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Biomanufacturing advances sustainable production and circular economy, while wastes-derived one-carbon (C1) compounds (e.g., CO2, methanol, formate and methane) expand substrate diversity, accelerate wastes valorization, and mitigate climate change. The design of C1 feedstocks-driven biorefineries is often hindered by: limited genetic toolkits, impaired cell growth, inefficient substrate utilization, and unclear metabolic mechanism. In this context, this review addresses these challenges through comprehensive analysis of: pathway exploitation, metabolic regulation, emerging technology, and biochemicals synthesis for optimizing C1-trophic performance. We first analyze key bottlenecks in enhancing assimilation efficiency of natural C1-utilizers, and then systematically summarize the strategies for harnessing nontraditional feedstocks using: engineered autotrophs, methylotrophs, formatotrophs, and methanotrophs. Importantly, we outline a bottom-up framework on systematic and modular redesign of C1-driven microbial cell factories for promoting industrial applications. Finally, we identify unresolved challenges and strategic opportunities to guide environmental preservation and performance optimization. Overall, this review provides a roadmap for transformative progress in sustainable biomanufacturing and wastes re-utilization. STATEMENT OF SIGNIFICANCEDeep analysis of C1 feedstocks assimilation: pathway design, recent progress, challenges, and future trends.Metabolic engineering and synthetic biology strategies for synthetic C1-trophic biorefineries and high-value bioproducts.Constructive guidance on accelerating the applications of next-generation biotechnology on greenhouse gas mitigation, environmental safety, sustainable processing, and circular bioeconomy strengthening.

Renewable elastic wood holds great potential to replace petroleum-based elastomers and supports a low-carbon circular economy, yet current research has remained largely focused on specific tree species, such as balsa, while fast-growing domestic species have been largely unexplored. Here, this study demonstrated a green and efficient strategy for preparing elastic and conductive wood using fast-growing Paulownia, through microwave puffing-assisted deep eutectic solvents (DES) treatment. Compared to conventional delignification methods, which mostly require at least 12 h and use corrosive chemicals, our synergistic approach reduced processing time to less than 7 h while employing biodegradable and recyclable deep eutectic solvents. After incorporation of polyvinyl alcohol and sodium chloride, the resulting wood composite retained 91% of its height after 50 compression cycles and the ionic conductivity reached 5.11 mS/cm, which was approximately 40 times higher than that of natural wood (0.13 mS/cm). As a piezoresistive sensor, it exhibited a high gauge factor of 33.77 within the strain range of 6.25% to 8.75%, enabling accurate detection of subtle human movements such as finger and wrist flexion, and demonstrating sensitive response to minute strains. This synergistic pretreatment not only efficiently overcomes mass transfer barriers in lignocellulose but also expands the raw material base for elastic wood production, offering a new, green, and efficient approach to developing high-performance elastic wood for soft and renewable devices.

Vaccine-preventable illnesses, such as pneumococcal disease, respiratory syncytial virus, influenza, and COVID-19 place a significant burden on Spain's population health, health system, and economy. However, uptake and funding constraints limit the full value potential of Spain's national immunization programs. A benefit - cost analysis was performed to assess the societal return on investment from adult vaccination by estimating benefit - cost ratios and net benefits (NBs). All outcomes were monetized using established methods. Program costs included all direct vaccination-related expenditures. Scenario and sensitivity analyses were performed to assess alternative program specifications and to test the robustness of the model. Spain's age-based respiratory immunization programs generate lifetime societal benefits of €1.9 when monetized mortality risk reduction is age-adjusted and €7.0 per €1 spent when monetized equally across all ages. This corresponds to NBs of €5.4 to €36.4 billion. Introducing adult RSV vaccination could increase NBs by up to 41%-21% compared to the status quo. Additionally, improving uptake across all programs would increase NBs by 134%-101%. Spain's adult respiratory vaccination programs generate positive socioeconomic returns. Including adult RSV vaccination and increasing vaccination uptake in general could further increase their societal benefits. Realizing these gains requires adequate public investment to improve vaccine uptake.

In Sweden, older adults and adults in clinical risk groups are recommended vaccination against pneumococcal disease, respiratory syncytial virus, influenza, and COVID-19. However, vaccine uptake remains inadequate. This study estimates the socioeconomic benefits of these immunization programs under current coverage compared to aspirational scenarios, assessing the value foregone due to suboptimal uptake. We conducted a benefit-cost analysis from a societal perspective applying life table-based disease models to estimate benefit-cost ratios (BCRs) and net benefits (NBs). Health impacts were monetized through the value-of-a-statistical-life and cost-of-illness approaches. Costs comprised vaccination program expenses. Scenario and sensitivity analyses explore coverage and program eligibility. Vaccination programs in older adults generated BCRs of 3:1 and NBs of SEK 54.4 billion over a lifetime (VSLY). When risk groups were included to model current strategies in Sweden, NBs increased to SEK 59.7 billion. Reaching aspirational coverage targets increased NBs by 18%, meanwhile restricting eligibility reduced NBs by 64%. Adult respiratory vaccinations in Sweden provide substantial value for the healthcare system, economy and society, with estimated benefits exceeding costs under modeled assumptions. These findings may inform policy discussions on strategies to sustain or expand vaccination budget, improve access and increase uptake, particularly among at-risk populations.

At present, the realm of nanobionics has garnered significant attention for its potential applications in microalgal systems, offering innovative strategies to augment growth, productivity, and metabolic performance. Present study influences nanotechnology to explore the multifaceted effects of novel biocompatible nanocomposite Ag-ZnO-PEEK (silver-zinc oxide- Polyether Ether Ketone) on isolated microalgae Chlorella vulgaris_AK, with a focus on improving the biomass production, mitigating oxidative stress, and enhancing the lipid biosynthesis. The morphometric demonstrations of Ag-ZnO-PEEK nanocomposite were characterized by Scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. Different concentrations of Ag-ZnO-PEEK (10, 20, 40, 80, and 160 ppm) were applied to the microalgae for observing the biomass enhancement and lipid yield. Among all the applied concentrations, 40 ppm exhibited the suitable one for high biomass and lipid yield of 4.25 g/L and 3.31 g/L respectively. Machine learning integrating forward prediction and E-UCB-based inverse design was employed to optimize microalgal growth conditions. Gradient boosting achieved the highest R2 of 0.9794, while ensemble uncertainty enabled reliable identification of high-performing unsampled conditions. Additionally, the effect of the as synthesized nanocomposite was also investigated as a potential antibacterial candidate against Bacillus sp. Hence, these advancements not only elevate the microalgae biomass production but also support the sustainable generation of biofuels and bioproducts from microalgae. Therefore, this study provides a scalable framework for integrating nanotechnology into renewable energy by maintaining circular bio-economy.

Childhood cancer has high cure rates; however, data on long-term socioeconomic challenges faced by survivors, particularly in low- and middle-income countries, are limited. We aimed to identify issues related to educational disruption, employment, and financial hardship among childhood cancer survivors. We conducted a cross-sectional study of survivors enrolled in the Childhood Cancer Survivorship Program at a tertiary cancer center in India (December 2020-March 2025). Eligible survivors were aged 21 years and younger at diagnosis and had completed therapy. Clinical and sociodemographic data were abstracted from records and structured proforma. Logistic regression with forward stepwise modeling was used to identify predictors of educational, financial, and employment challenges. We included 1,098 survivors. The median age was 16 years at evaluation, and 74.7% were male. Among those diagnosed at age 5-21 years (n = 764), 85% reported educational disruption (median 1.75 years). Relocation from the hometown for therapy (odds ratio [OR], 1.8; P = .01) and job loss within the family (OR, 2.1; P = .01) independently predicted educational disruption, whereas maternal education until or above high school was associated with lower odds of educational disruption (OR, 0.29; P = .001). Catastrophic health expenditure occurred in 91.3%. Younger age at diagnosis (OR, 1.03; P = .003) and relocation (OR, 1.61; P = .001) independently predicted higher treatment costs, &#x2265;$3,385 US Dollars. Cancer-related employment difficulties affected 30.2% of working-age survivors, with older age at diagnosis (OR, 1.15; P < .001) and longer time since treatment completion (OR, 1.08; P = .02) being independent predictors. For Indian childhood cancer survivors, cure carries hidden costs of disrupted education, financial strain, and workplace barriers. Survivorship care in resource-constrained settings should integrate school reintegration, financial protection, and vocational support.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, producing unprecedented clinical responses in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma, and multiple myeloma. Despite these advances, durable remission remains limited by disease relapse, with antigen escape emerging as one of the principal mechanisms of therapeutic resistance. This review comprehensively summarizes the biologic mechanisms underlying antigen escape and highlights emerging engineering strategies designed to overcome immune evasion and improve long-term CAR T-cell efficacy. We discuss both irreversible and reversible resistance pathways, including genetic alterations, alternative splicing, lineage plasticity, trogocytosis, epigenetic repression, and tumor microenvironment-mediated antigen modulation. Particular emphasis is placed on clinically relevant examples such as CD19 loss in B-ALL and BCMA dysregulation in multiple myeloma. The review further examines next-generation approaches developed to prevent antigen-negative relapse, including dual- and multi-target CAR constructs, logic-gated systems, pharmacologic enhancement of antigen density, epitope spreading, and TCR-mimic CAR platforms targeting intracellular antigens. In addition, we evaluate the major translational and biologic challenges associated with these advanced strategies, including structural complexity, manufacturing barriers, toxicity control, tumor heterogeneity, and limited long-term clinical validation. Finally, we discuss future perspectives involving single-cell and multi-omic technologies, computational modeling, and universal modular CAR systems that may enable the development of safer, more adaptable, and precision-guided cellular immunotherapies for hematologic malignancies.

This paper quantifies the impact of prenatal exposure to lead in drinking water on infant health at birth by exploiting a quasi-experiment in Jackson, Mississippi. This setting provides a unique context where behavioral changes to avoid lead-contaminated water are limited due to delayed water testing and dissemination of information about lead contamination. We apply synthetic control using other US cities and Mississippi counties as donors to identify the effect of lead exposure on birth outcomes. We find that prenatal lead exposure in Jackson increased the incidence of low birth weight by approximately 1.5 percentage points, relative to a synthetic Jackson.

Trauma is a major global cause of death, with uncontrolled hemorrhage as its leading preventable cause. Damage control resuscitation (DCR) is a cornerstone strategy for hemorrhagic shock, yet implementation varies by resource availability. This study compared DCR practices between high-income countries (HICs) and low- and middle-income countries (LMICs), predominantly represented by institutions from Latin America, particularly Brazil. A cross-sectional survey of trauma care providers was conducted between 2024 and 2025, assessing DCR practices, resuscitation strategies, and adjunctive therapies. Data from a Brazilian national survey were incorporated into the LMIC cohort. Countries were classified using World Bank 2024 income criteria, and comparisons were analyzed using hierarchical logistic regression with adjustment for multiple comparisons. Massive transfusion protocol availability result was significantly lower in LMICs than in HICs (47.4 vs. 89.1%; OR = 0.11, 95%CI 0.02-0.62; p(BH) < 0.001). LMICs also had reduced availability of fresh frozen plasma (OR = 0.04; p(BH) = 0.035), balanced crystalloids (OR = 0.21; p(BH) < 0.001), viscoelastic coagulation monitoring (TEG/ROTEM; OR = 0.04; p(BH) 0.001), prothrombin complex concentrate (OR = 0.01; p(BH) < 0.001), fibrinogen concentrate (OR = 0.10; p(BH) < 0.001), rapid infusers (OR = 0.04; p(BH) < 0.001), invasive temperature monitoring (OR = 0.02; p(BH) < 0.001), calcium replacement (OR = 0.17; p(BH) = 0.002), and active rewarming systems (OR = 0.21; p(BH) = 0.035). Whole blood use was lower in LMICs (5.8 vs. 17.4%) but did not reach statistical significance in the primary model (OR = 0.55, 95%CI 0.12-2.45). Tranexamic acid availability was nearly universal and did not differ between settings (96.1 vs. 97.8%). Although DCR principles are widely recognized, substantial disparities persist in access to critical resuscitation resources across income settings.

How do the social features of payment forms shape willingness to pay (WTP)? We conduct a purchasing experiment during Covid-19 in which 261 U.S. undergraduates are randomly assigned a payment form in which to complete a real transaction - either via debit card, credit card, or via one of the payment visibility settings within Venmo. We then elicit both stated preferences and WTP for ten household items. We find that the previously documented digital payment premium only persists when transactions are either private or are visible to the public at-large. When transactions are visible only to participants' friends, however, we find a large decrease in their WTP consistent with impression management when peers are frugal. We find that viewing others' transactions increases the magnitude of this effect. Payment visibility matters for WTP, but causes no differences in stated preference. These findings highlight the importance of considering social features of payment forms in addition to more well-documented features such as convenience, transparency and pain of payment.

The driving environment shapes hazard perception, but the underlying neurocognitive mechanisms are not fully understood. This study used electroencephalography (EEG) to investigate how road types influence hazard perception in 36 drivers using a 2 (urban street vs. expressway) &#xd7; 2 (hazard-present vs. hazard-absent) design. Analysis of intra-individual variability (ICV) revealed no significant differences in cognitive control stability between expressway and urban street conditions; however, expressway driving was associated with shorter reaction times and higher error rates. Although the influence of parallel mechanisms, such as reduced vigilance or attentional disengagement, cannot be entirely ruled out, this pattern is consistent with a shift in cognitive processing toward a less effortful, automated mode, suggesting that expressway environments may trigger a specific adaptive mechanism. At the neural level, hazard stimuli on expressways were accompanied by more pronounced parietal &#x3b1; oscillations and relatively weaker functional connectivity between frontal and parietal electrode sites in the &#x3b2;H band. This may reflect a neural state inertia in expressway environments, which hinders the flexible reallocation of cognitive resources when perceptual and attentional demands increase during hazardous situations. To quantify the difficulty of rapidly switching from automated to controlled processing, this study introduces a &#x3b2;H-&#x3b1; composite index for an exploratory characterization of this cognitive bias. Based on these findings, practical implications are provided for road environment design, in-vehicle or roadside warning systems, and driver state monitoring technologies.

This study aimed to examine in depth the spiritual care experiences of nurses working in hemodialysis units in T&#xfc;rkiye. A qualitative phenomenological design was employed, and data were collected through in-depth, face-to-face, semi-structured interviews with 10 hemodialysis nurses working in public hospitals in western T&#xfc;rkiye. A total of 12 eligible nurses were invited, and 10 participated in the study, resulting in a response rate of 83.3%. The data were analyzed using Colaizzi's seven-step phenomenological analysis method with MAXQDA 2022 software. The findings were grouped under four main themes: definition of spiritual care, effects of spiritual care, barriers to spiritual care, and suggestions for improving spiritual care. The results showed that nurses perceive spiritual care as a holistic approach involving empathy, respect for privacy, therapeutic communication, and emotional support. However, excessive workload, lack of time, and insufficient organizational support were identified as key barriers. Strengthening institutional support and training programs is recommended to improve the integration of spiritual care into clinical practice.

Harmful algal blooms (HABs) pose serious threats to coastal ecosystems, public health, and local economies. This study explores the potential of two native macroalgal genera, Padina sp. and Sargassum sp., collected from the Persian Gulf (Bandar Abbas) and the Gulf of Oman (Chabahar), as biological control agents against Cochlodinium polykrikoides. Species identification was achieved through morphological observations and DNA barcoding (rbcL and psbA), ensuring accurate classification despite overlapping traits. Methanolic extracts of Padina (sp. A and sp. C) and Sargassum (sp. B and sp. D) strains inhibited C. polykrikoides, with Padina sp. A showing the strongest activity (LC&#x2085;&#x2080; = 122.2&#xa0;&#xb5;g/mL) and Sargassum sp. D the weakest (LC&#x2085;&#x2080; = 371.2&#xa0;&#xb5;g/mL). Fractionation and identification of the most active extracts using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) revealed the presence of terpenoid and phenolic functional groups in the active fractions of Padina sp. A and Sargassum sp. B, respectively. These extracts exhibited negligible effects on non-target microalgae (Chlorella vulgaris, Isochrysis galbana) at concentrations&#x2009;>&#x2009;1&#xa0;mg/mL, shrimp larvae (Litopenaeus vannamei), and human endothelial cells (HUVEC), highlighting their selectivity and safety. These findings demonstrate that Padina and Sargassum produce bioactive compounds capable of selectively suppressing harmful microalgae, underscoring their promise as environmentally compatible agents for managing HABs in marine and aquaculture systems.

Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis and significantly affects health-related quality of life (HRQoL). In borderline resectable (BR) and locally advanced (LA) PDAC, neoadjuvant FOLFIRINOX may enable surgical resection, but its toxicity can further compromise HRQoL. Evidence on longitudinal HRQoL changes during FOLFIRINOX in this context remains limited. This study evaluated HRQoL trajectories in patients with BR and LA PDAC receiving neoadjuvant chemotherapy (NACT) within a surgical selection strategy. This longitudinal analysis included patients from the multicenter prospective PeRFormanCe trial (NCT05298722), investigating outcomes in BR and LA PDAC treated with FOLFIRINOX as NACT. HRQoL was assessed at baseline and after 4, 8, and 12 NACT cycles using EORTC QLQ-C30 and PAN26 questionnaires. Changes over time were analyzed using linear mixed-effect models. Clinically meaningful differences were defined as &#x2265;10-point mean changes with 95% confidence intervals. Twenty patients were included (35% female), 12 (60%) had LA PDAC. The median number of NACT cycles was 8 (IQR 7-12). Sixteen patients (80%) underwent surgical exploration, and 11 (55%) achieved resection. During NACT, patients reported improvements in insomnia, pain, hepatic symptoms, bloating and appetite loss. Muscle weakness, cognitive deterioration, and side effects increased. Among patients completing 12 cycles, weight loss and flatulence decreased, global health status (baseline 64, SE 4.05) and fatigue scores improved. In patients with BR and LA PDAC treated with FOLFIRINOX as NACT, HRQoL can be preserved over time despite variations in symptoms. These findings contribute to informed, patient-centered decision-making in the neoadjuvant setting. ClinicalTrials.gov Identifier NCT05298722. Date of registration March 28, 2022.

Obesity and type 2 diabetes are major global health concerns associated with substantial clinical and economic burdens. Bariatric metabolic surgery (BMS) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective interventions, but their long-term impact on health care utilization costs remains incompletely understood. To compare short- and long-term health care utilization costs among patients with obesity and diabetes treated with GLP-1RAs vs those who underwent BMS. This observational, retrospective cohort study used electronic medical records from Clalit Health Services, the largest health care organization in Israel. Adults (aged &#x2265;24 years) with obesity (body mass index [BMI] &#x2265;30) and diabetes who underwent their first BMS or initiated GLP-1RA therapy between January 1, 2010, and December 31, 2022, were identified. Propensity score matching yielded 2721 matched pairs, who were followed up for up to 12.5 years (mean [SD], 6.5 [3.5] years), through December 31, 2023. Data cleaning and analyses were conducted from June to October 2025. Treatment with GLP-1RAs or BMS. Health care utilization costs incurred by the health system, excluding costs of the index interventions. Attributable costs were estimated using a difference-in-differences approach and modeled with multivariable linear regression. The matched cohort included 5442 adults (mean [SD] age, 51 [10] years; 3243 women [59.6%]; mean [SD] BMI, 40.5 [6.0]). Mean (SD) monthly follow-up costs were higher among patients treated with GLP-1RAs than those who underwent BMS ($415.3 [$746.7] vs $304.9 [$628.5]). The adjusted difference-in-differences method showed $109.0 higher monthly costs per patient for GLP-1RA treatment (SE&#x2009;=&#x2009;$17.0; P&#x2009;<&#x2009;.001), associated primarily with hospitalization costs ($43.9; SE&#x2009;=&#x2009;$13.3; P&#x2009;=&#x2009;.001) and non-GLP-1 medication costs ($52.5; SE&#x2009;=&#x2009;$4.4; P&#x2009;<&#x2009;.001). Most cost differences accrued within the first 4 years. BMS was associated with greater early reductions in BMI and hemoglobin A1c, whereas GLP-1RA treatment showed more modest but sustained effects. This cohort study found that, among adults with obesity and diabetes, health care utilization costs were higher with GLP-1RA treatment than with BMS, excluding intervention costs, largely reflecting differences in early clinical trajectories. These findings suggest that, among patients eligible for both interventions, BMS may confer combined clinical and economic advantages over long-term follow-up.

Reliable prediction of CO2 injectivity decline is essential for safe geological carbon storage, yet existing machine learning models often provide deterministic point predictions that lack uncertainty quantification. This paper presents a physics-informed Gaussian process regression (PC-GPR) framework for Relative Injectivity Change (RIC) prediction, embedding constraints derived from two independently grounded physical laws: the Derjaguin-Landau-Verwey-Overbeek (DLVO) colloidal monotonicity condition and the Civan-Kozeny-Carman permeability impairment model. Four GP variants are developed and benchmarked on a curated laboratory dataset (n&#x2009;=&#x2009;44) under a three-tier validation protocol combining Leave-One-Out cross-validation, repeated k-fold cross-validation, and non-parametric bootstrap confidence intervals. Two complementary uncertainty quantification mechanisms are employed: GP posterior calibration via the Expected Calibration Error (ECE) and split-conformal prediction intervals. The GP-Base model achieves strong predictive performance (LOO R2&#x2009;=&#x2009;0.9401, 95% CI: [0.882, 0.978]) with well-calibrated uncertainty (ECE&#x2009;=&#x2009;0.026) and reliable coverage (97.7% at the nominal 95% level). The PC-GPR-M variant reduces DLVO monotonicity violations to 1.5% across the input domain, demonstrating effective soft constraint enforcement. Operationally, the proposed framework translates predictive uncertainty into actionable injection scheduling guidance, identifying high-risk regions at salinity >30,000 ppm and jamming ratio >0.04. These results provide an uncertainty-aware baseline for future PIML research in subsurface carbon storage.

Human-robot collaboration (HRC) is increasingly prevalent in hospitality and tourism, yet its affective implications for employees remain insufficiently understood. Drawing on Affective Events Theory and the Effort-Recovery Model, this study proposes state job apathy as a novel low-activation affective mechanism linking daily HRC to next-morning customer-directed behaviors, specifically enacted incivility toward customers and customer stewardship behavior. We further examine psychological detachment as a recovery-based moderator of this spillover process. A 10-day consecutive daily diary study was conducted with 206 hospitality and tourism employees in China, yielding 1016 matched within-person observations. Multilevel path analyses revealed that daily HRC frequency was positively associated with end-of-day state job apathy, which in turn predicted greater enacted incivility and reduced customer stewardship behavior the following morning. State job apathy partially mediated these cross-day relationships. Psychological detachment was also found to moderate the carryover of state job apathy to next-morning customer-directed behaviors: the indirect effects of HRC via apathy were significant when psychological detachment was low, but non-significant when psychological detachment was high. These findings advance HRC research by identifying a low-arousal affective pathway that complements existing threat-based accounts, suggesting that the potential behavioral risks associated with robot collaboration extend beyond the workday into subsequent customer interactions. Practically, the results highlight the importance of recovery-supportive workplace practices and job redesign strategies to mitigate the cumulative affective implications of robot-intensive work environments.

The outbreak of COVID-19 has caused a sharp increase in the amount of medical waste (MW), which is infectious and harmful to the environment and human body. However, existing MW disposal methods face challenges in achieving high treatment efficiency, and creates an urgent need for more cost-effective and environmentally friendly technologies. In this research, a comprehensive evaluation, including comprehensive environment assessment (CEA), life cycle assessment (LCA), and economic assessment (EA), was proposed for three typical MW treatment methodologies (i.e., in situ friction heat treatment technology, chemical disinfection, and microwave sterilization). Results showed that the in-situ friction heat treatment had the minimal environmental impact with CEA score of 5509.11, whereas the chemical disinfection technology had the highest value of 69384.62. In terms of LCA, microwave sterilization had a relatively low global warming potential (6.01 E+02 kg CO2 eq). From the EA perspective, chemical disinfection technology emerged as the most economically viable option, costing merely 29.64% of that of microwave sterilization. After environment-economy integration analysis, in situ friction heat treatment technology emerged as the best disposal method, which had a relatively low pollution emissions and reasonable cost among the three technologies. This study can serve as a guidance for treating MW in a more environmentally friendly and economical way in the future.