Search Results (653)

Background and Aim: Long-term treatment with biologic therapy alongside immunomAfodulators in patients with inflammatory bowel disease (IBD) can be associated with severe side effects. The objective of this study was to determine whether discontinuing anti-TNF treatment after two years in patients who have achieved mucosal healing is associated with lower relapse rates. Materials and Methods: A total of 67 patients with IBD from a single tertiary IBD Center who had achieved mucosal healing were enrolled in this retrospective study. In this single-center retrospective study (January 2014–December 2022), we screened 67 IBD patients in deep remission (endoscopic mucosal healing after ≥2 years of anti-TNF therapy). After excluding three patients without histologic data, 64 patients (25 ulcerative colitis, 39 Crohn’s disease) were analyzed. Mayo endoscopic sub-score and SES-CD were used to evaluate endoscopic activity after two years of anti-TNF therapy. Histological activity was assessed using the GHAS (for CD) and Nancy index (for UC). Results: A total of 67 patients were screened, of whom 3 were excluded due to a lack of biopsies. Of the 64 included patients, 39.06% (25/64) had UC and 60.9% (39/64) had CD, with a mean disease duration of 11.6 ± 8.0 years. All patients were in endoscopic remission at the time of therapy de-escalation, and 60.9% (39/64) also achieved histological remission (“deep remission”). In the follow-up of 38.6 months (IQR 30–48) after biologic therapy was stopped, 57.8% (37/64) relapsed with a median time to relapse of 13.5 months (IQR 8–24) off anti-TNF—a total of 34 patients required a restarting of biologic therapy. Using Spearman’s correlation, a moderate connection was observed between histological activity at withdrawal and subsequent relapse (rho = 0.467, p < 0.001). The probability of relapsing within 4 years after anti-TNF cessation was significantly higher (OR 2.72) in patients with histologically active disease at the time of de-escalation. Conclusions: Achieving ‘deep remission’ (clinical, endoscopic, and histological healing) may be a suitable parameter for making decisions on when to de-escalate therapy; however, given that over half of patients in endoscopic remission relapse after discontinuation, any de-escalation should be approached with caution and individualized patient assessment. Full article

Humane euthanasia is an endpoint for production animals succumbing to disease or trauma. Euthanasia performed with barbiturates or other anesthetic/sedative drugs observes zero withdrawal time, and drug residues may remain in tissues. Carcasses may be submitted for rendering, and rendered products can be used to manufacture pet foods. The purpose of this study was to determine the concentration of two drugs, xylazine and ketamine, that may be used during the euthanasia process of food animals and to determine the fate of these drugs following a simulated rendering process using a commercial autoclave. Twelve cattle were administered xylazine or xylazine and ketamine prior to euthanasia via penetrating captive bolt, and samples of muscle, fat, liver, and kidney were collected. The tissue samples were analyzed by LC-MS/MS, both raw and following rendering. The parent compounds xylazine and ketamine were detected in all tissues, both before and after rendering. The highest concentrations were found in rendered kidney for both drugs, and the lowest in rendered and raw fat for xylazine and ketamine, respectively. Full article

Background: Patients in Intensive Care Units (ICUs) often develop non-thyroidal illness syndrome. Potentially, thyroid hormones may be removed during continuous veno-venous hemodiafiltration (CVVHDF), as their molecular size is smaller than the filter pores’ cutoff. The study’s main aim was to assess whether the serum concentration of thyroid hormones changes over time during CVVHDF. Methods: This was a prospective observational trial that included 30 patients treated in an ICU. All patients developed acute kidney injury (AKI) and had clinical indications for implementation of CVVHDF. Blood samples were collected before initiation of CVVHDF and at 1, 2, 3, 6, 9 and 12 days after. The last sample was collected three days after CVVHDF withdrawal. Thyroid function was evaluated by determining the serum concentration of TSH, thyrotropin-releasing hormone (TRH), free triiodothyronine (fT₃), free thyroxine (fT₄), total triiodothyronine (tT₃), total thyroxine (tT₄) and reverse triiodothyronine (rT₃). We additionally calculated the total activity of peripheral deiodinases (G_D) using a mathematical model. Results: TRH and TSH levels remained mostly within normal ranges. fT4 and tT4 were in normal range or slightly below. In contrast, fT3 and tT3 were undetectably low in most patients throughout. Reverse T3 levels remained within normal limits. There were no statistically significant changes in any thyroid hormone levels over the CVVHDF treatment period. The calculated peripheral G_D activity was lower than normal, but importantly, it did not change significantly over time. Conclusions: Thyroid hormones are not lost due to hemodiafiltration. Decreased deiodinases activity is responsible for alterations in serum concentrations of thyroid hormones in patients during CVVHDF. Full article

This article examines the concept of ming 命 (mandate/command or fate/destiny) in the Analects, Mencius, and Zhuangzi, exploring its relationship to tian 天 (Heaven). Across these works, ming retains an intrinsic connection to tian—an inviolable cosmic force beyond human control. All three texts exhibit profound reverence and submission to tian, acknowledging the boundary between human control and cosmic inevitability, yet, at the same time, advocating active alignment with tian’s ordained patterns. In the Analects, a central tension emerges between tian’s teleological purpose—centered on preserving human culture and ethical cultivation—and the seemingly arbitrary fluctuations of individual fate, particularly regarding lifespan and personal fulfillment. This tension persists in the Mencius, articulated as a conflict between the political disorder of Mencius’ contemporary era and tian’s normative moral order. The Zhuangzi, by contrast, resolves this tension through advocating for withdrawal from the political life, as well as a radical reinterpretation of tian. Stripping tian off the Confucian moral–cultural imperatives, the text deconstructs dichotomies like life and death, championing inner equanimity via flowing with the cosmic transformation. Full article

This study investigates ground deformations in the southeastern Po Plain (northern Italy), focusing on the Bologna area—a densely populated region affected by natural and anthropogenic subsidence. Ground deformations in the area result from geological processes (e.g., sediment compaction and tectonic activity) and human activities (e.g., ground water production and underground gas storage—UGS). We apply a multidisciplinary approach integrating subsurface geology, ground water production, advanced differential interferometry synthetic aperture radar—DInSAR, gas storage data, and land use information to characterize and analyze the spatial and temporal variations in vertical ground deformations. Seasonal and trend decomposition using loess (STL) and cluster analysis techniques are applied to historical DInSAR vertical time series, targeting three representatives areas close to the city of Bologna. The main contribution of the study is the attempt to correlate the lateral extension of ground water bodies with seasonal ground deformations and water production data; the results are validated via knowledge of the geological characteristics of the uppermost part of the Po Plain area. Distinct seasonal patterns are identified and correlated with ground water production withdrawal and UGS operations. The results highlight the influence of superficial aquifer characteristics—particularly the geometry, lateral extent, and hydraulic properties of sedimentary bodies—on the ground movements behavior. This case study outlines an effective multidisciplinary approach for subsidence characterization providing critical insights for risk assessment and mitigation strategies, relevant for the future development of CO₂ and hydrogen storage in depleted reservoirs and saline aquifers. Full article

In medical research, random censoring often occurs due to unforeseen subject withdrawals, whereas progressive censoring is intentionally applied to minimize time and resource requirements during experimentation. This work focuses on estimating the parameters of a two-parameter exponential distribution under a progressive Type-II random censoring scheme, which integrates both censoring strategies. The use of symmetric properties in failure and censoring time models, arising from a shared location parameter, facilitates a balanced and robust inferential framework. This symmetry ensures interpretational clarity and enhances the tractability of both frequentist and Bayesian methods. Maximum likelihood estimators (MLEs) are obtained, along with asymptotic confidence intervals. A Bayesian approach is also introduced, utilizing inverse gamma priors, and Gibbs sampling is implemented to derive Bayesian estimates. The effectiveness of the proposed methodologies was assessed through extensive Monte Carlo simulations and demonstrated using an actual dataset. Full article

Antibiotic residues in poultry pose health and resistance risks, necessitating breed-specific WDTs. In this study, the residue elimination patterns of seven antibiotics in Taihang chicken tissues under free-range conditions were studied and the appropriate WDT was formulated. A total of 240 healthy Taihang chickens aged 100 days were randomly divided into 8 groups, each comprising 30 chickens. Chickens in groups 1 to 7 were administered oxytetracycline, chlortetracycline, erythromycin, tylosin, tylvalosin, lincomycin, and tiamulin, respectively. Regarding the administration method, we adopted the highest dose and maximum course of treatment recommended by the Veterinary Pharmacopoeia of the People’s Republic of China. Group 8 served as the control group. Muscle, sebum, liver, and kidney samples were collected at 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 13 d, and 16 d after drug withdrawal. Our results demonstrated that the drug residues after drug withdrawal gradually decreased with the increase in drug withdrawal days, and the elimination rate in the early stage of drug withdrawal was significantly faster than that in the later stage. At 4 h after drug withdrawal, the drug residues in various tissues reached their highest values. In most cases, the drug concentrations in the kidney and liver were higher than those in the muscles and sebum; however, some drugs also exhibited concentration peaks in the sebum. On the first day of drug withdrawal, the amount of residues in various tissues decreased rapidly. In general, the elimination rate of various drugs in the muscles, liver, and kidneys is faster but slower in the sebum. Based on the WDT calculation software WT1.4, the recommended WDTs for oxytetracycline, chlortetracycline, erythromycin, tylosin, tylvalosin, lincomycin, and tiamulin chickens are 4 d, 5 d, 11 d, 8 d, 13 d, 13 d, and 7 d, respectively. These findings support food safety and industry development. Full article

Four entire male sugar gliders (Petaurus breviceps) belonging to the same colony were presented for elective orchiectomy. After clinical examination, dexmedetomidine (120 μg/kg) in combination with ketamine (5 mg/kg) were administered subcutaneously (SC). Once righting and pedal withdrawal reflexes were lost, ringer lactate solution, enrofloxacin and meloxicam were administered SC and a bilateral intratesticular block with lidocaine 0.25% was performed. Heart, respiratory rates and pulse oximetry values were recorded every minute. Onset of sedation, additional use of isoflurane, duration of anaesthesia, duration of surgery, time of recovery after atipamezole administration, quality of recovery and time of food intake were recorded. Postoperative assessment (posture, level of activity, vocalisation, response to manipulation, attention to the surgical wound) was performed hourly until discharge, five hours after surgery. Dexmedetomidine in combination with ketamine provided adequate short-lasting anaesthesia for castration in 3 out of 4 sugar gliders. One sugar glider needed additional isoflurane administration to perform orchiectomy. No perioperative additional analgesia was needed in any sugar glider. Full article

Brain-derived neurotrophic factor (BDNF) is associated with nicotine use behaviours, the intensity of nicotine cravings, and the experience of withdrawal symptoms. Given the established influence of sex, brain-derived neurotrophic factor variants, personality traits and anxiety levels on nicotine use, this study aimed to conduct a comprehensive association analysis of these factors within a cohort of women who use nicotine. The study included 239 female participants: 112 cigarette users (mean age = 29.19, SD = 13.18) and 127 never-smokers (mean age = 28.1, SD =10.65). Study participants were examined using the NEO Five-Factor Inventory and the State–Trait Anxiety Inventory. Genotyping of rs6265, rs10767664, and rs2030323 was performed by real-time PCR using an oligonucleotide assay. We did not observe significant differences in the distribution of either genotype or allele of rs6265, rs10767664 and rs2030323 between groups. However, compared to the never-smokers, cigarette users scored significantly lower on the Agreeableness (5.446 vs. 6.315; p = 0.005767; d_Cohen’s = 0.363; η² = 0.032) and the Conscientiousness (5.571 vs. 6.882; p = 0.000012; d_Cohen’s = 0.591; η²= 0.08) scales. There was significant linkage disequilibrium between all three analysed polymorphic variants—between rs6265 and rs10767664 (D′ = 0.9994962; p < 2.2204 × 10⁻¹⁶), between rs6265 and rs2030323 (D′ = 0.9994935; p < 2.2204 × 10⁻¹⁶) and between rs10767664 and rs20330323 (D′ = 0.9838157; p < 2.2204 × 10⁻¹⁶), but the haplotype association analysis revealed no significant differences. While our study did not reveal an association between the investigated brain-derived neurotrophic factor polymorphisms (rs6265, rs10767664 and rs2030323) and nicotine use, it is essential to acknowledge that nicotine dependence is a complex, multifactorial phenotype. Our study expands the current knowledge of BDNF ’s potential role in addictive behaviours by exploring the understudied variants (rs10767664 and rs2030323), offering a novel contribution to the field and paving the way for future research into their functional relevance in addiction-related phenotypes. The lower Agreeableness and Conscientiousness scores observed in women who use nicotine compared to never-smokers suggest that personality traits play a significant role in nicotine use in women. The observed relationship between personality traits and nicotine use lends support to the self-medication hypothesis, suggesting that some women may initiate or maintain nicotine use as a coping mechanism for stress and negative affect. Public health initiatives targeting women should consider personality and psychological risk factors in addition to biological risks. Full article

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting. Full article

The objective of this study is to define groundwater management zones for a complex deformed and fissured Precambrian karst aquifer, which underlies one of the most important agricultural areas in the semi-arid region of Irecê, Bahia, Brazil. It is an unconfined aquifer, hundreds of meters thick, resulting from a large sequence of carbonates piled up by thrust faults during tectonic plate collisions. Groundwater recharge and flow in this aquifer are greatly influenced by karst features, through the high density of sinkholes and vertical wells. Over the past four decades, population and agricultural activities have increased in the region, resulting in unsustainable groundwater withdrawal and, at the same time, water quality degradation. Therefore, it is important to develop legal and environmental management strategies. This work proposes the division of the karst area into three well-defined management zones by mapping karst structures, land use, and urban occupation, as well as the concentrations of chloride and nitrate in the region’s groundwater. Zone 1 in the north possesses the lowest levels of karstification, anthropization, and contamination, while zone 2 in the central region has the highest levels and zone 3 in the south ranging in-between (except for stronger karstification). The delimitation of management zones will contribute to the development and implementation of optimized zone-specific groundwater preservation and restoration strategies. Full article

Droughts are predicted to intensify with climate change, posing a serious threat to global crop production. Increasing drought tolerance in plants requires an understanding of the underlying mechanisms. This study measured the physiological, phytohormonal and transcriptomic responses to drought in two apple rootstocks to identify drought ‘biomarkers’ and investigated whether the application of acibenzolar-S-methyl (ASM) to the roots could enhance drought tolerance. Two potted-plant trials were conducted on dwarfing (M9) and semi-dwarfing (CG202) apple rootstocks. In both trials, the response patterns in the roots and leaves were compared between irrigated and non-irrigated plants over a 14-day period. In trial 2, ASM was applied 14 days before and immediately before withdrawing irrigation. Drought induced significant decreases in transpiration, photosynthesis and stomatal conductance in both trials. This was accompanied by the accumulation of abscisic acid (ABA) metabolites and the upregulation of ABA pathway transcripts (CYP707A1/A2 and NCED3), a decrease in 12-oxophytodienoic acid (cis-OPDA) and the downregulation of ABA receptor genes (PYL4). The responses to drought were greater in the roots than the leaves, broadly similar across both rootstocks, but differed in strength and timing between the rootstocks. The application of ASM to the roots did not significantly affect the responsiveness to drought in either rootstock. The identified phytohormonal and transcriptomic biomarkers require further validation across a broader range of genotypes. Full article

Background/Objectives: Substance use disorders, particularly opioid addiction, continue to pose a major global health and toxicological challenge. Morphine dependence represents a significant problem in both clinical practice and preclinical research, particularly in modeling the pharmacodynamics of withdrawal. Rodent models remain indispensable for investigating the neurotoxicological effects of chronic opioid exposure and withdrawal. However, conventional behavioral assessments rely on manual observation, limiting objectivity, reproducibility, and scalability—critical constraints in modern drug toxicity evaluation. This study introduces MWB_Analyzer, an automated and high-throughput system designed to quantitatively and objectively assess morphine withdrawal behaviors in rats. The goal is to enhance toxicological assessments of CNS-active substances through robust, scalable behavioral phenotyping. Methods: MWB_Analyzer integrates optimized multi-angle video capture, real-time signal processing, and machine learning-driven behavioral classification. An improved YOLO-based architecture was developed for the accurate detection and categorization of withdrawal-associated behaviors in video frames, while a parallel pipeline processed audio signals. The system incorporates behavior-specific duration thresholds to isolate pharmacologically and toxicologically relevant behavioral events. Experimental animals were assigned to high-dose, low-dose, and control groups. Withdrawal was induced and monitored under standardized toxicological protocols. Results: MWB_Analyzer achieved over 95% reduction in redundant frame processing, markedly improving computational efficiency. It demonstrated high classification accuracy: >94% for video-based behaviors (93% on edge devices) and >92% for audio-based events. The use of behavioral thresholds enabled sensitive differentiation between dosage groups, revealing clear dose–response relationships and supporting its application in neuropharmacological and neurotoxicological profiling. Conclusions: MWB_Analyzer offers a robust, reproducible, and objective platform for the automated evaluation of opioid withdrawal syndromes in rodent models. It enhances throughput, precision, and standardization in addiction research. Importantly, this tool supports toxicological investigations of CNS drug effects, preclinical pharmacokinetic and pharmacodynamic evaluations, drug safety profiling, and regulatory assessment of novel opioid and CNS-active therapeutics. Full article

Background: Thymus numidicus Poiret. (Lamiaceae) is an endemic plant with well-known antibacterial properties. It has been largely used in traditional Algerian medicine. This study aimed to compare the chemical composition of essential oils (EOs) extracted from leaves and flowers using the gas chromatography–mass spectrometry method, as well as to investigate its analgesic and anti-inflammatory activities. Results: The EOs were rich in monoterpenes and classified as a thymol chemotype. In vivo experiments revealed that acute treatment with T. numidicus EO (20 and 80 mg/kg) significantly increased the thermal threshold on the hot-plate at all tested hours compared to the control animals (p < 0.001, respectively), while only the higher dose had a similar effect to the metamizole group at 2 and 3 h. In the mechanical stimulus test, both doses of the EO led to a late analgesic effect presented with increased paw withdrawal threshold only during the third hour compared to the control group (p < 0.05, respectively). In the plethysmometer test both doses of the EO dose-dependently reduced paw volume with nearly 10% and 15% compared to the control animals at all tested hours (p < 0.001, respectively), with a more pronounced volume reduction in the higher dose. In a neuropathic pain model, the EO (20 mg/kg and 80 mg/kg) dose-dependently increased the withdrawal latency time towards thermal stimuli and enhanced the paw withdrawal threshold in response to mechanical pressure at all tested hours compared to the CCI-group (p < 0.001, respectively). These findings demonstrate the potent analgesic and anti-inflammatory effects of T. numidicus EO in models of acute and neuropathic pain. Full article

Background: Polysubstance use, particularly combining opioids with stimulants such as cocaine, is rising among individuals with substance use disorders. This practice aims to balance cocaine’s stimulant effects with opioids’ sedative effect, potentially decreasing adverse outcomes. We hypothesized that concurrent exposure to cocaine and opioids would reduce the risk of neonatal opioid withdrawal syndrome (NOWS) compared to opioid use alone. Methods: This analysis draws from an ongoing prospective study of maternal substance use (SUD) at Regional One Health’s perinatal center in Memphis, TN, and included mothers and their infants born between 2018 and 2022. Maternal SUD was identified via screening questionnaires, urine toxicology, or umbilical cord tissue analysis. Participants were grouped into using (a) opioids with cocaine (OwC) and (b) opioids without cocaine (OwoC). Univariate and regression analyses were conducted to assess the risk of NOWS. Results: A total of 353 infants were born to 342 mothers, with 31% (110/353) of the infants born to women who used cocaine along with opioids. While maternal demographics were similar, the OwC group had significantly lower rates of prenatal care, chronic pain history, and MOUD enrollment (p = 0.03). Infants in the OwC group had significantly higher rates of NOWS (p < 0.01), longer hospital stays (p < 0.01), and 6.5 times greater odds of developing NOWS (p < 0.001). NOWS was associated with an average 15-day increase in the length of stay for term infants (95% CI: 11.2, 18.8; p < 0.001). Conclusions: Contrary to our hypothesis, our study highlights the significant impact of maternal cocaine use on the increased likelihood of NOWS and extended hospital stays for affected infants. Full article