Search Results (126)

Background: Ustekinumab (UST) is a monoclonal antibody (mAb) used in the treatment of inflammatory bowel disease (IBD). Elevated serum concentrations are typically associated with improved therapeutic outcomes, and therapeutic drug monitoring (TDM) is a useful tool for guiding mAbs treatment. This study aimed to develop a dried blood spot (DBS) method for TDM of UST in patients with IBD. Methods: The commercial enzyme-linked immunosorbent assay for plasma samples was optimized for DBS samples and subsequently validated according to international guidelines for classical and DBS-specific validation parameters. It was then applied to analyze serum and DBS samples obtained from venous and capillary blood of IBD patients undergoing UST therapy. Results: The method was linear (3–12 mg/L) with acceptable inter-day accuracy (90.1–106%) and precision (<12%). We confirmed that there was no hematocrit effect and that DBS samples were stable for one month under room conditions. A linear model was developed between venous DBS and serum UST concentrations, which showed no systemic bias, and 71% of the samples were within ±20% of the mean. In addition, a linear correlation between venous DBS and capillary DBS samples was established, showing no significant bias, with 84% of samples within ±20% of the mean. Finally, a novel strategy was developed to overcome the limitations of poor-quality samples (irregular shapes) based on area image analysis. Conclusions: The newly developed DBS method is the first to enable reliable measurement of UST in capillary blood, appropriate clinical interpretation of the measured concentrations, and remote monitoring of patients in the early phase of therapy. Full article

The thermal environment problem is one of the main focuses of current urban environment research. At present, there are various methods used in urban space thermal environment (USTE) research. As a simulation method to quantify the USTE, the urban weather generator (UWG) has undergone great development and achieved many progressive results. It is necessary to establish and review its current research status by synthesizing UWG multi-scale applications. This review adopts a literature review approach, leveraging the Web of Science Core Collection to obtain previous relevant publications from 2010 to 2025 using “urban weather generator” and “thermal environment” as keywords. The literature is categorized by research themes, including model development, parameter optimization, and application cases. Through innovative analyses of spatio-temporal-scale classification, parameter optimization, the integration of anthropogenic heat emissions, and the multi-domain simulation potential of the UWG, this review synthesizes the application outcomes of the UWG model in multi-scale research, addressing gaps in current urban climate studies. The paper aims to elaborate and analyze the model’s current research status considering the following six aspects. First, the basic parameters in UWG simulation are introduced, including the data and parameter determination settings used in such simulations. Secondly, we introduce the simulation model and its basic principles, the simulation process, and the main steps of this process. Third, we classify and define UWG simulations of spatial thermal environments at different time scales and spatial scales. Fourth, regarding how to improve the accuracy of the UWG model, the deterministic parameters and uncertainty parameters settings are analyzed, respectively. Then, the impacts of anthropogenic heat during the simulation process are also discussed. Fifth, the applications of the UWG model in some major fields and its possible future development directions are addressed. Finally, the existing problems are summarized, the future development trends are prospected, and research on possible expected mitigation measures for the USTE is described. Full article

Background: Inflammatory bowel disease (IBD) is defined as recurrent inflammatory bowel disorders, the most common of which are Crohn’s disease (CD) and ulcerative colitis (UC). Tumor necrosis factor inhibitors (anti-TNFs), primarily adalimumab (ADA), infliximab (IFX), ustekinumab (UST), and vedolizumab (VLZ), are used to treat moderate-to-severe cases of IBD in patients who either do not tolerate or fail to respond to conventional therapies. However, about one-third of patients are primary non-responders to these treatments, and an additional 30% lose response over time. Several studies have investigated the role of genetic variability in explaining these differences in treatment response among patients. The aim of this study was to design an array of 60 single-nucleotide variants (SNVs) to validate the biomarkers described in the literature in a population of more than 400 IBD patients treated with biological drugs. Method: The primary focus of this study was the most recent reviews published in PubMed, with all relevant SNVs selected for the array design. Subsequently, studies presenting original data on the association between variants and the response to biological treatment were identified. Results: A total of 55.9% of SNVs have been studied in CD, 18.6% have been in UC, and 25.4% have been studied in both pathologies. A total of 44.1% of SNVs have been observed to influence the response to IFX, 16.9% influence the response to ADA, and 37.3% influence the response to both IFX and ADA; however, only one study (1.7%) reported an influence on the response to UST and none reported an influence on the response to VLZ. Conclusions: An array comprising 38 genes and 59 SNVs has been designed to be used to validate biomarkers associated with responses to biologic drug treatments in IBD. Full article

Drosophila subobscura is a Palearctic species that colonized the west coast of South and North America in the last quarter of the 20th century. This species stands out for its large chromosomal inversion polymorphism that affects its five long chromosomes. Studies of natural populations revealed that the inversion polymorphism has an adaptive character and while the arrangement U_st was classified as adapted to cold, other arrangements, such as U₁₊₂₊₆ and U₁₊₈₊₂, were considered warm adapted. Characterization of the inversion breakpoints will allow a first approach to the genes included in the inversions and to find candidates to be affected by selection. In this work, we take advantage of the existence of a reference genomic sequence carrying the U₁₊₂ arrangement to locate the breakpoints of the U₆ and U₈ inversions, mapping paired-end Illumina reads from two homokaryotypic strains to U₁₊₂₊₆ and U₁₊₈₊₂, respectively. To date, most of the characterized inversion breakpoints in D. subobscura have been generated by non-homologous end-joining. In contrast, the U₆ and U₈ inversions seem to have originated by transposons, and, at the distal breakpoint of inversion U₈, we describe a new fold-back-like element characteristic of the suboscura species group that we have named Ziga-Zaga. Full article

Introduction: Evidence for the diagnostic yield of noninvasive diagnostic assessment for the diagnosis of peripheral arterial disease (PAD) in diabetic foot syndrome (DFS) is poor. Pulse volume recordings (PVRs) at the forefoot level could be a valuable diagnostic tool in the presence of medial arterial calcification. Patients and methods: Patients with DFS who underwent invasive angiography between 01/2020 and 11/2024 and had corresponding PVRs performed within 30 days prior to the procedure were included. DFS was classified according to the Wagner–Armstrong classification. Clinical characteristics and hemodynamic parameters, including systolic ankle pressures and ankle–brachial index were recorded. PVRs were analyzed semiquantitatively by investigators blinded to the clinical information and quantitatively with determination of upstroke time (UST), upstroke ratio (USR), and maximum systolic amplitude (MSA). Angiographic PAD severity was graded according to the GLASS classification. Statistical analysis included univariate significance tests, 2 × 2 contingency tables, receiver–operator characteristic (ROC) analysis and determination of interobserver agreement. Results: In this study, 90 extremities of 70 patients were analyzed, 47 of whom had an ABI ≥ 1.3. Critical limb-threatening ischemia with non-pulsatile PVRs was evident in 6.7%. An abnormal PVR curve morphology (mildly or severely abnormal) yielded a sensitivity and specificity of 63.3% and 85.7% for detection of severe PAD (GLASS stages 2 and 3). Interobserver agreement of semiquantitative PVR rating was substantial (Cohen’s kappa 0.8) in 51 evaluated cases. For detection of any PAD (GLASS ≥ 1) or severe PAD (GLASS ≥ 2), we found the highest diagnostic accuracy for MSA (area under the curve [AUC] 0.89 and 0.82). With a cut-off value of 0.58 mmHg, MSA had a sensitivity of 91.4% and a specificity of 80.8% for detection of any PAD (GLASS ≥ 1). MSA with a cut-off of 0.27 mmHg had a sensitivity of 72.2% and a specificity of 77.1% for detection of severe PAD, whereas the sensitivity and specificity for detection of inframalleolar disease were 62.9% and 69.4%, respectively. Results were consistent in subgroup analyses. Conclusions: PVRs with extraction of quantitative features offer promising diagnostic yield for detection of PAD in the setting of DFS. MSA outperformed UST and USR but showed limited capability of detecting impaired inframalleolar outflow. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that leads to significant deterioration in patients’ quality of life. Biologic therapy, including the use of ustekinumab (UST), is a modern approach to treating the moderate to severe form of CD, especially in patients refractory to traditional treatments. UST, which acts as an interleukin IL-12 and IL-23 antagonist, has shown high efficacy in reducing inflammation, improving quality of life, and promoting mucosal regeneration and fistula healing. However, the use of biologic therapies, such as UST, has challenges related to the timing of treatment and patient response, including the problem of immunogenicity. To determine the clinical efficacy and safety profile of UST in the treatment of CD, a review of the literature published in the PubMed database over the last 5 years was conducted. After excluding articles that did not meet the inclusion criteria, we analyzed 42 clinical studies. The review discusses the available data on the efficacy and safety of UST, as well as its comparison with other biologic therapies, such as infliximab and adalimumab. UST, although not significantly greater to adalimumab, has lower immunogenicity and higher treatment retention. The therapeutic value of UST is also confirmed by biosimilars such as ABP 65 and FYB202, which show comparable efficacy and safety profile. The analysis of predictive biomarkers, such as serum drug levels and baseline eosinophil levels, could be an important element in the future personalization of CD treatment. The review’s findings point to the importance of further research to improve the tailoring of therapies to individual patients and improve long-term treatment outcomes. Full article

This study investigates how sociolinguistically informed instruction and virtual exchanges affect the use of the second-person singular pronouns (usted, tú, and vos) by adult second language learners of Spanish enrolled in a third-semester course at a four-year college. The results from written contextualized tasks and oral discourse completion tasks show that participants who engaged in virtual exchanges with native speakers from Guatemala, Honduras, and El Salvador (experimental group) significantly improved their use of vos compared to those who did not participate in these exchanges (control group). Both groups increased their use of tú and vos over time, with notable differences between written and oral tasks. These findings provide empirical support for incorporating virtual exchanges into language learning curricula, demonstrating their effectiveness in teaching regional dialectal features such as voseo. Additionally, by focusing on the often-overlooked regionally variable pronoun vos, this study enriches the existing literature on Spanish language instruction and opens new avenues for research on dialectal variation and sociolinguistically informed pedagogy. Full article

Background/Objectives: In the current era of tailored therapy, biologics such as vedolizumab (VDZ) and ustekinumab (UST) are increasingly administered to inflammatory bowel disease (IBD) patients. The decision to discontinue biologics after side effects or a lack of response is usually simple, but the decision to stop treatment in patients in remission is more difficult: to date, no study has been conducted to investigate the effects of VDZ or UST withdrawal. Our study aims to investigate the rates and predictors of relapse of IBD after the discontinuation of VDZ and UST during a well-controlled disease phase and to evaluate the response to retreatment. Methods: In this observational, multicenter, retrospective study, we included IBD patients who discontinued VDZ or UST during a well-controlled disease phase after at least 1 year of treatment. We collected demographic and clinical data for each patient at the time of discontinuation and at follow-up visits. Results: We included 36 IBD patients from 5 different centers; 80.0%, 58.5%, and 48.3% of patients maintained clinical remission at 12, 24, and 48 months after discontinuation, respectively. Crohn’s disease (CD) patients were more likely to maintain remission than ulcerative colitis (UC) patients at 48 months (70.0% vs. 40.0%). No predictors of relapse were identified, but UC patients had a higher risk of early relapse than CD patients (HR = 3.23); 81.3% of retreated IBD patients achieved clinical remission after induction and at 12 months. Conclusions: No predictors of disease relapse after treatment discontinuation were identified. Half of the patients had a relapse within 48 months after discontinuation, but most of them achieved clinical remission after retreatment. Full article

Background/Objectives: Crohn’s disease (CD) is a progressive condition, and early treatment with infliximab combined with an immunosuppressant within six months has been shown to improve clinical outcomes. However, the impact of early ustekinumab (UST) use in biologic-naïve CD patients remains unclear. This study aims to address this gap by evaluating the clinical outcomes of early UST intervention in such patients. Methods: In this retrospective cohort study, we included biologic-naïve CD patients treated with UST, with a clinical follow-up period of at least six months from October 2020 to January 2024 across four medical centers. Patients who received UST within six months of CD diagnosis were categorized into the Early-UST group, while those who were initially treated with conventional therapies and subsequently received UST after six months were assigned to the control group. The primary endpoint was the improvement of clinical outcomes at six months. Results: A total of 60 biologic-naïve CD patients were enrolled. Baseline characteristics were comparable between the two groups. At six months, the Early-UST group (n = 24) demonstrated significantly lower Crohn’s Disease Activity Index (CDAI) scores (73.03 vs. 112.42, p = 0.038), lower Harvey–Bradshaw Index (HBI) scores (1.46 ± 1.69 vs. 2.72 ± 2.17, p = 0.020), higher rates of clinical remission (91.7% vs. 63.9%, p = 0.017), and higher rates of steroid-free clinical remission (79.2% vs. 50.0%, p = 0.031) compared to the control group (n = 36). At one year, the early-UST group continued to exhibit lower CDAI scores (39.94 vs. 91.48, p = 0.005). Conclusions: Initiating ustekinumab within six months of CD diagnosis is associated with improved clinical outcomes and enhanced quality of life in biologic-naïve Crohn’s disease patients. Full article

Background/Objectives: This study aimed to compare the association of ustekinumab (UST) drug clearance (CL) and trough drug concentrations with disease activity in patients with inflammatory bowel diseases (IBDs). Methods: A prospective cohort of 83 patients with IBD receiving maintenance therapy with 90 mg subcutaneous UST was analyzed using Bayesian PK modeling. UST concentrations and antibodies to UST (ATU) were collected at the trough and measured using a drug-tolerant homogenous mobility shift assay (HMSA). CL was estimated using Bayesian estimation methods with priors from a previous population pharmacokinetic study specifically reparametrized using HMSA. Outcomes were combined clinical and biochemical remission and endoscopic healing index (EHI) score, a validated marker of endoscopic active disease in IBD. Statistical analysis consisted of linear and nonlinear mixed effect models for repeated time-to-event analysis. Results: A total of 83 patients with IBD were enrolled (median age 42 years, 52% female) and evaluated across 312 dose cycles (median follow-up: 279 days, median of 3 cycles/patient). Median concentrations and CL were 5.0 µg/mL and 0.157 L/day, respectively. Most patients (89%) were exposed to other biologics before starting UST, which was associated with lower rates of clinical and biochemical remission (p = 0.01). Longitudinal changes in concentrations were not associated with remission (p = 0.53). Conversely, higher CL was associated with a lower likelihood of remission (p < 0.01). EHI > 50 points (endoscopic active disease, n = 303 cycles) was associated with higher UST CL (p < 0.01). Conclusions: UST CL was more strongly associated with clinical and biochemical outcomes than trough concentrations, highlighting its potential role in therapy optimization. Full article

Purpose: Currently, there is no clinical data reported on the therapy of dual biological agents in pediatric-onset inflammatory bowel disease (PIBD) patients in China. The purpose of this study was to evaluate the efficacy and safety of dual biologic therapy or biologics combined with small molecule drugs in refractory PIBD patients in China. Methods: Clinical, laboratory, endoscopic, and ultrasound data of PIBD patients from the Department of Gastroenterology of Beijing Children’s Hospital between January 2021 and October 2024 were retrospectively analyzed. PIBD patients who received dual biologic treatment or a combination of biologic and small molecule therapy were included in this study. Steroid-free clinical remission and adverse events were recorded. Results: In this retrospective study, out of 520 children with IBD, twelve children (2.3%) were diagnosed with refractory PIBD and met the criteria for dual biotherapy, including four with UC (33%) and eight with CD (67%). The median age of patients was 13.64 (range, 1.2–17.1) years at eligibility for dual biologic therapy. There are eight (67%) patients treated with infliximab/ustekinumab (IFX + UST), three (25%) patients with upadacitinib/ustekinumab (UPA + UST), one (8%) patient with infliximab/vedolizumab (IFX + VDZ). At 3, 6, and 12 months of dual biological treatment, 91.2% (11/12), 100% (12/12), and 100% (12/12) patients showed steroid-free clinical remission, respectively. The median fecal calprotectin decreased significantly from 1852.5 µg/g (IQR, 762.5–1988.25) at baseline to 359.0 (IQR, 217.5–730.25) μg/g at 3 months, 113 (IQR, 73.7–256) μg/g at 6 months, and 82.5 (IQR, 40.25–122.25) μg/g at 12 months. Only one CD patient with IFX + UST reported mild elevation of aminotransferase, who recovered after symptomatic treatment. Conclusions: Dual biologic or small molecule therapy may be effective and safe for children with refractory PIBD in China. Full article

Non-autoclaved aerated concrete (NAAC) is gaining attention for its strength-to-weight ratio and sustainability benefits. Produced by incorporating a blowing agent into a binder, aggregate, and water mixture, NAAC offers a lightweight and porous construction material. Ash and slag waste (ASW), primarily composed of silicon, aluminum, iron, and calcium oxides, presents significant potential as a sustainable additive. However, industrial-scale processing of ASW still needs to be explored in Kazakhstan. This study evaluates the feasibility of utilizing ASW from the Ust-Kamenogorsk Thermal Power Plant to produce earthquake-resistant NAAC. Incorporating 31.5% ASW by weight optimizes compressive strength, achieving 2.35 MPa and significantly improving the mechanical properties. Chemical and microstructural analyses confirm ASW’s suitability as a construction material. The study also introduces innovative processing methods and explores convolutional neural network models for predicting material structure changes, providing insights into optimizing production processes. The findings address the research objectives by confirming the viability of ASW in NAAC production and demonstrating its potential for sustainable construction. The results offer a pathway for industrial-scale applications, contributing to waste utilization and resource conservation. Full article

According to the Bureau of National Statistics of the Republic of Kazakhstan, by the end of 2023, approximately 120 million tons of municipal solid waste (MSW) had been generated across over 3200 landfills in the country. About 4.5 million tons are generated annually, of which only about 15% are recycled. The accumulation of both unsorted and sorted waste poses significant environmental risks, primarily through the generation of methane, a greenhouse gas that is 28 times more dangerous than carbon dioxide in contributing to the planet’s greenhouse effect over a century and 84 times more effective over a 20-year timeframe. The objective of this research is to examine the physicochemical composition, as well as the physical and thermal-chemical properties, of municipal solid waste from six cities in Kazakhstan: Astana, Almaty, Shymkent, Aktobe, Karaganda, and Ust-Kamenogorsk. Unlike existing studies, this study has a uniform waste sample, which includes the complete emptying of dozens of containers from different areas of the cities under consideration. Thus, the average composition of solid waste across the cities was maintained. Analysis of the physicochemical composition was conducted for both unsorted and sorted municipal solid waste from all cities, determining the total and analytical moisture content, ash content, and volatile matter, as well as the higher and lower calorific values. The calorific value of unsorted waste by city was as follows, in kJ/kg: Astana,8850.37; Almaty, 9244.57; Atobe, 9596.41; Shymkent, 9425.48; Karaganda, 8902.8; Ust-Kamenogorsk, 9669.07. The calorific value of sorted waste was as follows, in kJ/kg: Astana, 11,922.79; Almaty, 11,692.31; Atobe, 11,913.13; Shymkent, 12,494.38; Karaganda, 11,671.92; Ust-Kamenogorsk, 12,462.52. The efficiency of sorting was estimated as the first stage of MSW processing. The efficiency factor of the manual sorting process in practice was 0.4–0.8. The results obtained enable the evaluation of technologies for the effective management of municipal solid waste and facilitate experimental investigations into semi-industrial pyrolysis, combustion, plasma processing, and composting facilities. Full article

Background/Objectives: Vitamin D (VD) has immunoregulatory properties, generating interest in its potential to influence therapeutic outcomes in inflammatory bowel disease (IBD), other than affecting the expression of genes encoding enzymes and transporters involved in drug metabolism and transport. This study investigated VD-related single nucleotide polymorphisms (SNPs) as predictors of clinical responses in patients with Crohn’s disease (CD) and ulcerative colitis (UC) treated with vedolizumab (VDZ) or ustekinumab (UST) after 3 (T3) and 12 months (T12), as well as the achievement of fecal calprotectin (FC) levels < 250 mg/kg, a marker of mucosal healing. Methods: In this prospective study, 103 patients (67 CD, 36 UC) were enrolled, 40 receiving VDZ and 63 receiving UST. SNPs in the genes CYP24A1, GC, CYP27B1, and VD receptor (VDR) were analyzed via polymerase chain reaction (PCR) and associated with clinical and laboratory outcomes. Results: UST therapy demonstrated a higher clinical response rate at T12 compared to VDZ (p = 0.03). A correlation was found between response at T3 and T12 (p = 0.0002). GC 1296 AC polymorphism negatively predicted response at T12, with 63.6% of non-responders carrying this genotype. CYP24A1 8620 AG was a negative predictor for achieving FC < 250 mg/kg (p = 0.045). CYP24A1 22776 CT and VDR Cdx2 GG increased the likelihood of presenting CD over UC (OR 3.40, p = 0.009 and OR 3.74, p = 0.047, respectively). Additionally, CYP27B1 −1260 GT and +2838 CT increased the likelihood of non-ileal CD (OR 3.13, p = 0.054; OR 7.02, p = 0.01). Conclusions: This study reveals associations between VD-SNPs, clinical response to VDZ and UST, and IBD phenotype and localization, supporting the development of personalized IBD treatment and warranting further validation. Full article

Background: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist approved for the treatment of Crohn’s disease (CD). Only limited real-life data on the long-term outcomes of CD patients treated with UST are available. This study assessed UST’s long-term effectiveness and safety in a large population-based cohort of moderate to severe CD patients. Methods: This was a multicenter, retrospective, observational cohort study that included both naïve and biologic-experienced patients treated with UST who achieved clinical remission or clinical response after at least one year of treatment. Clinical activity was scored according to the Harvey–Bradshaw Index (HBI). The primary endpoints were the maintenance or achievement of clinical remission after a further 12-month period of treatment, defined as an HBI of ≤5, and safety. Other endpoints included steroid-free remission, mucosal healing (MH), steroid discontinuation, and the need for treatment optimization during the follow-up. Results: Out of 562 CD patients, after an overall 24-month follow-up, clinical remission was present in 450 (80.0%) patients, and at 12 months, clinical remission was observed in 417/437 (95.4%) patients; 33/125 (26.4%) showed clinical response at 12 months (p = 0.000). A total of 38/103 (36.9%) patients achieved MH. Only 2.1% (12/562), 3% (17/562), and 1.1% (6/562) of patients required surgery, optimization, and re-induction, respectively. Adverse events occurred in eight patients (1.42%). According to a multivariate analysis, the only predictor of long-term remission was the presence of remission at the 12-month follow-up (p = 0.000). Conclusions: Long-term treatment with UST presents good efficacy and safety profiles in CD patients, especially for patients who achieve remission after one year. Full article