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Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the

OBJECTIVE: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. METHODS: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. RESULTS: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. INTERPRETATION: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.

BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimers Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. TRIAL REGISTRATION: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Developmental exposures to PCBs are implicated in the etiology of neurodevelopmental disorders (NDDs). This observation is concerning given the continued presence of PCBs in the human environment and the increasing incidence of NDDs. Previous studies reported that developmental exposure to legacy commercial PCB mixtures (Aroclors) or single PCB congeners found in Aroclors caused NDD-relevant behavioral phenotypes in animal models. However, the PCB congener profile in contemporary human samples is dissimilar to that of the legacy Aroclors, raising the question of whether human-relevant PCB mixtures similarly interfere with normal brain development. To address this question, we assessed the developmental neurotoxicity of the Fox River Mixture (FRM), which was designed to mimic the congener profile identified in fish from the PCB-contaminated Fox River that constitute a primary protein source in the diet of surrounding communities. Adult female C57BL/6 J mouse dams (8-10 weeks old) were exposed to vehicle (peanut oil) or FRM at 0.1, 1.0, or 6.0 mg/kg/d in their diet throughout gestation and lactation, and neurodevelopmental outcomes were assessed in their pups. Ultrasonic vocalizations (USVs) and measures of general development were quantified at postnatal day (P) 7, while performance in the spontaneous alternation task and the 3-chambered social approach/social novelty task was assessed on P35. Triiodothyronine (T3) and thyroxine (T4) were quantified in serum collected from the dams when pups were weaned and from pups on P28 and P35. Developmental exposure to FRM did not alter pup weight or body temperature on P7, but USVs were significantly decreased in litters exposed to FRM at 0.1 or 6.0 mg/kg/d in the maternal diet. FRM also impaired male and female pups' performance in the social novelty task. Compared to sex-matched vehicles, significantly decreased social novelty was observed in male and female pups in the 0.1 and 6.0 mg/kg/d dose groups. FRM did not alter performance in the spontaneous alternation or social approach tasks. FRM increased serum T3 levels but decreased serum T4 levels in P28 male pups in the 1.0 and 6.0 mg/kg/d dose groups. In P35 female pups and dams, serum T3 levels decreased in the 6.0 mg/kg/d dose group while T4 levels were not altered. Collectively, these findings suggest that FRM interferes with the development of social communication and social novelty, but not memory, supporting the hypothesis that contemporary PCB exposures pose a risk to the developing brain. FRM had sex, age, and dose-dependent effects on serum thyroid hormone levels that overlapped but did not perfectly align with the FRM effects on behavioral outcomes. These observations suggest that changes in thyroid hormone levels are not likely the major factor underlying the behavioral deficits observed in FRM-exposed animals.

OBJECTIVE: The purpose of this study was to determine the in vitro effects of a single exposure of bupivacaine on the mechanical properties of bovine cartilage explants at 3 weeks. DESIGN: Femoral condyle articular cartilage explants were aseptically harvested from juvenile bovine stifle joints before being exposed to chondrogenic medium containing 0.50% (wt/vol) bupivacaine, 0.25% (wt/vol) bupivacaine, or no medication (control) for 1 hour. Explants were then washed and maintained in culture in vitro for 3 weeks before testing. Cell viability, tensile and compressive mechanical properties, histological properties, and biochemical properties were then assessed. RESULTS: Explants exhibited a dose-dependent decrease in mean tensile Youngs modulus with increasing bupivacaine concentration (9.86 MPa in the controls, 6.48 MPa in the 0.25% bupivacaine group [P = 0.048], and 4.72 MPa in the 0.50% bupivacaine group [P = 0.005]). Consistent with these results, collagen content and collagen crosslinking decreased with bupivacaine exposure as measured by mass spectrometry. Compressive properties of the explants were unaffected by bupivacaine exposure. Explants also exhibited a trend toward dose-dependent decreases in viability (51.2% for the controls, 47.3% for the 0.25% bupivacaine-exposed group, and 37.0% for the 0.50% bupivacaine-exposed group [P = 0.072]). CONCLUSIONS: Three weeks after 1-hour bupivacaine exposure, the tensile properties of bovine cartilage explants were significantly decreased, while the compressive properties remained unaffected. These decreases in tensile properties corresponded with reductions in collagen content and crosslinking of collagen fibers. Physicians should be judicious regarding the intra-articular administration of bupivacaine in native joints.

BACKGROUND: Reference to an intrinsic healing mechanism or an inner healer is commonplace amongst psychedelic drug-using cultures. The inner healer refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. AIMS: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived inner healing effects. METHODS: The item was issued to 59 patients after a single high (25 mg, n = 30) or placebo (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. RESULTS: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p

OBJECTIVE: Quantify the relationship between CT acquisition parameters and radiation dose, how often parameters are adjusted in real-world practice, and their degree of contribution to real-world dose distribution. Identify discrepancies between parameters that are impactful in theory and impactful in practice. METHODS: This study analyses 1.3 million consecutive adult routine abdomen exams performed between November 2015 and Jan 2021 included in the University of California, San Francisco International CT Dose Registry of 155 institutions. We calculated geometric standard deviation (gSD) for five parameters (kV, mAs, spiral pitch, number of phases, scan length) to assess variation in practice. A Gaussian mixed regression model was performed to predict the radiation dose-length product (DLP) using the parameters. Three conceptualizations of impact were computed for each parameter. To reflect the theoretical impact, we predict the increase in DLP per 10% (and 15%) increase in the parameter. To reflect the real-world practical impact, we predict the increase in DLP per gSD increase in the parameter. RESULTS: Among studied examinations, mAs, number of phases, and scan length were frequently manipulated (gSD 1.52-1.70); kV was rarely manipulated (gSD 1.07). Theoretically, kV is the most impactful parameter (29% increase in DLP per 10% increase in kV, versus 5-9% increase for other parameters). In real-world practice, kV is less impactful; for each gSD increase in kV, the DLP increases by 20%, versus 22-69% for other parameters. CONCLUSION: Despite the potential impact of kV on radiation dose, this parameter is rarely manipulated in common practice and this potential remains untapped. CLINICAL RELEVANCE STATEMENT: CT beam energy (kV) modulation has the potential to strongly reduce radiation over-dosage to the patient, theoretically more so than similar degrees of modulation in other CT acquisition parameters. Despite this, beam energy modulation rarely occurs in practice, leaving its potential untapped. KEY POINTS: • The relationship between CT acquisition parameter selection and radiation dose roughly coincided with established theoretical understanding. • CT acquisition parameters differ from each other in frequency and magnitude of manipulation, with beam energy (kV) being rarely manipulated. • Beam energy (kV) has the potential to substantially impact radiation dose, but because it is rarely manipulated, it is the least impactful CT acquisition parameter affecting radiation dose in practice.

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).

We compared the effects of different weekly calf training sets on muscle size changes. Sixty-one untrained young women performed a calf training program for 6 weeks, 3 d·wk–1 , with differences in resistance training volume. The participants were randomly assigned to one of the three groups: 6-SET, 9-SET, and 12-SET weekly calf training sets. The calf raise exercise was performed in sets of 15–20 repetitions maximum. The muscle thickness measurements of medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (SOL) were taken via B-mode ultrasound. We used the sum of the three-muscle thickness as a proxy for the triceps surae (TSSUM). The 12-SET group elicited greater increases than the 6-SET in LG (6-SET=+ 8.1% vs. 12-SET=+ 14.3%; P =0.017), SOL (6-SET=+ 6.7% vs. 12-SET=+ 12.7%; P =0.024), and TSSUM (6-SET=+ 6.9% vs. 12-SET=+ 12.0%; P =0.005), but there was no significant difference in MG changes (6-SET=+ 6.6% vs. 12-SET=+ 9.9%; P =0.067). There were no significant differences when comparing 9-SET vs. 6-SET and 12-SET (P ≥0.099). Although all groups experienced calf muscle hypertrophy, our results suggest that the higher dose range may optimize triceps surae muscle size gains. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown significant associations between individual fat-soluble vitamins (FSVs) and metabolic syndromes (MetS). However, evidence on the multiple FSVs co-exposure and MetS odds is limited. Given that individuals are typically exposed to different levels of FSVs simultaneously, and FSVs can interact with each other. It's necessary to explore the association between multiple FSVs co-exposure and MetS odds. This study aims to address this gap in general U.S. adults aged ≥ 20 years. Methods: We conducted a cross-sectional study utilizing data from the National Health and Nutrition Examination Surveys (NHANESs) 2003–2006 and 2017–2018. Three FSV, including vitamin A (VA), vitamin E (VE), and vitamin D (VD), and MetS diagnosed according to the ATP III guidelines were selected as exposure and outcome, respectively. Multivariable-adjusted logistic model was used to explore the associations of individual FSV exposure with MetS odds and MetS components. Restricted cubic splines were performed to explore the dose–response relationships among them. The quantile g-computation method was adopted to explore the associations of multiple FSVs co-exposure with MetS odds and MetS components. Results: The presented study included a total of 13,975 individuals, with 2400 (17.17%) were diagnosed with MetS. After adjusting for various confounders, a positive linear pattern was observed for serum VA and VE and MetS associations. Serum VD was found to be negatively associated with MetS in a linear dose–response way. For each component of MetS, higher serum VA and VE were associated with higher triglyceride and high-density lipoprotein; higher serum VD was negatively associated with triglyceride, blood pressure, and fasting plasma glucose. MetS odds increased by 15% and 13%, respectively, in response to one quartile increase in FSVs co-exposure index (qgcomp) in the conditional model (OR = 1.15, 95%CI: 1.06, 1.24) and the marginal structural model (OR = 1.13, 95%CI: 1.06, 1.20). Besides, co-exposure to VA, VE, and VD was positively associated with triglyceride, high-density lipoprotein, and blood pressure levels. Conclusion: Findings in the present study revealed that high serum VA and VE levels were associated with elevated MetS odds, while serum VD was inversely associated with MetS odds. FSVs co-exposure was positively associated with MetS odds. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between Weight Adjusted Waist Index (WWI) and cardiovascular disease among ethnic minority populations in Guizhou Province. Methods Based on the Longitudinal Study of Natural Population in Southwest Minority Aggregated Areas, a baseline survey was conducted among Dong, Miao, and Buyi ethnic groups aged 30 to 79 years in Qiandongnan and Qiannan regions of Guizhou Province from 2018 to 2019. Logistic regression analysis was performed to examine the association between WWI and cardiovascular disease and its subtypes among the ethnic minority population in Guizhou Province. Restricted Cubic Spline (RCS) was employed to explore the dose-response relationship between WWI and cardiovascular disease. Multiplicative and additive models were used to analyze the interaction effects of WWI with alcohol consumption and diabetes on cardiovascular disease. Results A total of 16 993 individuals were included, and the prevalence of cardiovascular disease among the ethnic minority population in Guizhou Province was 3.1%. After adjusting for all covariates, compared to the lowest quartile of WWI (QI), the odds ratios (ORs) for cardiovascular disease in the third quartile (Q3) and the fourth quartile (Q4) of WWI were 1.448 (95%CZ: 1.089-1.924) and 1350 (95%CI: 1,007-1.811), respectively. The RCS showed an approximately S-shaped non-linear dose-response relationship between WWI and cardiovascular disease (P for nonlinear = 0.029). The multiplicative interaction analysis revealed a positive interaction between WWI and alcohol consumption (OR =2.36: 95%CI: 1.22-4.55), while no multiplicative interaction was found between WWI and diabetes (Oi-二0.55, 95%CZ: 0.30-1.00). Conclusion WWI is positively associated with cardiovascular disease among ethnic minority populations in Guizhou Province, and there is a non-linear dose-response relationship. Additionally, there is a multiplicative interaction between WWI and alcohol consumption on cardiovascular disease. [ABSTRACT FROM AUTHOR]

Cerebral vascular angiography, or digital subtraction angiography (DSA), is essential for diagnosing neurological conditions but poses radiation risks. This study aims to analyze the impact of examination parameters and patient characteristics on the radiation dose received during DSA to optimize safety and minimize exposure. A retrospective analysis of 251 DSA procedures using the GE Innova IGS 630 dual-plane instrument was conducted. Data on dose area product (DAP) and air kerma (KERMA), along with patient and examination details, were collected. Statistical analyses, including Mann–Whitney, Kruskal–Wallis, and Spearman rank correlation tests, assessed the relationships between variables and radiation dose outcomes. Significant correlations were found between the sides examined (left, right, or both) and DAP (p < 0.0001) and KERMA (p < 0.0001) values, with bilateral studies showing the highest values. The post hoc Dunn tests showed that the 'L + P' group significantly differs from both the right group (p < 0.0001 and the left group (p < 0.0001). There is no significant difference between the 'P' group and the 'L' group (p-value = 0.53). These results suggest that the right and left (both) group have unique KERMA mGy values compared to the other two groups. A strong correlation (rS = 0.87) existed between DAP and KERMA. The number of projections significantly impacted radiation dose (rS = 0.61). Tube parameters (kV and mA) and skull size had low correlations with DAP and KERMA. Optimizing imaging protocols and individualizing parameters can significantly enhance patient safety and diagnostic efficacy while also reducing occupational exposure for medical staff. [ABSTRACT FROM AUTHOR]

Ingested arsenic is carcinogenic to the human urinary tract, but uncertainties remain regarding the dose–response relationship. To assess dose–response relationships between arsenic ingestion and urinary cancers, we evaluated the associations between the arsenic level in drinking water and mortality of cancers of the bladder, kidney, and prostate in Taiwan. We utilized the 1971–2000 Taiwan death registry data and calculated the age-standardized mortality rates (ASMRs) using the 1976 world standard population as the reference group. We used the data from a 1974–1976 census survey of wells on the arsenic levels in drinking water conducted by the government to assess exposure levels, which had been divided into three categories: below 0.05 ppm, 0.05–0.35 ppm, and above 0.35 ppm. The data were analyzed using multiple linear regression models and geographical information system. We found no increase in ASMR for all, or any, of the urinary cancers at exposure levels of 0.05–0.35 ppm arsenic, but at exposure levels > 0.35 ppm arsenic was associated with increased ASMR in both males and females for bladder cancer, kidney cancer, and all urinary cancers combined. There was no increased ASMR associated with prostate cancer observed for either exposure category. [ABSTRACT FROM AUTHOR]

Background and Objectives: This study aimed to evaluate the potential chemopreventive effect of antidiabetic medications, specifically metformin and pioglitazone, on lung cancer in patients with type 2 diabetes mellitus (T2DM). Additionally, the potential dose–response relationship for metformin use was analyzed. Methods: We conducted a retrospective cohort study utilizing comprehensive national health insurance and cancer registry databases to gather a large cohort of T2DM patients. Cox proportional hazards regression models were used to assess the risk of lung cancer across different antidiabetic medication groups, adjusting for potential confounders such as age and gender. A dose–response analysis was conducted for metformin users. Results: Our results indicated that metformin users had a significantly lower lung cancer risk than the reference group (HR = 0.69, 95% CI [0.55–0.86], p = 0.001). The risk reduction increased with higher cumulative metformin doses: a metformin cumulative dose between 1,370,000 and 2,976,000 had an HR of 0.61 (95% CI [0.49–0.75], p < 0.001) vs. cumulative metformin dose >2,976,000 which had an HR of 0.35 (95% CI [0.21–0.59], p < 0.001). No significant association between pioglitazone use and the risk of lung cancer was found (HR = 1.00, 95% CI [0.25–4.02]). Conclusions: This study shows that metformin may have a dose-dependent chemopreventive effect against lung cancer in T2DM, while the impact of pioglitazone remains unclear and requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Organic phosphorus insecticides (OPPs) are a class of environmental pollutants widely used worldwide with potential human health risks. We aimed to assess the association between exposure to OPPs and osteoarthritis (OA) particularly in participants with atherosclerotic cardiovascular disease (ASCVD). Methods: Participants' information was obtained from data in the National Health and Nutrition Examination (NHANES). Weighted logistic regression models were utilized to detect associations between OPPs metabolites and OA. Restricted cubic spline plots (RCS) were drawn to visualize the dose-response relationship between each metabolite and OA prevalence. Weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR), were applied to investigate the joint effect of mixtures of OPPs on OA. Results: A total of 6871 samples were included in our study, no significant associations between OPPs exposure and OA incidence were found in whole population. However, in a subset of 475 individuals with ASCVD, significant associations between DMP (odds ratio [OR] as a continuous variable = 1.22, 95% confidence interval [CI]: 1.07,1.28), DEP ((odds ratio [OR] of the highest tertile compared to the lowest = 2.43, 95% confidence interval [CI]: 1.21,4.86), and OA were observed. DMP and DEP showed an increasing dose-response relationship to the prevalence of OA, while DMTP, DETP, DMDTP and DEDTP showed a nonlinear relationship. Multi-contamination modeling revealed a 1.34-fold (95% confidence intervals:0.80, 2.26) higher prevalence of OA in participants with high co-exposure to OPPs compared to those with low co-exposure, with a preponderant weighting (0.87) for the dimethyl dialkyl phosphate metabolites (DMAPs). The BKMR also showed that co-exposure of mixed OPPs was associated with an increased prevalence of OA, with DMP showing a significant dose-response relationship. Conclusion: High levels of urine dialkyl phosphate metabolites (DAP) of multiple OPPs are associated with an increased prevalence of OA in patients with ASCVD, suggesting the need to prevent exposure to OPPs in ASCVD patients to avoid triggering OA and further avoid the occurrence of cardiovascular events caused by OA. [ABSTRACT FROM AUTHOR]

This review aims to investigate the dose–response relationship between walking speed and all-cause mortality. PubMed, Web of Science, Embase and Cochrane Library were searched to September, 2023 for cohort studies. A meta-analysis estimated the overall hazard ratio (HR) of mortality incidence and 95% Confidence Interval (CI) for individuals with the fastest walking speed compared to those with the slowest walking speed. Subgroup analyses were conducted based on sex, age and speed-measuring methods. Dose–response meta-analyses were examined by using "mvmeta" packages available in STATA. A total of 13 studies involving 530,841 participants were included. Of these, 11 studies provided data for dose–response meta-analyses. Individuals in the fastest walking-speed category had a 43% lower risk of all-cause mortality compared to those in the slowest walking-speed category (HR = 0.57, 95% CI 0.48–0.66). There was an inverse linear dose–response relationship between walking speed and all-cause mortality; for every 0.1 m/s increment in walking speed, the risk of mortality decreased by 6% (HR = 0.94; 0.92–0.96). There was an inverse nonlinear dose–response relationship between them when participants' age was larger than 65 years, but linear dose–response relationships were detected in both the timed walking speed test and self-reported walking speed measurements. [ABSTRACT FROM AUTHOR]

Existing research shows an inconsistent correlation between whole-grain intake and obesity risk, with limited study on the dose–response relationship. Here, we aimed to examine this association and dose–response relationship among U.S. adults who participated in a NHANES (2003–2018). The intake of whole grain was collected and calculated from two rounds of 24 h dietary recall. Obesity was categorized based on body mass index (BMI) and waist circumference (WC). Weighted multivariable logistic regression models were used to calculate the odds of obesity according to whole-grain intake, and the dose–response relationship was modeled by restricted cubic spline regression. Among the 27,862 participants, 38.3% had general obesity, while 58.3% had abdominal obesity. After multivariate adjustment of potential confounders, the participants in the highest quintile of whole-grain intake had a lower prevalence of general obesity (OR 0.79; 95% CI 0.72–0.88) and abdominal obesity (OR 0.80; 95% CI 0.73–0.89) compared with those in the lowest category. Spline regression showed an inversely linear dose–response association between whole-grain intake and the prevalence of general obesity and abdominal obesity. In conclusion, a higher whole-grain intake was associated with lower odds of obesity, both general and abdominal. Our findings highlight the importance of increasing the whole-grain intake to prevent and manage obesity. [ABSTRACT FROM AUTHOR]

Background: Glyphosate is the most widely applied herbicide in the world. Hormesis caused by low glyphosate doses has been widely documented in many plant species. However, the specific adaptative mechanism of plants responding to glyphosate hormesis stimulation remains unclear. This study focused on the biphasic relationship between glyphosate dose and tomato plant growth, and how glyphosate hormesis stimulates plant growth and enhances tolerance to environmental stress. Results: We constructed a hormesis model to describe the biphasic relationship with a maximal stimulation (MAX) of 162% above control by glyphosate at 0.063 g ha−1. Low‐dose glyphosate increased photosynthetic pigment contents and improve photosynthetic efficiency, leading to plant growth stimulation. We also found that glyphosate hormesis enhanced plant tolerance to diuron (DCMU; a representative photosynthesis inhibitor) by triggering the nonphotochemical chlorophyll fluorescence quenching (NPQ) reaction to dissipate excess energy stress from photosystem II (PSII). Transcriptomic analysis and quantitative real‐time polymerase chain reaction results revealed that the photosynthesis–antenna proteins pathway was the most sensitive to glyphosate hormesis, and PsbS (encoding photosystem II subunit S), ZEP (encoding zeaxanthin epoxidase) and VDE (encoding violaxanthin de‐epoxidase) involved in NPQ played crucial roles in the plant response to glyphosate hormesis. Conclusion: These results provide novel insights into the mechanisms of plant hormesis and is meaningful to the application of glyphosate hormesis in agriculture. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Abstract Background Previous studies have shown significant associations between individual fat-soluble vitamins (FSVs) and metabolic syndromes (MetS). However, evidence on the multiple FSVs co-exposure and MetS odds is limited. Given that individuals are typically exposed to different levels of FSVs simultaneously, and FSVs can interact with each other. It’s necessary to explore the association between multiple FSVs co-exposure and MetS odds. This study aims to address this gap in general U.S. adults aged ≥ 20 years. Methods We conducted a cross-sectional study utilizing data from the National Health and Nutrition Examination Surveys (NHANESs) 2003–2006 and 2017–2018. Three FSV, including vitamin A (VA), vitamin E (VE), and vitamin D (VD), and MetS diagnosed according to the ATP III guidelines were selected as exposure and outcome, respectively. Multivariable-adjusted logistic model was used to explore the associations of individual FSV exposure with MetS odds and MetS components. Restricted cubic splines were performed to explore the dose–response relationships among them. The quantile g-computation method was adopted to explore the associations of multiple FSVs co-exposure with MetS odds and MetS components. Results The presented study included a total of 13,975 individuals, with 2400 (17.17%) were diagnosed with MetS. After adjusting for various confounders, a positive linear pattern was observed for serum VA and VE and MetS associations. Serum VD was found to be negatively associated with MetS in a linear dose–response way. For each component of MetS, higher serum VA and VE were associated with higher triglyceride and high-density lipoprotein; higher serum VD was negatively associated with triglyceride, blood pressure, and fasting plasma glucose. MetS odds increased by 15% and 13%, respectively, in response to one quartile increase in FSVs co-exposure index (qgcomp) in the conditional model (OR = 1.15, 95%CI: 1.06, 1.24) and the marginal structural model (OR = 1.13, 95%CI: 1.06, 1.20). Besides, co-exposure to VA, VE, and VD was positively associated with triglyceride, high-density lipoprotein, and blood pressure levels. Conclusion Findings in the present study revealed that high serum VA and VE levels were associated with elevated MetS odds, while serum VD was inversely associated with MetS odds. FSVs co-exposure was positively associated with MetS odds.

Abstract Background Organic phosphorus insecticides (OPPs) are a class of environmental pollutants widely used worldwide with potential human health risks. We aimed to assess the association between exposure to OPPs and osteoarthritis (OA) particularly in participants with atherosclerotic cardiovascular disease (ASCVD). Methods Participants’ information was obtained from data in the National Health and Nutrition Examination (NHANES). Weighted logistic regression models were utilized to detect associations between OPPs metabolites and OA. Restricted cubic spline plots (RCS) were drawn to visualize the dose-response relationship between each metabolite and OA prevalence. Weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR), were applied to investigate the joint effect of mixtures of OPPs on OA. Results A total of 6871 samples were included in our study, no significant associations between OPPs exposure and OA incidence were found in whole population. However, in a subset of 475 individuals with ASCVD, significant associations between DMP (odds ratio [OR] as a continuous variable = 1.22, 95% confidence interval [CI]: 1.07,1.28), DEP ((odds ratio [OR] of the highest tertile compared to the lowest = 2.43, 95% confidence interval [CI]: 1.21,4.86), and OA were observed. DMP and DEP showed an increasing dose-response relationship to the prevalence of OA, while DMTP, DETP, DMDTP and DEDTP showed a nonlinear relationship. Multi-contamination modeling revealed a 1.34-fold (95% confidence intervals:0.80, 2.26) higher prevalence of OA in participants with high co-exposure to OPPs compared to those with low co-exposure, with a preponderant weighting (0.87) for the dimethyl dialkyl phosphate metabolites (DMAPs). The BKMR also showed that co-exposure of mixed OPPs was associated with an increased prevalence of OA, with DMP showing a significant dose-response relationship. Conclusion High levels of urine dialkyl phosphate metabolites (DAP) of multiple OPPs are associated with an increased prevalence of OA in patients with ASCVD, suggesting the need to prevent exposure to OPPs in ASCVD patients to avoid triggering OA and further avoid the occurrence of cardiovascular events caused by OA.

Objective To explore the relationship between cardiac metabolic index (CMI) and stroke in middle-aged and elderly individuals based on a large sample cohort study. Methods Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018. Multivariate logistic regression models were developed to explore the association between CMI and stroke, while restricted cubic spline (RCS) model was used to examine possible non-linear associations. Results A total of 6198 study participants were included in this study, with 349 strokes occurring during the 7-year follow-up and a baseline CMI level of 0.98 (0.61, 1.51). Logistic regression results showed that for each quartile increase in CMI, the prevalence risk of a new stroke was increased by 36.7% (OR=1.367, 95%CI: 1.188-1.574) and there was a cumulative effect (P for trend＜0.01). RCS showed that there was a dose-response relationship between CMI and stroke (P＜0.01), and it was a non-linear relationship (Pnon-linear＜0.01). Conclusion High levels of CMI have a high predictive value for the occurrence of stroke.

Abstract Objective Our study aimed to determine whether there exists an association between low-grade systemic inflammation, as measured by serum C-reactive protein (CRP), and the risk of lower-extremity deep venous thrombosis (LEDVT) in patients with primary intracerebral hemorrhage (ICH). Methods This observational study was retrospectively conducted on patients with primary ICH who were presented to two tertiary medical centers between January 2021 and August 2022. The primary outcome was detecting LEDVT occurrence within 14 days from the onset of the acute ICH episode. Weighted logistic regression and restricted cubic spline models were employed to estimate the association between CRP and LEDVT following 1:1 propensity score matching (PSM). Results Of the 538 patients with primary ICH who met the inclusion criteria, 76 (14.13%) experienced LEDVT. Based on the cut-off levels of CRP measured upon admission from the receiver operating characteristic (ROC) curve, patients with primary ICH were categorized into two groups: (i) CRP

Abstract Objective This study aimed to establish the dose-response relationship between volume base dose and tumor local control for vaginal cancer, including primary vaginal cancer and recurrent gynecologic malignancies in the vagina. Materials and methods We identified studies that reported volume base dose and local control by searching the PubMed, the Web of Science, and the Cochrane Library Database through August 12, 2023. The regression analyses were performed using probit model between volume based dose versus clinical outcomes. Subgroup analyses were performed according to stratification: publication year, country, inclusion time of patients, patients with prior radiotherapy, age, primaries or recurrent, tumor size, concurrent chemoradiotherapy proportion, dose rate, image modality for planning, and interstitial proportion. Results A total of 879 patients with vaginal cancer were identified from 18 studies. Among them, 293 cases were primary vaginal cancer, 573 cases were recurrent cancer in the vagina, and 13 cases were unknown. The probit model showed a significant relationship between the HR-CTV (or CTV) D90 versus the 2-year and 3-year local control, P values were 0.013 and 0.014, respectively. The D90 corresponding to probabilities of 90% 2-year local control were 79.0 GyEQD2,10 (95% CI: 75.3–96.6 GyEQD2,10). Conclusions A significant dependence of 2-year or 3-year local control on HR-CTV (or CTV) D90 was found. Our research findings encourage further validation of the dose-response relationship of radical radiotherapy for vaginal cancer through protocol based multicenter clinical trials.

Abstract Background Depression is a prevalent issue among older adults, affecting their quality of life and overall well-being. Exercise is an effective means of relieving depressive symptoms in older adults, but the optimal dose for different exercise types remains unclear. As such, the aim of this meta-analysis was to examine the dose–response relationship between overall and specific types of exercise with depression symptoms in older adults. Methods This systematic review and network meta-analysis included a search of PubMed, Medline, Embase, PsycINFO, Cochrane library, and Web of Science for randomized controlled trials of exercise in older adults with depression symptoms from inception to 15 July 2023. Comprehensive data extraction covered dose, treatment regimen, demographics and study duration. Dosage metrics, encompassing METs-min/week, were scrutinized in correlation with the Minimal Clinically Importance Difference (MCID). Results A total of 47 studies involving 2895 participants and 7 kinds of exercise were included in the review. Without considering the dose, the results of our network meta-analysis indicated that Walking was the most effective in alleviating depression in older adults, in addition to Aerobic exercise (AE), Yoga, Qigong, Resistance training (RT), and Tai Chi (TC), which were equally effective. However, the results of the dose–response analysis found that Aerobic exercise was most effective at a dose of 1000 METs-min/week. It is noteworthy that Walking is significantly effective in alleviating depressive symptoms in older adults at very low doses. In terms of clinical benefits, we found that overall exercise doses in the range of 600 ~ 970 METs-min/week were clinically effective. Considering the specific types of exercise, Aerobic exercise, Resistance training, Walking, and Yoga were found to be effective at doses ranging from 820 ~ 1000 METs-min/week, 520 ~ 1000 METs-min/week, 650 ~ 1000 METs-min/week, 680 ~ 1000 METs-min/week, respectively. At the same time, we found that when the age exceeded 81 years, even when participating in exercise, it did not achieve the effect of alleviating depressive symptoms in older adults. Conclusions In conclusion, including Walking, AE, Yoga, Qigong, RT, and TC, effectively alleviate depressive symptoms in older adults. Furthermore, we established statistically and clinically significant threshold doses for various exercise types. Early initiation of exercise is beneficial, but its efficacy diminishes from the age of 80, and beyond 81, exercise no longer significantly alleviates depressive symptoms.

Introduction Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated. Methods A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient’s cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring. Results Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal. Discussion Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.

Abstract Objective The current study aimed to determine the effects of low (i.e., balance task only) versus high (i.e., balance task combined with an additional motor task like dribbling a basketball) balance training complexity (6 weeks of training consisting of 2 × 30 min balance exercises per week) on measures of static and dynamic balance in 44 healthy male adolescents (mean age: 13.3 ± 1.6 years). Results Irrespective of balance training complexity, significant medium- to large-sized pretest to posttest improvements were detected for static (i.e., One-Legged Stance test, stance time [s], 0.001

Abstract Background Students’ physical fitness, particularly aerobic fitness, has seriously declined during the COVID-19 epidemic. However, in the post-epidemic era, there are few studies on the methods of improving aerobic fitness. Understanding the dose-response relationship between physical activity and aerobic fitness is crucial for developing effective exercise prescriptions. Method This retrospective study reviewed the Fun Running program at Wannan Medical College in China. We conducted a pre-post study design to analyze the impact of 15 weeks of Fun Running training on aerobic fitness. Middle and long-distance running pace (MLDR-P) was used as the primary indicator of aerobic fitness. A paired sample T-test was used to analyze the differences between the two MLDR-Ps. Pearson’s correlation was used to examine the correlation between variables. Multiple linear regression was used to determine the extent to which Fun Running components explain the variance in MLDR-P. Results A total of 3244 college students participated in this study. 15 weeks of Fun Running training can significantly improve the MLDR-P in both females (P

Objective : To explore the dose-response relationship between γ-aminobutyric acid (GABA), markers of oxidative stress and the risk of dyslipidemia, so as to provide reference for prevention and improvement of dyslipidemia. Methods : A total of 149 patients with dyslipidemia hospitalized in a Grade A hospital in Haikou City from August 2022 to August 2023 were selected as the case group, and 236 patients with normal blood lipids were selected as the control group. The basic information of the research objects was collected by questionnaire. Serum GABA level, superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) level were measured by the kit. GABA and oxidative stress markers (SOD, GSH-Px, MDA) were divided into four groups according to the quartile levels of the control group from low to high (Q1 group to Q4 group). Logistic regression was used to analyze the risk of dyslipidemia. Spearman correlation coefficient, generalized linear model and restricted cubic spline were used to analyze the correlation between GABA and oxidative stress markers, and the dose-response relationship between GABA and oxidative stress markers and dyslipidemia. Results: After adjusting for confounding factors, Logistic regression showed that compared with the SOD activity, GSH-Px activity and MDA level in group Q1, the risk of dyslipidemia in the Q4 group was 0R=0.537[95%(,7(0.294--0.980) ], 0R=0.400[95%(,7(0.213--0.750)] and OR=2.375 [95%(7(1.254--4.495) ], respectively. GABA levels were positively correlated with SOD and GSH-Px activities, and negatively correlated with MDA levels (all P<0.001). The generalized linear model and restricted cubic spline showed that the risk of dyslipidemia decreased with the increase of SOD and GSH-Px activities, and increased with the increase of MDA levels, which was a linear dose-response relationship (all P<0.05). Conclusion: GABA level was correlated with SOD activity, GSH-Px activity and MDA level. There was a linear dose-response relationship between SOD activity, GSH-Px activity and MDA level and the risk of dyslipidemia. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to establish the dose-response relationship between volume base dose and tumor local control for vaginal cancer, including primary vaginal cancer and recurrent gynecologic malignancies in the vagina. Materials and methods: We identified studies that reported volume base dose and local control by searching the PubMed, the Web of Science, and the Cochrane Library Database through August 12, 2023. The regression analyses were performed using probit model between volume based dose versus clinical outcomes. Subgroup analyses were performed according to stratification: publication year, country, inclusion time of patients, patients with prior radiotherapy, age, primaries or recurrent, tumor size, concurrent chemoradiotherapy proportion, dose rate, image modality for planning, and interstitial proportion. Results: A total of 879 patients with vaginal cancer were identified from 18 studies. Among them, 293 cases were primary vaginal cancer, 573 cases were recurrent cancer in the vagina, and 13 cases were unknown. The probit model showed a significant relationship between the HR-CTV (or CTV) D90 versus the 2-year and 3-year local control, P values were 0.013 and 0.014, respectively. The D90 corresponding to probabilities of 90% 2-year local control were 79.0 GyEQD2,10 (95% CI: 75.3–96.6 GyEQD2,10). Conclusions: A significant dependence of 2-year or 3-year local control on HR-CTV (or CTV) D90 was found. Our research findings encourage further validation of the dose-response relationship of radical radiotherapy for vaginal cancer through protocol based multicenter clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Our study aimed to determine whether there exists an association between low-grade systemic inflammation, as measured by serum C-reactive protein (CRP), and the risk of lower-extremity deep venous thrombosis (LEDVT) in patients with primary intracerebral hemorrhage (ICH). Methods: This observational study was retrospectively conducted on patients with primary ICH who were presented to two tertiary medical centers between January 2021 and August 2022. The primary outcome was detecting LEDVT occurrence within 14 days from the onset of the acute ICH episode. Weighted logistic regression and restricted cubic spline models were employed to estimate the association between CRP and LEDVT following 1:1 propensity score matching (PSM). Results: Of the 538 patients with primary ICH who met the inclusion criteria, 76 (14.13%) experienced LEDVT. Based on the cut-off levels of CRP measured upon admission from the receiver operating characteristic (ROC) curve, patients with primary ICH were categorized into two groups: (i) CRP < 1.59 mg/L and (ii) CRP ≥ 1.59 mg/L. After 1:1 PSM, the LEDVT events occurred in 24.6% of patients with CRP ≥ 1.59 mg/L and 4.1% of patients with CRP < 1.59 mg/L (P < 0.001). ROC curve revealed the area under the ROC curve of 0.717 [95% confidence interval (CI) 0.669–0.761, P < 0.001] for CRP to predict LEDVT with a sensitivity of 85.71% and specificity of 56.29%. After adjusting for all confounding variables, the occurrence of LEDVT in ICH patients with higher CRP levels (≥ 1.59 mg/L) was 10.8 times higher compared to those with lower CRP levels (95% CI 4.5–25.8, P < 0.001). A nonlinear association was observed between CRP and an increased risk of LEDVT in the fully adjusted model (P for overall < 0.001, P for nonlinear = 0.001). The subgroup results indicated a consistent positive link between CRP and LEDVT events following primary ICH. Conclusions: Higher initial CRP levels (CRP as a dichotomized variable) in patients with primary ICH are significantly associated with an increased risk of LEDVT and may help identify high-risk patients with LEDVT. Clinicians should be vigilant to enable early and effective intervention in patients at high risk of LEDVT. [ABSTRACT FROM AUTHOR]

Background: Cognitive decline is a prevalent health problem in older adults, and effective treatments remain to be produced. Serum vitamin D, a commonly used biochemical marker, is widely recognized as an indicator of various diseases. Existing research has not fully elucidated the relationship between vitamin D and cognitive function. The aim of this study is to investigate the real relationship between vitamin D and cognitive function and to identify indicators that have a strong predictive effect on cognitive decline. Methods: At first, we used the dataset of the genome-wide association studies studying vitamin D and cognitive performance to conduct Mendelian randomization analysis. Subsequently, we employed linear regression and smooth curve fitting methods to assess the relationship using the National Health and Nutrition Examination Survey data. Finally, we investigated other predictive features of cognitive performance utilizing a machine learning model. Results: We found that a 1-unit increase in vitamin D is associated with a 6.51% reduction (P < .001) in the risk of cognitive decline. The correlation between vitamin D and cognitive performance is nonlinear, with the inflection point at 79.9 nmol/L (left: β = 0.043, P < .001; right: β = -0.007, P = .420). In machine learning, the top 5 predictors are vitamin D, weight, height, age, and body mass index. Conclusion: There is a causal relationship between vitamin D and cognitive performance. 79.9 nmol/L could be the optimal dose for vitamin D supplementation in the elderly. Further consideration of other factors in vitamin D interventions is necessary. [ABSTRACT FROM AUTHOR]

The effect of weekend catch-up sleep (WCS) on depressive symptoms is inconsistent among different populations, with limited evidence in Americans. Therefore, we aimed to investigate the association between WCS and depressive symptoms in American adults. We recruited 7719 participants from the National Health and Nutrition Examination Survey (NHANES) 2017–2020. Information on sleep duration and depressive symptoms were assessed by several self-reported questions and Patient Health Questionnaire-9 (PHQ-9), respectively. Then, WCS duration was calculated as weekend sleep duration minus weekday sleep duration, and WCS was further defined as WCS duration >0 h. Survey designed regression analyses were used to assess the association of WCS and depressive symptoms. In fully adjusted multivariate logistic regression models, the odds ratio (95 % confidence interval) for depressive symptoms and the β (95 % confidence interval) for PHQ-9 score in response to WCS were 0.746 (0.462, 1.204; P = 0.218) and −0.429 (−0.900, 0.042; P = 0.073), respectively. Besides, the smooth relationship presented L-shaped, and only WCS duration of 0–2 h was statistically significantly associated with depressive symptoms or PHQ-9 score. Subgroup analyses showed that the negative associations were stronger among men, adults younger than 65 years, and those with short weekday sleep duration (P for interaction <0.05). Limitations. The cross-sectional design limits the capability for causal relationship between WCS and depressive symptoms. This study suggests that moderate WCS is associated with reduced odds of depressive symptoms, which provides additional epidemiological evidence for the effects of sleep on depressive symptoms. • We firstly explored the effects of WCS on depressive symptoms in American adults. • WCS duration of 0–2 h was related to decreased odds of depressive symptoms. • Continuous WCS duration showed a non-linear association with depressive symptoms. • Specific subgroups were more sensitive to the benefits of WCS. • Our findings offer more evidence to help alleviate depressive symptoms in Americans. [ABSTRACT FROM AUTHOR]

Purpose: Stretch-induced force deficit suggests an acute stretch-specific strength capacity loss, which is commonly attributed to EMG reductions. Since those deficits could also be attributed to general fatigue induced by overloading the muscle, this study aimed to compare stretching with an exhausting calf raise programme to compare strength and stretching responses. Method: This study included 16 participants with different, high-duration calf muscle stretching effects (10, 20, 30 min of stretching) with resistance training (RT) (3 × 12 repetitions) performed until muscle failure, by using a cross-over study design with pre-post comparisons. Strength was tested via isometric plantar flexor diagnostics, while flexibility was assessed using the knee-to-wall test (KtW) and an isolated goniometer test. Results: Using a three-way ANOVA, RT strength decreases were greater compared to 10 and 20 min of stretching (p = 0.01–0.02), but similar to those of 30 min of stretching. ROM in the KtW showed no specific stretch-induced increases, while only the stretching conditions enhanced isolated tested ROM (p < 0.001–0.008). No RT-related isolated ROM increases were observed. Conclusions: The results showed both interventions had similar effects on strength and ROM in the calf muscles. More holistic explanatory approaches such as fatigue and warm-up are discussed in the manuscript and call for further research. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Hormesis in soil enzymes is well-established, yet the underlying mechanism remains elusive. In this novel study, we investigated the effects of low-dose Cd exposure (0, 0.03, 0.3, 3, and 30 mg·kg−1) in farmland soil within a typical constructed wetland environment. We assessed the activities of four soil enzymes (urease (URE), denitrification enzyme (DEA), dehydrogenase (DHA), and alkaline phosphatase (ALP)) at varying exposure durations (0 h, 24 h, and 48 h), evaluating hormetic characteristics across these time intervals. Additionally, we determined kinetic parameters, specifically the Michaelis constant (Km) and maximum reaction velocity (Vmax), for these enzymes while examining potential alterations in microbial community structure. Our findings revealed hormesis in all four soil enzymes at 24 h of exposure, with varying stimulus width and maximum hormesis rates. Interestingly, heavy metals did not significantly influence the diversity of soil microbial communities, but they did inhibit the ability of soil microbial communities to secrete extracellular enzymes. This resulted in a reduction in the soil enzyme pool and a consequential shift in overall soil enzyme activities. The conclusion of this study is that low-dose Cd primarily reduced extracellular enzyme secretion by soil microorganisms, leading to a reduction in the size of the soil enzyme pool and thereby inducing hormesis in soil enzyme activities. [ABSTRACT FROM AUTHOR]

Objective: The current study aimed to determine the effects of low (i.e., balance task only) versus high (i.e., balance task combined with an additional motor task like dribbling a basketball) balance training complexity (6 weeks of training consisting of 2 × 30 min balance exercises per week) on measures of static and dynamic balance in 44 healthy male adolescents (mean age: 13.3 ± 1.6 years). Results: Irrespective of balance training complexity, significant medium- to large-sized pretest to posttest improvements were detected for static (i.e., One-Legged Stance test, stance time [s], 0.001 < p ≤ 0.008) and dynamic (i.e., 3-m Beam Walking Backward test, steps [n], 0.001 < p ≤ 0.002; Y-Balance-Test-Lower-Quarter, reach distance [cm], 0.001 < p ≤ 0.003) balance performance. Further, in all but one comparison (i.e., stance time with eyes opened on foam ground) no group × test interactions were found. These results imply that balance training is effective to improve static and dynamic measures of balance in healthy male adolescents, but the effectiveness seems unaffected by the applied level of balance training complexity. [ABSTRACT FROM AUTHOR]

Objective: Recent reports have demonstrated that a wider pulse pressure upon admission is correlated with heightened in-hospital mortality following spontaneous supratentorial intracerebral hemorrhage (ssICH). However, the underlying mechanism remains ambiguous. We investigated whether a wider pulse pressure was associated with hematoma expansion (HE). Methods: Demographic information, clinical features, and functional outcomes of patients diagnosed with ssICH were retrospectively collected and analyzed. Multivariate logistic regression was conducted to identify independent predictors of HE. Weighted logistic regression, restricted cubic spline models, and propensity score matching (PSM) were employed to estimate the association between pulse pressure and HE. Results: We included 234 eligible adult ssICH patients aged 60 (51–71) years, and 55.56% were male. The mean pulse pressure was 80.94 ± 23.32 mmHg. Twenty-seven patients (11.54%) developed early HE events, and 116 (49.57%) experienced a poor outcome (modified Rankin scale 3–6). A wider mean pulse pressure as a continuous variable was a predictor of HE [odds ratios (OR) 1.026, 95% confidence interval (CI) 1.007–1.046, p = 0.008] in multivariate analysis. We transformed pulse pressure into a dichotomous variable based on its cutoff value. After adjusting for confounding of HE variables, the occurrence of HE in patients with ssICH with wider pulse pressure levels (≥98 mmHg) had 3.78 times (OR 95% CI 1.47–9.68, p = 0.006) compared to those with narrower pulse pressure levels (<98 mmHg). A linear association was observed between pulse pressure and increased HE risk (P for overall = 0.036, P for nonlinear = 0.759). After 1:1 PSM (pulse pressure ≥98 mmHg vs. pulse pressure <98 mmHg), the rates of HE events and poor outcome still had statistically significant in wider-pulse pressure group [HE, 12/51 (23.53%) vs. 4/51 [7.84%], p = 0.029; poor outcome, 34/51 (66.67%) vs. 19/51 (37.25%), p = 0.003]. Conclusion: Widened acute pulse pressure (≥98 mmHg) levels at admission are associated with increased risks of early HE and unfavorable outcomes in patients with ssICH. [ABSTRACT FROM AUTHOR]

Aims: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target‐mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. Methods: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non‐log‐linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target‐mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). Results: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first‐order (CL = 1.318 mL/day/kg) and Michaelis–Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight‐dependent. Critical concentrations (Vmax/CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P =.013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. Conclusions: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target‐mediated elimination in therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Purpose: Fracture risk assessment is recommended at three months after glucocorticoid (GC) therapy initiation. This study aimed to assess whether GC exposure in the initial 90 days of GC therapy is associated with subsequent hip and clinical vertebral fracture risk using the nationwide health insurance claims database of Japan (NDBJ). Methods: Patients aged ≥ 50 years who were prescribed GC (≥ 70 mg prednisolone or equivalent; PSL) in the initial 90 days of GC therapy and were followed for hip and clinical vertebral fracture incidences for the subsequent 1080 days were selected from NDBJ. Associations of GC exposure with hip or clinical vertebral fracture risk were evaluated by Cox regression analysis adjusted for potential confounders. Results: We selected 316,396 women and 299,871 men for the GC-exposed group and 43,164 women and 33,702 men for the reference group. Higher GC doses and longer prescription days in the initial 90 days of GC therapy were significantly and dose-dependently associated with increased fracture risk relative to the reference group. Patients receiving GC ≥ 5 mg PSL/day had a significantly increased fracture risk in the stratum of 30–59 days of GC prescription. In addition, female patients who received GC (≥ 1 and < 2.5 mg PSL/day) for 90 days in the initial 90 days of GC therapy had a significantly increased fracture risk. Conclusions: GC exposure in the initial 90 days of GC therapy was dose-dependently associated with hip and clinical vertebral fracture risk. GC may increase fracture risk with lower doses for shorter durations than previously reported. Summary: Fracture risk assessment three months after glucocorticoid (GC) therapy initiation is recommended. We found that GC exposure in the initial 90 days of GC therapy at lower daily doses for shorter durations than previously reported were significantly and dose-dependently associated with fracture risk using a nationwide health insurance claims database. [ABSTRACT FROM AUTHOR]

Superiority of perineural over intravenous dexamethasone at extending nerve block analgesia has been suggested but without considering the dose–response relationships for each route of administration. Randomised control studies that evaluated intravenous or perineural dexamethasone as an adjuvant to unilateral peripheral nerve blocks in adults were searched up to October 2023 in MEDLINE, Central, Google Scholar, and reference lists of previous systematic reviews. The Cochrane Risk-of-Bias tool was used. A maximum effect (E max) model-based network meta-analysis was undertaken to evaluate the dose–response relationships of dexamethasone. A total of 118 studies were selected (9284 patients; 35 with intravenous dexamethasone; 106 with perineural dexamethasone; dose range 1–16 mg). Studies with unclear or high risk of bias overestimated the effect of dexamethasone. Bias-corrected estimates indicated a maximum fold increase in analgesia duration of 1.7 (95% credible interval (CrI) 1.4–1.9) with dexamethasone, with no difference between perineural and intravenous routes. Trial simulations indicated that 4 mg of perineural dexamethasone increased the mean duration of analgesia for long-acting local anaesthetics from 11.1 h (95% CrI 9.4–13.1) to 16.5 h (95% CrI 14.0–19.3) and halved the rate of postoperative nausea and vomiting. A similar magnitude of effect was observed with 8 mg of intravenous dexamethasone. Used as an adjuvant for peripheral nerve block, intravenous dexamethasone can be as effective as perineural dexamethasone in prolonging analgesic duration, but is less potent, hence requiring higher doses. The evidence is limited because of the observational nature of the dose–response relationships and the quality of the included studies. PROSPERO CRD42020141689. [ABSTRACT FROM AUTHOR]

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Background: Magnesium (Mg) is an essential element and participates in many metabolic pathways. Many studies have found a certain negative correlation between magnesium and blood glucose parameters, but the dose–response relationship between them is still a relatively narrow research field. We aim to explore the dose–response relationship between plasma and dietary Mg and type 2 diabetes (T2DM) among childbearing women in a nationally representative sample. And we will also initially explore the threshold of dietary and plasma magnesium in the prevention of T2DM and their consistency. Methods: A total of 2912 18–44 year-old childbearing women were recruited from the China Adult Chronic Disease and Nutrition Surveillance (2015). Multivariate logistic regression was used to explore the dose–response relationship between plasma and dietary Mg and glucose parameters. The threshold effect between Mg and T2DM was explored by a restricted cubic spline regression. Results: It was found that when plasma Mg was increased by 0.041 mmol/L, the risk of T2DM, impaired fasting glucose (IFG), and HbA1c-hyperglycemia was reduced by 18%, 19%, and 18%, respectively. The possible threshold value for plasma Mg to prevent the risk of T2DM was 0.87 mmol/L. Through the quality control of the sample dietary survey data, 2469 cases were finally included for dietary analysis. And the possible threshold value for dietary Mg to prevent the risk of T2DM was 408 mg/d. Taking the recommended dietary Mg intake of 330 mg/d as the reference group, when the Mg intake reached 408 mg/d, the risk of T2DM was significantly reduced. And the average plasma Mg level of the people whose dietary intake reached 408 mg/d was 0.87 mmol/L. Conclusions: These results indicate that dietary Mg and plasma Mg have good consistency on the threshold effect of glucose parameters in women of childbearing age. [ABSTRACT FROM AUTHOR]

BackgroundMild cognitive impairment (MCI) represents a prodromal stage of dementia, characterized by cognitive decline exceeding that expected with normal aging. Exercise interventions have emerged as a promising approach to counter functional decline and enhance cognitive function in the elderly MCI population. However, the optimal exercise modalities and dosage (dose-response relationship) are understudied.ObjectiveIt aims to determine the most effective exercise modality for MCI patients by optimizing the dose-response relationship to ensure sufficient intensity to induce positive neurological adaptations.MethodsA systematic search of electronic databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials was conducted from inception to April 15, 2024. Studies evaluating the efficacy of exercise interventions in MCI participants were included. Primary outcomes of interest are global cognition and executive function. Random-effects models will be utilized for both pairwise and network meta-analysis.ResultsFollowing the application of specific inclusion and exclusion criteria, a total of 42 articles, encompassing 2832 participants, were chosen for inclusion in a network meta-analysis. The findings revealed that multi-component exercise demonstrated superior efficacy in mitigating the deterioration of global cognition, as evidenced by standard mean differences (SMDs) of 1.09 (95% CI: 0.68 to 1.51) compared to passive controls. Additionally, multi-component exercise exhibited a significant impact on executive function, with SMDs of 2.50 (95% CI: 0.88 to 4.12) when contrasted with passive controls. Our research has demonstrated that sessions lasting 30 minutes, occurring 3-4 times per week, with interventions lasting 12-24 weeks and an intensity of 60-85% of maximum heart rate, yield higher effect sizes in improving global cognition. However, sessions lasting 30-61 minutes, with interventions lasting 25 weeks or longer, show greater effectiveness in enhancing executive function.ConclusionA network meta-analysis identified multi-component exercise as the most effective intervention for improving global cognitive and executive function in patients with mild cognitive impairment. Notably, moderate-intensity exercise performed at least three times weekly appears beneficial, with evidence suggesting shorter sessions and higher frequencies may optimize cognitive outcomes.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42024534922.

BackgroundAcute pancreatitis, among the most prevalent gastrointestinal disorders, exhibits a continual rise in its incidence recent years. This study endeavor to explore the correlation between smoking exposure and the severity of acute pancreatitis (AP).MethodsFive hundred and eight patients diagnosed as acute pancreatitis (AP) were included in our data analysis. Patients were categorized based on their smoking pack-years into four groups: light, moderate, heavy, and non-smokers. Outcomes were classified as two: “mild acute pancreatitis (MAP)” and “moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP)”. We conducted propensity score matching (PSM) to adjust confounding factors and multivariable logistic regression analysis to determine adjusted odds ratios and 95% confidence intervals. Additionally, a dose-dependent association analysis between smoking exposure and the incidence rate of “MSAP or SAP” was performed.ResultsSmokers exhibited a higher risk of “MSAP or SAP” compared to non-smokers, both before (17.1 vs. 54.9%, p < 0.001) and after (9.4 vs. 24.7%, p < 0.001) PSM. With an area under the ROC curve of 0.708, smoking showed a moderate level of predictive ability. Furthermore, propensity score matching analysis showed that patients who smoked compared to non-smokers had significantly higher risks of “MSAP or SAP” for light smoking (OR 3.76, 95% CI 1.40–10.07, p = 0.008), moderate smoking (OR 4.94, 95% CI 2.23–10.92, p < 0.001), and heavy smoking (OR 8.08, 95% CI 3.39–19.25, p < 0.001).ConclusionSmoking is an independent risk factor that can raise the severity of pancreatitis. Moreover, the severity of acute pancreatitis escalates in tandem with the accumulation of pack-years of smoking.

ObjectiveThis study was undertaken to describe the safety, tolerability, pharmacokinetics, and immunogenicity of elezanumab (ABT-555), a fully human monoclonal antibody (mAb) directed against repulsive guidance molecule A (RGMa), in healthy and multiple sclerosis (MS) study participants.MethodsThe single-center, first-in-human, single ascending dose (SAD) study evaluated elezanumab (50-1,600mg intravenous [IV] and 150mg subcutaneous) in 47 healthy men and women. The multicenter multiple ascending dose (MAD; NCT02601885) study evaluated elezanumab (150mg, 600mg, and 1,800mg) in 20 adult men and women with MS, receiving either maintenance or no immunomodulatory treatment.ResultsNo pattern of study drug-related adverse events was identified for either the SAD or MAD elezanumab regimens. Across both studies, the Tmax occurred within 4 hours of elezanumab IV infusion, and the harmonic mean of t1/2 ranged between 18.6 and 67.7 days. Following multiple dosing, elezanumab Cmax , area under the curve, and Ctrough increased dose-proportionally and resulted in dose-dependent increases in elezanumab cerebrospinal fluid (CSF) concentrations. Elezanumab CSF penetration was 0.1% to 0.4% across both studies, with CSF levels of free RGMa decreased by >40%. Changes in CSF interleukin-10 (IL-10) and free RGMa demonstrated dose/exposure-dependence.InterpretationThe elezanumab pharmacokinetic profile supports monthly, or bimonthly, administration of up to 1,800mg with the option of a loading dose of 3,600mg. Elezanumab partitioning into CSF is within the range expected for mAbs. Reduced CSF levels of free RGMa demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1,800mg IV. Exposure-associated increases in CSF IL-10, an anti-inflammatory cytokine with neuroprotective/neurorestorative properties, support potential pathway modulation in MS participants. ANN NEUROL 2023;93:285-296.

The aim of this study was to conduct a comprehensive review with meta-analysis to determine the effects of the dose-response relationship between monensin supplementation and dairy cow performance and milk composition. Results from 566 full-text articles and 48 articles with 52 studies were meta-analyzed for pooled estimates. Monensin supplementation up to 23 ppm increased milk production, with the optimal dose being 12.6 ppm. Monensin supplementation at doses ranging from 16 to 96 ppm increased milk production in the prepartum phase (- 28 to 0 day relative to calving). From 60 to 150 DIM, monensin supplementation up to 21 ppm had a significant positive effect on this outcome, while supplementation in the 37 to 96 ppm range caused a decrease in this variable. At 0 to 60 and > 150 DIM, monensin supplementation had no effect on milk yield. At dosages of 22 to 96 ppm, 12 to 36 ppm, and below 58 ppm and 35 ppm, respectively, monensin supplementation resulted in significant decreases in dry matter intake (DMI), milk protein percentage, milk fat percentage, and milk fat yield. Overall, based on the results of this meta-analysis and considering all variables, the recommended optimal dose of monensin could be about 16 ppm.

Abstract In the present study, an attempt has been made to assess the impact of vehicular noise upon the 3-wheeler tempo drivers and to know whether there is any relationship between hearing loss and cumulative noise exposure. For this purpose, 3-wheeler tempo drivers (Exposed group) and non-commercial light motor vehicle car drivers (Unexposed group) were chosen as study subjects. Three traffic routes were selected to assess the noise level during waiting and running time in the exposed and unexposed groups. Among all three routes, the highest mean noise level (Leq) was observed on the Chowk to Dubagga route for waiting and en-route noise measurement. It was measured as 84.13 dB(A) and 86.36 dB(A) for waiting and en-route periods of 7.68 ± 3.46 and 31.05 ± 6.6 min, respectively. Cumulative noise exposure was found to be significantly different (p

Yaru Bi,1,&ast; Yang Yang,2,&ast; Xiaojie Yuan,3 Jiping Wang,3 Zhiyuan Liu,4 Suyan Tian,5 Chenglin Sun1,3 1Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, 130000, People’s Republic of China; 2Department of Health Examination Center, First Hospital of Jilin University, Changchun, 130000, People’s Republic of China; 3Department of Clinical Nutrition, First Hospital of Jilin University, Changchun, 130000, People’s Republic of China; 4Department of Clinical Medicine, Yanbian University, Yanji, 136200, People’s Republic of China; 5Division of Clinical Research, First Hospital of Jilin University, Changchun, 130000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Suyan Tian; Chenglin Sun, Email wmxt@jlu.edu.cn; chenglins@jlu.edu.cnAim: Multiple studies have investigated the association between alanine aminotransferase (ALT) and diabetes mellitus (DM); however, only a few studies have specifically examined the relationship between ALT and diabetic kidney disease (DKD). This study aimed to investigate the relationship between ALT and DKD using clinical data.Methods: A cross-sectional study was conducted on 668 individuals that included non-DM (N=281), DM without DKD (N=160), and DKD (N=227) patients. A generalized additive model (GAM) was used to examine the dose–response relationship between ALT and DKD risk. We also analyzed the data from the US National Health and Nutrition Examination Survey (NHANES) 2015– 2018 using the same statistical methods; 4481, 1110, and 671 individuals were included in the non-DM, DM without DKD, and DKD groups, respectively.Results: The changes in ALT activity among the non-DM, DM without DKD, and DKD groups showed a similar pattern in both our clinical data and the NHANES dataset. ALT activity increases with the onset of DM, whereas ALT activity decreases when DM progresses to DKD. The GAM revealed a nonlinear U-shaped relationship between ALT and DKD risk in the two datasets, and the lowest range of ALT was 40– 50 IU/L. Both lower (< 40 IU/L) and higher (> 50 IU/L) ALT activity were found to be positively associated with DKD risk.Conclusion: A U-shaped nonlinear association between ALT and DKD was found in our clinical data and NHANES data. DKD risk was increased by both lower or higher ALT activity. To confirm the causality of nonlinear relationship, larger prospective studies or Mendelian randomization analysis are required.Keywords: alanine aminotransferase, diabetic kidney disease, dose–response relationship, NHANES