, characterised by a peak of positive stimulation at lower dosage followed by inhibition at higher dosage. In this study, a new logistic model was developed to describe such trend and disentangle substrate-specific positive and negative effects of plant litter. The model was tested on 35 litter types applied to the common phytometer Lepidium sativum; all litter types were collected in Mediterranean shrublands of Campania region (southern Italy). Model fitting resulted to be generally higher relative to the widely used linear log response model, although in only half of the cases it also gave more parsimonious results in terms of minimising information loss. Positive and negative effects of plant litter resulted to be uncorrelated, showing that the overall trend is probably the result of the combined action of separate factors rather than the effect of a single factor behaving differently at the different doses. The results of this work provide new tools to finely tune the optimal doses in experiments on hormesis and litter phytotoxicity, through the identification of the most suited doses to centre the range of nearly linear response to litter concentration. A wide screening is also presented on the phytotoxicity profiles of a number of spontaneous plant species widely distributed in the Mediterranean area. [ABSTRACT FROM AUTHOR]

High throughput screening (HTS) is widely used in drug discovery and chemical biology to identify and characterize agents having pharmacologic properties often by evaluation of large chemical libraries. Standard HTS data can be simply plotted as an x–y graph usually represented as % activity of a compound tested at a single concentration vs compound ID, whereas quantitative HTS (qHTS) data incorporates a third axis represented by concentration. By virtue of the additional data points arising from the compound titration and the incorporation of logistic fit parameters that define the concentration–response curve, such as EC50 and Hill slope, qHTS data has been challenging to display on a single graph. Here we provide a flexible solution to the rapid plotting of complete qHTS data sets to produce a 3-axis plot we call qHTS Waterfall Plots. The software described here can be generally applied to any 3-axis dataset and is available as both an R package and an R shiny application. [ABSTRACT FROM AUTHOR]

Ethanedinitrile is a chemical soil fumigant with promising efficacy against several key pests including weeds, nematodes, and soil-borne pathogens. The efficacy of 12 concentrations of ethanedinitrile, ranging from 8.7 to 1,751 mg kg− 1 soil, to control seeds and tubers of five weed species (Cyperus esculentus, C. rotundus, Malva parviflora, Portulaca oleracea, and Stellaria media), two nematode species (Globodera rostochiennsis and Tylenchulus semipenetrans), and four pathogenic fungal species (Fusarium oxysporum, Macrophomina phaseolina, Pythium ultimum, and Verticillium dahlia) were evaluated in acidic sand (pH: 5.6) and alkaline sandy loam (pH: 7.5–7.6), under controlled laboratory conditions. These pathogens and weeds are common in strawberry and vegetable fields and have been targeted by soil fumigants. Ethanedinitrile was injected into microcosms for 24 h. Lower doses of ethanedinitrile controlled fungal pathogens and nematodes better in acidic sand than in alkaline sandy loam. However, the reverse tended to be true for weed control as higher doses of ethanedinitrile in the acidic sand were required to control weeds than in the alkaline sandy loam. Results showed that ethanedinitrile can provide excellent control of soil-borne nematodes, pathogenic fungi, and key weed species in acidic sand and alkaline sandy loam. [ABSTRACT FROM AUTHOR]

Key summary points: Aim: This systematic review and meta-analysis aims to quantitatively investigate the relationships between the pattern of antioxidant intakes and risks of dementia and cognitive decline. Findings: For the risk of all-cause dementia, it is supplemental, not dietary, use of vitamin E or vitamin C that can significantly reduce the risk. For AD risk, dietary plus supplemental, not supplemental alone, intakes of vitamin E or vitamin C decrease markedly the risk. Furthermore, linear dose-response analyses further verified the positive effect of dietary plus supplemental intake of vitamin C on a reduced incidence of Alzheimer's dementia, with an association of every 20 mg/day increase in vitamin C and a 2% decrease in AD risk by diet plus supplement intake. Message: The findings support dietary guidelines that recommend increased intake of vitamin-C-rich foods accompanied by supplemental use of vitamin C which may be more beneficial to reduce the risk of Alzheimer-type dementia. Background: Previous studies have suggested that increased antioxidant intakes might reduce risk of cognitive disorders including Alzheimer's disease (AD). Which avenue of antioxidant intake (vitamin E/C) is more effective for decreasing risk, however, is largely unknown. Objectives: To quantitatively investigate the relationships between the pattern of antioxidant intakes and risks of dementia and cognitive decline. Methods: We searched all related prospective cohort studies reporting antioxidant intakes (diet and/or supplement) from patients with cognitive disorders. We conducted dose–response meta-analyses to assess potential linear and non-linear dose–response relationships. Summary RRs and 95% CIs were calculated using a random- or fixed-effects model. Results: 73 eligible cohort studies totaling > 28,257 participants were included in the meta-analysis; the pooled relative risks of AD were 0.75 (95% CI 0.57–0.99; I2 = 59.9%) for the dietary only intake of vitamin E, 0.73 (95% CI 0.54–1.00; I2 = 0%) for the dietary plus supplemental intake of vitamin E, and 0.70 (95% CI 0.51–0.95; I2 = 0%) for the dietary plus supplemental intake of vitamin C. Moreover, pooled RRs of AD and vitamin C intake per 20 mg/day increase were 0.98 (95% CI 0.97–0.99) via dietary plus supplemental intake, 0.98 (95% CI 0.96–1.00) in the dietary only intake and 0.98 (95% CI 0.98–0.99) in the overall intake. There were no significant associations of all-cause dementia or cognitive impairment no dementia with the antioxidant intake. Conclusions: The risk of incident AD is significantly reduced by higher consumption of vitamin C by the intake avenue of diet plus supplement. [ABSTRACT FROM AUTHOR]

Despite the recent advancements in developing bioactive nutraceuticals as anticancer modalities, their pharmacodynamics, safety profiles, and tolerability remain elusive, limiting their success in clinical trials. The failure of anticancer drugs in clinical trials can be attributed to the changes in drug clearance, absorption, and cellular responses, which alter the dose-response efficacy, causing adverse health effects. Flavonoids demonstrate a biphasic dose-response phenomenon exerting a stimulatory or inhibitory effect and often follow a U-shaped curve in different preclinical cancer models. A double-edged sword, bioflavonoids’ antioxidant or prooxidant properties contribute to their hormetic behavior and facilitate redox homeostasis by regulating the levels of reactive oxygen species (ROS) in cells. Emerging reports suggest a need to discuss the pharmacodynamic broad-spectrum of plant flavonoids to improve their therapeutic efficacy, primarily to determine the ideal dose for treating cancer. This review discusses the dose-response effects of a few common plant flavonoids against some types of cancers and assesses their safety and tolerability when administered to patients. Moreover, we have emphasized the role of dietary-rich plant flavonoids as nutraceuticals in cancer treatment and prevention. [ABSTRACT FROM AUTHOR]

Aims: Given the notable rise in the prevalence of metabolic syndrome (MS) in China, it is urgent to identify early screening indicators. Extensive dose–response meta-analyses have been conducted to investigate the association between resting heart rate (RHR) and MS, and additional relevant studies have been updated in the last five years. Therefore, this paper aims to update the results of previous meta-analyses.PubMed, Cochrane Library, Web of Science, and Embase databases were searched from the inception to 25th May 2023. Additional relevant references were manually screened. Quality assessment was performed independently by authors using the Newcastle–Ottawa Scale. Stata 15.0 software was applied for data analysis. A random-effects model was adopted to pool the effect size of hazard ratio (HR) and 95% confidence interval (CI). A restricted cubic spline function was utilized to assess dose–response relationships. The protocol was prospectively registered in PROSPERO (number CRD42023458979). 35 studies from 21 reports were included, with 433,365 adults and 84,354 events of MS and/or diabetes mellitus. The highest RHR tertile was positively associated with the risk of MS [HR = 1.80, 95% CI (1.60, 2.04)]. Dose–response analysis suggested a non-linear correlation between RHR and MS, with a 3.5% increase in risk per unit increase in RHR, at a RHR of 42.5.Both high RHR and its increasing rate are significantly associated with the risk of MS. Therefore, RHR might be a non-invasive and convenient community-based screening tool for the management and monitoring of MS.Data synthesis: Given the notable rise in the prevalence of metabolic syndrome (MS) in China, it is urgent to identify early screening indicators. Extensive dose–response meta-analyses have been conducted to investigate the association between resting heart rate (RHR) and MS, and additional relevant studies have been updated in the last five years. Therefore, this paper aims to update the results of previous meta-analyses.PubMed, Cochrane Library, Web of Science, and Embase databases were searched from the inception to 25th May 2023. Additional relevant references were manually screened. Quality assessment was performed independently by authors using the Newcastle–Ottawa Scale. Stata 15.0 software was applied for data analysis. A random-effects model was adopted to pool the effect size of hazard ratio (HR) and 95% confidence interval (CI). A restricted cubic spline function was utilized to assess dose–response relationships. The protocol was prospectively registered in PROSPERO (number CRD42023458979). 35 studies from 21 reports were included, with 433,365 adults and 84,354 events of MS and/or diabetes mellitus. The highest RHR tertile was positively associated with the risk of MS [HR = 1.80, 95% CI (1.60, 2.04)]. Dose–response analysis suggested a non-linear correlation between RHR and MS, with a 3.5% increase in risk per unit increase in RHR, at a RHR of 42.5.Both high RHR and its increasing rate are significantly associated with the risk of MS. Therefore, RHR might be a non-invasive and convenient community-based screening tool for the management and monitoring of MS.Conclusions: Given the notable rise in the prevalence of metabolic syndrome (MS) in China, it is urgent to identify early screening indicators. Extensive dose–response meta-analyses have been conducted to investigate the association between resting heart rate (RHR) and MS, and additional relevant studies have been updated in the last five years. Therefore, this paper aims to update the results of previous meta-analyses.PubMed, Cochrane Library, Web of Science, and Embase databases were searched from the inception to 25th May 2023. Additional relevant references were manually screened. Quality assessment was performed independently by authors using the Newcastle–Ottawa Scale. Stata 15.0 software was applied for data analysis. A random-effects model was adopted to pool the effect size of hazard ratio (HR) and 95% confidence interval (CI). A restricted cubic spline function was utilized to assess dose–response relationships. The protocol was prospectively registered in PROSPERO (number CRD42023458979). 35 studies from 21 reports were included, with 433,365 adults and 84,354 events of MS and/or diabetes mellitus. The highest RHR tertile was positively associated with the risk of MS [HR = 1.80, 95% CI (1.60, 2.04)]. Dose–response analysis suggested a non-linear correlation between RHR and MS, with a 3.5% increase in risk per unit increase in RHR, at a RHR of 42.5.Both high RHR and its increasing rate are significantly associated with the risk of MS. Therefore, RHR might be a non-invasive and convenient community-based screening tool for the management and monitoring of MS.Graphical abstract: Given the notable rise in the prevalence of metabolic syndrome (MS) in China, it is urgent to identify early screening indicators. Extensive dose–response meta-analyses have been conducted to investigate the association between resting heart rate (RHR) and MS, and additional relevant studies have been updated in the last five years. Therefore, this paper aims to update the results of previous meta-analyses.PubMed, Cochrane Library, Web of Science, and Embase databases were searched from the inception to 25th May 2023. Additional relevant references were manually screened. Quality assessment was performed independently by authors using the Newcastle–Ottawa Scale. Stata 15.0 software was applied for data analysis. A random-effects model was adopted to pool the effect size of hazard ratio (HR) and 95% confidence interval (CI). A restricted cubic spline function was utilized to assess dose–response relationships. The protocol was prospectively registered in PROSPERO (number CRD42023458979). 35 studies from 21 reports were included, with 433,365 adults and 84,354 events of MS and/or diabetes mellitus. The highest RHR tertile was positively associated with the risk of MS [HR = 1.80, 95% CI (1.60, 2.04)]. Dose–response analysis suggested a non-linear correlation between RHR and MS, with a 3.5% increase in risk per unit increase in RHR, at a RHR of 42.5.Both high RHR and its increasing rate are significantly associated with the risk of MS. Therefore, RHR might be a non-invasive and convenient community-based screening tool for the management and monitoring of MS. [ABSTRACT FROM AUTHOR]

Background: Determining the cytotoxicity of test substances is essential for the safety assessment of chemicals. To quantify the cytotoxicity, dose–response curves are determined and the half-maximum inhibitory concentration (IC50) is subsequently calculated. Results often rely on a single endpoint evaluation which typically requires manual sampling and subsequent sample analysis to determine the IC50. Hence, no information on culture behavior are available during treatment. Here, measurement of the oxygen transfer rate (OTR) was applied as a method for time-resolved assessment of the cytotoxicity to (a) provide information on culture behavior during treatment and (b) quantitatively assess the cytotoxic effect of a test substance. Results: To investigate the applicability of the method, different types and concentrations of test substances were added and the OTR was measured for two different CHO suspension cell lines in shake flasks: (a) For CHO cell line one, culture behavior was not affected when 0.1 mM ZnCl2 was added. However, for both cell lines, adding up to 0.2 mM CoCl2 led to a decrease in the OTR that was concentration dependent. For CHO cell line two, adding up to 5% DMSO led to a concentration-dependent decrease in the OTR and in the slope of the OTR; (b) From the measured OTR, dose–response curves were established and used to calculate the IC50. For cell line one, the IC50 for CoCl2 was 0.03 mM while the IC50 from a comparative measurement based on trypan blue exclusion was 0.06 mM. Cell line two was less susceptible to CoCl2 as the IC50 was not reached at the concentrations tested. For DMSO, single OTR values and determined slopes were used for evaluation. In both cases, the IC50 was calculated to 2.3%. Conclusions: Our approach provides a method for analyzing the cytotoxicity of a test substance based on OTR measurements. This method provides (i) insights on culture behavior, (ii) information on the progression of cytotoxicity, (iii) dose–response curves, and (iv) a first indication of IC50 values. Quantitative assessment of cytotoxicity is possible non-invasively and in real-time during treatment. Compared to traditional endpoint evaluation, our method simplifies experimentations and enhances the comparison of assay results. [ABSTRACT FROM AUTHOR]

Objectives: To quantify the association between income and antibiotic misuse including unprescribed use, storage of antibiotics and non-adherence.Methods: We identified pertinent studies through database search, and manual examination of reference lists of selected articles and review reports. We performed a dose-response meta-analysis of income, both continuous and categorical, in relation to antibiotic misuse. Summary odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated under a random-effects random effects model.Results: Fifty-seven studies from 22 countries of different economic class were included. Overall, the data are in agreement with a flat linear association between income standardized to socio-economic indicators and antibiotic misuse (OR per 1 unit increment = 1.00, p-value = 0.954, p-value non-linearity = 0.429). Data were compatible with no association between medium and high income with general antibiotic misuse (OR 1.04; 95% CI 0.89, 1.20 and OR 1.03; 95% CI 0.82, 1.29). Medium income was associated with 19% higher odds of antibiotic storage (OR 1.19; 95% CI 1.07, 1.32) and 18% higher odds of any aspect of antibiotic misuse in African studies (OR 1.18; 95% CI 1.00, 1.39). High income was associated with 51% lower odds of non-adherence to antibiotic treatment (OR 0.49; 95% CI 0.34, 0.60). High income was also associated with 11% higher odds of any antibiotic misuse in upper-middle wealth countries (OR 1.11; 95% CI 1.00, 1.22).Conclusions: The association between income and antibiotic misuse varies by type of misuse and country wellness. Understanding the socioeconomic properties of antibiotic misuse should prove useful in developing related intervention programs and health policies. [ABSTRACT FROM AUTHOR]

Purpose: This multi-study programme investigated the optimal concentration of l-menthol delivered as an oral mouth rinse to modulate thermo-behaviour during exercise in a hot environment (35 °C).In study 1, 38 participants completed a survey to establish an effective and tolerable range of l-menthol concentration. 31 participants completed an RPE-protocol examining 1. the dose–response effect of l-menthol mouth rinse on exercise performance (n = 16) and 2. the temporal effectiveness of administering l-menthol in an incremental and decremental dosing pattern (n = 15). Power output, heart rate, body core temperature and thermal sensation were reported throughout.The optimal menthol concentration for peak power was between 0.01 and 0.1% (~ 6% increase, P < 0.05) and 0.5% (~ 9% increase, P < 0.05) with respect to control. Work completed was increased at 0.01% (~ 5%, P < 0.05), at 0.1% (~ 3%, P < 0.05) and had a detrimental effect at 0.5% (− 10% decrease, P < 0.05). There were no differences between an ascending dose protocol (0.01 to 0.5%), descending dose protocol (0.5–0.01%) or a constant 0.01% dose protocol. There were no reported differences in body core temperature or heart rate across trials (P > 0.05).The optimal dose of l-menthol when delivered via oral rinsing is between 0.01 and 0.1%. At lower concentrations, l-menthol appears to be less effective and at higher concentrations (> 0.5%) l-menthol appears to elicit greater irritation and may not positively modulate thermo-behaviour during exercise in a hot environment.Method: This multi-study programme investigated the optimal concentration of l-menthol delivered as an oral mouth rinse to modulate thermo-behaviour during exercise in a hot environment (35 °C).In study 1, 38 participants completed a survey to establish an effective and tolerable range of l-menthol concentration. 31 participants completed an RPE-protocol examining 1. the dose–response effect of l-menthol mouth rinse on exercise performance (n = 16) and 2. the temporal effectiveness of administering l-menthol in an incremental and decremental dosing pattern (n = 15). Power output, heart rate, body core temperature and thermal sensation were reported throughout.The optimal menthol concentration for peak power was between 0.01 and 0.1% (~ 6% increase, P < 0.05) and 0.5% (~ 9% increase, P < 0.05) with respect to control. Work completed was increased at 0.01% (~ 5%, P < 0.05), at 0.1% (~ 3%, P < 0.05) and had a detrimental effect at 0.5% (− 10% decrease, P < 0.05). There were no differences between an ascending dose protocol (0.01 to 0.5%), descending dose protocol (0.5–0.01%) or a constant 0.01% dose protocol. There were no reported differences in body core temperature or heart rate across trials (P > 0.05).The optimal dose of l-menthol when delivered via oral rinsing is between 0.01 and 0.1%. At lower concentrations, l-menthol appears to be less effective and at higher concentrations (> 0.5%) l-menthol appears to elicit greater irritation and may not positively modulate thermo-behaviour during exercise in a hot environment.Results: This multi-study programme investigated the optimal concentration of l-menthol delivered as an oral mouth rinse to modulate thermo-behaviour during exercise in a hot environment (35 °C).In study 1, 38 participants completed a survey to establish an effective and tolerable range of l-menthol concentration. 31 participants completed an RPE-protocol examining 1. the dose–response effect of l-menthol mouth rinse on exercise performance (n = 16) and 2. the temporal effectiveness of administering l-menthol in an incremental and decremental dosing pattern (n = 15). Power output, heart rate, body core temperature and thermal sensation were reported throughout.The optimal menthol concentration for peak power was between 0.01 and 0.1% (~ 6% increase, P < 0.05) and 0.5% (~ 9% increase, P < 0.05) with respect to control. Work completed was increased at 0.01% (~ 5%, P < 0.05), at 0.1% (~ 3%, P < 0.05) and had a detrimental effect at 0.5% (− 10% decrease, P < 0.05). There were no differences between an ascending dose protocol (0.01 to 0.5%), descending dose protocol (0.5–0.01%) or a constant 0.01% dose protocol. There were no reported differences in body core temperature or heart rate across trials (P > 0.05).The optimal dose of l-menthol when delivered via oral rinsing is between 0.01 and 0.1%. At lower concentrations, l-menthol appears to be less effective and at higher concentrations (> 0.5%) l-menthol appears to elicit greater irritation and may not positively modulate thermo-behaviour during exercise in a hot environment.Conclusion: This multi-study programme investigated the optimal concentration of l-menthol delivered as an oral mouth rinse to modulate thermo-behaviour during exercise in a hot environment (35 °C).In study 1, 38 participants completed a survey to establish an effective and tolerable range of l-menthol concentration. 31 participants completed an RPE-protocol examining 1. the dose–response effect of l-menthol mouth rinse on exercise performance (n = 16) and 2. the temporal effectiveness of administering l-menthol in an incremental and decremental dosing pattern (n = 15). Power output, heart rate, body core temperature and thermal sensation were reported throughout.The optimal menthol concentration for peak power was between 0.01 and 0.1% (~ 6% increase, P < 0.05) and 0.5% (~ 9% increase, P < 0.05) with respect to control. Work completed was increased at 0.01% (~ 5%, P < 0.05), at 0.1% (~ 3%, P < 0.05) and had a detrimental effect at 0.5% (− 10% decrease, P < 0.05). There were no differences between an ascending dose protocol (0.01 to 0.5%), descending dose protocol (0.5–0.01%) or a constant 0.01% dose protocol. There were no reported differences in body core temperature or heart rate across trials (P > 0.05).The optimal dose of l-menthol when delivered via oral rinsing is between 0.01 and 0.1%. At lower concentrations, l-menthol appears to be less effective and at higher concentrations (> 0.5%) l-menthol appears to elicit greater irritation and may not positively modulate thermo-behaviour during exercise in a hot environment. [ABSTRACT FROM AUTHOR]

The thermoluminescence technique was employed to study bioglass matrix prepared using the traditional technique of glass making. The synthesized bioglass matrix were investigated using X-ray diffraction (XRD), and differential thermal analysis (DTA) has been studied. The highest thermoluminescent intensity was found for composition bioglass 26.91 % CaO, 45.68 % SiO2, 2.50 % P2O5, 25.094 %Na2O (mol%), with only one glow peak at 460 k. The TL response illustration is slightly sub-linear in the high gamma dose range from 25 to 1000 Gy. This new glass system might become useful in high-dose fields for dosimetry. [ABSTRACT FROM AUTHOR]

Some steps of the soil nitrogen (N) cycle are sensitive to environmental pressures like soil moisture or contamination, which are expected to evolve during the next decades. Individual stresses have been well studied, but their combination is not yet documented. In this work, we aimed at assessing the importance of the soil moisture on the impact of copper (Cu) contaminations on the N cycling soil function using the potential nitrification activities (PNA) as bioindicator. A two-step experiment was performed. First, a loamy soil was incubated 5 weeks in either 30, 60, or 90% of its water holding capacity (WHC) or alternating drought and rewetting periods. Thereafter, soil samples were exposed to a gradient of Cu concentrations through a bioassay involving nitrification. The dose–response curves of PNA in function of added Cu were modeled to calculate the effective Cu concentrations, namely ECx with x being the percentage of PNA inhibition. These values were then compared between experimental conditions to highlight differences in threshold values. The preincubation moisture treatments significantly affected the PNA responses to the secondary Cu stress with, for instance, hormetic responses in all cases except for the dry-rewetting treatment. Small PNA inhibitions were estimated for high Cu doses in the soils with low water contents (30% WHC) or submitted to dry-rewetting cycles, contrarily to the patterns observed for the soils with high water contents (90% WHC) or submitted to a single period of drought. Overall, significant differences were found in estimated ECx values between moisture treatments. [ABSTRACT FROM AUTHOR]

Purpose: Previous meta-analyses assessed the association of adherence to the Mediterranean dietary pattern (MedDiet) with the risk of type 2 diabetes (T2D). Since then, new large-scale cohort studies have been published. In addition, dose–response relation was not previously investigated and the certainty of evidence was not assessed. We aimed to explore the dose–response relationship between adherence to the MedDiet and the risk of T2D. Methods: We did a systematic search using PubMed, Scopus, and ISI Web of Science upto April 2021 for prospective cohort studies of the relationship between adherence to the MedDiet and the risk of T2D in the general population. The summary relative risks (RR) and 95%CI were estimated by applying a random-effects model. Results: Fourteen prospective cohort studies (410,303 participants and 41,466 cases) were included. There was an inverse association for the highest versus lowest category of adherence to the MedDiet (RR: 0.79, 95%CI 0.72, 0.88; I2 = 82%, n = 14; Risk difference: – 21 per 1000 person, 95%CI – 28, – 12; GRADE = moderate certainty), and for a 2-point increment in the MedDiet adherence score (RR: 0.86, 95%CI 0.82, 0.91; n = 13). The RR remained significant after controlling for important confounders and in almost all subgroups, especially subgroups defined by geographical region. We observed an inverse linear association between MedDiet adherence score and T2D incidence. Conclusion: Adherence to the MedDiet was inversely related to T2D risk in a dose–response manner. Adherence to a Mediterranean-style diet may be a good advice for the primary prevention of T2D. Registry and registry number: PROSPERO (CRD42021246589). [ABSTRACT FROM AUTHOR]

Stress from cumulative adverse childhood experiences (ACEs) can pose a serious risk of experiencing anxiety, depression, and other mood disorders in adolescence. However, there is a paucity of research identifying specific profiles or combinations of exposure to other forms of stressful life events and their impact on adolescent psychopathology. This study attempted a conceptual expansion of the ACE checklist by examining these stressful events. The study used cross-sectional data from a modified version of the CASE Study survey where 864 adolescents (56% female, n = 480), aged from 11 – 18 years were recruited from four post-primary schools in the North-West region of NI. Latent class analysis of the 20-item stressful events checklist revealed 3 distinct risk classes: a low-risk class (53.5%), at-risk class (42.7%), and an immediate-risk class (3.8%). Results showed those at most risk of adolescent psychopathology had the highest probability of encountering interpersonal relationship issues, experiencing family dysfunction, and having close friends experiencing psychological difficulties. Findings indicate that the original ten ACE categories may be too narrow in focus and do not capture the wide range of childhood adversity. Expanding the ACE checklist to include other stressful events is discussed as these may also be antecedents to psychopathologic responses. [ABSTRACT FROM AUTHOR]

Artificial Light at Night (ALAN) is expanding worldwide, and the study of its influence remains limited mainly to documenting impacts, overlooking the variation in key characteristics of the artificial light such as its intensity. The potential dose–response of fitness-related traits to different light intensities has not been assessed in sandy beach organisms. Hence, this study explored dose-responses to ALAN by exposing the intertidal sandy beach isopod Tylos spinulosus to a range of light intensities at night: 0 (control), 20, 40, 60, 80 and 100 lx. We quantified the response of this species at the molecular (RNA:DNA ratios), physiological (absorption efficiency) and organismal (growth rate) levels. Linear and non-linear regressions were used to explore the relationship between light intensity and the isopod response. The regressions showed that increasing light intensity caused an overall ~ threefold decline in RNA:DNA ratios and a ~ threefold increase in absorption efficiency, with strong dose-dependent effects. For both response variables, non-linear regressions also identified likely thresholds at 80 lx (RNA:DNA) and 40 lx (absorption efficiency). By contrast, isopod growth rates were unrelated (unaltered) by the increase in light intensity at night. We suggest that ALAN is detrimental for the condition of the isopods, likely by reducing the activity and feeding of these nocturnal organisms, and that the isopods compensate this by absorbing nutrients more efficiently in order to maintain growth levels. [ABSTRACT FROM AUTHOR]

Background: In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose–response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates. Methods: We included all patients who underwent yttrium-90 (90Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose–response and hepatic dose-toxicity relationships. Results: A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170 Gy, for stable disease 101 Gy, and for progressive disease 67 Gy. No significant dose-toxicity relationship could be identified. Conclusion: In patients with neuroendocrine tumor liver metastases, treated with 90Y-radioembolization, a clear dose–response relationship was found. We propose to perform 90Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150 Gy. [ABSTRACT FROM AUTHOR]

Rationale: Adverse psychosocial factors during early childhood or adolescence compromise neural structure and brain function, inducing susceptibility for many psychiatric disorders such as substance use disorder. Nevertheless, the mechanisms underlying early life stress-induced addiction vulnerability is still unclear, especially for opioids. Objectives: To address this, we used a mouse heroin self-administration model to examine how chronic early social isolation (ESI) stress (5 weeks, beginning at weaning) affects the behavioral and neural responses to heroin during adulthood. Results: We found that ESI stress did not alter the acquisition for sucrose or heroin self-administration, nor change the motivation for sucrose on a progressive ratio schedule. However, ESI stress induced an upward shift of heroin dose-response curve in female mice and increased motivation and seeking for heroin in both sexes. Furthermore, we examined the neuronal activity (measured by c-Fos expression) within the key brain regions of the mesocorticolimbic system, including the prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc) core and shell, caudate putamen, and ventral tegmental area (VTA). We found that ESI stress dampened c-Fos expression in the PrL, IL, and VTA after 14-day forced abstinence, while augmented the neuronal responses to heroin-predictive context and cue in the IL and NAc core. Moreover, ESI stress disrupted the association between c-Fos expression and attempted infusions during heroin-seeking test in the PrL. Conclusions: These data indicate that ESI stress leads to increased seeking and motivation for heroin, and this may be associated with distinct changes in neuronal activities in different subregions of the mesocorticolimbic system. [ABSTRACT FROM AUTHOR]

The key aim of this paper is to suggest a more quantitative approach to designing a dose–response experiment, and more specifically, a concentration–response experiment. The work proposes a departure from the traditional experimental design to determine a dose–response relationship in a developmental toxicology study. It is proposed that a model-based approach to determine a dose–response relationship can provide the most accurate statistical inference for the underlying parameters of interest, which may be estimating one or more model parameters or pre-specified functions of the model parameters, such as lethal dose, at maximal efficiency. When the design criterion or criteria can be determined at the onset, there are demonstrated efficiency gains using a more carefully selected model-based optimal design as opposed to an ad-hoc empirical design. As an illustration, a model-based approach was theoretically used to construct efficient designs for inference in a developmental toxicity study of sea urchin embryos exposed to trimethoprim. This study compares and contrasts the results obtained using model-based optimal designs versus an ad-hoc empirical design. [ABSTRACT FROM AUTHOR]

Associations and dose-response relationships between different kinds of urine polycyclic aromatic hydrocarbons (PAHs) metabolites and lung functions in general American adults were unknown. Data from the National Health and Nutrition Examination Survey database of the 2009–2012 cycles were used. The independent variables were urine PAHs adjusted for urine creatinine, including 1-hydroxynaphthalene (1-NAP), 2-hydroxynaphthalene (2-NAP), 3-hydroxyfluorene (3-FLU), 2-hydroxyfluorene (2-FLU), 3-hydroxyphenanthrene (3-PHE), 1-hydroxyphenanthrene (1-PHE), 2-hydroxyphenanthrene (2-PHE), 1-hydroxypyrene (1-PYR), and 9-hydroxyfluorene (9-FLU). The dependent variables were lung function indices including the forced vital capacity (FVC), the 1st second of a forceful exhalation (FEV1), the ratio of FEV1/FVC, the forced expiratory flow rate 25–75% (FEF25%-75%), and the fractional exhaled nitric oxide (FENO). Multivariate linear regression analyses and the restricted cubic splines were used. Except for 1-PHE and 9-FLU, FEF25%-75% decreased in quartile (Q) 4 of all the remaining seven PAHs; FEV1 decreased in Q4 of 2-NAP, 3-PHE, 2-PHE, and 9-FLU, with β (SE) of −121.89 (45.46), −105.21 (33.57), −143.67 (40.60), and −127.71 (37.14), respectively. FVC decreased only in Q3 of 9-FLU, with β (SE) of −142.24 (56.54); FEV1/FVC decreased in Q4 of all PAHs except for 2-FLU. Besides, FENO decreased in Q4 of all PAHs in smokers, while in non-smokers, the results were opposite. The dose-response relationships were non-linear. In conclusion, we found that urine PAHs may relate to the changes in lung functions. Besides, smoking status had a significant influence on FENO; FENO decreased in smokers while increased in non-smokers, suggesting that PAHs exposure may relate to airway inflammation. [ABSTRACT FROM AUTHOR]

In the present study, native bacterial strains isolated from abandoned gold mine and Chromobacterium violaceum (MTCC-2656) were applied for bioleaching of metals from waste printed circuit boards (WPCBs). Toxicity assessment and dose–response analysis of WPCBs showed EC50 values of 128.9, 98.7, and 90.8 g/L for Bacillus sp. SAG3, Bacillus megaterium SAG1 and Lysinibacillus sphaericus SAG2, respectively, whereas, for C. violaceum EC50 was 83.70 g/L. This indicates the viable operation range and technological feasibility of metals bioleaching from WPCBs using mine isolates. The influencing factors such as pH, pulp density, temperature, and precursor molecule (glycine) were optimized by one-factor at a time method (OFAT). The maximum metal recovery occurred at an initial pH of 9.0, a pulp density of 10 g/L, a temperature of 30 °C and a glycine concentration of 5 g/L, except for L. sphaericus which showed optimum activity at initial pH of 8.0. Under optimal conditions the metals recovery of Cu and Au from WPCBs were recorded as 87.5 ± 8% and 73.6 ± 3% for C. violaceum and 72.7 ± 5% and 66.6 ± 6% for B. megaterium, respectively. Kinetic modeling results showed that the data was best described by first order reaction kinetics, where the rate of metal solubilization from WPCBs depended upon microbial lixiviant production. This is the first report on bioleaching of metals from e-waste using bacterial isolates from the gold mine of Solan, HP. Our study demonstrated the potential of bioleaching for resource recovery from WPCBs dust, aimed to be disposed at landfills, and its effectiveness in extraction of elements those are at high supply risk and demand. [ABSTRACT FROM AUTHOR]

Summary: Background: We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV‑2 spike (S) protein encapsulated in lipid nanoparticles (LNP). Methods: This is an interim analysis of a dosage escalation phase 1 study in healthy 18–60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV‑2 S‑protein and receptor binding domain (RBD), and SARS-CoV‑2 neutralizing titers (MN50). Results: In 245 volunteers who received 2 CVnCoV vaccinations (2 μg, n = 47, 4 μg, n = 48, 6 μg, n = 46, 8 μg, n = 44, 12 μg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S‑protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S‑protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 μg group. Responses to 12 μg were comparable to those observed in convalescent sera from known COVID-19 patients. Conclusion: In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 μg dosages elicited levels of immune responses that overlapped those observed in convalescent sera. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the impact of meteorological indicators (temperature, rainfall, and humidity) on total COVID-19 cases in Pakistan, its provinces, and administrative units from March 10, 2020, to August 25, 2020. The correlation analysis showed that COVID-19 cases and temperature showed a positive correlation. It implies that the increase in COVID-19 cases was reported due to an increase in the temperature in Pakistan, its provinces, and administrative units. The generalized Poisson regression showed that the rise in the expected log count of COVID-19 cases was 0.024 times for a 1 °C rise in the average temperature in Pakistan. Second, the correlation between rainfall and COVID-19 cases was negative in Pakistan. However, the regression coefficient between the expected log count of COVID-19 cases and rainfall was insignificant in Pakistan. Third, the correlation between humidity and the total COVID-19 cases was negative, which implies that the increase in humidity is beneficial to stop the transmission of COVID-19 in Pakistan, its provinces, and administrative units. The reduction in the expected log count of COVID-19 cases was 0.008 times for a 1% increase in the humidity per day in Pakistan. However, humidity and COVID-19 cases were positively correlated in Sindh province. It is required to create awareness among the general population, and the government should include the causes, symptoms, and precautions in the educational syllabus. Moreover, people should adopt the habit of hand wash, social distancing, personal hygiene, mask-wearing, and the use of hand sanitizers to control the COVID-19. [ABSTRACT FROM AUTHOR]

Purpose: Cardiovascular disease (CVD) is a leading cause of mortality globally and is strongly influenced by dietary risk factors. The aim was to assess the association between egg consumption and risk of CVD risk/mortality, including coronary heart disease (CHD), stroke, and heart failure. Methods: MEDLINE, Embase, and Web of Science databases were searched through April 2020 for prospective studies. Two independent reviewers screened and extracted the data through standardized methods. Size effects were calculated as summary relative risks (SRRs) in a dose–response fashion through random-effects meta-analyses. Results: Thirty-nine studies including nearly 2 million individuals and 85,053 CHD, 25,103 stroke, 7536 heart failure, and 147,124 CVD cases were included. The summary analysis including 17 datasets from 14 studies conducted on CVD (incidence and/or mortality) showed that intake of up to six eggs per week is inversely associated with CVD events, when compared to no consumption [for four eggs per week, SRR = 0.95 (95% CI: 0.90; 1.00)]; a decreased risk of CVD incidence was observed for consumption of up to one egg per day [SRR = 0.94 (95% CI: 0.89; 0.99)]. The summary analysis for CHD incidence/mortality including 24 datasets from 16 studies showed a decreased risk up to two eggs per week [(SRR = 0.96 (95% CI: 0.91; 1.00)]. No associations were retrieved with risk of stroke. The summary analysis for heart failure risk including six datasets from four studies showed that intake of one egg per day was associated with increased risk raising for higher intakes compared to no consumption [for 1 egg per day, SRR = 1.15 (95% CI:1.02; 1.30)]. After considering GRADE criteria for strength of the evidence, it was rated low for all outcomes but stroke, for which it was moderate (yet referring to no risk). Conclusion: There is no conclusive evidence on the role of egg in CVD risk, despite the fact that higher quality studies are warranted to obtain stronger evidence for a possible protection of CVD associated with moderate weekly egg consumption compared to no intake; equally, future studies may strengthen the evidence for increased heart failure risk associated with high regular egg consumption. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a cognitive state falling between normal aging and dementia. The relation between alcohol intake and risk of MCI as well as progression to dementia in people with MCI (PDM) remained unclear. Objective: To synthesize available evidence and clarify the relation between alcohol intake and risk of MCI as well as PDM. Method: We searched electronic databases consisting of PubMed, EMBASE, Cochrane Library, and China Biology Medicine disc (CBM) from inception to October 1, 2019. Prospective studies reporting at least three levels of alcohol exposure were included. Categorical meta-analysis was used for quantitative synthesis of the relation between light, moderate and heavy alcohol intake with risk of MCI and PDM. Restricted cubic spline and fixed-effects dose–response models were used for dose–response analysis. Result: Six cohort studies including 4244 individuals were finally included. We observed an unstable linear relation between alcohol intake (drinks/week) and risk of MCI (P linear = 0.0396). It suggested that a one-drink increment per week of alcohol intake was associated with an increased risk of 3.8% for MCI (RR, 1.038; 95% CI 1.002–1.075). Heavy alcohol intake (> 14 drinks/week) was associated with higher risk of PDM (RR = 1.76; 95% CI 1.10–2.82). And we found a nonlinear relation between alcohol intake and risk of PDM. Drinking more than 16 drinks/week (P nonlinear = 0.0038, HR = 1.42; 95% CI 1.00–2.02), or 27.5 g/day (P nonlinear = 0.0047, HR = 1.46; 95% CI 1.00–2.11) would elevate the risk of PDM. Conclusion: There was a nonlinear dose–response relation between alcohol intake and risk of PDM. Excessive alcohol intake would elevate the risk of PDM. [ABSTRACT FROM AUTHOR]

Purpose: Obesity, measured by body mass index (BMI), is implicated in adverse pregnancy outcomes for women seeking in vitro fertilization (IVF) care. However, the shape of the dose-response relationship between BMI and IVF outcomes remains unclear. Methods: We therefore conducted a dose-response meta-analysis using a random effects model to estimate summary relative risk (RR) for clinical pregnancy (CPR), live birth (LBR), and miscarriage risk (MR) after IVF. Results: A total of 18 cohort-based studies involving 975,889 cycles were included. For each 5-unit increase in BMI, the summary RR was 0.95 (95% CI: 0.94–0.97) for CPR, 0.93 (95% CI: 0.92-0.95) for LBR, and 1.09 (95% CI: 1.05-1.12) for MR. There was evidence of a non-linear association between BMI and CPR (Pnon-linearity < 10−5) with CPR decreasing sharply among obese women (BMI > 30). Non-linear dose-response meta-analysis showed a relatively flat curve over a broad range of BMI from 16 to 30 for LBR (Pnon-linearity = 0.0009). In addition, we observed a J-shaped association between BMI and MR (Pnon-linearity = 0.006) with the lowest miscarriage risk observed with a BMI of 22–25. Conclusions: In conclusion, obesity contributed to increased risk of adverse IVF outcomes in a non-linear dose-response manner. More prospective trials in evaluating the effect of body weight control are necessary. [ABSTRACT FROM AUTHOR]