Explore the vast range of titles available.

This study reviews the use of the distributed lag non‐linear model (DLNM) in public health research, focusing on environmental‐exposure, health–outcome relationships, and providing recommendations for future studies. Embase, PubMed, Web of Science, and Scopus databases were searched for literature published from January 2020 to November 2024 using the DLNM to analyze the environmental exposures and health outcomes. After screening, removing duplicates, and reviewing full‐text articles, eligible studies were assessed using the DLNM to examine the health effects related to environmental exposure, particularly temperature and other environmental factors. From 2,847 studies, 274 studies from 36 countries were selected for analysis, primarily from China (164), Europe (28), and North America (23). There were 174 exclusive climate data sources, no standardized heat thresholds, and 131 unique sources of air pollutant data. Among the 53 adverse health outcomes identified using the DLNM, morbidity was the most prevalent (n=102$n=102$ ), followed by hospitalization (n=39$n=39$ ), hospital admission (n=40$n=40$ ), and emergency room visits (n=22$n=22$ ). This review highlights the utility of the DLNM in capturing complex temporal relationships between environmental exposure and health, clarifying lagged effects. Despite the challenges of standardization and computational efficiency, ongoing developments are enhancing the utility of the DLNM. Future research should focus on advanced statistical techniques, such as machine learning and neural networks, and extend applications to other environmental health scenarios. Plain Language Summary The study reviews the use of distributed lag non‐linear models (DLNM) in public health research, particularly in examining the relationships between environmental exposures and health outcomes. It analyzed 274 studies from various countries, primarily China, Europe, and North America, focusing on health effects related to environmental factors like temperature and air pollutants. The review found that morbidity was the most common adverse health outcome identified. It emphasizes the importance of DLNM in understanding the complex and delayed effects of environmental exposures on health. The study suggests that future research should explore advanced statistical methods, including machine learning, to further enhance the application of DLNM in environmental health. Key Points This study reviews the use of DLNM to analyze complex, lagged health effects from environmental exposures like temperature and air pollution Most DLNM studies focus on CVDs, RDs, and infectious diseases, with limited applications to mental, neurological, and renal health Integrating DLNM with Machine Learning and Bayesian models can enhance predictive accuracy and address complex multiexposure health risks

Objective This cohort study aims to compare the performance of alternative frequency weightings of hand-transmitted vibration (HTV) for the assessment of the exposure–response relationships for neurosensory disorders and reduced work ability among HTV-exposed workers. Methods In a 3-year follow up study, the occurrence of neurosensory symptoms and reduced work ability, and the response to quantitative sensory testing (grip force, manipulative dexterity, touch sensation) were investigated in 249 HTV-exposed workers and 138 healthy controls. Among the HTV-exposed workers, the sensory outcomes were related to measures of daily vibration exposure expressed in terms of 8-hour energy-equivalent frequency-weighted acceleration magnitude [A(8)]. To calculate A(8), the acceleration magnitudes of vibration were weighted by means of four alternative frequency weightings of HTV. Results The occurrence of neurosensory symptoms, reduced work ability, and abnormalities of sensory tests was greater among the HTV-exposed workers than the controls. Among the HTV-exposed workers, the deterioration of neurosensory outcomes and the reduction of work ability increased on par with the measures of vibration exposure. Exposure–response models revealed that the four alternative frequency weightings of HTV provided the same predictions for the probability of finger numbness among the exposed workers (observed 36% versus predicted 32%). Conclusions The findings of this study revealed significant dose–response relationships between measures of vibration exposure, sensory disorders, and reduced work ability among the HTV-exposed workers. There were no differences in the prediction of finger numbness between measures of vibration exposure calculated with alternative frequency weightings of HTV.

Objective The aim of this study was to investigate the performance of four frequency weightings for handtransmitted vibration to predict the incidence of vibration-induced white finger (VWF). Methods In a longitudinal study of vibration-exposed forestry and stone workers (N=206), the incidence of VWF was related to measures of vibration exposure expressed in terms of 8-hour frequency-weighted energyequivalent root-mean-square (rms) acceleration magnitude [A(8)] and years of follow-up. To calculate A(8), the rms acceleration magnitudes of vibration were weighted by means of four frequency weightings: (i) Wh (the frequency weighting specified in ISO 5349-1: 2001); (ii) Wh-bl. (the band-limiting component of Wh); (iii) Whf (a frequency weighting based on finger vibration power absorption); and (iv) WhT (a frequency weighting based on a Japanese study of VWF prevalence). The relations of VWF to alternative measures of vibration exposure were assessed by the generalized estimating equations (GEE) method to account for the within-subject dependency of the observations over time. Results Data analysis with a GEE logistic model and a measure of statistical fit suggested that calculating, A(8) by weighting the tool rms accelerations with Wh-bl gave better predictions of the cumulative incidence of VWF than the other alternative measures of daily vibration exposure. Values of, A(8) derived from the currently recommended ISO frequency weighting Wh produced poorer predictions of the incidence of VWF than those obtained with frequency weightings Whf or WhT. Conclusions This prospective cohort study suggests that measures of daily vibration exposure which give relatively more weight to intermediate and high frequency vibration are more appropriate for assessing the probability of VWF.

The exposure-response relationship between vedolizumab (VDZ) trough levels (VTLs) and efficacy outcomes has been extensively studied, but data on early VTLs in Asian populations are limited. We assessed clinical outcomes and biochemical response using fecal calprotectin (BioRES[FC]) or C-reactive protein (BioRES[CRP]) at week 14 (W14) and W54, endoscopic healing (EH) at available follow-up time points, and the need for drug optimization during maintenance therapy among 67 patients treated with VDZ (39 Crohn’s disease [CD], and 28 ulcerative colitis [UC]). Associations between early VTLs and outcomes were assessed, with VTL cut-offs proposed using the area under the receiver operating curve (AUC). CD patients achieving W14 BioRES[CRP] had higher VTLs at W6 and W14. W54 BioRES[FC] responders and those not requiring drug optimization had higher W14 VTLs (11.2 vs. 3.8 µg/mL, P  = 0.036; 2.2 vs. 5.8 µg/mL, P  = 0.004). Proposed W14 VTL cut-offs were 5.3 µg/mL (AUC 0.859) for BioRES[FC] and 4.6 µg/mL (AUC 0.765) for drug optimization. In UC patients, higher early VTLs were noted in those achieving W14 corticosteroid-free clinical remission, W14 BioRES[FC], and W14 EH, but not consistently linked to W54 results. This real-life study suggests higher early VTLs correlated with better outcomes, with W14 VTLs potentially predicting long-term outcomes in CD patients. Future studies are needed to confirm these findings and guide VDZ therapy.

Population aging poses significant public health challenges in China. Emerging studies have linked air pollution to physiological aging, yet evidence regarding particulate matter with an aerodynamic diameter ≤ 1 μm (PM 1 ) remains sparse. This two-wave panel study included 5391 Chinese adults aged 45–80 to explore the effects of long-term exposure to PM 1 on biological aging acceleration. The Klemera−Doubal method (KDM) was employed to estimate biological aging acceleration (KDM-BAA) using 11 clinical biomarkers at both the 2011 baseline and the 2015 follow-up survey. Multivariate linear models with natural cubic splines were performed to estimate the association between PM 1 exposure and KDM-BAA changes from baseline to follow-up. Sensitivity analyses and stratified analyses were also performed. The exposure–response curve indicated that exposure to ambient PM 1 was significantly positively associated with changes in KDM-BAA, with the association becoming substantially stronger when PM 1 exposure exceeded the median exposure level of 32.5 μg/m 3 . Per 10 μg/m 3 increment in PM 1 exposure was associated with an acceleration of 1.55 (95% CI: 0.79, 2.31) years in KDM-BAA. Elderly adults over 60 years and smokers demonstrated greater susceptibility to the aging effects of ambient PM 1 exposure, whereas leisure engagement was observed to have a beneficial effect in mitigating the aging response of PM 1 exposure. Long-term exposure to ambient PM 1 may accelerate biological aging among middle-aged and older adults in China, especially in the elderly. These findings highlight the urgency for policies aimed at mitigating PM 1 pollution to promote healthy aging within an increasingly aging population.

Toxic metals are vital risk factors affecting serum ion balance; however, the effect of their co-exposure on serum ions and the underlying mechanism remain unclear. We assessed the correlations of single metal and mixed metals with serum ion levels, and the mediating effects of mineralocorticoids by investigating toxic metal concentrations in the blood, as well as the levels of representative mineralocorticoids, such as deoxycorticosterone (DOC), and serum ions in 471 participants from the Dongdagou–Xinglong cohort. In the single-exposure model, sodium and chloride levels were positively correlated with arsenic, selenium, cadmium, and lead levels and negatively correlated with zinc levels, whereas potassium and iron levels and the anion gap were positively correlated with zinc levels and negatively correlated with selenium, cadmium and lead levels (all P  < 0.05). Similar results were obtained in the mixed exposure models considering all metals, and the major contributions of cadmium, lead, arsenic, and selenium were highlighted. Significant dose–response relationships were detected between levels of serum DOC and toxic metals and serum ions. Mediation analysis showed that serum DOC partially mediated the relationship of metals (especially mixed metals) with serum iron and anion gap by 8.3% and 8.6%, respectively. These findings suggest that single and mixed metal exposure interferes with the homeostasis of serum mineralocorticoids, which is also related to altered serum ion levels. Furthermore, serum DOC may remarkably affect toxic metal-related serum ion disturbances, providing clues for further study of health risks associated with these toxic metals.

Background Under a changing climate, the joint effects of temperature and relative humidity on tuberculosis (TB) are poorly understood. To address this research gap, we conducted a time-series study to explore the joint effects of temperature and relative humidity on TB incidence in China, considering potential modifiers. Methods Weekly data on TB cases and meteorological factors in 22 cities across mainland China between 2011 and 2020 were collected. The proxy indicator for the combined exposure levels of temperature and relative humidity, Humidex, was calculated. First, a quasi-Poisson regression with the distributed lag non-linear model (DLNM) was constructed to examine the city-specific associations between humidex and TB incidence. Second, a multivariate meta-regression model was used to pool the city-specific effect estimates, and to explore the potential effect modifiers. Results A total of 849,676 TB cases occurred in the 22 cities between 2011 and 2020. Overall, a conspicuous J-shaped relationship between humidex and TB incidence was discerned. Specifically, a decrease in humidex was positively correlated with an increased risk of TB incidence, with a maximum relative risk (RR) of 1.40 (95% CI: 1.11–1.76). The elevated RR of TB incidence associated with low humidex (5th humidex) appeared on week 3 and could persist until week 13, with a peak at approximately week 5 (RR: 1.03, 95% CI: 1.01–1.05). The effects of low humidex on TB incidence vary by Natural Growth Rate (NGR) levels. Conclusion A J-shaped exposure-response association existed between humidex and TB incidence in China. Humidex may act as a better predictor to forecast TB incidence compared to temperature and relative humidity alone, especially in regions with higher NGRs.

Purpose Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-β (TGF-β) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)–pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-β is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs). Methods The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 ( n  = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration ( C avg ), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-β inhibition across various dosing regimens was derived. Results The probability of bleeding AEs increased with increasing C avg ; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding. Conclusion A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.

PurposeData on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight and body mass index (BMI) on trough levels of oral oncolytics with an exposure–response relationship. The oral oncolytics of interest were abiraterone, alectinib, cabozantinib, crizotinib, imatinib, pazopanib, sunitinib and trametinib.MethodsThis retrospective cohort study included patients treated with the selected oral oncolytics at the standard dose, with a measured trough level at steady state and with available body weight. The Spearman’s correlation test was used to determine the correlation between body weight and trough levels. The Fisher’s exact text was used to compare the frequency of inadequate trough levels between BMI categories.Results1265 patients were included across the different oral oncolytics. A negative correlation coefficient was observed between weight and trough levels for crizotinib (n = 75), imatinib (n = 201) and trametinib (n = 310), respectively, ρ = − 0.41, ρ = − 0.24 and ρ = − 0.23, all with a p-value < 0.001. For crizotinib, a higher percentage of patients with a body weight > 100 kg had inadequate trough levels. No statistically significant differences were observed in the frequency of inadequate trough levels between BMI categories.ConclusionHigher body weight was only correlated with lower plasma trough levels for crizotinib, imatinib, and trametinib. Therefore, patients with a high body weight may require dose escalation to obtain adequate target levels when treated with these oral oncolytics.

Background/Objectives: Pixavir marboxil is a novel oral cap-dependent endonuclease inhibitor that is rapidly converted to its active metabolite pixavir. This study aimed to characterize the population pharmacokinetics (PopPK) of pixavir, identify clinical covariates affecting its pharmacokinetics, and evaluate the exposure–response relationship to inform optimal dosing in the treatment of acute influenza. Methods: Data were pooled from three clinical studies spanning Phase I to Phase III trials and included adults and adolescents aged ≥12 years. PopPK modeling was conducted using NONMEM software. Individual exposure metrics, including the 24-h post-dose concentration, maximum concentration, and area under the concentration-time curve from time zero to infinity, were derived using Bayesian estimation based on the final PopPK model. Efficacy endpoints included time to alleviation of influenza-related symptoms and changes in viral titer and viral RNA load from baseline to Day 2. Safety was evaluated through the incidence of treatment-related adverse events. Results: Pixavir pharmacokinetics were best described by a two-compartment model. Body weight significantly influenced clearance and central volume of distribution, while dose amount had a notable effect on bioavailability. Food, sex and age had no clinically meaningful impact on pharmacokinetics. Exposure–response analysis showed no clear relationship between pixavir exposure and both efficacy and safety endpoints within the studied dosing range. Conclusions: The weight-based dosing regimen of pixavir marboxil (40 mg for <80 kg and 80 mg for ≥80 kg) is supported, as it reduces body-weight-driven exposure variability and maintains exposure within the clinically characterized range in adults and adolescents with acute influenza.