The pooling problem is a fundamental and economically critical optimization challenge in petroleum refining, petrochemical manufacturing, and wastewater treatment. Its inherent non-convexity, arising from bilinear blending constraints, makes global optimization computationally intractable at industrial scale. When extended to a two-stage stochastic setting, the resulting two-stage stochastic pooling problem (2SPP) becomes a stochastic Mixed-Integer Nonlinear Program (MINLP) for which classical decomposition methods such as Benders decomposition are inapplicable, because the non-convex recourse function violates the convexity assumptions on which standard optimality cuts rely. This paper proposes a surrogate modelling framework in which a deep ReLU neural network is trained offline on feasibility-biased Monte Carlo samples to learn the profit landscape of feasible, near-optimal sampled solutions of the 2SPP, and its exact MILP reformulation is embedded directly into a Gurobi optimization model. On a problem comprising three sources, five pools, and three product targets, the surrogate-embedded MILP is solved to a certified zero optimality gap with respect to the embedded surrogate, rather than to global optimality of the original 2SPP, yielding high-quality candidate solutions in 120 and 250 seconds for the deterministic and stochastic cases respectively; by contrast, the classical non-convex solver fails to close its optimality gap below 15% after more than six hours. SHAP analysis is consistent with the surrogate having internalized cost sensitivity and the expected-value structure of the two-stage problem. A surrogate-guided warm-start procedure then verifies these candidate solutions against the exact bilinear model, in which the surrogate's predicted first-stage binaries and flows are passed to Gurobi, in 24 and 45 min for the deterministic and stochastic cases respectively.
Background: Although the "digital native" has been empirically discredited as a scientific category, it survives as a folk figure through which adults register wonder and alarm at children's platform lives. Research on children and the internet has relied largely on Western, survey-based studies of children's experiences and parents' reported concerns, or on episodic moral panics amplified by professional media.Aims: This study maps how Persian-language Twitter users publicly construct the intersection of children and the internet, examining the temporal architecture of the discourse across the September 2022 blocking of Instagram in Iran, its thematic structure, its frames of concern and their gendering, and the engagement dynamics that determine which talk travels.Methodology: A corpus of 1,467 Persian tweets posted by 1,385 accounts between February 2021 and May 2025 was analyzed by combining non-negative matrix factorization topic modeling (benchmarked against LDA and a co-word network decomposition), dictionary-based frame analysis, PELT change-point detection, and negative binomial engagement regressions, with the full corpus closely read and all excerpts translated by the author.Findings: The dominant genre is lateral family surveillance: young adults publicly exhibiting the online conduct of younger relatives, with an exact child age stated in 31.6% of all posts. The 2022 blocking contracted the discourse by 38% before it recovered above baseline; the children-in-protest frame briefly saturated the corpus and then evaporated. Concern is sharply gendered, 96% of sexualization posts and 88% of child-influencer posts are girl-marked, the influencer economy is the only growing frame, and state child-protection vocabulary appears in 0.5% of posts. Kinship anecdotes drive conversational reciprocity; policy indignation does not.Conclusion: The public moral order of Persian social media is constructed from the family outward, not from the state downward.
Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease–mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I2 statistic. Risk of bias was assessed using design-specific tools, including the Newcastle–Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists. A total of 109 studies met the inclusion criteria and were included. In our meta-analysis, higher circulating α-Klotho levels were significantly associated with lower odds of frailty (OR = 0.61, 95
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune CNS disease that frequently causes severe optic neuritis, yet the molecular mechanisms driving retinal damage remain incompletely understood, especially across different NMOSD subgroups. Müller glial cells, which maintain retinal water–ion homeostasis through AQP4 and Kir4.1 channels, may represent a primary retinal target of circulating NMOSD-related autoantibodies and serum factors. We investigated how sera from AQP4-IgG+, MOG-IgG+, and double-seronegative (DSN) NMOSD patients affect the expression and localization of key Müller cell biomarkers. Human MIO-M1 Müller cells were stimulated with complement-inactivated patient or healthy control sera, and protein/mRNA levels of AQP4, Kir4.1, CRALBP, VEGF, and IL-6 were evaluated using immunofluorescence, Western blotting, and RT-qPCR. AQP4 membrane localization and internalization were assessed using WGA and EEA1 colocalization analyses. AQP4-IgG+ sera uniquely induced a marked reduction in AQP4 and Kir4.1 protein expression, together with mild AQP4 internalization and reduced membrane association. Despite protein loss, AQP4 and Kir4.1 transcripts were significantly upregulated, indicating a compensatory transcriptional response to antibody-mediated depletion. MOG-IgG + sera produced no major changes in the examined markers. In contrast, DSN sera selectively increased VEGF expression at both protein and mRNA levels, suggesting an alternative, antibody-independent mechanism of Müller cell activation. IL-6 expression showed non-significant changes across groups. These findings demonstrate subgroup-specific retinal glial responses to patient sera, with AQP4-IgG mediating early complement-independent loss of the AQP4–Kir4.1 water–ion channel complex, and DSN sera engaging distinct VEGF-related pathways. Our study establishes Müller cells as active contributors to NMOSD-associated retinal pathology and provides a foundation for exploring subgroup-tailored changes.
Potassium citrate is widely used as oral alkali therapy for the prevention of recurrent nephrolithiasis. Despite its long-standing clinical use, systematically collected real-world safety data remain limited. We performed a pharmacovigilance analysis to characterize adverse event reports associated with potassium citrate using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). FAERS reports submitted between 2014 and 2025 listing potassium citrate as the primary suspect drug were analyzed. Duplicate records were removed, and adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) at both the system organ class and standardized event term levels (preferred terms, PTs). Disproportionality analyses were conducted using reporting odds ratio, proportional reporting ratio, bayesian confidence propagation neural network, and multi-item gamma poisson shrinker methods. A total of 408 unique reports were included. Most reports involved adults and were physician-reported from the United States. Disproportionality analysis identified potential safety issues (signals), defined as drug event associations reported more frequently than expected in FAERS and therefore warranting further evaluation, although not establishing causality. The strongest associations involved product-related issues, laboratory investigations, and gastrointestinal disorders. When these potential safety issues were described using standardized MedDRA event terms most reflected formulation- and administration-related problems, including tablet residue in stool, abnormal solubility, swallowing difficulty, throat irritation, and foreign body sensations. Reports of rash were infrequent. This first FAERS-based analysis of potassium citrate highlights that most reported adverse events are related to formulation and administration characteristics rather than drug toxicity. These findings support the overall tolerability of potassium citrate while underscoring the importance of adherence, patient education, and formulation-specific considerations in clinical practice. As a spontaneous reporting system, FAERS is valuable for hypothesis generation, label expansion, and post-marketing surveillance, but it is not suitable for estimating the incidence or absolute risk of adverse events.
