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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).

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]

Findings on the association of dietary intake and tissue biomarkers of linoleic acid (LA) with the risk of prostate cancer are conflicting. Also, no meta-analysis summarized available findings in this regard. Therefore, the current systematic review and dose-response meta-analysis were done to summarize the findings of prospective cohort studies that assessed dietary intake and tissue biomarkers of LA in relation to prostate cancer risk in adults. We conducted a systematic search using online databases, including PubMed, Scopus, and ISI Web of Science, to identify eligible articles published up to January 2023. We included prospective cohort studies that examined the associations of dietary intake and tissue biomarkers of LA with the risk of prostate cancer (total, advanced, and fatal prostate cancer). Summary relative risks (RR) and 95% confidence intervals (CI) were calculated for the highest versus lowest intakes/tissue levels of LA using a fixed-effects model. Also, linear and non-linear dose-response analyses were conducted. In total, 15 prospective cohort studies were included. These studies recruited a total sample size of 511,622 participants with an age range of ≥18 years. During the follow-up periods ranging from 5 to 21 years, 39,993 cases of prostate cancer, 5,929 cases of advanced prostate cancer, and 1,661 cases of fatal prostate cancer were detected. In the meta-analysis, we found that higher tissue levels of LA were associated with a reduced risk of prostate cancer (RR: 0.86, 95% CI: 0.77–0.96) so that in the dose-response analysis, each 5% increase in levels of LA was associated with a 14% lower risk of prostate cancer. Such a significant association was not seen for advanced prostate cancer (RR: 0.86, 95% CI: 0.65–1.13). Also, we found no significant association between dietary intake of LA and risk of total (RR:1.00, 95% CI: 0.97–1.04), advanced (RR: 0.98, 95% CI: 0.90–1.07), and fatal prostate cancer (RR: 0.97, 95% CI: 0.83–1.13). Our findings support the protective association between tissue levels of LA and the risk of prostate cancer in men. [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]

Introduction: Gout is a common type of inflammatory arthritis. Vitamin C is a potent antioxidant that neutralizes reactive oxygen species. However, the association between dietary vitamin C levels and gout remains unclear. This study evaluated the relationship between dietary vitamin C intake and gout. Methods: Cross-sectional data from individuals aged > 20 years who participated in the National Health and Nutrition Examination Survey between 2013 and 2018 were collected. Details on gout, dietary vitamin C intake, and several other essential variables were recorded. Results: There were 12589 participants, 5% (652/12589) of whom experienced gout. Compared with individuals with lower vitamin C consumption in the Q1 group (=19.9 mg/day), the adjusted odds ratio(OR)values for dietary vitamin C intake and gout in the Q2 group (19.9-49.7 mg/day), Q3 group (49.7-110.375 mg/day), and Q4 group (=110.375 mg/day) were 0.87 (95% confidence interval (CI): 0.69-1.1, P = 0.237), 0.81 (95% CI: 0.64-1.02, P = 0.076), and 0.77 (95% CI: 0.6-0.99, P= 0.042), respectively. Accordingly, the association between dietary vitamin C intake and gout exhibited an L-shaped curve (nonlinear, P = 0.245) in a restricted cubic spline. Subgroup analysis revealed significant interactions between vitamin C levels and gout according to sex (P < 0.05). When we used data on dietary vitamin C from the second survey, we observed a similar inverse association between vitamin C intake and gout. The vitamin C was also negatively associated with hyperuricemia (OR, 0.94; 95% CI, 0.9-0.98, P=0.005). Compared with Q1, the adjusted OR values for dietary vitamin C and hyperuricemia in Q2, Q3, and Q4 were 0.77 (95% CI: 0.69-0.86, P = 0.65), 0.81 (95% CI: 0.72-0.91, P = 0.014), and 0.72 (95% CI: 0.64-0.81, P < 0.001), respectively. No association was observed between vitamin C supplementation and gout. Conclusion: The population-based data indicate that dietary vitamin C intake is inversely associated with gout. These findings support the potential role of vitamin C in preventing gout. [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]

Ecuadorian cocoa possesses important organoleptic characteristics such as aroma and flavor, called fine and aromatic cocoa. The objective of this study was to evaluate the initial growth responses of young cocoa seedlings to glyphosate in a dose progression in 45 cocoa plants (5 months old), which were transplanted into pots with substrate adjusted to pH 6.0–6.5. Glyphosate doses (0 to 904 g e.e. ha−1) were applied every two weeks, evaluating the impact at 30 and 60 days post-application. Data on shikimate accumulation parameters, chlorophyll content and PSII quantum efficiency were subjected to multivariate analysis using a three-dimensional scatter plot. The results indicated that high concentrations of glyphosate contributed to higher shikimate concentration and lower PSII quantum efficiency. The findings for the variables crop damage, stem height and stem diameter were evaluated by ANOVA. Similarities were reported between the results of the variables height and diameter, and significant differences (p < 0.05) in the variable crop damage for all treatments were also reported. In terms of phytotoxic reaction and growth parameters, the most efficient treatment was DO4, since the seedlings with this dosage showed a low percentage of damage (10%) and the best indices in terms of height and diameter. The least efficient treatment was D15. The control plants (DO1) showed a crop damage of >50% because the absence of control favored weed proliferation. These indications highlight the need to adjust glyphosate doses according to the specific needs of each crop and the development stage of the plant in order to reduce negative effects and maximize potential benefits. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to determine the dose–response relationship between targeted nanocarriers released from a novel, sustained release formulation and their ability to specifically deplete cells responsible for the development of posterior capsular opacification (PCO) in month-long, dynamic cell cultures. Methods: Injectable, thermosensitive poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic acid) triblock copolymer hydrogels were loaded with either a low or a high dose of doxorubicin-loaded antibody-targeted nanocarriers (G8:3DNA:Dox). Human rhabdomyosarcoma cells, selected for their expression of PCO marker brain-specific angiogenesis inhibitor 1 (BAI1), were kept under dynamic media flow and received either a low or high dose of nanocarriers. Cells were fixed and stained at predetermined time points to evaluate targeted depletion of BAI1+ cells. Results: A lower dose of nanocarriers in hydrogel depleted BAI1+ cells at a slower rate than the higher dose, whereas both reached over 90% BAI1+ cellular nonviability at 28 days. Both treatment groups also significantly lowered the relative abundance of BAI1+ cells in the population compared with the control group. Conclusions: Controlled release of a lower dose of nanocarriers can still achieve therapeutically relevant effects in the prevention of PCO, while avoiding potential secondary effects associated with the administration of a higher dose. [ABSTRACT FROM AUTHOR]

Context Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder in women of reproductive age. Vitamin D supplementation is a promising complementary therapy for PCOS, yet there is no consensus on an optimal dose, leading to a lack of evidence-based supplementation guidelines. Objective The objective of this study was to conduct a vitamin D dose–response meta-analysis among women with PCOS. Data sources MEDLINE, CINAHL, and EMBASE databases from inception to November 2022 were searched for relevant articles. Data extraction Study screening and bias assessment were conducted by 2 independent reviewers. Eight relevant studies were identified; data for serum 25(OH)D (nmol/L) at baseline and at 12 weeks in each intervention group (mean ± SD) and vitamin D dose were extracted. Data analysis Estimates across studies were used to create a pooled curve, using restricted cubic splines with knots at the 10th, 50th, and 90th percentiles of the distribution of doses, to estimate the mean difference in effect for serum 25(OH)D at each dose compared with 0 IU/day. Sensitivity analyses were conducted fixing knots at 4000 IU/day and 7000 IU/day, which were a priori identified as potentially important thresholds, and to assess model fit and estimate heterogeneity. The pooled analysis demonstrated strong evidence of a dose–response relationship (P < .001), suggesting an increasing effect with increasing dose. An initial increase in serum 25(OH)D was evident until doses of approximately 3000 IU/day; this was followed by a plateau in effect between approximately 3000 IU/day and 5000 IU/day. The effect of supplementation with >5000 IU/day was unclear, given the minimal data at higher doses. The curve produced robust results for moderate doses (3000 IU/day to 4000 IU/day), which were not sensitive to model specification. Conclusion Women with PCOS are responsive to vitamin D supplementation, but the benefit of providing doses of >3000 IU/day appears minimal. Further data is required to determine dose–response at doses of >5000 IU/day, and whether higher intakes provide a clinically meaningful advantage in this population. Systematic Review Registration PROSPERO registration no. CRD42021259396. [ABSTRACT FROM AUTHOR]

To analyze the reporting completeness of the TIDieR items 8-12, in particular intensity, dose, and dosage, in active pediatric upper limb neurorehabilitation trials. We searched PubMed Central, Scopus, CINAHL, OTseeker, and Web of Science for eligible publications. We included publications analyzing active pediatric upper limb neurorehabilitation interventions and assessed the reporting completeness of 11 items for each intervention and control group. Two raters independently screened titles and abstracts and selected the publications using the RYYAN platform. We unblinded the results after the raters had completed their selection and resolved the disagreements by discussion. We used the same procedures to review the full texts. We included 52 randomized controlled trials with 65 intervention and 48 control groups. Authors did not report all 11 items in any of the study groups. The overall reporting completeness varied between 1% (intensity) to 95% (length of the intervention). The reporting completeness of the TIDieR items ranged from 2% (modifications) to 64% (when and how much). We found no significant differences in the reporting completeness between the intervention and control groups. Information essential for dose-response calculations is often missing in randomized controlled trials of pediatric upper limb neurorehabilitation interventions. Reporting completeness should be improved, and new measures to accurately quantify intensity should be discussed and developed. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study investigates factors contributing Amaranthus albus control failure in processing tomato fields in northern Israel. The study region is characterized by a significant climate gradient from east to west, providing the opportunity to investigate the effect of critical elements of the agricultural environment, e.g., temperature. Eight populations were collected from commercial fields in this region. Post‐emergence herbicide efficacy of metribuzin, a photosystem II inhibitor, and rimsulfuron, an acetolactate synthase (ALS) inhibitor, was assessed through dose–response analyses at various growth stages. Temperature effects on control efficacy and resistance mechanisms were also explored. RESULTS: Standard metribuzin dose (X) was ineffective on A. albus plants with more than six true‐leaves, whereas 2X dose proved effective. Rimsulfuron at 16X dose was ineffective on plants with more than four true‐leaves. We report here the first case of target site resistance to ALS inhibitors in A. albus, due to point mutation in the ALS gene (Pro197 to Leu). Furthermore, our findings suggest potential involvement of CYT P450 enzymes in enhanced metabolizing of rimsulfuron. An overall decrease in dry weight was observed in response to both herbicides at 16/22 °C (P < 0.0001). Rimsulfuron was effective against only one population when applied at 28/34 °C. A possible fitness cost associated with target site‐resistant biotypes was observed under low temperature conditions, leading to effective control. CONCLUSION: This regional‐scale study highlights the challenges faced by growers, emphasizes the need for adapting management practices to the local climatic conditions and lays the groundwork for implementing location‐specific weed management strategies in commercial fields. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

A logarithmic sprayer was suggested about 70 years ago, but it has not yet been seriously used in research and development, and subsequent registration of plant protection products. Logarithmic sprayers have resorted to mere demonstration experiments to show end users and others how plant protection products work. Fitting dose–response curves in field experiments, however, generates much essential information, e.g., extraction of various effective field rate levels (e.g., ED20, ED50, and ED80). One of the reasons for it rarely being used in the registration of plant protection products is that the dose–response curve regression was hitherto difficult to fit; the registration requirement solely focuses on analyses of variance. Another alleged obstacle is that the logarithmic plots have systematically, not randomly distributed field rates. This paper goes through some of the problems of how to non‐randomly analyze field rates by taking autocorrelation into account to make the logarithmic sprayer palatable as registration documentation by assessing efficacy, selectivity, environmental side effects, general toxicity of plant protection products, and cost‐effectiveness. The development in precision agriculture, drone technology, and automation of data capture and subsequent analysis could make the logarithmic sprayer a cost‐effective alternative to numerous ANOVA experiments with very few fixed field rates to aid the precision spraying of pesticides and thus reduce unnecessary environmental side effects. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Abstract 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.

Background Stroke, as a major chronic non-communicable disease, seriously affects the health of the nation and imposes a heavy burden on patients, families and society. Alcohol consumption is common in China, and there is a close relationship between alcohol intake and stroke incidence, but the relationship between alcohol intake and stroke incidence is still controversial. Objective To investigate the relationship between alcohol intake and risk of stroke. Methods PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP, Wanfang Data, and SinoMed were searched for prospective cohort studies on the relationship between alcohol intake and risk of stroke from inception to December 2023. Literature screening, data extraction, and literature quality evaluation were performed independently by 2 researchers. Stata/MP 17.0 was used for dose-response meta-analysis. Results A total of 16 papers with 548 595 study subjects were included. Meta-analysis results showed that alcohol intake was associated with the risk of stroke (RR=1.17, 95%CI=1.10-1.26, P40 g increased the risk of stroke by 35% (RR=1.35, 95%CI=1.23-1.49, P

Background and Objectives: Current evidence on the associations of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumption with the risk of inflammatory bowel disease (IBD) is inconsistent. This study aimed to investigate the relationship between dietary EPA and DHA consumption with the incidence of IBD in a population of the United States, which potentially provides insights for global nutritional prevention and control strategies for IBD. Methods and Study Design: Data were sourced from the National Health and Nutrition Examination Survey for the years 2009-2010. EPA and DHA consumption was measured using twice 24-h dietary recall questionnaires. In the arthritis questionnaire, the incidence of IBD was inquired via a subanalysis for arthropathy. To assess the relationship between dietary EPA and DHA consumption with the incidence of IBD, binary logistic regression and limited cubic spline models were used. Results: A total of 4,242 individuals aged 20 years and older participated in this survey. IBD was diagnosed in 52 individuals, representing a prevalence of 1.23%. The 95% confidence interval for crude odds ratios (ORs) of IBD in quartiles 2 and 3 of dietary EPA consumption was 0.14 (0.04-0.55) (p<0.05) and 0.36 (0.18-0.73) (p<0.05) when compared to quartile 1, respectively. The 95% confidence interval for crude ORs of IBD in quartile 4 of dietary DHA consumption was 0.09(0.02-0.35) (p<0.05) when compared to quartile 1. Conclusions: For the National Health and Nutrition Examination Survey in 2009-2010, increased dietary EPA and DHA consumption may be related to a decreased risk of IBD in Americans aged 20 and above. [ABSTRACT FROM AUTHOR]

Although handgrip strength is associated with all-cause mortality in patients with chronic kidney disease (CKD), whether this relationship is dose-related is unknown. Therefore, we examined dose-response relationships between handgrip strength and all-cause mortality in CKD patients based on previous studies by meta-analysis. Data sources included three electronic databases (PubMed, Web of Science, and Embase) from inception through October 2023. The included cohort was a CKD population not limited to disease stage, and their handgrip strength was objectively measured. Two researchers independently screened studies, extracted data, and assessed the risk of bias. We utilized estimates of handgrip strength categories using robust-error meta-regression (REMR), pooled study-specific estimates, and established dose-response relationships. Outcomes of interest included only all-cause mortality. A total of 18 studies with 4810 participants (aged 47–71 years) were included. REMR modeling showed a U-shaped trend of association between handgrip strength and all-cause mortality in patients with CKD. Higher handgrip strength values, from 10 kg to approximately 28 kg, were associated with lower mortality risk. After that, the risk of death increased slightly. A U-shaped association exists between handgrip strength and all-cause mortality risk in CKD patients. Future studies with quantitative measurements for each CKD stage will help to determine precise relative risk estimates between handgrip strength and mortality risk in patients with different stages of CKD. [ABSTRACT FROM AUTHOR]

Abstract Plants must cope with ever-changing temperature conditions in their environment. In many plant species, suboptimal high and low temperatures can induce adaptive mechanisms that allow optimal performance. Thermomorphogenesis is the acclimation to high ambient temperature, whereas cold acclimation refers to the acquisition of cold tolerance following a period of low temperatures. The molecular mechanisms underlying thermomorphogenesis and cold acclimation are increasingly well understood but neither signalling components that have an apparent role in acclimation to both cold and warmth, nor factors determining dose-responsiveness, are currently well defined. This can be explained in part by practical limitations, as applying temperature gradients requires the use of multiple growth conditions simultaneously, usually unavailable in research laboratories. Here we demonstrate that commercially available thermal gradient tables can be used to grow and assess plants over a defined and adjustable steep temperature gradient within one experiment. We describe technical and thermodynamic aspects and provide considerations for plant growth and treatment. We show that plants display the expected morphological, physiological, developmental and molecular responses that are typically associated with high temperature and cold acclimation. This includes temperature dose-response effects on seed germination, hypocotyl elongation, leaf development, hyponasty, rosette growth, temperature marker gene expression, stomatal conductance, chlorophyll content, ion leakage and hydrogen peroxide levels. In conclusion, thermal gradient table systems enable standardized and predictable environments to study plant responses to varying temperature regimes and can be swiftly implemented in research on temperature signalling and response.

Abstract Background Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care. Methods Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose–response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness. Discussion This project seeks to gain an understanding of the dose–response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia. Trial registration ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 ( https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true ).

Abstract Background Mesenchymal stem cells (MSCs) have emerged as living biodrugs for myocardial repair and regeneration. Recent randomized controlled trials (RCTs) have reported that MSC-based therapy is safe and effective in heart failure patients; however, its dose-response relationship has yet to be established. We aimed to determine the optimal MSC dose for treating HF patients with reduced ejection fraction (EF) (HFrEF). Methods The preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane Handbook guidelines were followed. Four databases and registries, i.e., PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other websites, were searched for RCTs. Eleven RCTs with 1098 participants (treatment group, n = 606; control group, n = 492) were selected based on our inclusion/exclusion criteria. Two independent assessors extracted the data and performed quality assessments. The data from all eligible studies were plotted for death, major adverse cardiac events (MACE), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and 6-minute walk distance (6-MWD) as safety, efficacy, and performance parameters. For dose-escalation assessment, studies were categorized as low-dose (

Abstract Objective Research the dose–response relationship between overall and certain types of exercise and cognitive function in older adults with Alzheimer's disease and dementia. Design Systemic and Bayesian Model-Based Network Meta-Analysis. Methods In our study, we analyzed data from randomized controlled trials investigating the effects of different exercises on cognitive outcomes in older adults with AD. We searched the Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and Embase up to November 2023. Using the Cochrane Risk of Bias tool (Rob2) for quality assessment and R software with the MBNMA package for data analysis, we determined standard mean differences (SMDs) and 95% confidence intervals (95%CrI) to evaluate exercise's impact on cognitive function in AD. Results Twenty-seven studies with 2,242 AD patients revealed a nonlinear relationship between exercise and cognitive improvement in AD patients. We observed significant cognitive enhancements at an effective exercise dose of up to 1000 METs-min/week (SMDs: 0.535, SD: 0.269, 95% CrI: 0.023 to 1.092). The optimal dose was found to be 650 METs-min/week (SMDs: 0.691, SD: 0.169, 95% CrI: 0.373 to 1.039), with AE (Aerobic exercise) being particularly effective. For AE, the optimal cognitive enhancement dose was determined to be 660 METs-min/week (SMDs: 0.909, SD: 0.219, 95% CrI: 0.495 to 1.362). Conclusion Nonlinear dose–response relationship between exercise and cognitive improvement in Alzheimer’s disease, with the optimal AE dose identified at 660 METs-min/week for enhancing cognitive function in AD.

The relative efficacy of various mind–body exercises in the treatment of depressive symptoms remains uncertain. We examined the optimal modalities (Tai Chi, qigong, yoga) and dose of mind–body exercise to improve depressive symptoms in adults. A systematic search of six electronic databases for randomized controlled trials on the relationship between exercise and depression was carried out, encompassing data from their inception up to November 2023. Pairwise analyses, network analyses and dose–response meta‐analyses using random‐effects models were performed to analyse the effect of exercise on depression. Forty studies were included. Results showed that Yoga [standardised mean difference (SMD) = −0.55; 95% confidence interval (CI): (−0.76, −0.35)] was the most effective form of exercise for improving depressive symptoms, followed by Qigong (SMD = −0.52; 95%CI: −0.92, −0.11) and Tai Chi exercise (SMD = −0.42; 95%CI: −0.71, −0.13). In addition, a non‐linear dose–response relationship was found between overall mind–body exercise dose and depression levels and a significant response was observed after 260 METs‐min. Our study examined the effectiveness of different types of mind–body exercise in improving depression and found that yoga may be the most effective adjunctive intervention. There was a non‐linear dose–response relationship between total exercise and depression levels. However, caution should be exercised in interpreting and applying these results. [ABSTRACT FROM AUTHOR]

Network meta-analysis has been used to answer a range of clinical questions about the preferred intervention for a given condition. Although the effectiveness and safety of pharmacological agents depend on the dose administered, network meta-analysis applications typically ignore the role that drugs dosage plays in the results. This leads to more heterogeneity in the network. In this paper, we present a suite of network meta-analysis models that incorporate the dose–effect relationship using restricted cubic splines. We extend existing models into a dose–effect network meta-regression to account for study-level covariates and for groups of agents in a class-effect dose–effect network meta-analysis model. We apply our models to a network of aggregate data about the efficacy of 21 antidepressants and placebo for depression. We find that all antidepressants are more efficacious than placebo after a certain dose. Also, we identify the dose level at which each antidepressant's effect exceeds that of placebo and estimate the dose beyond which the effect of antidepressants no longer increases. When covariates were introduced to the model, we find that studies with small sample size tend to exaggerate antidepressants efficacy for several of the drugs. Our dose–effect network meta-analysis model with restricted cubic splines provides a flexible approach to modelling the dose–effect relationship in multiple interventions. Decision-makers can use our model to inform treatment choice. [ABSTRACT FROM AUTHOR]

Arguably the most famous principle of toxicology is "The dose makes the poison" formulated by Paracelsus in the 16th century. Application of the Paracelsus's principle to mechanistic toxicology may be challenging as one compound may affect many molecular pathways at different doses with different and often nonlinear dose-response relationships. As a result, many mechanistic studies of environmental and occupational compounds use high doses of xenobiotics motivated by the need to see a clear signal indicating disruption of a particular molecular pathway. This approach ignores the possibility that the same xenobiotic may affect different molecular mechanism(s) at much lower doses relevant to human exposures. To amend mechanistic toxicology with a simple and concise guiding principle, I suggest recontextualization of Paracelsus's following its letter and spirit: "The dose disrupts the pathway". Justification of this statement includes observations that many environmental and occupational xenobiotics affect a broad range of molecular cascades, that most molecular pathways are sensitive to chemical exposures, and that different molecular pathways are sensitive to different doses of a chemical compound. I suggest that this statement may become a useful guidance and educational tool in a range of toxicological applications, including experimental design, comparative analysis of mechanistic hypotheses, evaluation of the quality of toxicological studies, and risk assessment. [ABSTRACT FROM AUTHOR]

Depression is a growing public health concern, and exercise is an adjunctive treatment modality to improve depression, but the optimal form of exercise and the optimal dose are still unclear. This systematic review examined the efficacy of four major types of exercise (aerobic, resistance, mixed, and mind-body) on depression, as well as the dose-response relationship between total and specific exercise and depressive symptoms. We included randomized controlled trials that included participants aged 18 years or older with a diagnosis of major depressive disorder or a depressive symptom score above a threshold as determined by a validated screening measure, implemented one or more exercise therapy groups, and assessed depressive symptoms at baseline and follow-up. Forty-six studies (3164 patients) were included in the meta-analysis. Aerobic (standardised mean difference (SMD) = -0.93; 95% CI: -1.25 to -0.62) and mind-body exercise (SMD) = -0.81; 95% CI: -1.19 to -0.42) improved depressive symptoms better compared to controls, followed by mixed (SMD = -0.77; 95% CI: -1.20 to -0.34) and resistance exercise (SMD = -0.76; 95% CI: -1.24 to -0.28). This dose-response meta-analysis showed a U-shaped curve between exercise dose and depressive symptoms. The minimum effective dose was estimated to be 320 metabolic equivalent (METs) -min per week and the optimal response was 860 METs-min per week. These findings lead us to advocate that clinicians carefully select the appropriate dose of exercise based on the patient's individual characteristics and needs, in conjunction with psychological care interventions. • Aerobic, resistance, mixed and mind-body exercise interventions have significant and comparable benefits in improving clinical depressive symptoms in patients with MDD. • There was a U-shaped dose-response relationship between overall exercise volume and depression level, with the maximum significant response occurring at 860 METs-min, and a minimal clinically meaningful difference (MCID) in depression improvement with 477 METs-min of exercise per week. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated condition of the central nervous system (CNS). Intake of fruits and vegetables high in vitamins, minerals, fiber, and active molecules contributes to the body's overall health, immunity, and physiological function. This study sought to review the literature and investigate the relationship between fruits and vegetables consumption and MS odds. In the current systematic review and meta-analysis, a systematic search of original databases from inception to 21 Dec 2022 was conducted based on the PRISMA 2020 statement. Human observational studies examining the association between fruits or vegetables consumption and MS prevalence were included if they reported and provided effect size with 95% confidence intervals (CIs). The systematic review and meta-analysis included eight studies. Random effect model showed the protective effect of fruits (I2 = 81.0%, P for heterogeneity < 0.001; pooled OR = 0.52, 95%CI = 0.27, 0.97, P-value = 0.042) and vegetables consumption (I2 = 73.5%, P for heterogeneity = 0.002; pooled OR = 0.61, 95%CI = 0.38, 1.00, P-value = 0.050) on MS odds. According to a linear dose–response meta-analysis of four case–control studies, an increase of 100 grams of fruits per day reduced the odds of MS by 9% (I2 = 0.0%, P for heterogeneity = 0.77; pooled OR = 0.91, 95%CI = 0.83, 0.99, P-value = 0.021). Consumption of fruits and vegetables may be associated with a potential protective effect against MS. However, further confirmation is required through prospective longitudinal studies and randomized clinical trials. [ABSTRACT FROM AUTHOR]

The association between underweight and pressure injuries (PIs) has been established in several studies. However, there is a lack of well-designed research investigating the connection between overweight and obesity with these injuries. This meta-analysis aims to investigate the dose-response relationship between body mass index (BMI) and the risk of PIs in adult hospitalized patients. PubMed, Web of Science, and MEDLINE Databases were searched from inception to May 2024. Observational articles with at least three BMI categories were included in the study. BMI was defined as underweight, normal weight, overweight, and morbid obesity for the meta-analysis. The non-linear relationship between BMI and the risk of PIs in hospitalized adults was investigated using restricted cubic spline models. Fractional polynomial modeling was used. Eleven articles reporting at least 3 categories of BMI met the inclusion criteria, including 31,389 participants. Compared to patients with normal weight, those with underweight, obesity, and morbid obesity exhibited an increased risk of PIs, with odds ratios of 1.70 (95%CI:1.50–1.91), 1.12 (95%CI:1.02–1.24), 1.70 (95%CI:1.13–2.55), respectively. A J-shaped dose-response model was established for the relationship between PI risk and BMI (P non-linearity < 0.001, P linearity = 0.745). The J-shaped dose-response pattern revealed that underweight, obesity and morbid obesity heightened the risk of PIs in hospitalized adults. Lower and higher BMI values may signify an increased risk for PIs, particularly among the elderly with lower BMI, providing valuable guidance for medical staff. • A J-shaped dose-response model was established for the relationship between PI risk and BMI (P non-linearity < 0.001). • Underweight, obese, and morbidly obese patients have higher PI risk than normal weight ones. • Lower and higher BMI values may signify an increased risk for PIs, particularly among the elderly with lower BMI. [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]

Plants must cope with ever-changing temperature conditions in their environment. In many plant species, suboptimal high and low temperatures can induce adaptive mechanisms that allow optimal performance. Thermomorphogenesis is the acclimation to high ambient temperature, whereas cold acclimation refers to the acquisition of cold tolerance following a period of low temperatures. The molecular mechanisms underlying thermomorphogenesis and cold acclimation are increasingly well understood but neither signalling components that have an apparent role in acclimation to both cold and warmth, nor factors determining dose-responsiveness, are currently well defined. This can be explained in part by practical limitations, as applying temperature gradients requires the use of multiple growth conditions simultaneously, usually unavailable in research laboratories. Here we demonstrate that commercially available thermal gradient tables can be used to grow and assess plants over a defined and adjustable steep temperature gradient within one experiment. We describe technical and thermodynamic aspects and provide considerations for plant growth and treatment. We show that plants display the expected morphological, physiological, developmental and molecular responses that are typically associated with high temperature and cold acclimation. This includes temperature dose-response effects on seed germination, hypocotyl elongation, leaf development, hyponasty, rosette growth, temperature marker gene expression, stomatal conductance, chlorophyll content, ion leakage and hydrogen peroxide levels. In conclusion, thermal gradient table systems enable standardized and predictable environments to study plant responses to varying temperature regimes and can be swiftly implemented in research on temperature signalling and response. [ABSTRACT FROM AUTHOR]

AbstractObjectivesMethodResultsConclusionTo evaluate and rank the effectiveness of specific non-pharmacological treatments (NPTs) in improving the global cognitive function in individuals with Alzheimer’s disease (AD) and to examine the dose-response relationship.We conducted a systematic search in PubMed, MEDLINE, Embase, PsycINFO, CENTRAL, WOS, and CNKI from their inception to 15 February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models.We included 68 studies involving 5053 participants in this meta-analysis. The treatments with the highest cumulative probabilities for improving global cognitive function were transcranial direct current stimulation (tDCS), followed by physical exercise (PE), and repetitive transcranial magnetic stimulation (rTMS). Additionally, cognitive stimulation (CS), cognitive training CT), multidisciplinary program (MD), and reminiscence treatment (RT) also significantly improve the global cognitive function of people with AD. A non-linear dose-response association was observed for tDCS, PE, rTMS, CS, and CT with global cognitive improvement. Notably, no minimal threshold was identified for the beneficial effects of PE on cognition. The estimated minimal doses for clinically relevant changes in cognition were 33 min per week for tDCS, 330 MET-min per week for PE, and 8000 pulses per week for rTMS.tDCS, PE, and rTMS are the better effective NPTs for enhancing global cognitive function in individuals with AD. Properly dosing these treatments can yield significant clinical benefits. Our findings support the clinical utility of low-dose exercise in improving cognition in people with AD. [ABSTRACT FROM AUTHOR]

Objective: To examine the dose-response relationship between specific types of exercise for alleviating Timed up and Go (TUG) in Parkinson's disease PD. Design: Systematic review and Bayesian network meta-analysis. Data sources: PubMed, Medline, Embase, PsycINFO, Cochrane Library, and Web of Science were searched from inception until February 5th, 2024. Study analysis: Data analysis was conducted using R software with the MBNMA package. Effect sizes of outcome indicators were expressed as mean deviation (MD) and 95% confidence intervals (95% CrI). The risk of bias in the network was evaluated independently by two reviewers using ROB2. Results: A total of 73 studies involving 3,354 PD patients. The text discusses dose- response relationships in improving TUG performance among PD patients across various exercise types. Notably, Aquatic (AQE), Mix Exercise (Mul_C), Sensory Exercise (SE), and Resistance Training (RT) demonstrate effective dose ranges, with AQE optimal at 1500 METs-min/week (MD: -8.359, 95% CI: -1.398 to -2.648), Mul_C at 1000 METs-min/week (MD: -4.551, 95% CI: -8.083 to -0.946), SE at 1200 METs-min/week (MD: -5.145, 95% CI: -9.643 to -0.472), and RT at 610 METs-min/week (MD: -2.187, 95% CI: -3.161 to -1.278), respectively. However, no effective doses are found for Aerobic Exercise (AE), Balance Gait Training (BGT), Dance, and Treadmill Training (TT). Mind-body exercise (MBE) shows promise with an effective range of 130 to 750 METs-min/week and an optimal dose of 750 METs-min/week (MD: -2.822, 95% CI: -4.604 to -0.996). According to the GRADE system, the included studies' overall quality of the evidence was identified moderate level. Conclusion: This study identifies specific exercise modalities and dosages that significantly enhance TUG performance in PD patients. AQE emerges as the most effective modality, with an optimal dosage of 1,500 METs-min/week. MBE shows significant benefits at lower dosages, catering to patients with varying exercise capacities. RT exhibits a nuanced "U-shaped" dose-response relationship, suggesting an optimal range balancing efficacy and the risk of overtraining. These findings advocate for tailored exercise programs in PD management, emphasizing personalized prescriptions to maximize outcomes. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. Methods: The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. Results: Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. Conclusions: Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. [ABSTRACT FROM AUTHOR]

Background and aims: Increasing levels of alcohol use are associated with a risk of developing an alcohol use disorder (AUD), which, in turn, is associated with considerable burden. Our aim was to estimate the risk relationships between alcohol consumption and AUD incidence and mortality. Method: A systematic literature search was conducted, using Medline, Embase, PsycINFO and Web of Science for case–control or cohort studies published between 1 January 2000 and 8 July 2022. These were required to report alcohol consumption, AUD incidence and/or AUD mortality (including 100% alcohol‐attributable deaths). The protocol was registered with PROSPERO (CRD42022343201). Dose–response and random‐effects meta‐analyses were used to determine the risk relationships between alcohol consumption and AUD incidence and mortality and mortality rates in AUD patients, respectively. Results: Of the 5904 reports identified, seven and three studies from high‐income countries and Brazil met the inclusion criteria for quantitative and qualitative syntheses, respectively. In addition, two primary US data sources were analyzed. Higher levels of alcohol consumption increased the risk of developing or dying from an AUD exponentially. At an average consumption of four standard drinks (assuming 10 g of pure alcohol/standard drink) per day, the risk of developing an AUD was increased sevenfold [relative risk (RR) = 7.14, 95% confidence interval (CI) = 5.13–9.93] and the risk of dying fourfold (RR = 3.94, 95% CI = 3.53–4.40) compared with current non‐drinkers. The mortality rate in AUD patients was 3.13 (95% CI = 1.07–9.13) per 1000 person‐years. Conclusions: There are exponential positive risk relationships between alcohol use and both alcohol use disorder incidence and mortality. Even at an average consumption of 20 g/day (about one large beer), the risk of developing an alcohol use disorder (AUD) is nearly threefold that of current non‐drinkers and the risk of dying from an AUD is approximately double that of current non‐drinkers. [ABSTRACT FROM AUTHOR]

Rhipicephalus microplus is the parasitic species that causes the most damage to Mexican and global livestock due to direct and indirect losses, such as the increase in multidrug resistance and cross-resistance. Currently, there are few studies on resistance to macrocyclic lactones in Mexico, most of them in the south. This study aimed to evaluate the status of ivermectin resistance in R. microplus in northeastern Mexico and its associated risk factors. A total of 20 populations of Rhipicephalus microplus were collected in the states of Veracruz, Nuevo León, Tamaulipas, and San Luis Potosí, and they were analyzed with the larval immersion test. Mortality data were subjected to a Probit analysis, estimating lethal concentrations (LC) of 50 % and 99 % and their respective 95 % confidence intervals (95 % CI), and to determine possible risk factors, a multivariate analysis and 2 x 2 contingency tables were performed for the exposure variables, with a 95 % confidence interval, and a binomial logistic regression model for those variables with a P=0.05. Eighty (80) percent of the analyzed populations showed resistance with ranges of RR50= 2.07-11.14 and RR99= 3.03-47.93 (P=0.05), and through the binomial logistic regression, it was observed that the variable of frequency of treatments obtained a P=0.0134, a result that proved to be significant. [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]

Background: Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care. Methods: Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose–response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness. Discussion: This project seeks to gain an understanding of the dose–response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia. Trial registration: ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 (https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true). [ABSTRACT FROM AUTHOR]

Compared to common salt, low-sodium salt can reduce blood pressure to varying degrees. However, the exact dosage relationship remains unclear. We aimed to investigate the dose–response relationships between low-sodium salt intake and systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as the risk of hypertension, and to determine the optimal range for low-sodium salt intake. We investigated the basic characteristics and dietary profile of 350 individuals who consumed low-sodium salt. The samples were divided into three groups according to the 33.3rd and 66.6th percentiles of low-sodium salt intake in condiments (Q1: <4.72 g/d, Q2: ≥4.72 g/d, and <6.88 g/d, and Q3: ≥6.88 g/d). The restricted cubic spline results indicated that low-sodium salt intake decreased linearly with SBP and DBP, while low-sodium intake demonstrated a non-linear, L-shaped relationship with the risk of hypertension, with a safe range of 5.81 g to 7.66 g. The multiple linear regression analysis revealed that compared with group Q1, the DBP in group Q2 decreased by 2.843 mmHg (95%CI: −5.552, −0.133), and the SBP in group Q3 decreased by 4.997 mmHg (95%CI: −9.136, −0.858). Exploratory subgroup analyses indicated that low-sodium salt intake had a significant impact on reducing SBP in males, DBP in females, SBP in rural populations, and DBP in urban populations. The intake of low-sodium salt adheres to the principle of moderation, with 5.81–7.66 g potentially serving as a pivotal threshold. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) have emerged as living biodrugs for myocardial repair and regeneration. Recent randomized controlled trials (RCTs) have reported that MSC-based therapy is safe and effective in heart failure patients; however, its dose-response relationship has yet to be established. We aimed to determine the optimal MSC dose for treating HF patients with reduced ejection fraction (EF) (HFrEF). Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane Handbook guidelines were followed. Four databases and registries, i.e., PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other websites, were searched for RCTs. Eleven RCTs with 1098 participants (treatment group, n = 606; control group, n = 492) were selected based on our inclusion/exclusion criteria. Two independent assessors extracted the data and performed quality assessments. The data from all eligible studies were plotted for death, major adverse cardiac events (MACE), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and 6-minute walk distance (6-MWD) as safety, efficacy, and performance parameters. For dose-escalation assessment, studies were categorized as low-dose (< 100 million cells) or high-dose (≥ 100 million cells). Results: MSC-based treatment is safe across low and high doses, with nonsignificant effects. However, low-dose treatment had a more significant protective effect than high-dose treatment. Subgroup analysis revealed the superiority of low-dose treatment in improving LVEF by 3.01% (95% CI; 0.65–5.38%) compared with high-dose treatment (-0.48%; 95% CI; -2.14-1.18). MSC treatment significantly improved the 6-MWD by 26.74 m (95% CI; 3.74–49.74 m) in the low-dose treatment group and by 36.73 m (95% CI; 6.74–66.72 m) in the high-dose treatment group. The exclusion of studies using ADRCs resulted in better safety and a significant improvement in LVEF from low- and high-dose MSC treatment. Conclusion: Low-dose MSC treatment was safe and superior to high-dose treatment in restoring efficacy and functional outcomes in heart failure patients, and further analysis in a larger patient group is warranted. [ABSTRACT FROM AUTHOR]

Objective: The effect of hormone replacement therapy (HRT) on colorectal cancer (CRC) mortality and all‐cause mortality remains unclear. We conducted a systematic review and dose–response meta‐analysis to determine the effects of HRT on CRC mortality and all‐cause mortality. Methods: We searched the electronic databases of PubMed, Embase, and The Cochrane Library for all relevant studies published until January 2024 to investigate the effects of HRT exposure on survival rates for patients with CRC. Two reviewers independently extracted individual study data and evaluated the risk of bias between the studies using the Newcastle‒Ottawa Scale. We performed a two‐stage random‐effects dose–response meta‐analysis to examine a possible nonlinear relationship between the year of HRT use and CRC mortality. Results: Ten cohort studies with 480,628 individuals were included. HRT was inversely associated with the risk of CRC mortality (hazard ratios (HR) = 0.77, 95% CI (0.68, 0.87), I2 = 69.5%, p < 0.05). The pooled results of seven cohort studies revealed a significant association between HRT and the risk of all‐cause mortality (HR = 0.71, 95% CI (0.54, 0.92), I2 = 89.6%, p < 0.05). A linear dose–response analysis (p for nonlinearity = 0.34) showed a 3% decrease in the risk of CRC for each additional year of HRT use; this decrease was significant (HR = 0.97, 95% CI (0.94, 0.99), p < 0.05). An additional linear (p for nonlinearity = 0.88) dose–response analysis showed a nonsignificant decrease in the risk of all‐cause mortality for each additional year of HRT use. Conclusions: This study suggests that the use of HRT is inversely associated with all‐cause and colorectal cancer mortality, thus causing a significant decrease in mortality rates over time. More studies are warranted to confirm this association. [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]

Simple Summary: The house fly is a pest that not only causes economic losses but also threatens human health, posing nuisance problems and mechanically transmitting pathogens that cause diseases. Although the use of pesticides has provided efficient control, resistance development has been hindering the success of traditional pesticides. In this study, we evaluated 17 essential oil components (EOCs) for their toxicity and repellency against the strains of resistant and susceptible house flies. Thymol, (+)-pulegone, eugenol, and carvacrol exhibited high toxicity to house flies with little to no resistance to the tested strains. Seven of the EOCs exhibited repellent activity towards house flies at certain concentrations. Two EOCs were attractive to house flies and can potentially serve as attractants for traps. Thymol could potentially be used as a lure and insecticide as it exhibits high toxicity and is attractive to house flies. Our screening of a wide range of EOCs provides a deeper understanding of the potential of using EOCs not only as pesticides but also as trap attractants, encouraging further investigations in house fly management using those EOCs. The house fly is a significant pest in agriculture and human health that is increasingly difficult to manage due to multiple limitations including resistance development. To explore alternative pesticides, the topical toxicity and repellency profiles of 17 essential oil components (EOCs) were evaluated against a resistant and a susceptible strain of house fly, Musca domestica L., using topical application and Y-tube olfactometers, respectively. Six of the most toxic EOCs based on the LD50 were further investigated against a susceptible strain of house fly. Thymol, (+)-pulegone, eugenol, and carvacrol were always the top four most toxic chemicals tested against the resistant house fly strain. Little to no resistance was observed to the top six EOCs based on the comparison of the results between resistant and susceptible house fly strains. P-Cymene, citronellic acid, R-(+)-limonene, linalool, γ-terpinene, estragole, and eugenol were repellent to adult house flies at certain concentrations while (-)-carvone and thymol were attractive to adult house flies. This screening of a wide variety of individual EOCs provides a stronger foundation of information for further research. This should encourage further investigation into the topical toxicity and repellency in field studies, which will provide more insight into the performance of biopesticides for house fly management and potential commercialization. [ABSTRACT FROM AUTHOR]

Carbon dioxide (CO2) is gaining interest as a tool to combat aquatic invasive species, including zebra mussels (Dreissena polymorpha). However, the effects of water chemistry on CO2 efficacy are not well described. We conducted five trials in which we exposed adult zebra mussels to a range of CO2 in water with adjusted total hardness and specific conductance. We compared dose–responses and found differences in lethal concentration to 50% of organisms (LC50) estimates ranging from 108.3 to 179.3 mg/L CO2 and lethal concentration to 90% of organisms (LC90) estimates ranging from 163.7 to 216.6 mg/L CO2. We modeled LC50 and LC90 estimates with measured water chemistry variables from the trials. We found sodium (Na+) concentration to have the strongest correlation to changes in the LC50 and specific conductance to have the strongest correlation to changes in the LC90. Our results identify water chemistry as an important factor in considering efficacious CO2 concentrations for zebra mussel control. Additional research into the physiological responses of zebra mussels exposed to CO2 may be warranted to further explain mode of action and reported selectivity. Further study could likely develop a robust and relevant model to refine CO2 applications for a wider range of water chemistries. Environ Toxicol Chem 2024;43:1312–1319. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Rationale: Clear definition of optimal positive airway pressure therapy usage in patients with obstructive sleep apnea is not possible because of scarce data on the relationship between usage hours and major clinical outcomes. Objective: To investigate the dose-response relationship between positive airway pressure usage and healthcare resource utilization and determine the minimum device usage required for benefit. Methods: A linked data set combined deidentified payer-sourced administrative medical/pharmacy claims data from more than 100 U.S. health plans and individual patient positive airway pressure usage data. Eligible adults (age ⩾18 yr) had a new obstructive sleep apnea diagnosis between June 2014 and April 2018. All received positive airway pressure therapy (AirSense 10; ResMed) with claims data for ⩾1 year before, and 2 years after, device setup. Healthcare resource utilization was determined on the basis of the number of all-cause hospitalizations and emergency room visits over 3, 12, and 24 months after positive airway pressure initiation. Results: Data from 179,188 patients showed a clear dose-response relationship between daily positive airway pressure usage and healthcare utilization. Minimum device usage required for benefit was 1-3 hours per night. There was a statistically significant decrease in hospitalizations and emergency room visits at all time points (all Ps

Background: Findings of available randomized controlled trials (RCTs) on the effects of chia are inconsistent. Although previous meta-analyses summarized available findings in this regard, some limitations may distort their findings. Moreover, none of these meta-analyses examined the dose-response association of chia on cardiometabolic risk factors (CMRFs). Therefore, the present study aimed to evaluate the effect of chia consumption on CMRFs. Methods: Relevant RCTs were included by searching the ISI Web of Science, PubMed, and Scopus databases up to June 2, 2023. Mean differences (MD) and 95 % confidence intervals (CI) were pooled using random-effects model. Results: Ten publications were included in this systematic review and the meta-analysis. The results showed a significant reduction in systolic blood pressure (SBP) (MD = -7.87 mmHg; 95 % CI: − 12.92 to − 2.82; I2 = 71.3 %, P heterogeneity = 0.004), diastolic blood pressure (MD = -6.33 mmHg; 95 %CI: − 7.33 to − 5.34, I2 = 0 %, P heterogeneity = 0.42) and high-density lipoprotein cholesterol (HDL-c) (MD = -4.09 mg/dl; 95 %CI: − 6.76 to − 1.43, I2 = 12.4 %, P heterogeneity = 0.33). However, the effects of chia on the other risk factors were not significant. Based on the dose-response analysis, a 10-g/d increase in chia consumption significantly reduced SBP (MD = -2.20 mmHg; 95 %CI: − 3.75 to − 0.66, I2 = 78.9 %, P heterogeneity < 0.001) and HDL-c (MD = -1.10 mg/dl; 95 %CI: − 1.72 to − 0.49, I2 = 0 %, P heterogeneity = 0.52). Conclusion: Chia consumption might have a beneficial effect on lowering blood pressure. Chia consumption can also lead to a slight reduction in HDL-c levels. As the quality of the included studies was mostly low, the findings should be interpreted with caution. Well-designed trials with larger sample sizes and longer duration of follow-up are needed to provide additional insight into the dose-dependent effects of chia consumption.

T-cell engagers (TCEs) represent a promising therapeutic strategy for various cancers and autoimmune disorders. These bispecific antibodies act as bridges, connecting T-cell receptors (TCRs) to target cells (either malignant or autoreactive) via interactions with specific tumour-associated antigens (TAAs) or autoantigens to form trimeric synapses, or trimers, that co-localise T-cells with target cells and stimulate their cytotoxic function. Bispecific TCEs are expected to exhibit a bell-shaped dose-response curve, with a defined optimal TCE exposure for maximizing trimer formation. The shape of the dose-response is determined by a non-trivial interplay of binding affinities, exposure and antigens expression levels. Furthermore, excessively low binding to the TCR may reduce efficacy, but mitigate risk of over-stimulating cytokine secretion or induce effector cell exhaustion. These inevitable trade-off highlights the importance of quantitatively understanding the relationship between TCE concentration, target expression, binding affinities, and trimer formation. We utilized a mechanistic target engagement model to show that, if the TCE design parameters are close to the recommended ranges found in the literature, relative affinities for TCR, TAA and target expression levels have qualitatively different, but predictable, effects on the resulting dose-response curve: higher expression levels shift the curve upwards, higher antigen affinity shifts the curve to the left, and higher TCR affinity shifts the curve upwards and to the left.

Background: A high body mass index (BMI) increases the risk of hypertension. However, little is known about the dose-dependent association between BMI and hypertension. Therefore, this study investigated the prevalence of hypertension in 7568 subjects from the Jiangsu Province, Eastern China, and analyzed the dose–response relationship between BMI and hypertension risk. Methods: The eligible subjects completed a structured questionnaire and clinical biochemical indicators were measured according to standardized protocols. Multivariate logistic regression models were used to evaluate the association between BMI and hypertension. Restricted cubic spline (RCS) analysis was used to analyze the dose–response relationship between BMI and hypertension risk. Moreover, sensitivity analysis was performed to verify the robustness of our findings. Results: The prevalence of hypertension was 35.3 % in the total population. BMI was significantly associated with systolic and diastolic blood pressure. The fully-adjusted odds ratio (OR) with 95 % confidence interval (CI) for hypertension was 1.17 (1.15, 1.19) for every 1 kg/m2 increase in BMI. Furthermore, the OR (95 % CI) for hypertension in the highest BMI group (Obesity) was 4.14 (3.45, 4.96) after adjusting for covariates compared with the normal group. Multivariable adjusted RCS analysis showed a positive and linear dose–response relationship between BMI and hypertension risk both in male and female populations (all P for non-linearity > 0.05). Conclusion: Our study demonstrated a positive and linear dose–response relationship between BMI and the risk of hypertension. The results of this study provide evidence for BMI-related clinical interventions to reduce the risk of hypertension.

ObjectiveThe aim of this cross-sectional study was to investigate the association of HEI-2015 and overactive bladder (OAB) in a large population.MethodsData were retrieved from the National Health and Nutrition Examination Survey (NHANES) 2005–2020 datasets. Univariate and multivariate logistic regression were performed to evaluate the association between HEI-2015 and OAB. The restricted cubic spline (RCS) model was conducted to investigate the dose–response relationship.ResultsTotally, this study included 29,206 participants with 6,184 OAB patients among them. The higher continuous HEI-2015 value was independently associated with lower OAB incidence (OR: 0.87; 95%CI: 0.78, 0.98). Similarly, the highest quartile categorical HEI-2015 was significantly associated with a lower OAB odds (OR: 0.72; 95%CI: 0.52, 0.99) when compared with the lowest quartile. The RCS curve also showed a favorable non-linear dose–response relationship between HEI-2015 and OAB.ConclusionA higher HEI-2015 had a favorable association with OAB and there was a non-linear dose–response relationship between them. We suggest adherence to the United States diet recommendation as a potential behavioral prevention of OAB. Large-scale long term prospective cohort studies across various regions are needed to verify the findings of this paper.

PurposeThis cross-sectional study conducted in the general US population investigated the association between dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the prevalence of AMD.MethodsData from the National Health and Nutrition Examination Survey (NHANES) were utilized, including 4,842 participants aged 40 years and older. Dietary EPA and DHA intake data were collected through two 24-h dietary recall interviews and adjusted for weight. AMD was determined by a standardized grading system based on the presence of key features of AMD in color photographs of the macula. Multivariate logistic regression and restricted cubic spline models evaluated the associations between dietary EPA and DHA intake and AMD. Subgroup analysis and interaction analysis explored the influence of covariates.ResultsA total of 4,842 participants were included. In the multivariate-adjusted model 2, the odds ratios (ORs) with 95% confidence intervals (CIs) for AMD were 0.86 (0.75, 0.99) and 0.88 (0.80, 0.97) per unit increase in dietary EPA and DHA intake, respectively. Interaction testing revealed significant effect modification by age, education, and BMI on the EPA-AMD association, indicating these factors significantly impacted this inverse relationship (p-interaction < 0.05). Similarly, age, education, BMI, and cataract surgery history modified the inverse DHA-AMD association (p-interaction < 0.05). Dose-response analyses demonstrated a negative correlation between dietary EPA and DHA intake with AMD prevalence (p-nonlinearity = 0.184 and 0.548, respectively).ConclusionOur findings suggested that higher dietary EPA and DHA intake could be associated with lower AMD risk in older US adults. Age, education level, BMI, and history of cataract surgery may influence this inverse association.