To assess the pharmacokinetics (PK) and conduct a clinical laboratory evaluation of acetaminophen in Beagle and Galgo Español (GE) dogs.
Prospective randomized experimental trial.
A total of 20 ...healthy dogs - 10 Beagles and 10 GE (six males and four females in both groups).
Acetaminophen (10 and 20 mg kg
) was administered intravenously (IV) to the dogs on two different occasions. Plasma concentrations were analysed by high-performance liquid chromatography. PK analysis was undertaken using compartmental modelling with ADAPT 5 software. Simulations after multiple IV doses were investigated. Clinical laboratory values such as red blood cell (RBC) count, haemoglobin (Hb), haematocrit (Ht), white blood cell (WBC) count, platelet count, total proteins, alanine aminotransferase (ALT), aspartate aminotransferase, urea and creatinine were measured before and 24 hours after acetaminophen administration in combination with clinical examination to assess side effects resulting from the drug.
A two-compartmental model best described time-concentration profiles of acetaminophen. PK parameters were different as a result of a breed effect. For doses of 10 and 20 mg kg
, respectively, clearance values were 1.70 (1.15-2.27) and 1.62 (1.06-2.86) L kg
hour
for Beagles and 1.18 (0.70-1.39) and 1.08 (0.67-1.35) L kg
hour
for GE; elimination half-life values were 2.64 (0.52-4.46) and 2.86 (0.87-4.63) hours for Beagles and 3.49 (1.89-7.80) and 4.57 (2.08-8.90) hours for GE. Significant differences were also found between GE and Beagles in the RBC count, Ht, Hb, WBC count and serum ALT before drug administration, and these differences were maintained 24 hours later, independent of the dosage used. For each breed, no side effects resulting from IV acetaminophen administration were observed at doses of either 10 or 20 mg kg
.
IV PK of acetaminophen was different between Beagles and GE dogs. Side effects were not detected. Further studies are necessary to evaluate the PK in a clinical context.
Introduction
In patients with uncontrolled atrial fibrillation, atrioventricular (AV) node ablation after permanent His bundle pacing (p‐HBP) could be a therapeutic option for heart rate (HR) ...control. We aimed to demonstrate the advantages of AV node ablation with p‐HBP, and to describe its effectiveness and safety.
Methods
This descriptive observational study included patients with uncontrolled permanent atrial arrhythmias who were candidates for HR control (January 2019 to July 2020) and underwent p‐HBP and AV node ablation.
Results
A total of 39 patients were included. The median left ventricular ejection fraction (LVEF) was 55% (45–60); 46.1% in NYHA class II and 43.6% in NYHA class III. p‐HBP was achieved in 92.3% (n = 36), and AV node ablation was successfully performed in all patients. The LVEF improved in patients with reduced LVEF (baseline, 35% 23.8–45.3%; follow‐up, 40% 35–56.5%, p < 0.05); the NYHA class also showed improvement (baseline, 71.4% patients in class III and 7.1% in class II, and at follow‐up, 78.6% patients in class II and 14.3% in class I). In patients with previously normal LVEF, LVEF remained stable; nevertheless, a significant NYHA class improvement was observed (baseline, 63.6% class II and 31.8% class III patients; follow‐up, 54.5% class I and 45.5% class II patients). The His thresholds and lead parameter values did not significantly change during the follow‐up and remained stable.
Conclusions
In patients with uncontrolled atrial arrhythmias who underwent AV node ablation after p‐HBP, the NYHA class improved and the LVEF increased in those with reduced baseline LVEF. The values of pacing parameters were acceptable and remained stable during the follow‐up.
This paper investigates the paleoenvironmental evolution of a core extracted in the middle sector of the Tinto River estuary, SW Spain, one of the most polluted areas in the world due to mining over ...thousands of years (>4 kyr BP) and recent industrial discharges. This evolution includes alluvial sands (>6.4 cal kyr BP), bioclastic sands and silts deposited in subtidal and intertidal channels during and after the Holocene transgression maximum (6.4-4.3 cal kyr BP), the sedimentation of clayey-sandy silts in low and high marshes during the last 2.4 kyr BP and a final anthropic filling. Three sharp peaks of pollution have been detected, representing a) a natural origin during the Holocene transgression; b) the impact of the first mining activities (~4.5 cal kyr BP); and c) the effect of industrial discharge and a new period of mining activity throughout the 19th and 20th centuries. Foraminifera, ostracods and molluscs disappeared during these last two peaks.
Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform ...(GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.
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•The high activity glutaminase isoform, GLS1, is augmented in NASH•GLS1 inhibition reduces steatosis in NASH by increasing VLDL export•GLS1 inhibition diminishes oxidative stress in pre-clinical models of NASH•GLS1 targeting may be a valuable therapeutic approach in NASH
Simon et al. show that the glutaminase GLS1 isoform is augmented in both NASH clinical biopsies and pre-clinical mouse models. GLS1 silencing significantly reduced steatosis and oxidative stress through complex metabolic reprogramming, involving increased VLDL export, indicating that GLS1 may be a valuable therapeutic target for the treatment of NASH.
Introduction
Permanent His bundle pacing (p‐HBP) could be an alternative for traditional cardiac resynchronization therapy (CRT), but an important limitation is that p‐HBP cannot always correct the ...left bundle branch block (LBBB). The purpose of this article is to assess electrocardiographic patterns of LBBB that can predict electrocardiographic response (QRS narrowing) to His bundle pacing.
Methods
We designed a prospective descriptive study of patients with LBBB and CRT indication proposed for CRT by p‐HBP. We analyzed the correlation between the different electrocardiographic patterns and the correction of conduction disturbance (LBBB).
Results
We included 70 patients. Pacing at the location where His bundle electrogram was recorded narrowed the QRS in 81.4% (n = 57). Basically, we identified two electrocardiographic patterns in lead V1: QS or rS. The QS pattern was a sensitivity of 56%, a specificity of 84.6%, and a positive predictive value (PPV) of 94.1% to predict the correction of the LBBB (area under the curve AUC = .70). In patients with rS pattern, a ratio between the descending and the ascending S wave component duration ≥0.64 was a very good predictor of the correction of the LBBB (AUC = .968); with a value ≥0.64, the sensitivity, specificity, and PPV was 92%, 100%, and 100%, respectively.
Conclusions
In patients with LBBB and CRT indication, the QS pattern in lead V1 predicts the correction of the QRS with HBP. In the case of rS pattern in lead V1, the ratio descending/ascending S wave component duration has a strong correlation with the LBBB correction.
Summary
Background
Gluten‐free diet (GFD) is the only treatment for patients with coeliac disease (CD)
and its compliance should be monitored to avoid cumulative damage.
Aims
To analyse gluten ...exposures of coeliac patients on GFD for at least 24 months using different monitoring tools and its impact on duodenal histology at 12‐month follow‐up and evaluate the interval of determination of urinary gluten immunogenic peptides (u‐GIP) for the monitoring of GFD adherence.
Methods
Ninety‐four patients with CD on a GFD for at least 24 months were prospectively included. Symptoms, serology, CDAT questionnaire, and u‐GIP (three samples/visit) were analysed at inclusion, 3, 6, and 12 months. Duodenal biopsy was performed at inclusion and 12 months.
Results
At inclusion, 25.8% presented duodenal mucosal damage; at 12 months, this percentage reduced by half. This histological improvement was indicated by a reduction in u‐GIP but did not correlate with the remaining tools. The determination of u‐GIP detected a higher number of transgressions than serology, regardless of histological evolution type. The presence of >4 u‐GIP‐positive samples out of 12 collected during 12 months predicted histological lesion with a specificity of 93%. Most patients (94%) with negative u‐GIP in ≥2 follow‐up visits showed the absence of histological lesions (p < 0.05).
Conclusion
This study suggests that the frequency of recurrent gluten exposures, according to serial determination of u‐GIP, could be related to the persistence of villous atrophy and that a more regular follow‐up every 6 months, instead of annually, provides more useful data about the adequate adherence to GFD and mucosal healing.
Clinical utility of urinary gluten immunogenic peptides in the follow‐up of patients with coeliac disease.
The SARS-CoV-2 pandemic has overwhelmed hospital services due to the rapid transmission of the virus and its severity in a high percentage of cases. Having tools to predict which patients can be ...safely early discharged would help to improve this situation. 333 patients were included. At admission, 307 patients were classified as mild patients. Age, oxygen saturation, Lactate Dehydrogenase, D-dimers, neutrophil-lymphocyte ratio (NLR), and oral corticosteroids treatment were predictors of early discharge (area under curve (AUC), 0.786; sensitivity (SE) 68.5%; specificity (S), 74.5%; positive predictive value (PPV), 74.4%; and negative predictive value (NPV), 68.9%). When cytokines were included, lower interferon-gamma-inducible protein 10 and higher Interleukin 1 beta levels were associated with early discharge (AUC, 0.819; SE, 91.7%; S, 56.6%; PPV, 69.3%; and NPV, 86.5%). The model to predict worsening included male sex, oxygen saturation, no corticosteroids treatment, C-reactive protein and Nod-like receptor as independent factors (AUC, 0.903; SE, 97.1%; S, 68.8%; PPV, 30.4%; and NPV, 99.4%). The model was slightly improved by including the determinations of interleukine-8, Macrophage inflammatory protein-1 beta and soluble IL-2Ralpha (CD25) (AUC, 0.952; SE, 97.1%; S, 98.1%; PPV, 82.7%; and NPV, 99.6%). Clinical and routine laboratory data at admission strongly predict non-worsening during the first two weeks; therefore, these variables could help identify those patients who do not need a long hospitalization and improve hospital overcrowding. Determination of pro-inflammatory cytokines moderately improves these predictive capacities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Peritoneal metastasis in patients with locally advanced colon cancer (T4 stage) is estimated to recur at a rate of approximately 25% at 3 years from surgical resection and is associated ...with poor prognosis. There is controversy regarding the clinical benefit of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. OBJECTIVE: To assess the efficacy and safety of intraoperative HIPEC in patients with locally advanced colon cancer. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3 randomized clinical trial was conducted in 17 Spanish centers from November 15, 2015, to March 9, 2021. Enrolled patients were aged 18 to 75 years with locally advanced primary colon cancer diagnosed preoperatively (cT4N02M0). INTERVENTIONS: Patients were randomly assigned 1:1 to receive cytoreduction plus HIPEC with mitomycin C (30 mg/m2 over 60 minutes; investigational group) or cytoreduction alone (comparator group), both followed by systemic adjuvant chemotherapy. Randomization of the intention-to-treat population was done via a web-based system, with stratification by treatment center and sex. MAIN OUTCOMES AND MEASURES: The primary outcome was 3-year locoregional control (LC) rate, defined as the proportion of patients without peritoneal disease recurrence analyzed by intention to treat. Secondary end points were disease-free survival, overall survival, morbidity, and rate of toxic effects. RESULTS: A total of 184 patients were recruited and randomized (investigational group, n = 89; comparator group, n = 95). The mean (SD) age was 61.5 (9.2) years, and 111 (60.3%) were male. Median duration of follow-up was 36 months (IQR, 27-36 months). Demographic and clinical characteristics were similar between groups. The 3-year LC rate was higher in the investigational group (97.6%) than in the comparator group (87.6%) (log-rank P = .03; hazard ratio HR, 0.21; 95% CI, 0.05-0.95). No differences were observed in disease-free survival (investigational, 81.2%; comparator, 78.0%; log-rank P = .22; HR, 0.71; 95% CI, 0.41-1.22) or overall survival (investigational, 91.7%; comparator, 92.9%; log-rank P = .68; HR, 0.79; 95% CI, 0.26-2.37). The definitive subgroup with pT4 disease showed a pronounced benefit in 3-year LC rate after investigational treatment (investigational: 98.3%; comparator: 82.1%; log-rank P = .003; HR, 0.09; 95% CI, 0.01-0.70). No differences in morbidity or toxic effects between groups were observed. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of HIPEC to complete surgical resection for locally advanced colon cancer improved the 3-year LC rate compared with surgery alone. This approach should be considered for patients with locally advanced colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02614534
Abstract
Microalgae wastewater treatment systems have the potential for producing added-value products. More specifically, cyanobacteria are able to accumulate polyhydroxybutyrates (PHBs), which can ...be extracted and used for bioplastics production. Nonetheless, PHB production requires proper culture conditions and continue monitoring, challenging the state-of-the-art technologies. The aim of this study was to investigate the application of hyperspectral technologies to monitor cyanobacteria population growth and PHB production. We have established a ground-breaking measurement method able to discern spectral reflectance changes from light emitted to cyanobacteria in different phases. All in all, enabling to distinguish between cyanobacteria growth phase and PHB accumulation phase. Furthermore, first tests of classification algorithms used for machine learning and image recognition technologies had been applied to automatically recognize the different cyanobacteria species from a complex microbial community containing cyanobacteria and microalgae cultivated in pilot-scale photobioreactors (PBRs). We have defined three main indicators for monitoring PHB production: (i) cyanobacteria specific-strain density, (ii) differentiate between growth and PHB-accumulation and (iii) chlorosis progression. The results presented in this study represent an interesting alternative for traditional measurements in cyanobacteria PHB production and its application in pilot-scale PBRs. Although not directly determining the amount of PHB production, they would give insights on the undergoing processes.
The clinical presentation and severity of Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C) is widespread and presents a very low mortality rate in high-income countries. ...This research describes the clinical characteristics of MIS-C in critically ill children in middle-income countries and the factors associated with the rate of mortality and patients with critical outcomes.
An observational cohort study was conducted in 14 pediatric intensive care units (PICUs) in Colombia between April 01, 2020, and January 31, 2021. Patient age ranged between one month and 18 years, and each patient met the requirements set forth by the World Health Organization (WHO) for MIS-C.
There were seventy-eight children in this study. The median age was seven years (IQR 1-11), 18 % (14/78) were under one year old, and 56 % were male. 35 % of patients (29/78) were obese or overweight. The PICU stay per individual was six days (IQR 4-7), and 100 % had a fever upon arrival to the clinic lasting at least five days (IQR 3.7-6). 70 % (55/78) of patients had diarrhea, and 87 % (68/78) had shock or systolic myocardial dysfunction (78 %). Coronary aneurysms were found in 35 % (27/78) of cases, and pericardial effusion was found in 36 %. When compared to existing data in high-income countries, there was a higher mortality rate observed (9 % vs. 1.8 %; p=0.001). When assessing the group of patients that did not survive, a higher frequency of ferritin levels was found, above 500 ngr/mL (100 % vs. 45 %; p=0.012), as well as more cardiovascular complications (100 % vs. 54 %; p = 0.019) when compared to the group that survived. The main treatments received were immunoglobulin (91 %), vasoactive support (76 %), steroids (70.5 %) and antiplatelets (44 %).
Multisystem Inflammatory Syndrome in Children due to SARS-CoV-2 in critically ill children living in a middle-income country has some clinical, laboratory, and echocardiographic characteristics similar to those described in high-income countries. The observed inflammatory response and cardiovascular involvement were conditions that, added to the later presentation, may explain the higher mortality seen in these children.
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