Perioperative chemotherapy with docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) for the treatment of locally advanced gastric or gastro-esophageal junction adenocarcinoma (MATCH): an open-label, randomized, phase 2 clinical trial.

BACKGROUND: It remains unclear whether addition of docetaxel to the combination of a platinum and fluoropyrimidine could provide more clinical benefits than doublet chemotherapies in the perioperative treatment for locally advanced gastric/gastro-esophageal junction (LAG/GEJ) cancer in Asia. In this randomized, phase 2 study, we assessed the efficacy and safety of perioperative docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) in LAG/GEJ adenocarcinoma patients. METHODS: Patients with cT3-4 Nany M0 G/GEJ adenocarcinoma were randomized (1:1) to receive 4 cycles of preoperative DOS or SOX followed by D2 gastrectomy and another 4 cycles of postoperative chemotherapy. The primary endpoint was major pathological response (MPR). RESULTS: From Aug, 2015 to Dec, 2019,154 patients were enrolled and 147 patients included in final analysis, with a median age of 60 (26-73) years. DOS resulted in significantly higher MPR (25.4 vs. 11.8%, P = 0.04). R0 resection rate, the 3-year PFS and 3-year OS rates were 78.9 vs. 61.8% (P = 0.02), 52.3 vs. 35% (HR 0.667, 95% CI: 0.432-1.029, Log rank P = 0.07) and 57.5 vs. 49.2% (HR 0.685, 95% CI: 0.429-1.095, Log rank P = 0.11) in the DOS and SOX groups, respectively. Patients who acquired MPR experienced significantly better survival. DOS had similar tolerance to SOX. CONCLUSIONS: Perioperative DOS improved MPR significantly and tended to produce longer PFS compared to SOX in LAG/GEJ cancer in Asia, and might be considered as a preferred option for perioperative chemotherapy and worth further investigation.

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

Statistical inference and power analysis for direct and spillover effects in two-stage randomized experiments.

Two-stage randomized experiments become an increasingly popular experimental design for causal inference when the outcome of one unit may be affected by the treatment assignments of other units in the same cluster. In this paper, we provide a methodological framework for general tools of statistical inference and power analysis for two-stage randomized experiments. Under the randomization-based framework, we consider the estimation of a new direct effect of interest as well as the average direct and spillover effects studied in the literature. We provide unbiased estimators of these causal quantities and their conservative variance estimators in a general setting. Using these results, we then develop hypothesis testing procedures and derive sample size formulas. We theoretically compare the two-stage randomized design with the completely randomized and cluster randomized designs, which represent two limiting designs. Finally, we conduct simulation studies to evaluate the empirical performance of our sample size formulas. For empirical illustration, the proposed methodology is applied to the randomized evaluation of the Indian National Health Insurance Program. An open-source software package is available for implementing the proposed methodology.

Impacts of land use/cover and slope on the spatial distribution and ecological risk of trace metals in soils affected by smelting emissions.

The soil contamination around smelting sites shows high spatial heterogeneity. This study investigated the impacts of distance, land use/cover types, land slopes, wind direction, and soil properties on the distribution and ecological risk of trace metals in the soil around a copper smelter. The results demonstrated that the average concentrations of As, Cd, Cu, Pb, and Zn were 248.0, 16.8, 502.4, 885.6, and 250.2 g mg kg-1, respectively, higher than their background values. The hotspots of trace metals were primarily distributed in the soil of smelting production areas, runoff pollution areas, and areas in the dominant wind direction. The concentrations of trace metals decreased with the distance to the smelting production area. An exponential decay regression revealed that, depending on the metal species, the influence distances of smelting emissions on trace metals in soil ranged from 450 to 1000 m. Land use/cover types and land slopes significantly affected trace element concentrations in the soil around the smelter. High concentrations of trace metals were observed in farmland, grassland, and flatland areas. The average concentrations of trace metals in the soil decreased in the order of flat land > gentle slope > steep slope. Soil pH values were significantly positively correlated with Cd, Cu, Pb, Zn, and As, and SOM was significantly positively correlated with Cd, Pb, and Zn in the soil. Trace metals in the soil of the study area posed a significant ecological risk. The primary factors influencing the distribution of ecological risk, as determined by the Ctree analysis, were land slope, soil pH, and distance to the source. These results can support the rapid identification of high-risk sites and facilitate risk prevention and control around smelting sites.

Effects of Simulated Reclaimed Water on Soil Particle Sizes and Cd Adsorption and Migration in Soils at Smelting Sites.

This work studied the vertical migration characteristics of Cd in soil profiles from a zinc smelting site under the influence of simulated reclaimed water containing NaCl and Na2SO4. The isothermal adsorption curves of Cd in the soils of miscellaneous fill and weathered slate well fitted the Freundlich and Langmuir models, with R2 ranging from 0.991 to 0.998. The maximum adsorption capacity of Cd in the soils decreased significantly under the salt ion treatments with NaCl and Na2SO4. After leaching, the Cd concentrations in the leachates and Cd contents in the subsoil layers of 10-60 cm followed the order NaCl treatment > Na2SO4 treatment > CK (p < 0.05), suggesting that the salt ions promoted the vertical migration of exogenous Cd. The proportion of coarse particles (> 0.02 mm) decreased, while that of fine particles (< 0.02 mm) increased under salt ion treatments (p < 0.05). The morphological characterization indicated that salt ions accelerated the erosion and fragmentation of coarse particles to form fine particles. The use of reclaimed water to flush smelting sites may increase the risk of Cd migration with small-sized soil particles from the soil to groundwater.

Spatial heterogeneity and source apportionment of soil metal(loid)s in an abandoned lead/zinc smelter.

Metal smelting have brought severe metal(loid)s contamination to the soil. Spatial distribution and pollution source analysis for soil metal(loid)s in an abandoned lead/zinc smelter were studied. The results showed that soil was contaminated heavily with metal(loid)s. The mean of lead (Pb), arsenic (As), cadmium (Cd), mercury (Hg) and antimony (Sb) content in topsoil is 9.7, 8.2, 5.0, 2.3, and 1.2 times higher than the risk screening value for soil contamination of development land of China (GB36600-2018), respectively. Cd is mainly enriched in the 0-6 m depth of site soil while As and Pb mainly deposited in the 0-4 m layer. The spatial distribution of soil metal(loid)s is significantly correlated with the pollution source in the different functional areas of smelter. As, Hg, Sb, Pb and copper (Cu) were mainly distributed in pyrometallurgical area, while Cd, thallium (Tl) and zinc (Zn) was mainly existed in both hydrometallurgical area and raw material storage area. Soil metal(loid)s pollution sources in the abandoned smelter are mainly contributed to the anthropogenic sources, accounting for 84.5%. Specifically, Pb, Tl, As, Hg, Sb and Cu mainly from atmospheric deposition (55.9%), Cd and Zn mainly from surface runoff (28.6%), While nickel (Ni) mainly comes from parent material (15.5%). The results clarified the spatial distribution and their sources in different functional areas of the smelter, providing a new thought for the risk prevention and control of metal(loid)s in polluted site soil.

Biweekly oxaliplatin plus S1 for Chinese elderly patients with advanced gastric or gastroesophageal junction cancer as the first-line therapy: a single-arm, phase 2 study.

BACKGROUND: SOX (oxaliplatin and S1, every 3 weeks) is one of the most common first-line chemotherapy for advanced or metastatic G/GEJ (gastric or gastroesophageal junction) cancer in Asia, but it has noticeable hematological and neurological toxicity. In China, the majority of gastric cancer patients are middle-aged and elderly with poor tolerance to 3-weekly chemotherapy. Therefore, we aimed to assess efficacy and safety of biweekly SOX for Chinese advanced G/GEJ cancer patients aged ≥ 60 years as the first-line treatment in a single arm phase 2 study. METHODS: Oxaliplatin was administered intravenously on day 1 at 85 mg/m2. S-1 was given at 80, 100 or 120 mg/day, depending on the body surface area (< 1.25 m2, 1.25 to < 1.5 m2, or ≥ 1.5 m2), twice daily, on day 1-10, every 2 weeks. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. RESULTS: Between May 2016 and Sep 2018, 42 patients were enrolled. The median follow-up was 43.6 months. The ORR and DCR were 52.4% and 85.7%, respectively. The median PFS was 4.6 months (95%CI 2.486-6.714), and the median OS was 11.1 months (95%CI 8.001-14.199). The most common treatment-related adverse events (TRAEs) of any grade included thrombocytopenia (59.5%), neutropenia (57.1%), appetite loss (57.1%) and nausea (54.8%). Only two patients suffered from grade 3 TRAEs (4.8%), including neutropenia (1 patient, [2.4%]) and diarrhea (1 patient, [2.4%]). No ≥ grade 4 TRAEs occurred. CONCLUSIONS: Biweekly SOX seemed to have favorable tolerance without compromising the efficacy as the first-line therapy in Chinese elderly patients aged ≥ 60 years with advanced G/GEJ cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04694404 (5/1/2021). This study was approved by the Ethical Committee of National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, (17-048/1303).

Electrically driven liquid crystal network actuators.

Soft actuators based on liquid crystal networks (LCNs) have aroused great scientific interest for use as stimuli-controlled shape-changing and moving components for robotic devices due to their fast, large, programmable and solvent-free actuation responses. Recently, various LCN actuators have been implemented in soft robotics using stimulus sources such as heat, light, humidity and chemical reactions. Among them, electrically driven LCN actuators allow easy modulation and programming of the input electrical signals (amplitude, phase, and frequency) as well as stimulation throughout the volume, rendering them promising actuators for practical applications. Herein, the progress of electrically driven LCN actuators regarding their construction, actuation mechanisms, actuation performance, actuation programmability and the design strategies for intelligent systems is elucidated. We also discuss new robotic functions and advanced actuation control. Finally, an outlook is provided, highlighting the research challenges faced with this type of actuator.

Adsorption of Cd on Soils with Various Particle Sizes from an Abandoned Non-ferrous Smelting Site: Characteristics and Mechanism.

Soil particle size could intensively impact the Cd adsorption in soils. The adsorption characteristics of Cd on miscellaneous fill (MF) and weathered slate (WS), collected from a zinc smelting site, were studied by batch experiments under conditions of different initial Cd concentrations and soil particle sizes. The results showed that the adsorption kinetics of Cd for soil particles from MF and WS were well fitted with the pseudo-first-order model, and the Cd adsorption isotherms well conformed to the Freundlich model. Soil particle size had an inconspicuous influence on adsorption rate, while the adsorption capacity decreased with particle size increase. The Cd adsorption on soil particles could be due to the exchange with Fe/Al, and -OH/C=O sites were the predominant adsorption sites. The MF may cause secondary pollution risk due to its low adsorption ability for Cd in smelting sites.

Dynamic AIE crosslinks in liquid crystal networks: visualizing for actuation-guiding, re-bonding for actuation-altering.

Covalent adaptable liquid crystal networks (CALCNs) are highly potential actuating materials due to their actuation properties and shape reprogrammability. Given the importance of network crosslinking state in a CALCN actuator, we sought an all-in-one strategy to probe and visualize its dynamic network while ensuring actuation and reprogramming. Here, tetraphenylethylene derivatives were incorporated into liquid crystal networks via the Diels-Alder (DA) reaction, acting simultaneously as reversible crosslinkers and aggregation-induced emission (AIE) fluorescent probes. The thermally tunable fluorescence of the resulting network can correlate to and thus visualize the actuator's crosslinking status, actuation capability and temperature in real-time and in situ, yielding an intriguing actuation limit-alerting function. Furthermore, we verified unprecedented reprogrammability of the AIE-type CALCNs through both associative and dissociative exchange mechanisms of DA chemistry.

Molecular motion activated by residual stress in a glassy polymer thin film.

The activation, by residual stress, of the fast portion of rotational motion of single fluorescent probe molecules inside a polymer thin film near its glass transition temperature is studied at a single molecular level. Spin-casted poly n-butyl methacrylate thin films without thermal annealing are chosen as the model system and single molecule fluorescence defocused microscopy is adopted as the method. The rotational motion of the probes under residual stress is found to be more activated than that under mere thermal activation, and the kinetic energy exhibits a monotonic increase with the stress strength. A rough linear dependence of rotational kinetic energy at low stress is found, yielding the value of characteristic volume for the residual stress to activate the motion of the probes. The values of the volume are close to the van der Waals volume of the probes, indicating that the activation of the fast dynamics by residual stress is localized. The activation effect is weakened and vanishes at or above the glass transition temperature due to stress relaxation. The effect is also absent at temperatures far below Tg due to the frozen molecular motion with a much higher activation energy.

"Self-Lockable" Liquid Crystalline Diels-Alder Dynamic Network Actuators with Room Temperature Programmability and Solution Reprocessability.

Novel main-chain liquid crystalline Diels-Alder dynamic networks (LCDANs) were prepared that exhibit unprecedented ease for actuator programming and reprocessing compared to existing liquid crystalline network (LCN) systems. Following cooling from 125 °C, LCDANs are deformed with aligned mesogens self-locked at room temperature by slowly formed Diels-Alder (DA) bonds, which allows for the formation of solid 3D actuators capable of reversible shape change, and strip walker and wheel-capable light-driven locomotion upon either thermally or optically induced order-disorder phase transition. Any actuator can readily be erased at 125 °C and reprogrammed into a new one under ambient conditions. Moreover, LCDANs can be processed directly from melt (for example, fiber drawing) and from solution (for example, casting tubular actuators), which cannot be achieved with LCNs using exchangeable covalent bonds. The combined attributes of LCDANs offer significant progress toward developing easily programmable/processable LCN actuators.

Selective Decrosslinking in Liquid Crystal Polymer Actuators for Optical Reconfiguration of Origami and Light-Fueled Locomotion.

The ability to optically reconfigure an existing actuator of a liquid crystal polymer network (LCN) so that it can display a new actuation behavior or function is highly desired in developing materials for soft robotics applications. Demonstrated here is a powerful approach relying on selective polymer chain decrosslinking in a LCN actuator with uniaxial LC alignment. Using an anthracene-containing LCN, spatially controlled optical decrosslinking can be realized through photocleavage of anthracene dimers under 254 nm UV light, which alters the distribution of actuation (crosslinked) and non-actuation (decrosslinked) domains and thus determines the actuation behavior upon order-disorder phase transitions. Based on this mechanism, a single actuator having a flat shape can be reconfigured in an on-demand manner to exhibit reversible shape transformation such as self-folding into origami three-dimensional structures. Moreover, using a dye-doped LCN actuator, a light-fueled microwalker can be optically reconfigured to adopt different locomotion behaviors, changing from moving in the laser scanning direction to moving in the opposite direction.

A sensitivity analysis for missing outcomes due to truncation by death under the matched-pairs design.

The matched-pairs design enables researchers to efficiently infer causal effects from randomized experiments. In this paper, we exploit the key feature of the matched-pairs design and develop a sensitivity analysis for missing outcomes due to truncation by death, in which the outcomes of interest (e.g., quality of life measures) are not even well defined for some units (e.g., deceased patients). Our key idea is that if 2 nearly identical observations are paired prior to the randomization of the treatment, the missingness of one unit's outcome is informative about the potential missingness of the other unit's outcome under an alternative treatment condition. We consider the average treatment effect among always-observed pairs (ATOP) whose units exhibit no missing outcome regardless of their treatment status. The naive estimator based on available pairs is unbiased for the ATOP if 2 units of the same pair are identical in terms of their missingness patterns. The proposed sensitivity analysis characterizes how the bounds of the ATOP widen as the degree of the within-pair similarity decreases. We further extend the methodology to the matched-pairs design in observational studies. Our simulation studies show that informative bounds can be obtained under some scenarios when the proportion of missing data is not too large. The proposed methodology is also applied to the randomized evaluation of the Mexican universal health insurance program. An open-source software package is available for implementing the proposed research.

Identification of causal effects with latent confounding and classical additive errors in treatment.

In this paper, we discuss the identifiability and estimation of causal effects of a continuous treatment on a binary response when the treatment is measured with errors and there exists a latent categorical confounder associated with both treatment and response. Under some widely used parametric models, we first discuss the identifiability of the causal effects and then propose an approach for estimation and inference. Our approach can eliminate the biases induced by latent confounding and measurement errors by using only a single instrumental variable. Based on the identification results, we give guidelines for determining the existence of a latent categorical confounder and for selecting the number of levels of the latent confounder. We apply the proposed approach to a data set from the Framingham Heart Study to evaluate the effect of the systolic blood pressure on the coronary heart disease.

Novel human microbe-disease association prediction using network consistency projection.

BACKGROUND: Accumulating biological and clinical reports have indicated that imbalance of microbial community is closely associated with occurrence and development of various complex human diseases. Identifying potential microbe-disease associations, which could provide better understanding of disease pathology and further boost disease diagnostic and prognostic, has attracted more and more attention. However, hardly any computational models have been developed for large scale microbe-disease association prediction. RESULTS: In this article, based on the assumption that microbes with similar functions tend to share similar association or non-association patterns with similar diseases and vice versa, we proposed the model of Network Consistency Projection for Human Microbe-Disease Association prediction (NCPHMDA) by integrating known microbe-disease associations and Gaussian interaction profile kernel similarity for microbes and diseases. NCPHMDA yielded outstanding AUCs of 0.9039, 0.7953 and average AUC of 0.8918 in global leave-one-out cross validation, local leave-one-out cross validation and 5-fold cross validation, respectively. Furthermore, colon cancer, asthma and type 2 diabetes were taken as independent case studies, where 9, 9 and 8 out of the top 10 predicted microbes were successfully confirmed by recent published clinical literature. CONCLUSION: NCPHMDA is a non-parametric universal network-based method which can simultaneously predict associated microbes for investigated diseases but does not require negative samples. It is anticipated that NCPHMDA would become an effective biological resource for clinical experimental guidance.

Semi-IPNs with Moisture-Triggered Shape Memory and Self-Healing Properties.

Moisture or water has the advantages of being green, inexpensive, and moderate. However, it is challenging to endow water-induced shape memory property and self-healing capability to one single polymer because of the conflicting structural requirement of the two types of materials. In this study, this problem is solved through introducing two kinds of supramolecular interactions into semi-interpenetrating polymer networks (semi-IPNs). The hydrogen bonds function as water-sensitive switches, making the materials show moisture-induced shape memory effect. The host-guest interactions (ß-cyclodextrin-adamantane) serve as both permanent phases and self-healing motifs, enabling further increased chain mobility at the cracks and self-healing function. In addition, these polyvinylpyrrolidone/poly(hydroxyethyl methacrylate-co-butyl acrylate) semi-IPNs also show thermosensitive triple-shape memory effect.

Injection therapies for lateral epicondylalgia: a systematic review and Bayesian network meta-analysis.

BACKGROUND: There are many injection therapies for lateral epicondylalgia but there has been no previous comprehensive comparison, based on the Bayesian method. METHODS: The MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for appropriate literature. The outcome measurement was the pain score. Direct comparisons were performed using the pairwise meta-analysis, and network meta-analysis, based on a Bayesian model, was used to calculate the results of all of the potentially possible comparisons and rank probabilities. A sensitivity analysis was performed by excluding low-quality studies. The inconsistency of the model was assessed by means of the node-splitting method. Metaregression was used to assess the relationship between the sample size and the treatment effect. RESULTS: All of the injection treatments showed a trend towards better effects than placebo. Additionally, the peppering technique did not add additional benefits when combined with other treatments. No significant changes were observed by excluding low-quality studies in the sensitivity analysis. No significant inconsistencies were found according to the inconsistency analysis, and metaregression revealed that the sample size was not associated with the treatment effects. CONCLUSIONS: Some commonly used injection therapies can be considered treatment candidates for lateral epicondylalgia, such as botulinum toxin, platelet-rich plasma and autologous blood injection, but corticosteroid is not recommended. Hyaluronate injection and prolotherapy might be more effective, but their superiority must be confirmed by more research. The peppering technique is not helpful in injection therapies.

When is the difference method conservative for assessing mediation?

Assessment of indirect effects is useful for epidemiologists interested in understanding the mechanisms of exposure-outcome relationships. A traditional way of estimating indirect effects is to use the "difference method," which is based on regression analysis in which one adds a possible mediator to the regression model and examines whether the coefficient for the exposure changes. The difference method has been criticized for lacking a causal interpretation when it is used with logistic regression. In this article, we use the counterfactual framework to define the natural indirect effect (NIE) and assess the relationship between the NIE and the difference method. We show that under appropriate assumptions, the difference method consistently estimates the NIE for continuous outcomes and is always conservative for binary outcomes. Thus, the difference method can be used to provide evidence for the presence of mediation but not for the absence of mediation.

Distinguishing the contributions of different smelting emissions to the spatial risk footprints of toxic elements in soil using PMF, Bayesian isotope mixing models, and distance-based regression.

Toxic element pollution of soils emanating from smelting operations is an escalating global concern due to its severe impact on ecosystems and human health. In this study, soil samples were collected and analyzed to quantify the risk contributions and delineate the spatial risk footprints from smelting emissions for 8 toxic elements. A comprehensive health risk contribution and delineation framework was utilized, consisting of Positive matrix factorization (PMF), spatial interpolation, an advanced Bayesian isotope mixing model via Mixing Stable Isotope Analysis in R (MixSIAR), and distance-based regression. The results showed that the mean concentrations of As, Cd, Cu, Hg, Pb, and Zn exceeded the background levels, indicating substantial contamination. Three sources were identified using the PMF model and confirmed by spatial interpolation and MixSIAR, with contributions ranked as follows: industrial wastewater discharge and slag runoff from the smelter site (48.9 %) > natural geogenic inputs from soil parent materials (26.7 %) > atmospheric deposition of dust particles from smelting operations (24.5 %). Among the identified sources, smelter runoff posed the most significant risk, accounting for 97.9 % of the non-carcinogenic risk (NCR) and 59.9 % of the carcinogenic risk (CR). Runoff also drove NCR and CR exceedances at 7.8 % and 4.7 % of sites near the smelter, respectively. However, atmospheric deposition from smelting emissions affected soils across a larger 0.8 km radius. Although it posed lower risks, contributing just 1.1 % to NCR and 22.6 % to CR due to the limited elevation of toxic elements, deposition reached more distant soils. Spatial interpolation and distance-based regression delineated high NCR and CR exposure hotspots within 1.4 km for runoff and 0.8 km for deposition, with exponentially diminishing risks at further distances. These findings highlight the need for pathway-specific interventions that prioritize localized wastewater containment and drainage controls near the smelter while implementing broader regional air pollution mitigation measures.