Effects of N-acetylcysteine on hepatocellular carcinoma in chronic hepatitis C.

Hepatitis C virus (HCV) infection significantly contributes to global hepatocellular carcinoma (HCC) incidence. N-Acetylcysteine (NAC), known for its antioxidant properties, is a potential therapeutic agent. However, evidence on its efficacy in reducing HCC risk among HCV patients is limited. A retrospective cohort analysis using Taiwan's National Health Insurance Research Database (2008-2018) included ≥18-year-old HCV patients. NAC usage (≥28 cumulative defined daily doses [cDDDs]) was assessed for its association with HCC risk using Cox regression models and propensity score matching. The study comprised 269,647 HCV patients, with detailed NAC dosage characterization and hazard ratios (HRs) for HCC risk. Post-matching, NAC usage emerged as the significant predictor of reduced HCC risk (adjusted HR: 0.39, 95% CI: 0.37-0.41, P<0.0001). Dose-response analysis showed reduced HCC risk with increasing cDDDs of NAC (P<0.0001). Higher daily NAC dosage (≥1 DDD) was associated with significantly lower HCC risk (adjusted HR: 0.33, 95% CI: 0.31-0.36, P<0.0001). The study provides compelling evidence for NAC's potential in reducing HCC risk among HCV patients. Insights into dose-dependent effects and optimal daily intensity thresholds offer valuable directions for future therapeutic strategies and clinical trials targeting HCC burden in HCV-infected individuals.

Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative schedules.

The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a pre-surgical study of alternative exemestane schedules. Postmenopausal women candidate for breast surgery for estrogen receptor-positive breast cancer were randomized to exemestane 25 mg once daily (QD), 25 mg three times/week (TIW), or 25 mg per/week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in non-malignant tissue. Estradiol was nearly suppressed in all groups in the non-malignant tissue (QD vs TIW p = .364 and QD vs QW p = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in non-malignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy.

Dose-response association between walking speed and all-cause mortality: A systematic review and meta-analysis of cohort studies.

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.

A dose-response correlation between smoking and severity of acute pancreatitis: a propensity score-matched study.

Background: Acute 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). Methods: Five 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. Results: Smokers 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). Conclusion: Smoking 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.

Vitamin D and Cognitive Performance in Older Adults: A Cross-Sectional and Mendelian Randomization Study.

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: ß = 0.043, P < .001; right: ß = -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.

Association between Whole-Grain Intake and Obesity Defined by Different Anthropometric Indicators and Dose-Response Relationship Analysis among U.S. Adults: A Population-Based Study.

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.

Association between organophosphorus insecticides exposure and osteoarthritis in patients with arteriosclerotic cardiovascular disease.

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.

Dose-response relationship between arsenic in drinking water and mortality of urinary cancers in Taiwan.

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.

C-reactive protein is a predictor for lower-extremity deep venous thrombosis in patients with primary intracerebral hemorrhage.

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.

Association between urinary polycyclic aromatic hydrocarbons and risk of metabolic associated fatty liver disease.

OBJECTIVE: To investigate the effect of urinary PAHs on MAFLD. METHODS: The study included 3,136 adults from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2016. Among them, 1,056 participants were diagnosed with MAFLD and were designated as the case group. The analysis of the relationship between monohydroxy metabolites of seven PAHs in urine and MAFLD was carried out using logistic regression and Bayesian kernel regression (BKMR) models. RESULTS: In single-pollutant models, the concentration of 2-hydroxynaphthalene (2-OHNAP) was positively correlated with MAFLD (OR = 1.47, 95% CI 1.18, 1.84), whereas 3-hydroxyfluorene (3-OHFLU) and 1-hydroxypyrene (1-OHPYR) demonstrated a negative correlation with MAFLD (OR = 0.59, 95% CI 0.48 0.73; OR = 0.70, 95% CI 0.55, 0.89). Conversely, in multi-pollutant models, 2-OHNAP, 2-hydroxyfluorene (2-OHFLU), 2-hydroxyphenanthrene, and 3-hydroxyphenanthrene (2&3-OHPHE) displayed positive correlations with MAFLD (OR = 6.17, 95% CI 3.15, 12.07; OR = 2.59, 95% CI 1.37, 4.89). However, 3-OHFLU and 1-OHPYR continued to exhibit negative correlations with MAFLD (OR = 0.09, 95% CI 0.05, 0.15; OR = 0.62, 95% CI 0.43, 0.88). Notably, the BKMR analysis mixtures approach did not indicate a significant joint effect of multiple PAHs on MAFLD, but identified interactions between 3-OHFLU and 2-OHFLU, 1-OHPYR and 2-OHFLU, and 1-OHPYR and 3-OHFLU. CONCLUSION: No significant association was found between mixed PAHs exposure and the risk of MAFLD. However, interactions were observed between 3-OHFLU and 2-OHFLU. Both 2-OHFLU and 2&3-OHPHE exposure are significant risk factors for MAFLD, whereas 3-OHFLU is a key protective factor for the disease.

Optimal dose and type of exercise to improve depressive symptoms in older adults: a systematic review and network meta-analysis.

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.

Dose-response relationship between volume base dose and tumor local control in definitive radiotherapy for vaginal cancer.

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.

Resistance Training Causes the Stretch-Induced Force Deficit-A Randomized Cross-Over Study.

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.

The relationship between caffeine consumption and colon cancer prevalence in a nationally representative population.

Aims: This study examines the correlation between caffeine consumption and the prevalence of colon cancer. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) for the years 2001 to 2014, we applied weighted logistic regression to evaluate the association between caffeine consumption and the prevalence of colon cancer. This analysis accounted for variables including age, gender, race, education, poverty income ratio, smoking status, alcohol consumption, and diabetes. The findings were expressed as weighted odds ratios (ORs) with accompanying 95% confidence intervals (CIs). The restricted cubic spline analysis was performed to exam the dose-dependent relationship. Results: The study included 27,637 participants, of which 144 were diagnosed with colon cancer and 27,493 served as controls. Individuals in the highest quartile (Q4) of caffeine consumption (Q4) displayed a significantly increased risk of colon cancer compared to those in the lowest quartile (Q1), with a weighted OR of 2.00 (95% CI: 1.11-3.59; p = 0.022). Additionally, restricted cubic spline analysis indicated a significant correlation between higher caffeine intake and increased colon cancer risk, with an overall association p-value of 0.007. Conclusion: These findings suggest a potential relationship between higher levels of caffeine consumption and an increased risk of colon cancer. The dose-response relationship suggests a notable correlation at higher caffeine intake levels. Further investigations are warranted to confirm these results and elucidate potential underlying mechanisms.

Quantifying and normalizing the combined phytotoxicity of mixed-valence chromium in soil integrated by toxicity equivalence.

When Cr(VI) and Cr(III) coexist, the reasonable assessment of the combined toxicity of chromium in soil and its ecological risk is still not well resolved. In the present study, exogenous mixed concentration combinations were set up to determine the interaction and combined toxicity of Cr(VI) and Cr(III), which were quantified as measured total and resin extractable forms for dose-response experiments with barley root elongation. The concept of toxicity equivalence "α" (the ratio of toxicity intensity coefficient between Cr(VI) and Cr(III), which can be expressed as the relative toxic strength of Cr(VI) to Cr(III)) was proposed for the toxicity assessment of mixed-valence chromium in soil. The results showed that the dose-response relationship was determined more precisely by the extended independent action model (e-IA) than traditional models (e.g., concentration addition model), and the mutual antagonism for resin extractable form (Resin-Cr) was stronger than the measured total form (T-Cr). The values of toxicity equivalence (α) between coexisting Cr(VI) and Cr(III) as Resin-Cr and T-Cr were 0.74 and 160, respectively, which indicated Resin-Cr(III) had relatively stronger toxicity than Resin-Cr(VI), while T-Cr(III) was much less than T-Cr(VI). The α values between Cr(VI) and Cr(III) decreased with their more active forms (decreased to about 0.5% of the original), even as total concentration and activity in solutions, making a dialectical view of the toxicity of both in different forms necessary. Finally, the log-logistic models were developed, enabling mixed-valence Cr toxicity to be assessed from a unilateral perspective using the Cr(III) equivalence concentration (Cr(III)-eq). This work provided innovative ideas for ecological threshold studies for mixed-valence metals in soils.

Evaluation of major adverse events of clozapine based on accordance to an international titration guideline.

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.

Exploration of quantitative-effectiveness association between acupuncture temporal parameters and stable chronic obstructive pulmonary disease: A systematic review and dose-response meta-analysis of randomized controlled trials.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a globally common chronic respiratory disease with a high morbidity and mortality rate. Acupuncture has been proven effective for COPD. A dose-response meta-analysis was conducted to assess the correlation between the acupuncture temporal parameters(session, frequency, and duration) and its effectiveness in patients with stable COPD. METHODS: Acupuncture randomized controlled trials on COPD were searched in eight databases from their inception to June 2023. The "doses" were defined as the acupuncture session, frequency, and duration. The outcomes mainly included Forced Expiratory Volume in one-second rate (FEV1%) and Six-minute Walking Distance (6MWD). The assessment of bias risk and literature quality were conducted independently using the Cochrane risk of bias tool and the Standards for reporting interventions in clinical trials of acupuncture. The dose-response relationship was modeled using robust error element regression, and meta-analysis was operated by R 4.3.1 and Stata 15.0. The protocol was registered in PROSPERO with the registration number CRD42023401406. RESULT: Out of 1669 records, 17 RCTs with 1165 participants were finally included in the meta-analysis. There was notable heterogeneity among the studies, but sensitivity analysis demonstrated good robustness. The findings revealed a significant improvement in the following outcomes for stable COPD patients in the acupuncture group: FEV1% (MD=3.50, 95%CI: 2.05-4.95), 6MWD (MD=47.39, 95%CI: 29.29-65.50), St. George's respiratory questionnaire (SGRQ; MD=-8.25, 95%CI: -11.38 to -5.12); COPD assessment test (CAT; MD=-2.91, 95%CI: -3.99 to -1.83). The relationship between the acupuncture session, duration, and FEV1%, 6MWD followed a "Λ" curve pattern, while the relationship between acupuncture frequency and FEV1%, 6MWD exhibited logarithmic growth. Firstly, After 12 acupuncture sessions, FEV1% and 6MWD increased by 7.06% (95%CI: 4.56-9.55) and 36.28 m (95%CI: 20.37-52.20), respectively. The peak improvement in FEV1% and 6MWD was observed after 18 acupuncture sessions (MD=7.89, 95% CI: 5.33-10.45) and 45 sessions (MD=125.43, 95% CI: 72.80-178.07) each. Additionally, weekly acupuncture resulted in a 4.14% improvement in FEV1% (95% CI: 2.55-5.72) and a 42.49 m increase in 6MWD (95%CI: 17.16-67.81). Notably, the maximum effects on FEV1% and 6MWD improvement were achieved with different acupuncture frequencies, specifically three times a week (MD=6.00, 95% CI: 5.34-6.66) and once a day(MD=112.41, 95% CI: 77.27-147.56), respectively. Furthermore, after a 28-day duration of acupuncture treatment, FEV1% increased by 4.74% (95% CI: 3.73-5.75) and 6MWD increased by 47.34 m (95%CI: 22.01-72.67). During 60 days of acupuncture treatment, the FEV1% and 6MWD improvement reached their highest levels at 8.76% (95% CI: 7.05-10.47) and 88.06 m (95% CI: 45.96-130.16), respectively. CONCLUSION: Acupuncture was effective in improving FEV1%, 6MWD, SGRQ, and CAT in patients with stable COPD. There was a dose-response relationship between the time parameters of acupuncture (session, frequency, and duration) and the efficacy of COPD treatment (FEV1% and 6MWD). The minimal clinically important difference could be achieved after 12 acupuncture sessions. Acupuncture with a medium-frequency (2-3 times per week) over 60 days may result in the greatest improvement in FEV1%, while higher-frequency acupuncture (5-7 times per week) for 2 months may lead to the maximum improvements in 6MWD. It indicated that the optimal acupuncture duration for different indicators remains consistent, while the optimal frequencies may differ. To confirm these results, it is necessary to conduct multicenter, large-scale randomized controlled trials. ETHICS AND DISSEMINATION: Ethical approval is not required for literature-based studies. The results will be published in peer-reviewed journals or conferences.

Combined healthy lifestyle behaviours and incident dementia: A systematic review and dose-response meta-analysis of cohort studies.

BACKGROUND: The associations of combined healthy lifestyle behaviours and incident dementia have not been systematically reviewed and the dose-response relationship was uncertain. OBJECTIVES: To evaluate the associations of combined healthy lifestyle behaviours with incident dementia and other cognitive outcomes, assess the dose-response relationship between the number of lifestyle behaviours and incident dementia, and summarise the adherence to healthy lifestyle behaviours. DESIGN: Systematic review and meta-analysis. METHODS: PubMed, EMBASE, Web of Science and PsycINFO were searched from inception to 20 Jan 2024. Cohort studies reporting associations of combined healthy lifestyle behaviours with incident dementia or other cognitive outcomes were included. We used the random-effects meta-analysis to pool the risk estimates and the robust error meta-regression method to examine the dose-response relationship. The methodological quality was assessed using the Newcastle-Ottawa Scale. RESULTS: A total of 22 articles including 25 cohort studies mostly from high-income economics were included, with all assessed as high methodological quality. Adherence to a healthy lifestyle was associated with a decreased risk of incident dementia, either per healthy lifestyle behaviour increase (pooled hazard ratio 0.89, 95 % confidence interval 0.85-0.94) or the highest level versus the lowest level (pooled hazard ratio 0.61, 95 % confidence interval 0.49-0.76). An inverse, linear dose-response relationship (Pnon-linear = 0.845) between the number of healthy lifestyle behaviours and incident dementia was observed, with an 11 % risk reduction for each healthy behaviour increase. A relatively limited number of included studies indicated that adherence to a healthy lifestyle combination could yield benefits for cognitive decline, global cognition, memory and executive function. In addition, the adherence rates typically decreased as the number of healthy lifestyle behaviours increased. CONCLUSIONS: Adherence to a healthy lifestyle was associated with a lower risk of incident dementia and other cognitive outcomes. It is important to find a subtle balance between the benefits and adherence. Further large cohort studies for combined lifestyle behaviours with specific cognitive outcomes and dose-response relationships are required, especially based on middle- and low-income populations. REGISTRATION: The study was registered in PROSPERO (CRD42023418509). TWEETABLE ABSTRACT: Engaging in a greater number of healthy lifestyle behaviours yields increased benefits in preventing dementia, albeit with lower adherence rates as a trade-off. Finding a delicate balance between the benefits and adherence is crucial.

Low salinity influences the dose-dependent transcriptomic responses of oysters to cadmium.

Species in estuaries tend to undergo both cadmium (Cd) and low salinity stress. However, how low salinity affects the Cd toxicity has not been fully understood. Investigating the impacts of low salinity on the dose-response relationships between Cd and biological endpoints has potential to enhance our understanding of the combined effects of low salinity and Cd. In this work, changes in the transcriptomes of Pacific oysters were analyzed following exposure to Cd (5, 20, 80 µg/L Cd2+) under normal (31.4 psu) and low (15.7 psu) salinity conditions, and then the dose-response relationship between Cd and transcriptome was characterized in a high-throughput manner. The benchmark dose (BMD) of gene expression, as a point of departure (POD), was also calculated based on the fitted dose-response model. We found that low salinity treatment significantly influenced the dose-response relationships between Cd and transcripts in oysters indicated by altered dose-response curves. In details, a total of 219 DEGs were commonly fitted to best models under both normal and low salinity conditions. Nearly three quarters of dose-response curves varied with salinity condition. Some monotonic dose-response curves in normal salinity condition even were replaced by nonmonotonic curves in low salinity condition. Low salinity treatment decreased the PODs of differentially expressed genes induced by Cd, suggesting that gene differential expression was more prone to being triggered by Cd in low salinity condition. The changed sensitivity to Cd in low salinity condition should be taken into consideration when using oyster as an indicator to assess the ecological risk of Cd pollution in estuaries.