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Objectives: The present study aimed to meta-analytically estimate the dose-response relationship of atomoxetine for treating children with ADHD. Methods: We systematically searched double-blind randomized placebo-controlled trials that evaluated the effectiveness of atomoxetine for treating ADHD in children. The search was carried out in PubMed, Cochrane Library, CINHAL, and ClinicalTrials.gov databases, covering articles from their inception until January 20, 2023. In addition, a dose-response meta-analysis was conducted. Results: In this dose-response meta-analysis, 12 double-blind randomized placebo-controlled trials involving 2,250 patients were included. The efficacy of atomoxetine increased up to a dosage of 1.4 mg/kg, after which it reached a plateau. Conclusions: The first dose-response meta-analysis of atomoxetine dosing for children with ADHD conducted here enhances the robustness of the Food and Drug Administration and the European Medicines Agency dose recommendations. [ABSTRACT FROM AUTHOR]

Combination therapies with multiple mechanisms of action can offer improved efficacy and/or safety profiles when compared to a single therapy with one mechanism of action. Consequently, the number of combination therapy studies have increased multi-fold, both in oncology and non-oncology indications. However, identifying the optimal doses of each drug in a combination therapy can require a large sample size and prolong study timelines, especially when full factorial designs are used. In this paper, we extend the MCP-Mod design of Bretz, Pinheiro, and Branson to a three-dimensional space to model the dose-response surface of a two-drug combination under the framework of Combination (Comb) MCP-Mod. The resulting model yields a set of dosages for each drug in the combination that elicits the target response so that an optimal dose for the combination can be selected for pivotal studies. We construct three-dimensional dose-response models for the combination and formulate the contrast test statistic to select the best model, which can then be used to select the optimal dose. Guidance to calculate power and sample size calculations are provided to assist study design. Simulation studies show that Comb MCP-Mod performs as well as the conventional multiple comparisons approach in controlling the family-wise error rate at the desired alpha level. However, Comb MCP-Mod is more powerful than the classical multiple comparisons approach in detecting dose-response relationships when treatment is non-null. The probability of correctly identifying the underlying dose-response relationship is generally higher when using Comb MCP-Mod than when using the multiple comparisons approach. [ABSTRACT FROM AUTHOR]

Background: Deep sternal wound infection (DSWI) constitutes a serious complication after coronary artery bypass grafting (CABG) surgery. The aim of this study is to evaluate the dose-response relationship between glycated hemoglobin (HbA1c) level and the risk of DSWI after CABG. Methods: PubMed, Scopus, and Cochrane Library databases were searched to identify potentially relevant articles. According to rigorous inclusion and exclusion criteria, fourteen studies including 15,570 patients were enrolled in our meta-analysis. Odds ratio (OR) with 95% confidence intervals (CIs) was used as the summary statistic. The robust-error meta-regression model was used to synthesize the dose-response relationship. Results: Our meta-analysis shows that among patients undergoing CABG, preoperative elevated HbA1c was associated with the risk of developing DSWI (OR = 2.67, 95% CI 2.00–3.58) but with low prognostic accuracy (diagnostic OR = 2.70, 95% CI 1.96–3.73; area under the curve = 0.66, 95% CI 0.62–0.70) for predicting postoperative DSWI. Subgroup analyses showed the relationship became nonsignificant in patients without diabetes and studies adopting lower HbA1c thresholds. Dose-response analysis showed a significant nonlinear (p = 0.03) relationship between HbA1c and DSWI, with a significantly increased risk of DSWI when HbA1c was > 5.7%. Conclusions: An elevated HbA1c level of > 5.7% was related to a higher risk of developing DSWI after CABG, and the risk increased as the HbA1c level grew. The association between HbA1c and DSWI was nonsignificant among nondiabetic patients while significant among diabetic patients. [ABSTRACT FROM AUTHOR]

Background: The N-methyl-D-aspartate antagonist ketamine has rapid onset antidepressant activity in treatment-resistant depression (TRD). Aims: To evaluate mood rating, safety and tolerability data from patients with TRD treated with ketamine and the psychoactive control fentanyl, as part of a larger study to explore EEG biomarkers associated with mood response. Methods: We evaluated the efficacy and safety of intramuscular racemic ketamine in 25 patients with TRD, using a double-blind active-controlled randomized crossover design. Ketamine doses were 0.5 and 1 mg/kg, and the psychoactive control was fentanyl 50 mcg, given at weekly intervals. Results/outcomes: Within 1 h of ketamine dosing, patients reported reduced depression and anxiety ratings, which persisted for up to 7 days. A dose–response profile for ketamine was noted for dissociative side effects, adverse events and changes in blood pressure; however, changes in mood ratings were broadly similar for both ketamine doses. Overall, 14/25 patients (56%) were responders (⩾50% reduction at 24 h compared with baseline) for either ketamine dose for the Hospital Anxiety and Depression Scale (HADS), and 18/25 (72%) were responders for the HADS-anxiety scale. After fentanyl, only 1/25 (HADS-depression) and 3/25 (HADS-anxiety) were responders. Ketamine was generally safe and well tolerated in this population. Conclusions: Our findings add to the literature confirming ketamine's activity against depressive and anxiety symptoms in patients with TRD. [ABSTRACT FROM AUTHOR]

The solution combustion synthesis method is employed to prepare Magnesium, Zinc, Aluminate doped with dysprosium (Dy3+) using the general formula Mg(1‐x‐y) Zn(y)Al2O4:xDy (x = 0.05 and y = 0.3 mol%). From X‐ray diffraction studies, the crystal structure belongs to a cubic close‐packed spinel structure with space group Fd3ˉm and an average crystallite size is 26.18 nm. In the Fourier transform infrared spectra, the peaks at 683.69 cm−1, 503.12 cm−1 correspond to the AlO6 groups. The peak temperature (Tm) from the Thermoluminescent glow curve is recorded at 235°C, 237°C, and 235°C, at irradiation doses of 600 Gy, 800 Gy, and 1000 Gy, respectively. The kinetic parameters are evaluated from the thermoluminescent glow curve by calculating the activation energy (E), order of kinetics (b), and frequency factor (s−1). Nanophosphor Mg0.65Zn0.3Al2O4:0.05Dy shows sub linear dose relationship at doses 600–675 Gy and 925–1000 Gy. Further, at doses between 675 and 925 Gy, it shows a super linear relationship. The optimum activation energy (E) of 0.77–0.82 eV and negligible fading make it suitable for high radiation thermoluminescent dosimetry. [ABSTRACT FROM AUTHOR]

Background: Ondansetron has been reported to attenuate the incidence of spinal anaesthesia-induced hypotension (SAIH) and norepinephrine requirement during caesarean section. However, no quantitative study has evaluated the extent of this effect. This study aimed to determine the dose-response of prophylactic infusion of norepinephrine to prevent SAIH in parturients who received intravenous ondansetron or placebo before spinal anaesthesia for caesarean section. The median effective dose (ED50) and 90% effective dose (ED90) were compared to evaluate the effect of ondansetron versus placebo on the norepinephrine requirement. Materials and methods: One hundred fifty parturients undergoing caesarean section were randomized to receive either 0.1 mg/kg ondansetron (group O) or saline control (group C) 10 min before spinal anaesthesia. The parturients were randomly assigned to one of five different norepinephrine infusion groups: 0.02, 0.04, 0.06, 0.08 or 0.10 μg/kg/min. An effective infusion dose of norepinephrine was defined as non-occurrence of hypotension during the study period. The values for ED50 and ED90 of norepinephrine infusion were determined using probit regression. Differences between the two groups were evaluated by comparing the relative median potency with 95% CIs. Results: The ED50 values were 0.033 (95% CIs, 0.024-0.043) μg/kg/min in group C and 0.021 (95%CIs, 0.013-0.029) μg/kg/min in group O. The ED90 values were 0.091 (95% CIs 0.068-0.147) μg/kg/min in group C and 0.059 (95% CIs 0.044-0.089) μg/kg/min in group O, respectively. The estimate of the relative median potency for norepinephrine in group C versus group O was 0.643 (95% CIs, 0.363-0.956). The incidence of side effects was comparable between groups. No significant difference in neonatal outcomes. Conclusion: Intravenous ondansetron 0.1 mg/kg before spinal anaesthesia significantly reduced the dose requirement of prophylactic norepinephrine infusion in parturients undergoing elective caesarean section. This finding is potentially useful for clinical practice and further research. [ABSTRACT FROM AUTHOR]

Whether coffee consumption is associated with changes in estimated glomerular filtration rate (eGFR) is unknown. We investigated the relationship between coffee consumption and annual eGFR change in a large Dutch population-based study. This study was performed in 78,346 participants without chronic kidney disease (CKD) in the population-based Lifelines Cohort Study. Coffee consumption was assessed at baseline using food frequency questionnaires. Outcomes were annual eGFR change and a composite kidney outcome (defined as eGFR <60 mL/min per 1.73 m2 or >20 % eGFR decline). Multivariable linear and logistic regression analyses were used to evaluate the associations of coffee consumption (categories and cups/day) with kidney outcomes. Overall, 90 % of the participants drank coffee daily and 36 % drank >2–4 cups/day. Unadjusted mean ± SD annual eGFR change ranged from −2.86 ± 2.96 (for non-coffee drinkers) to −2.35 ± 2.62 (for participants consuming >6 cups/day) mL/min per 1.73 m2. During 3.6 ± 0.9 years follow-up, 11.1 % of participants reached the composite kidney outcome. As compared to non-coffee drinkers, higher coffee consumption was associated with less annual eGFR decline in multivariable models (β [95 % CIs] ranged from 0.15 [0.07, 0.22] for >0–2 cups/day to 0.29 [0.20, 0.38] for >6 cups/day, P-trend <0.001). Consumption of one more cup of coffee per day was associated with a 3 % lower risk of the composite kidney outcome (OR [95%CI], 0.97 [0.96, 0.99]). The inverse association was more pronounced in a subgroup of individuals with diabetes. Coffee consumption was inversely associated with annual eGFR change and CKD risk in a large Dutch population-based cohort. • In a general Dutch population, coffee drinkers experienced a slower kidney function decline over time, compared to non-coffee drinkers. • Coffee was related to a lower risk of chronic kidney disease in a dose-dependent manner, especially in individuals with diabetes. • Filtered, unsweetened coffee may be considered as a healthy beverage in a kidney-friendly diet. • Beneficial effects of coffee on the kidneys warrant confirmation in randomised controlled trials. [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]

Although dose-response analyses are a fundamental tool in developmental toxicology, few studies have examined the impacts of toxicant dose on the non-genetic paternal inheritance of offspring disease and dysgenesis. In this study, we used geometric morphometric analyses to examine the impacts of different levels of preconception paternal alcohol exposure on offspring craniofacial shape and symmetry in a mouse model. Procrustes ANOVA followed by canonical variant analysis of geometric facial relationships revealed that Low-, Medium-, and High-dose treatments each induced distinct changes in craniofacial shape and symmetry. Our analyses identified a dose threshold between 1.543 and 2.321 g/kg/day. Below this threshold, preconception paternal alcohol exposure induced changes in facial shape, including a right shift in facial features. In contrast, above this threshold, paternal exposures caused shifts in both shape and center, disrupting facial symmetry. Consistent with previous clinical studies, changes in craniofacial shape predominantly mapped to regions in the lower portion of the face, including the mandible (lower jaw) and maxilla (upper jaw). Notably, high-dose exposures also impacted the positioning of the right eye. Our studies reveal that paternal alcohol use may be an unrecognized factor contributing to the incidence and severity of alcohol-related craniofacial defects, complicating diagnostics of fetal alcohol spectrum disorders.

BackgroundHearing loss (HL) is increasingly recognized as a significant global public health issue, and research on its relationship with vitamin D levels has gained wider attention. However, the association between serum biomarkers 25-hydroxyvitamin D2 (25(OH)D2) and D3 (25(OH)D3) with different types of HL remains unclear. This study aimed to investigate the potential association of serum 25(OH)D2 and 25(OH)D3 with HL in US adults.MethodsA sample of 3,684 individuals aged 20–69 years from the 2015–2016 National Health and Nutrition Examination (NHANES) was analyzed in this study. HL was defined as a pure tone average > 25 dB in either ear at low frequencies (500, 1,000, 2000 Hz), speech frequencies (500, 1,000, 2000, 4,000 Hz), and high frequencies (3,000, 4,000, 6,000, 8,000 Hz). Logistic regression was employed to examine the association between serum 25(OH)D2 and 25(OH)D3 and HL. The study population was then stratified by age, gender, race, and education level to analyze potential differences between adults in different subgroups.ResultsIn the multivariate analysis, it was found that serum 25(OH)D2 was independently associated with low-frequency hearing loss (LFHL) (OR: 1.012 [95% CI, 1.005–1.020]) and speech-frequency hearing loss (SFHL) (OR: 1.011 [95% CI, 1.003–1.018]). Restrictive cubic spline analysis demonstrated a linear dose–response relationship between serum 25(OH)D2 levels and LFHL (p for linearity

Background Insulin resistance (IR) is closely linked to cardiometabolic diseases. Preventing and improving IR in nondiabetic populations is critically important. We aimed to investigate the relationship between Life's Essential 8 (LE8), the latest tool from the American Heart Association quantifying cardiovascular health, and IR among nondiabetic populations in the United States. Methods and Results This cross‐sectional study used data on 11 246 nondiabetic adults aged ≥20 years from the 2005 to 2018 the National Health and Nutrition Examination Survey. The LE8 score was classified into 2 subscale scores: health factor score and health behavior score. IR was measured by homeostasis model assessment of insulin resistance (HOMA‐IR). Weighted logistic and linear regression models analyzed associations among the LE8 score, health behavior score, health factor score, and IR. Restricted cubic spline models assessed dose–response relationships. Adjusted subgroup analyses and inverse probability of treatment weighting method also evaluated the LE8‐IR relationship. Of the 11 246 participants, 4860 (43.2%) had IR. The mean LE8 score was 70.07 (95% CI, 69.57–70.58). In fully adjusted models, higher LE8 scores were associated with lower IR odds (odds ratio per 10‐unit increase, 0.57 [95% CI, 0.54–0.61]). Nonlinear LE8‐IR dose–response was observed. Similar patterns were seen for health behavior and health factor subscores, with stronger IR correlations for health factors. The inverse LE8‐IR association was significantly more pronounced among White participants and those with higher education, higher income, and without hypertension, cardiovascular disease, or chronic kidney disease. Significant negative LE8‐IR associations persisted after inverse probability of treatment weighting. Conclusions LE8 and subscale scores are negatively associated with IR in a nonlinear relationship. Promoting optimal cardiovascular health adherence may improve IR in nondiabetic populations.

BackgroundAlcohol consumption has been associated with the occurrence of many health conditions. We analyzed UK Biobank data to explore associations of various conditions to type and amount of alcohol consumed. UK Biobank is a large biomedical database providing information from UK participants, including lifestyle questionnaires and diagnosis data.MethodsUsing UK Biobank, we examined the relationship between weekly alcohol consumption, alcohol type and the incidence of eight select conditions. We calculated counts of individuals consuming each type diagnosed with these conditions. To assess the effect of alcohol consumption on each condition’s prevalence, we used log-logistic regression models to generate dose–response models for each alcohol type.ResultsThe alcohol consumed included: red wine (228,439 participants), white wine (188811), beer (182648), spirits (129418), and fortified wine (34598). We observed increased condition prevalence with increasing amounts of alcohol. This was especially seen for chronic obstructive lung disease, cirrhosis of liver, hypertension, gastritis, and type 2 diabetes. Beer consumers showed higher prevalence for most conditions while fortified wine had the largest increases in incidence rates. Only white wine showed decreased incidence for acute myocardial infarction. In general, the prevalence of many conditions was higher among alcohol consumers, particularly for hypertension, 33.8%, compared to 28.6% for non-drinkers.ConclusionAlthough many conditions were already prevalent among non-drinkers, participants consuming increasing amounts of alcohol had increased incidence rates for many of the studied conditions. This was especially true for consumers of beer and fortified wine, but also true to a lesser extent for consumers of spirits, red and white wine.

Background Engaging in appropriate physical activity can significantly lower the risk of various diseases among middle-aged and older adults. Investigating optimal levels of physical activity (PA) is crucial for enhancing the health of this demographic. This study aims to explore the dose–response relationship between weekly PA levels and the frequency of colds among Chinese middle-aged and elderly individuals, identifying the necessary PA level to effectively diminish the risk of colds. Methods We conducted a cross-sectional study using a web-based survey targeting individuals aged 40 and older (n = 1, 683) in China. The survey collected information on PA and the frequency of colds. Data was analyzed using Kruskal–Wallis test and the χ2 test. We explored the dose–response relationship between weekly PA and cold frequency over the past year through an ordered multivariate logistic regression model and a restricted cubic spline model. Results (1) Brisk walking emerged as the preferred physical exercise for those over 40. The findings suggest that engaging in moderate (odds ratio (OR) = 0.64, P

Purpose: Although examining the dose-response curves of physical activity (PA) and sitting time with health-related outcomes is an important research agenda, the results for older Japanese adults are extremely limited. We examined the dose-response associations of PA and sitting time with all-cause mortality among older Japanese. Methods: Initially, 8,069 non-disabled residents (4,073 men; 3,996 women) aged 65–84 years of Ota City, Japan, were analyzed. Moderate-to-vigorous PA (MVPA) and sitting time were evaluated using the International Physical Activity Questionnaire-Short Form. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of MVPA and sitting time for all-cause mortality were calculated, and the dose-response curves were examined using restricted cubic splines (RCS). Results: During 4.1 years of follow-up, 458 participants (5.7%; 331 men and 127 women) died. Compared with the low MVPA (3,000 METs·minutes/week) MVPA groups (moderate: HR 0.66; 95% CI, 0.54–0.82; high: HR 0.58; 95% CI, 0.45–0.75; P < 0.001 for trend). RCS showed that the HR for mortality reduced linearly up to approximately 2,000 METs·minutes/week of MVPA, and maximal risk reduction was seen at approximately 3,000–4,500 METs·minutes/week of MVPA. No significant dose-response association of sitting time with mortality was observed. Conclusion: Higher MVPA levels reduced all-cause mortality risk, in a significant inverse non-linear dose-response manner. Sitting time was not significantly associated with all-cause mortality. It is important to disseminate the significance of even a slight increase in the MVPA for reducing mortality risk.

Abstract Background Effective exercise for the frail elderly has been found to contribute to healthy aging; the corresponding relationship between intensity and volume of exercise and health effects remains unclear. The present study aimed to investigate the dose–response effects of resistance training on muscle strength and physical fitness in frail older adults. Methods In this randomized controlled trial, participants were randomized into seven groups: moderate‐volume low‐intensity, moderate‐volume moderate‐intensity, moderate‐volume high‐intensity, high‐volume low‐intensity, high‐volume moderate‐intensity, high‐volume high‐intensity and routine care, receiving 12 weeks of resistance training of different intensities and volumes of exercise. The outcomes were muscle strength (assessed by ergonomics force gauges) and physical fitness function (assessed by the 6‐min walking test [6MWT], the 30‐s sit‐to‐stand test [30sSTST] and the 8‐foot up‐and‐go test [8‐FUGT]) before and at 6 and 12 weeks of intervention. Results A total of 161 participants completed the exercise intervention. There were no significant differences in age, sex, height, body weight and body mass index among the seven groups. The exercise volume of resistance training showed linear relationships with muscle strength of the lower limbs, 30sSTST and 6MWT results and a non‐linear relationship with 8‐FUGT. Resistance training intensity was found to have a linear relationship with muscle strength of the lower limbs and 6MWT and non‐linear relationships with 30sSTST and 8‐FUGT. The mixed linear model analysis revealed that the lower limb muscle strength differed significantly before and during the intervention (W = 8571.5, Padj

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.

Background: Running can improve health status from a biopsychosocial perspective. However, isolation strategies, like the COVID-19 pandemic-induced lockdown, produce deleterious effects on both health status and sport performance. The aim of our study was to investigate recreational runners’ sporting habits, subjective vitality (SV), and well-being after the COVID-19 pandemic-induced lockdown. Methods: After data filtration, 5542 recreational runners (74.5% men and 25.5% women, >18 years) were selected for further analyses. The participants answered preliminary questions regarding sporting habits and completed the validated Spanish version of the Subjective Vitality as a Dynamic Reflection of Well-Being questionnaire for assessing their SV after lockdown. Results: Subjective vitality scores did not differ between men and women, nor between age groups (p = 0.41 and p = 0.11, respectively). Subjective vitality was greater with weekly training frequency up to 5 days/week, where this enhancement plateaued, while average training session duration was positively related to SV, stabilizing at 91–120 min/session (p < 0.001 for both). Conclusions: There is a dose–response relationship between both weekly training frequency and training session duration, and mental health benefits in recreational runners. Further longitudinal studies are needed in order to determine the optimal dose–response relationship for simultaneously enhancing mental health outcomes and running performance in recreational runners, especially regarding weekly training frequency, training session duration, and exercise intensity.

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.

BackgroundTrauma is the leading cause of death and disability in children in the USA. Tranexamic acid (TXA) reduces the blood transfusion requirements in adults and children during surgery. Several studies have evaluated TXA in adults with hemorrhagic trauma, but no randomized controlled trials have occurred in children with trauma. We propose a Bayesian adaptive clinical trial to investigate TXA in children with brain and/or torso hemorrhagic trauma.Methods/designWe designed a double-blind, Bayesian adaptive clinical trial that will enroll up to 2000 patients. We extend the traditional Emax dose-response model to incorporate a hierarchical structure so multiple doses of TXA can be evaluated in different injury populations (isolated head injury, isolated torso injury, or both head and torso injury). Up to 3 doses of TXA (15 mg/kg, 30 mg/kg, and 45 mg/kg bolus doses) will be compared to placebo. Equal allocation between placebo, 15 mg/kg, and 30 mg/kg will be used for an initial period within each injury group. Depending on the dose-response curve, the 45 mg/kg arm may open in an injury group if there is a trend towards increasing efficacy based on the observed relationship using the data from the lower doses. Response-adaptive randomization allows each injury group to differ in allocation proportions of TXA so an optimal dose can be identified for each injury group. Frequent interim stopping periods are included to evaluate efficacy and futility. The statistical design is evaluated through extensive simulations to determine the operating characteristics in several plausible scenarios. This trial achieves adequate power in each injury group.DiscussionThis trial design evaluating TXA in pediatric hemorrhagic trauma allows for three separate injury populations to be analyzed and compared within a single study framework. Individual conclusions regarding optimal dosing of TXA can be made within each injury group. Identifying the optimal dose of TXA, if any, for various injury types in childhood may reduce death and disability.

Background: Radiotherapy is considered a compromise between the amount of killed tumor cells and the damage caused to the healthy tissue. Regarding this, radiobiological modeling is performed to individualize and optimize treatment strategies.Objective: This study aimed to determine the normal tissue complication probability (NTCP) of acute ocular pain following radiotherapy.Material and Methods: In this prospective observational study, the clinical data were collected from 45 patients with head and neck cancers and skull-base tumors, and dosimetric data were recorded after contouring the eye globe. Acute ocular pain was prospectively assessed with a three-month follow-up. The Lyman-Kutcher-Berman (LKB) parameters were estimated using the Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) maximization and Maximum Likelihood (MLH) methods, and the NTCP of acute ocular pain was then determined using generalized LKB radiobiological model. The model performance was evaluated with AUC, Brier score, and Hosmer-Lemeshow tests.Results: Six out of 45 (13.33%) patients developed acute ocular pain (grade 1 or more). LKB model showed a weak dose-volume effect (n=0.09), tolerance dose for a 50% complication (TD50) of 27.54 Gy, and slope parameter (m) of 0.38. The LKB model showed high prediction performance. The LKB model predicted that NTCP would be less than 25% if the generalized equivalent uniform dose (gEUD) was kept below 20 Gy. Conclusion: The LKB model showed a high performance in determining the NTCP of ocular pain so that the probability of ocular pain will be less than 25% if the eye globe mean dose is kept below 12 Gy.

Background: Vascular health is increasingly recognized for its roles in the pathogenesis and progression of Alzheimer’s disease (AD). The objective of this study was to investigate effects of exercise training, dose, and cardiorespiratory fitness (CRF) on neurotrophic factors in community-dwelling, older adults with mild-to-moderate AD dementia. Methods: This was a pilot blood ancillary study of the FIT-AD trial. Participants in the parent study were randomized to 6-month aerobic exercise (AEx) or stretching control. For this ancillary study, resting plasma brain-derived neurotrophic factor (BDNF), irisin, fibroblast growth factor-21 (FGF-21), and insulin-like growth factor-1 (IGF-1) biomarkers were assessed at baseline, 3, and 6 months. Estimates of within- and between- group effect sizes were calculated (Cohen’s d). Relationships of biomarker change with dose and CRF change were explored with multivariable linear regression and repeated measures correlations. Results: The sample (n = 26, 18 AEx/8 stretching) averaged 77.6 ± 6.9 years old, with the majority being male (65.4%), and non-Hispanic White (92.3%); between-group effect sizes were generally small except for irisin (d = −0.44)), AEx group relative to stretching group. Associations of dose and changes in CRF with changes in neurotrophic biomarker were weak (r2 ≤ 0.025). Conclusions: The effects of exercise on BDNF, irisin, IGF-1, and FGF-21 were heterogeneous in AD. Our findings need validation in future, adequately powered exercise studies in AD.

Abstract 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. Graphical Abstract

Abstract Background Numerous cardio-metabolic risk factors influence screen-related behaviors in children and adolescents. Numerous studies with inconsistent results revealed a relationship between blood pressure and screen time in the children and adolescents. This systematic review and meta-analysis summarized the data regarding the relationship between screen time and hypertension (HTN) in children and adolescents. Methods We examined three electronic databases, including Scopus, PubMed, and Embase to find the recent research on the relationship between screen time and HTN up to 19 July 2022. Twenty papers were included in the final two-class and dose–response meta-analysis. We conducted subgrouping to identify the source of heterogeneity. Results The highest category of screen time increased the odds of HTN by 8% [odds ratio (OR): 1.15; 95% confidence interval (CI): 1.08, 1.23; P

PurposeEvidence regarding the dose–response curve shapes of physical activity (PA) and sedentary time (ST) in older adults with functional disability (FD) is extremely limited. Moreover, these associations may differ depending on with/without frailty. We examined the dose–response associations between moderate-to-vigorous PA (MVPA) and ST with FD among older adults with/without frailty.MethodsWe included 7,480 initially nondisabled adults (3,795 men and 3,685 women) aged 65–84 years in Ota City, Tokyo, Japan. MVPA and ST were evaluated using the International Physical Activity Questionnaire-Short Form. FD was prospectively identified using a nationally unified database of the long-term care insurance system. Frailty was determined using Check-List 15, validated against Fried’s frailty criteria. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of MVPA and ST for FD were calculated, and dose–response curves were examined using restricted cubic splines.ResultsDuring 3.6 years of follow-up, 1,001 (13.4%) participants had FD. Among all participants, compared with no MVPA, the HRs for FD reduced linearly up to approximately 2000 metabolic equivalents (METs)■min/week of MVPA, and the lowest HR (HR: 0.61, 95% CI: 0.51–0.74) was reached at around 3,000–4,000 METs■min/week. Although the shape of this association was consistent regardless of with/without frailty, the magnitude of the association tended to be stronger in frail older adults than in non-frail older adults. Compared with those for the median (300 min/day) of ST, the HRs for FD increased linearly as ST reached approximately 600 min/day or more, independent of MVPA, with a maximum HR of 1.31 (95% CI: 1.01–1.71) for 1,080 min/day among all participants. This association was more pronounced among non-frail older adults but not statistically significant among frail older adults.ConclusionHigher MVPA levels consistently reduced the incidence of FD regardless of frailty in a significant inverse nonlinear dose–response manner. A significant positive nonlinear dose–response association between ST and FD risk was identified among non-frail older adults but not among frail older adults. Increasing MVPA and reducing prolonged ST are important for preventing FD among non-frail older adults. However, reducing ST alone may be insufficient; increasing MVPA, even if by only small increments, is highly recommended for frail older adults.

Summary: Background: Ultra-processed food (UPF) consumption continues to increase worldwide. However, evidences from meta-analyses are limited regarding the effects on cardiovascular events (CVEs). Methods: A meta-analysis was performed to assess the dose–response relationship of UPF consumption and CVEs risk (including the morbidity and mortality of cardiovascular causes, and myocardial infarction, stroke, transient ischemic attack, coronary intervention). Databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched for observational studies published in English language up to October 24, 2023. Generalized least squares regression and restricted cubic splines were used to estimate the linear/nonlinear relationship. PROSPERO CRD 42023391122. Findings: Twenty studies with 1,101,073 participants and 58,201 CVEs cases with a median follow-up of 12.2 years were included. A positive linear relationship between UPF intake and CVEs risk was identified. In addition, positive correlation between coronary heart disease and UPF consumption in terms of daily serving and daily energy proportion. No significant association of UPF consumption with the risk of cerebrovascular disease was observed. Briefly, 10% increase of UPF by daily weight proportion was associated with a 1.9% increase of CVEs risk (RR = 1.019; 95% CI, 1.007–1.031; P = 0.002), an additional daily serving corresponding to 2.2% CVEs risk increase (RR = 1.022; 95% CI, 1.013–1.031; P

PurposeX-linked retinoschisis (XLRS), due to loss-of-function mutations in the retinoschisin (RS1) gene, is characterized by a modest to severe decrease in visual acuity. Clinical trials for XLRS utilizing intravitreal (IVT) gene therapy showed ocular inflammation. We conducted a subretinal dose–response preclinical study using rAAV2tYF-CB-hRS1 utilizing the Rs1 knockout (Rs1-KO) mouse to investigate short- and long-term retinal rescue after subretinal gene delivery.MethodsRs1-KO mice were subretinally injected with 2 μL of rAAV2tYF-CB-hRS1 vector with 8E9 viral genomes (vg)/eye, 8E8 vg/eye, 8E7 vg/eye, or sham injection, and compared to untreated eyes. Reconstitution of human RS1 protein was detected using western blotting. Analysis of retinal function by electroretinography (ERG) and structural analysis by optical coherence tomography (OCT) were performed at 1, 2, 3, 5, 7, and 12 months post injection (MPI). Immunohistochemistry (IHC) was performed to evaluate cone rescue on the cellular level. Functional vision was evaluated using a visually guided swim assay (VGSA).ResultsWestern blotting analysis showed human RS1 protein expression in a dose-dependent manner. Quantification of western blotting showed that the RS1 protein expression in mice treated with the 8E8 vg dose was near the wild-type (WT) expression levels. ERG demonstrated dose-dependent effects: At 1 MPI the 8E8 vg dose treated eyes had higher light-adapted (LA) ERG amplitudes in 3.0 flash and 5 Hz flicker compared to untreated (p

Background: Methylphenidate can be used for the treatment of cancer-related fatigue (CRF), although randomized controlled trials have shown conflicting results. The aim of this study was to use ‘real-world’ data to evaluate the effect and side effects of using methylphenidate in palliative cancer care with a focus on the late palliative phase and dose-response. Method: A retrospective review of medical records from a palliative care unit in Sweden was performed to evaluate the effect and adverse events (AEs) of using methylphenidate to treat CRF. Univariable and multivariable regression was performed and odds ratio (OR) calculated. Adjustments were made for sex, age, cancer type, dose and starting treatment

Depressive symptoms is an important public health problem. The aim of the present study is to examine the association of dietary flavonoid intake with risk of depressive symptoms. In this study, we conducted an assessment to investigate the potential association between dietary flavonoid intake and the risk of depressive symptoms. Our analysis was based on a nationally representative sample of 9674 adults who participated in the 2007–2010 and 2017–2018 National Health and Nutrition Examination Surveys. Flavonoid intake was measured using a 24-hour dietary recall method, while depressive symptoms was evaluated using the Patient Health Questionnaire-9. To examine the relationship between dietary flavonoid intake and the risk of depressive symptoms, we employed logistic regression, subgroup and restricted cubic spline models. Following multivariate adjustment, the study found a negative association between total flavonoids, anthocyanidins, flavanones, flavones, isoflavones and the risk of depressive symptoms. In subgroup analysis, total flavonoid intake was inversely associated with risk of depressive symptoms among women whereas no association was found among man. Additionally, a non-linear relationship was observed between total flavonoid intake and depressive symptoms, with statistical significance (P for nonlinearity <0.001). The present study employed a cross-sectional design, which precludes the establishment of causality. Furthermore, the data relied on self-reported measures. In present study, moderate total flavonoids intake, but not high intake, was associated with lower odds of depressive symptoms suggesting a U-shaped association. • Following multivariate adjustment, the study found a negative association between anthocyanidins, flavanones, flavones, isoflavones, total flavonoids and the risk of depression symptom. • In subgroup analysis, total flavonoid intake was inversely associated with risk of depression symptom among women whereas no association was found among man. • a non-linear relationship was observed between total flavonoid intake and depression, with statistical significance (P for nonlinearity <0.001). • We included and adjusted the known and potential risk factors of depressive symptom. In addition, we conducted a doseresponse analysis to evaluate the correlation between total flavonoid intake and depression symptom. [ABSTRACT FROM AUTHOR]

Tamarixia radiata (Waterston) (Hymenoptera: Eulophidae) is the key parasitoid of the Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera: Liviidae), in several citrus‐producing regions of the world. Chemical control is common to suppress ACP. Insecticides from globally used classes of insecticides for controlling ACP were tested on its primary parasitoid, T. radiata. Evaluations included dose–response of dimethoate, fenpropathrin, and imidacloprid in a topical application and lethal and sublethal effects from residues of imidacloprid, fenpropathrin, horticultural mineral oil (HMO), pyrethrin, and spirotetramat at 1, 3, and 7 days after application (DAA) of sprays on citrus trees in the orchard. The parasitism potential of the females that survived insecticide exposure was evaluated on untreated nymphs of ACP developing on citrus shoots and untreated parasitoid females were evaluated on nymphs treated with insecticides. In the topical application, imidacloprid was 8× more toxic to T. radiata than dimethoate and fenpropathrin. The lethal effect of the residues from imidacloprid and fenpropathrin sprays was more detrimental than other insecticides. Parasitoid mortality from 1‐ to 3‐day‐old residues averaged 90–96% for imidacloprid, 83–94% for fenpropathrin, 38–77% for pyrethrin, 43–44% for HMO, and 17–33% for spirotetramat. Parasitism by females that survived insecticide exposure was reduced by 71–88% from fenpropathrin, 28–59% from pyrethrin, 31–55% from imidacloprid, 44–4% from spirotetramat, and 39–11% from HMO compared to untreated females. The lethal and sublethal effects of all insecticides on T. radiata were significantly reduced at 7 DAA, suggesting a lower impact on its establishment and performance if releases are made after a week from spray application. [ABSTRACT FROM AUTHOR]

• Analogous to model-informed drug development (MIDD), we outline a clinical pharmacology-based framework termed as model-informed vaccine development (MIVD) for quantitative vaccine dose and dosing-regimen optimization. • MIVD approaches can optimize vaccine doses using the dose/exposure-response and immunogenicity-reactogenicity trade-off paradigms (analogous to therapeutic window determination for conventional drugs). • We illustrate possible advantages of an MIVD approach over conventional empirical approaches with hypothetical examples that mimic real-world scenarios arising during various phases of vaccine development. Historically, vaccine development and dose optimization have followed mostly empirical approaches without clinical pharmacology and model-informed approaches playing a major role, in contrast to conventional drug development. This is attributed to the complex cascade of immunobiological mechanisms associated with vaccines and a lack of quantitative frameworks for extracting dose-exposure-efficacy-toxicity relationships. However, the Covid-19 pandemic highlighted the lack of sufficient immunogenicity due to suboptimal vaccine dosing regimens and the need for well-designed, model-informed clinical trials which enhance the probability of selection of optimal vaccine dosing regimens. In this perspective, we attempt to develop a quantitative clinical pharmacology-based approach that integrates vaccine dose-efficacy-toxicity across various stages of vaccine development into a unified framework that we term as model-informed vaccine dose-optimization and development (MIVD). We highlight scenarios where the adoption of MIVD approaches may have a strategic advantage compared to conventional practices for vaccines. [ABSTRACT FROM AUTHOR]

Fluoride is a naturally occurring substance that is also added to drinking water, dental hygiene products, and food supplements for preventing dental caries. Concerns have been raised about several other potential health risks of fluoride. To conduct a robust synthesis of evidence regarding human health risks due to exposure to fluoride in drinking water, and to develop a point of departure (POD) for setting a health-based value (HBV) for fluoride in drinking water. A systematic review of evidence published since recent reviews of human, animal, and in vitro data was carried out. Bradford Hill considerations were used to weigh the evidence for causality. Several key studies were considered for deriving PODs. The current review identified 89 human studies, 199 animal studies, and 10 major in vitro reviews. The weight of evidence on 39 health endpoints was presented. In addition to dental fluorosis, evidence was considered strong for reduction in IQ scores in children, moderate for thyroid dysfunction, weak for kidney dysfunction, and limited for sex hormone disruptions. The current review identified moderate dental fluorosis and reduction in IQ scores in children as the most relevant endpoints for establishing an HBV for fluoride in drinking water. PODs were derived for these two endpoints, although there is still some uncertainty in the causal weight of evidence for causality for reducing IQ scores in children and considerable uncertainty in the derivation of its POD. Given our evaluation of the overall weight of evidence, moderate dental fluorosis is suggested as the key endpoint until more evidence is accumulated on possible reduction of IQ scores effects. A POD of 1.56 mg fluoride/L for moderate dental fluorosis may be preferred as a starting point for setting an HBV for fluoride in drinking water to protect against moderate and severe dental fluorosis. Although outside the scope of the current review, precautionary concerns for potential neurodevelopmental cognitive effects may warrant special consideration in the derivation of the HBV for fluoride in drinking water. [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]

Goosegrass (Eleusine indica) is a plant that has caused many problems in Brazil, mainly due to the problems associated to chemical control in grain producing areas. The objective of this work was to investigate the eventual cross-resistance to ACCase (acetyl-CoA carboxylase enzyme) inhibitor herbicides in a biotype collected in Paranacity (PR). Herbicides evaluated included fluazifop-p-butyl; quizalofop-pethyl, haloxyfop-p-methyl, sethoxydim and clethodim. Dose-response curves were elaborated under greenhouse conditions using completely randomized design trials in a 9x2 factorial scheme with four replicates. The levels of the first factor correspond to the nine doses of each herbicide and the levels of the second factor refer to the susceptible and suspected resistance biotypes. The selected doses corresponded to 0; 1/16; 1/8; 1/4; 1/2; 1; 2; 4; and 8 times the labeled dose for each herbicide and all herbicides were applied at the stage of one tiller. The results indicated that the Paranacity biotype was susceptible to clethodim and quizalofop-p-ethyl, however, it was poorly controlled by fluazifop-p-butyl, haloxyfop-p-methyl and sethoxydim. The resistance factor for these herbicides were determined to be 10.66; 5.64; and 9.8, respectively. The biotype from Paranacity was characterized as resistant to fluazifopp-butyl, haloxyfop-p-methyl and sethoxydim. constituting the first case of cross-resistance to ACCase inhibitors in the state of Paraná. [ABSTRACT FROM AUTHOR]

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Background: 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. Methods: 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. Results: 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. Conclusion: 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]

Background: Physical activity after surgical resection for colon cancer is associated with significantly longer disease-free survival. Inflammation is hypothesized to mediate the association between physical activity and disease-free survival in colon cancer. Methods: In this exploratory analysis of a randomized dose-response trial, 39 colon cancer survivors who completed standard therapy were stratified by cancer stage and randomized in a 1:1:1 ratio to one of three treatment groups for 24 weeks of usual-care control, 150 min/wk of moderate-intensity aerobic exercise (low-dose), or 300 min/wk of moderate-intensity aerobic exercise (high-dose). Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL6), and soluble tumor necrosis factor-alpha receptor 2 (sTNFaR2). Mixed models for repeated measures were used to test the hypothesis that exercise was associated with dose-response reductions in inflammation; exploratory analyses examined treatment effects by cancer stage. Results: In the overall population, aerobic exercise was not associated with dose-response reductions in hs-CRP, IL6, or sTNFaR2. Cancer stage modified the association between randomized group and hs-CRP (P=0.022) and IL6 (P<0.001) but not sTNFaR2 (P=0.39). In stage I-II disease, compared to control, exercise was not associated with inflammation outcomes. In stage III disease, compared to control, low-dose exercise reduced hs-CRP: -35.4% (95% CI: -70.1, -0.7) and IL6: -29.6% (95% CI: -58.4, -0.8) but not sTNFaR2: 2.7% (95% CI: sTNFaR2: -15.7, 21.1); high-dose exercise was not associated with inflammation outcomes in stage III disease. Conclusion: This exploratory analysis offers preliminary data to support the hypothesis that inflammation may mediate the association between physical activity and disease-free survival in colon cancer. [ABSTRACT FROM AUTHOR]

In this study, the thermoluminescence (TL) glow curve test results performed with eleven different dose values were used as training data, and its attempted to estimate the test results of the curves performed at four different doses using artificial intelligence methods. While the dose values of the data used for training were 10, 20, 50, 100, 150, 220, 400, 500, 600, 700, and 900 Gy, the selected dose values of the data for the testing were 40, 276, 320, and 800 Gy. The success of the experimental and artificial neural network results was determined according to the mean squared error (RMSE), regression error (R2), root squared error (RSE), and mean absolute error (MAE) criteria. Studies have been carried out on seven different neural network types. These networks are adaptive network-based fuzzy inference system (ANFIS), general regression neural network (GRNN), radial basis neural network (RBNN), cascade-forward backprop neural network (CFBNN), Elman backprop neural network (EBNN), feed-forward backprop neural network (FFBNN), and layer recurrent neural network (LRNN). This study concluded that the neural network with the Elman backpropagation network type demonstrated the best network performance. In this network, the training success rate is 80.8%, while the testing success rate is 87.95%. [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 paper assesses the judgments of leading radiation geneticists and cancer risk assessment scientists from the mid-1950s to mid-1970s that background radiation has a significant effect on human genetic disease and cancer incidence. This assumption was adopted by the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel for genetic diseases and subsequently applied to cancer risk assessment by other leading individuals/advisory groups (e.g., International Commission on Radiation Protection-ICRP). These recommendations assumed that a sizeable proportion of human mutations originated from background radiation due to cumulative exposure over prolonged reproductive periods and the linear nature of the dose-response. This paper shows that the assumption that background radiation is a significant cause of spontaneous mutation, genetic diseases, and cancer incidence is not supported by experimental and epidemiological findings, and discredits erroneous risk assessments that improperly influenced the recommendations of national and international advisory committees, risk assessment policies, and beliefs worldwide. [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]

AbstractCarrots are main dietary sources of several potential anti-cancer compounds, including polyacetylenes, while β-carotene has shown no benefits in controlled cancer trials. Accordingly, associations between carrot intake and cancer incidence were quantified, where necessary using α-carotene as a non-causal biomarker of carrot consumption, by searching for studies published before June 2022 reporting risk estimates for relationships of cancer incidence with carrot intake or α-carotene intake or α-carotene plasma concentration, supplemented with hand searches of included studies and reviews. Meta-analyses comparing highest and lowest reported intakes in prospective studies using a random-effects model estimated summary relative risks (RRs) with 95% confidence intervals (CIs), separately for carrot intake or α-carotene plasma concentration, and the corresponding dose-responses. Of 198 observational studies, in 50 prospective studies with 52000 cases recording carrot intake, the cancer-risk was substantially reduced (RR 0.90, 95% CI 0.87–0.94, p ˂ 0·00004). In 30 prospective studies with 9331 cases reporting plasma α-carotene levels, summary RR was 0.80 (0.72–0.89, p ˂ 0·00006). For both exposure types, inter-study heterogeneity was moderate, interaction with cancer types insignificant, and the dose-response significant (p ˂ 0·01). In conclusion, carrot consumption is robustly associated with decreased cancer-risk; carrot consumption should be encouraged, and the causal mechanisms further investigated. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify and describe trajectories of change in distress among highly challenging patients who had received long and intensive psychoanalytic psychotherapy. Methods: The longitudinal version of the K‐means algorithm was applied to the outcome measures data of 74 patients treated in four public mental health centers. The patients were measured five times at 6‐month intervals for three outcome measures. Results: For the OQ45 and Symptom Checklist‐90, one trajectory was marked by a lower initial distress level. In this trajectory, the improvement occurred in the first half of the measurements, with a plateau thereafter. A second trajectory was characterized by higher initial severity and an improvement, mainly in the second part of the measurements. For the Beck Depression Inventory, one trajectory was marked by lower initial distress. In this group, the improvement occurred throughout the entire period. The remaining patients were characterized by higher initial distress and a decreased level of distress in the last part of treatment. They began to improve only during the third year of therapy. Conclusion: The response to treatment is not uniform in long‐term treatment for highly challenging patients. A significant number of patients require a longer period of therapy to ignite improvement. [ABSTRACT FROM AUTHOR]

Zebra (Dreissena polymorpha Pallas, 1771) and quagga (Dreissena rostriformis bugensis Andrusov, 1897) mussels are important pests in North America and Europe, where they cause costly economic damage to water infrastructure and severe environmental impacts to lake ecosystems. Strategies for combating these invasive mussels do not differentiate between the species, and little is known about how they may differ in terms of their susceptibility to chemical control methods. In this study, adult zebra and quagga mussels were collected from Lake Ontario and exposed to three different concentrations of EarthTec QZ - 60, 120, and 180 µg/L as liquid ionic copper - until 100% mortality was reached. Quagga mussels died significantly faster and at lower doses of copper ion than zebra mussels. Dry tissue collected from the mollusks at the time of death was analyzed for the copper concentration in each species and results revealed that zebra mussels accumulated and were able to tolerate much higher concentrations of copper in their tissues than quagga mussels. After 10 days' exposure to the highest dose rate (180 µg/L) zebra mussels had experienced less than 20% mortality while accumulating more than 1,000 mg/kg copper, whereas the quagga mussels treated at the same 180 ug/L suffered 100% mortality after 10 days despite having accumulated only 300 mg/kg of copper. While more research is needed to explain the precise mechanisms whereby zebra mussels are able to tolerate the much higher bodily concentrations of copper than quagga mussels, these results have direct management implications when copper is used for dreissenid control. [ABSTRACT FROM AUTHOR]

Background: Cimex lectularius L. (bed bug) (Hemiptera: Cimicidae) is a serious indoor pest worldwide, and this nuisance needs to be controlled using different methods in integrated pest management (IPM). Beauveria bassiana (Bals.‐Criv.) Vuill. (Hypocreales: Cordycipitaceae) kills bed bugs, and insect pathogenic fungi may be utilized to control bed bugs in IPM. To increase knowledge of this methodology, forced exposure experiments were conducted with different formulations, doses, and substrates, using bed bugs in variable physiological states. Results: Both oil‐ and water‐formulated fungal products showed significant improvement when conidial concentrations were raised in five steps from 0.02 to 2.0%. At low concentrations (0.02% in water) effects from substrate and application strategy were observed. Application on soft substrates (cotton and polyester) yielded significantly higher bed bug mortality rates than on harder substrates (paper, wood, and linoleum) with a final mortality of 35–63% against 8–10%. Multiple applications over time also improved B. bassiana's ability to kill bed bugs, and at low concentrations only a triple application on cotton showed 100% final mortality. Bed bug age and reproductive status significantly affected survival. Older and reproducing individuals showed higher mortality compared to newly emerged adults. Differences in feeding status also yielded differences in mortality timing, but only minor differences in final mortality rates. Egg production and hatching success were significantly reduced by some treatments. Conclusion: B. bassiana appears to be an asset in the fight against bed bugs. Substrate, dosage, application strategy, and bed bug physiology are important factors to consider for optimal efficacy and safe indoor control with insect pathogenic fungi. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The increased prevalence of multidrug-resistant organisms (MDROs), healthcare associated infections (HAIs), and the recent COVID-19 pandemic has caused the photoinactivation industry to explore alternative wavelengths. Blue light (BL405) has gained significant interest as it is much less harmful to the skin and eyes than traditional germicidal wavelengths; therefore, in theory, it can be used continuously with human exposure. At present, the viricidal effects of BL405 are largely unknown as the literature predominately addresses bacterial disinfection performed with this wavelength. This work provides novel findings to the industry, reporting on the virucidal effects of BL405 on surfaces. This research utilizes three surfaces: ceramic, PTFE, and stainless steel. The efficacy of BL405 inactivation varied by surface type, which was due to surface characteristics, such as the contact angle, porosity, zeta potential, and reflectivity. Additionally, the effect of the dew point on BL405 inactivation efficacy was determined. This research is the first to study the effects of the dew point on the virucidal effectiveness of BL405 surface inactivation. The effects of the dew point were significant for all surfaces and the control experiments. The high-dew-point conditions (18 °C) yielded higher levels of BL405 inactivation and viral degradation for the experiments and controls, respectively. [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]

Abstract Context Diet is emerging as a modifiable component of lifestyle for influencing the incidence of liver cancer. Objective To investigate and quantify the potential relationship between food groups and liver cancer. Data sources PubMed and Web of Science were searched for eligible observational studies until 31st March, 2023. Data extraction The meta-analysis was conducted by pooling relative risk (RR), odds ratio (OR) or hazards ratio (HR) with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by subgroup analysis. Sensitivity analysis and publication bias test were also carried out. Data analysis Through stepwise screening, a total of 27 studies were included. The pooled estimates of liver cancer for whole grains and legumes intake were 0.66 (95% CI: 0.54–0.82; I 2 = 25.3%) and 0.86 (95% CI: 0.75–0.99; I 2 = 14.3%), respectively. However, there were null associations of nuts, poultry, egg and sweetened beverages consumption with liver cancer and the association between refined grains and liver cancer was inconclusive. In dose-response meta-analysis, the pooled estimates of liver cancer were 0.77 (95% CI: 0.65–0.91) for every 50 g/day increment in whole grains intake. Non-linear dose-response relationship (P = 0.031) was observed in the association between the intake of legumes and liver cancer, and the protective effect occurred with the dose ranging from 8 g/day to 40 g/day. Conclusions This meta-analysis shows that whole grains and legumes were inversely associated with liver cancer, whereas intake of nuts, poultry, egg and sweetened beverages may not be associated with liver cancer. Further quantitative research needs to be undertaken within a range of populations to investigate the relationship between food groups and liver cancer. Systematic review registration PROSPERO registration no. CRD42021246142