Clearance Levels Research Articles

Analysis of the Efficacy and Safety of PEGylated Interferon-α2b Treatment in Inactive HepatitisB Surface Antigen Carriers.

IntroductionHepatitis B virus (HBV) infection is associated with the onset of several major liver diseases. Inactive hepatitis B surface antigen (HBsAg) carriers (IHCs) may be successfully treated with PEGylated interferon-α2b (PEG-IFNα2b)-based antiviral therapy; however, studies on this treatment have been insufficient. In this study, we evaluated the efficacy and safety of PEG-IFNα2b treatment in IHCs.MethodsNineteen IHCs were treated with subcutaneous PEG-IFNα2b (180 μg/week) for 48 weeks (treatment group). Patients were followed up for 24 weeks after treatment discontinuation. Twenty untreated control patients were observed for 72 weeks (control group). HBsAg clearance (HBsAg < 0.05 IU/mL), HBsAg seroconversion, and alanine aminotransferase levels were monitored.ResultsOf the 19 patients treated with PEG-IFNα2b, 16 showed HBsAg loss (84.2%), and 13 showed HBsAg seroconversion (68.4%) at 72 weeks. All patients in the treatment group exhibited virological response (serum HBV DNA level < 10 IU/mL) at the time of drug withdrawal. In the control group, no patients experienced HBsAg loss during the observational period. There were no serious adverse events during treatment, and the therapy was well tolerated.ConclusionsShort PEG-IFNα2b therapy in IHCs produced a high functional cure rate and good safety profile, suggesting that PEG-IFNα2b treatment may be the best choice for clinical cure of some IHCs.

Murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism

Background and Aims: Compared to humans, rodents have higher synthesis of cholesterol and bile acids, and faster clearance and lower levels of serum LDL cholesterol. They also paradoxically increase bile acid synthesis in response to bile duct ligation. Another species difference is their production of hydrophilic 6-hydroxylated muricholic acids (MCAs) capable of antagonizing the activation of farnesoid-X-receptors by human bile acids and to exert anti-diabetogenic effects. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans.

Detection of subclinical nephrotoxicity induced by aminoglycosides in critically ill elderly patients using trough levels and urinary neutrophil gelatinase-associated lipocalin

ObjectivesEarly detection of aminoglycoside-induced acute kidney injury (AKI) is crucial in intensive care unit (ICU) patients, but it is not adequately reflected by serum creatinine (SrCr) levels. This study proposed...

ASSESSMENT OF NORM LEVELS AND RADIOLOGICAL HAZARDS FROM PETROLEUM EXTRACTION IN THE ONSHORE OIL FIELDS, EGYPT.

Forty-nine different samples (crude oil, surface soil, produced water and sludge) from onshore oil fields in the Western Desert of Egypt were assessed for naturally occurring radioactive material (NORM) levels using HPGe gamma-ray spectrometer. The average activity concentrations of 226Ra, 232Th and 40K were 25±1.3, 26±1.0 and 21±1.5; 9.8±0.50, 11±0.40 and 94±6.9; 130±6.6, 91±3.4 and 41±3.0; and 180±16, 70±6.9 and 1300±110Bqkg-1 for crude oil, surface soil, produced water and sludge, respectively. The obtained NORM levels are much below the International Atomic Energy Agency NORM clearance levels. Radiological parameters (radium equivalent activity, absorbed dose rate and annual effective dose) were calculated and compared with the international acceptable limits. The annual effective doses are below 1 and 20mSv, the ICRP safety limits for the public and workers, respectively. Consequently, insignificant radiological hazards could present for the workers and surrounding environment from petroleum extraction activities in the studied area.

Hypercapnia Induces Inositol-Requiring Enzyme 1α-Driven Endoplasmic Reticulum-associated Degradation of the Na,K-ATPase β-Subunit.

Acute respiratory distress syndrome is often associated with elevated levels of CO2 (hypercapnia) and impaired alveolar fluid clearance. Misfolding of the Na,K-ATPase (NKA), a key molecule involved in both alveolar epithelial barrier tightness and resolution of alveolar edema, in the endoplasmic reticulum (ER) may decrease plasma membrane abundance of the transporter. Here, we investigated how hypercapnia affects the NKA β-subunit (NKA-β) in the ER. Exposing murine precision-cut lung slices and human alveolar epithelial A549 cells to elevated CO2 levels led to a rapid decrease of NKA-β abundance in the ER and at the cell surface. Knockdown of ER mannosidase α class 1B member 1 and ER degradation-enhancing α-mannosidase like protein 1 by siRNA or treatment with the mannosidase α class 1B member 1 inhibitor kifunensine rescued loss of NKA-β in the ER, suggesting ER-associated degradation (ERAD) of the enzyme. Furthermore, hypercapnia activated the unfolded protein response by promoting phosphorylation of inositol-requiring enzyme 1α (IRE1α), and treatment with an siRNA against IRE1α prevented the decrease of NKA-β in the ER. Of note, the hypercapnia-induced phosphorylation of IRE1α was triggered by a Ca2+-dependent mechanism. In addition, inhibition of the inositol trisphosphate receptor decreased phosphorylation levels of IRE1α in precision-cut lung slices and A549 cells, suggesting that Ca2+ efflux from the ER might be responsible for IRE1α activation and ERAD of NKA-β. In conclusion, here we provide evidence that hypercapnia attenuates maturation of the regulatory subunit of NKA by activating IRE1α and promoting ERAD, which may contribute to impaired alveolar epithelial integrity in patients with acute respiratory distress syndrome and hypercapnia.

Persistent Somatic Mutation at Remission Is Associated with Poor Survival and Higher Risk of Relapse in Patients with Acute Myeloid Leukemia

IntroductionMinimal residual disease (MRD) measured by multi-color flow cytometry has been associated with an increased risk of relapse in patients with acute myeloid leukemia (AML). There is also a strong interest in using somatic mutation as an MRD marker and persistence of NPM1 mutation after 2 cycles of induction therapy has been shown to increase the risk of relapse in AML (Ivey et al, NEJM 2016). However, only one third of AML patients carry NPM1 mutation and prognostic impact of persistent mutations in the context of other co-occurring mutations and association with flow cytometry measured MRD is not well understood.MethodsWe studied 95 patients with previously untreated AML who received frontline induction chemotherapy and subsequently achieved complete remission (CR). Paired bone marrow samples obtained at pre-treatment and CR (median day 31) were analyzed by targeted capture exome sequencing of 295 genes (median 309x coverage). Mutect and Pindel was used to call single nucleotide variants (SNVs) and small indels, respectively. We defined two levels of mutation clearance (MC) based on the variant allele frequency (VAF) of the detected mutations at CR: 1) MC2.5, if persistent mutation with VAF <2.5%, and 2) MC1.0 if persistent mutation with VAF <1%. Overall survival (OS), relapse free survival (RFS), event free survival (EFS), and cumulative incidence of relapse (CIR) considering non-relapse death as a competing event were calculated from the date of CR.ResultsOf 95 patients, 49 (52%) were male and 46 (48%) were female. The median age was 53 (range: 17-76). Conventional karyotyping showed one (1%) patient with favorable cytogenetics (CG), 70 (74%) with intermediate CG, and 21 (22%) with adverse CG (all defined by ELN criteria). Eighty nine (94%) patients had de novo AML and 6 (6%) had secondary AML. Thirty-nine (41%) patients underwent allogeneic stem cell transplant in first CR. In the pre-treatment samples of 95 AML patients, we detected 299 high-confidence somatic mutations (192 SNVs and 107 indels) in 60 genes in 85 (89%) patients. The most frequently mutated genes were NPM1 (31%) followed by DNMT3A (29%), FLT3 (18%), and IDH2 (18%). In the matching CR samples, 84 (28%) and 108 (36%) mutations persisted at the level of VAF ≥2.5% and ≥1%, respectively, which corresponded to 41 (48%) and 31 (36%) patients achieving MC2.5 and MC1.0, respectively. Pattern of MC was distinct between mutated genes and affected molecular pathways (Table1). Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), DNA methylation, and splicing had low rate of MC, whereas mutations in transcription factor genes or receptor tyrosine kinase (RTK) pathway had high rate of MC. With the median follow-up of 41 months (95% CI: 39-47), patients who achieved MC1.0 had significantly better RFS, EFS, OS and lower CIR than those without MC1.0, while there was no significant difference in any of the above outcomes by MC2.5 (Table 2). Flow cytometry-based MRD (flow-MRD) data were available in 92 (97%) patients at CR. Positive flow-MRD was associated with significantly worse RFS, EFS, OS and CIR (Table2). Among 61 patients with negative flow-MRD, 25 (41%) and 32 (52%) had persistent mutations with VAF ≥2.5% and ≥1%, respectively. Multivariable analysis considering mutations that were prognostic in univariable analysis (NPM1, IDH1), age, ELN-defined adverse cytogenetics, flow-MRD and MC revealed that MC1.0 was a significant prognostic factor for RFS (p = 0.03, HR 0.36, 95%CI: 0.14-0.91) and CIR (p = 0.03, HR 0.42, 95%CI: 0.19-0.92). MC1.0 in DNA methylation (2-year EFS: 85% (95% CI: 51-96) in MC1.0 vs. 40% (95% CI: 23-56) in non-MC1.0, p = 0.01; 2-year OS: 85% (95% CI: 51-96) in MC1.0 vs. 58% (95% CI: 39-72) in non-MC1.0, p = 0.03) or in chromatin-cohesin pathways (2-year EFS: 73% (95% CI: 37-90) in MC1.0 vs. 15% (95% CI: 3-39) in non-MC1.0, p < 0.01; 2-year OS: 82% (95% CI: 45-95) in MC1.0 vs. 39% (95% CI: 14-63) in non-MC1.0, p < 0.01) was associated with significantly better EFS and OS.ConclusionIn patients with AML treated with induction chemotherapy, persistent somatic mutation at CR with VAF >1% was associated with increased risk of death and relapse. Assessment of both mutation clearance and flow-based MRD at CR may help further risk stratification of AML. [Display omitted] DisclosuresDaver:Immunogen: Research Funding; Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Consultancy; Pfizer Inc.: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Kantarjian:Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Novartis: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

Uranium Decontamination from Waste Soils by Chlorination with ZrCl4 in LiCl-KCl Eutectic Salt

The dissolution behavior of U, contained in the soils, was examined through chlorination with ZrCl4 to reduce the U concentration to clearance levels. Natural soils, composed of Si, Al, and approximately 2 ppm U, acted as surrogates for the contaminated soils. A salt mixture of LiCl-KCl-ZrCl4 was prepared in an Al2O3 crucible at 500°C, and SiO2 or natural soils were loaded for the chemical reactions. The reaction of SiO2 and Al2O3 with ZrCl4 was monitored by cyclic voltammetry, and no obvious change was observed. The results showed that SiO2 and Al2O3 were stable against ZrCl4. The reaction of natural soils with ZrCl4 indicated that the U content decreased from 2 to 1.2 ppm, while ∼0.4 ppm U appeared in the salt. Thus, the U, in the soils, dissolved into the salt by chlorination with ZrCl4. Therefore, based on these results, a new method to remediate U-contaminated soil wastes by chlorination with ZrCl4, followed by electrorefining of U, is suggested.

Muscles Affecting Minimum Toe Clearance.

The aim of this study was to investigate how the anterior and posterior muscles in the shank (Tibialis Anterior, Gastrocnemius Lateralis and Medialis), influence the level of minimum toe clearance (MTC). With aging, MTC deteriorates thus, greatly increasing the probability of falling or tripping. This could result in injury or even death. For this study, muscle activity retention taping (MART) was used on young adults, which is an accepted method of simulating a poor MTC—found in elderly gait. The subject's muscle activation was measured using surface electromyography (SEMG), and the kinematic parameters (MTC, knee and ankle joint angles) were measured using an optical motion capture system. Our results indicate that MART produces significant reductions in MTC (P < α), knee flexion (P < α) and ankle dorsiflexion (P < α), as expected. However, the muscle activity increased significantly, contrary to the expected result (elderly individuals should have lower muscle activity). This was due to the subject's muscle conditions (healthy and strong), hence the muscles worked harder to counteract the external restriction. Yet, the significant change in muscle activity (due to MART) proves that the shank muscles do play an important role in determining the level of MTC. The Tibialis Anterior had the highest overall muscle activation, making it the primary muscle active during the swing phase. With aging, the shank muscles (specifically the Tibialis Anterior) would weaken and stiffen, coupled with a reduced joint range of motion. Thus, ankle-drop would increase—leading to a reduction in MTC.

MO1011IDENTIFICATION OF EARLY BIOMARKERS OF PERITONEAL MEMBRANE DYSFUNCTION IN CHILDREN ON PERITONEAL DIALYSIS USING METABOLOMICS ANALYSIS -PRELIMINARY RESULTS OF AN ONGOING PROSPECTIVE STUDY

Abstract Background and Aims Peritoneal dialysis (PD) are the main renal replacement treatment for children and adolescents with end stage kidney disease (ESRD). Peritoneal fibrosis is a major complication in long-term PD patients. Aim of the present study is to record the metabolic "fingerprint" of children on PD and to investigate its correlation with PD history and dialysis adequacy as well as the emergence of potential biomarkers that could detect early or predict peritoneal dysfunction. Method Samples of serum, urine and peritoneal effluent collected from 15 children with ESRD on PD. At the same time and 6 months later was performed PET-test as well as assessment of KT/V and creatinine clearance. Samples were subjected to targeted metabolomic analysis of amino acids and derivatives. Regarding metabolic technologies used, all samples (peritoneal fluid, urine, blood) were analyzed by a hydrophilic interaction liquid chromatography coupled to mass spectrometry (HILIC-MS / MS) method previously developed and validated in our laboratory for the simultaneous determination of amino acids and their derivatives in biological fluids. Αalso, high flow analysis was carried out (LC-q-tof analysis – HPLC /MS ). Results Using (HILIC-MS / MS) method, we found out that peritoneal dialysis duration, presence or absence of diuresis and PD creatinine clearance values are associated with significant differences in the levels of several metabolites, including glycine, creatinine, proline and 4-hydroxyproline, leucine, valine, glutamine and glutamic acid. Using (LC-q-tof analysis – HPLC /MS) approximately 200 metabolites were analyzed in the aforementioned samples. Figure 1 illustrates the number of metabolites detected in each matrix, as well as the common metabolites between the three matrices. These metabolites were associated with peritoneal dialysis duration, creatine clearance and presence or absence of diuresis. Several metabolites showed statistical difference between the examined groups. In detail, regarding serum analysis, five metabolites, including hydroxy phenyl acetic acid, glutathione ox, glucosamine-6-P, indole acetic acid and riboflavin showed statistical difference between the examined groups based on PD vintage. Based on urine excretion four metabolites named histidine, shikimic acid, thiamine and methionine were statistically different. Concerning urine analysis, two metabolites namely uridine and itaconic acid showed statistical difference when patients sub grouped based on PD vintage. Peritoneal fluid analysis highlighted one metabolite, uridine, that levels are significantly lower in patients on PD therapy for more than 4 years while based on creatinine clearance levels subgroups, two metabolites, lactate and pantothenic acid present statistically significant difference. Conclusion Metabolomics may be a tool in the evaluation of patients with ESRD on PD as it appears to reflect the clinical phenotype of the patient and the functional phenotype of the peritoneal membrane. Our results are the preliminary results of an ongoing prospective study. Limitation of the study is the small sample of patients, which does not allow safe clinical interpretation.

Novel two-step process for remediation of Cs-contaminated soil assisted by magnetic composites

In this study, a new approach to remediate Cs+-contaminated soil using magnetic composites to improve both the efficiency of separation of clay particles and Cs+ desorption is proposed. An ultrasonic dispersion and magnetic separation process were first performed to selectively remove clay particles from soil. In the soil dispersion solution, polyethylenimine-grafted Fe3O4 nanoparticles were selectively bonded with clay particles through electrostatic attraction, enabling the clay particles to be easily separated from the solution under an external magnetic field. In a Cs+ desorption process, Cs+ removal increased with increasing HNO3 concentration and temperature; the addition of K+ to the acid solution further enhanced Cs+ desorption by replacing Cs+ on the accessible sites of the sand. The addition of a magnetic adsorbent (Fe3O4@SiO2@KTiFC, where KTiFC is potassium titanium(IV) hexacyanoferrate) to the acid treatment substantially improved Cs+ desorption (95.2%) by preventing re-adsorption of Cs+ onto the sand. Based on these results, we evaluated the applicability of the proposed process to the decontamination of radioactive soil. The clay separation process substantially reduced the radioactivity level of the soil from 1630 to 222 Bq/kg by concentrating most of the 137Cs into the magnetic fraction. After treatment of the residual sand using the optimized Cs+ desorption method, the final radioactivity of the treated soil (73.5 wt% of initial soil) was 53 Bq/kg, which is less than the clearance level (100 Bq/kg). Therefore, the proposed method is potentially an effective and practical approach for the decontamination of radioactive soil.

Исследование качества ДНК для полимеразной цепной реакции, экстрагированной разными способами из подсолнечника

Studying of plants DNA with PCR method plays an important role in the agrarian activity. Preceding stage of DNA studying is its extraction from plant material. We studied quality of DNA extracted by the different methods from seeds, seedlings, and green leaves of sunflower. We used an inbred sunflower line as a research object. For analysis we used embryos, dry and presoaked during 24 h seeds, roots, 7-day seedlings, green leaves. DNA was extracted using five methods: 1 – a standard method of extraction (1% CTAB), 2 – a modified method (2% CTAB), 3–4 – extraction with sets (Diamond DNA Plant Kit D, Russia; Lumiprobe, Germany), 5 – extraction from green leaves (2% CTAB with absorbent carbon). Amplification was conducted in thermocycler S1000тм (BioRad, USA). Spectrophotometery was done at scanning spectrophotometer LEKI SS2110UV (Russia). Analyzing all used methods we concluded they allow extracting of DNA from dry seeds, seedlings and green leaves of sunflower with sufficient reliability and repeatability, it is proved by PCR results. We couldn’t extract DNA from roots and presoaked seeds with the modified method (2% CTAB). The most economically profitable is first method (1% CTAB). Due to the results of spectrophotometery, the highest level of DNA clearance can be reached with method 3 – extraction by a set Diamond DNA Plant Kit D from seedlings and method 5 – extraction by 2% СТАВ with absorbent carbon from green leaves. The method 3 is more preferable by time necessary for DNA extraction.

CovChain: Blockchain-Enabled Identity Preservation and Anti-Infodemics for COVID-19

The intangible nature of the COVID-19 virus and the changing strains have created panic and fear among people, leading to an increase in discrimination against COVID-19 positive patients and their families in society. Moreover, the spread of infodemics creates daunting challenges for peaceful livelihood and fighting the pandemic. In this article, we propose CovChain, a blockchain-based Internet of Things solution for identity preservation and anti-infodemics. Toward this, we propose storing patient information on a private blockchain and exploiting its immutability feature, which helps combat infodemics. We further propose encrypting the data using a distributed attribute-based encryption (d-ABE) scheme to facilitate restricted access to information based on the clearance level. We also propose reducing the load on the miners by using geographically-aware fog nodes. As data in a blockchain is immutable, we delete the blocks corresponding to recovering patients and store the information in a forked CovChain. The cardinality of the two chains helps in maintaining a global census by the cloud servers. Through system implementations, we present the feasibility of CovChain on resource-constrained devices within tolerable delays of 1 s, upload and download rates of 35 kb/s, and CPU (single-core) and memory utilization under 70 percent.

Relationship Between the Free and Total Methotrexate Plasma Concentration in Children and Application to Predict the Toxicity of HD-MTX.

High-dose methotrexate (HD-MTX) can be highly effective as well as extremely toxic. Many drug molecules can bind to plasma proteins to different extents in vivo, whereas only the free drug can reach the site of action to exert a pharmacological effect and cause toxicity. However, free MTX concentrations in plasma have not been reported. Traditional analyses of free drugs are both cumbersome and inaccurate. We collected 92 plasma samples from 52 children diagnosed with ALL or NHL or other lymphomas that were treated with HD-MTX. The hollow fiber centrifugal ultrafiltration (HFCF-UF) was used to prepare plasma samples for analysis of the free MTX concentration. Protein precipitation was employed to measure the total MTX concentration. The HFCF-UF is a simple method involving a step of ordinary centrifugation; the validation parameters for the methodological results were satisfactory and fell within the acceptance criteria. A linearity coefficient r 2 of 0.910 was obtained for the correlation between the free and total MTX plasma concentrations in 92 plasma samples. However, the free and total MTX concentrations was only weakly correlated in 16 clinical plasma specimens with total MTX concentrations >2 μmol L−1 (r 2 = 0.760). Both the free and total MTX concentrations at 42 h were negatively correlated with the creatinine clearance (CCr) level (P = 0.023, r = −0.236 for total MTX and P = 0.020, r = −0.241for free MTX, respectively). The free MTX concentration could not be accurately estimated from the total MTX concentration for patients with high MTX levels which are conditions under which toxic reactions are more likely to occur. High plasma MTX levels could become a predictor of the occurrence of MTX nephrotoxicity to draw people's attention. The proposed HFCF-UF method is a simple and accurate way to evaluate efficacy and toxicity in clinical therapeutic drug monitoring.

Clinical characteristics of sleep apnea in middle-old and oldest-old inpatients: symptoms and comorbidities

BackgroundObstructive sleep apnea (OSA) is prevalent in older adults but still underdiagnosed for many reasons, such as underreported symptoms, non-specific ones because of the comorbidities and polypharmacy, or the social belief of sleep problems as normal with aging. ObjectivesTo identify salient symptoms and comorbidities associated with OSA, diagnosed by nocturnal respiratory polygraphy in geriatric inpatients. MethodWe conducted a retrospective, cross-sectional study in a sample of 102 geriatric inpatients from a French Geriatric University Hospital. We reviewed medical records to collect demographic, medical information including comorbidities, the geriatric cumulative illness rating scale (CIRS-G), subjective sleep-related symptoms and data of overnight level three portable sleep polygraphy recording. ResultsAmong classic OSA symptoms, only excessive daytime sleepiness (p = 0.02) and nocturnal choking (p = 0.03) were more prevalent in older inpatients with OSA (n = 64) than in those without (n = 38). The prevalence of comorbidities and mean CIRS-G scores were not different between groups except for the lower prevalence of chronic obstructive pulmonary disease and the higher level of creatinine clearance in OSA patients. Multivariate analysis showed OSA was associated with excessive daytime sleepiness (OR = 2.83, p = 0.02) in symptoms-related model and with composite CIRS-G score (OR 1.26, p = 0.04) in comorbidities-related model. ConclusionsOnly excessive daytime sleepiness and comorbidity severity (composite CIRS-G score) were associated with the objective diagnosis of OSA, while other usual clinical OSA symptoms and comorbidities in geriatric inpatients were not. These findings emphasize the importance of excessive daytime sleepiness symptom, when reported in comorbid older patients, strongly suggesting OSA and requiring adequate nocturnal exploration.

An evaluation on the association of vancomycin trough concentration with mortality in critically ill patients: A multicenter retrospective study.

To determine the impact of initial vancomycin trough concentration (VTC) on mortality in adult patients in the intensive care unit (ICU) undergoing vancomycin therapy. During their first ICU stay, patients with initial VTC records after vancomycin treatment were recruited from the eICU Collaborative Research Database to this multicenter retrospective cohort study, and classified into four groups according to VTC: less than 10, 10–15, 15–20, and greater than 20 mg/L. Multivariable logistic regression and sensitivity analyses were performed to explore the association of VTC, as a continuous and categorical variable, with mortality. This study enrolled 7220 patients from 335 different ICUs at 208 hospitals. Multivariable logistic regression models indicated that VTC was positively correlated with ICU (odds ratio [OR], 1.028, 95% confidence interval [CI], 1.019–1.037) and hospital (OR 1.028, 95% CI, 1.020–1.036) mortalities. Moreover, compared with VTC less than 10 mg/L, VTCs of 10–15, 15–20, and greater than 20 mg/L were associated with a higher risk of ICU mortality (OR, 1.330, 95% CI, 1.070–1.653; OR, 1.596, 95% CI, 1.265–2.015; abd OR, 1.875, 95% CI, 1.491–2.357, respectively), and VTCs of 15–20 and greater than 20 mg/L were also correlated with increased hospital mortality (OR, 1.482, 95% CI, 1.225–1.793; and OR, 1.831, 95% CI, 1.517–2.210, respectively). Similar results persisted in patients with different Acute Physiology and Chronic Health Evaluation Ⅳ scores, creatinine clearance levels, ages, and body mass indexes. Our findings indicated a potential relationship of initial VTC with ICU and hospital mortalities in patients in the ICU. However, due to the retrospective nature of this study, future prospective studies or randomized controlled trials are needed to validate those results.

Limited sampling strategies for accurate determination of extended half-life factor VIII pharmacokinetics in severe haemophilia A patients.

Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies. Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose+peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population. The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

Ischemic stroke, hemorrhage, and mortality in patients with non-valvular atrial fibrillation and renal dysfunction treated with rivaroxaban: sub-analysis of the EXPAND study

The EXPAND Study demonstrated the effectiveness and safety of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) in routine clinical practice in Japan. This sub-analysis was conducted to reveal the effectiveness and safety of rivaroxaban in Japanese NVAF patients according to baseline creatinine clearance (CrCl) levels and rivaroxaban doses in the EXPAND Study. We examined 6806 patients whose baseline CrCl data were available and classified them into 2 groups: normal renal function group with CrCl ≥ 50 mL/min (n = 5326, 78%) and renal dysfunction group with CrCl < 50 mL/min (n = 1480, 22%). In the normal renal function group, 1609 (30%) received 10 mg/day (under-dose), while in the renal dysfunction group, 108 (7%) received 15 mg/day (over-dose). In the normal renal function group, under-dose of rivaroxaban was associated with higher all-cause mortality, while in the renal dysfunction group, over-dose was associated with higher incidence of major bleeding. In contrast, the incidence of stroke or systemic embolism was not different between the 2 groups regardless of the dose of rivaroxaban. In the propensity score matched analysis to adjust the difference in characteristics according to doses of rivaroxaban, the incidences of clinical outcomes were comparable between the 2 dose groups in both renal function groups. These results indicate that the dose of rivaroxaban should be reduced depending on the renal function, considering the balance between risks of bleeding and ischemia.

Ursolic and betulinic semisynthetic derivatives show activity against CQ-resistant Plasmodium falciparum isolated from Amazonia.

ACT's low levels of Plasmodium parasitemia clearance are worrisome since it is the last treatment option against P. falciparum. This scenario has led to investigations of compounds with different mechanisms of action for malaria treatment. Natural compounds like ursolic acid (UA) and betulinic acid (BA), distinguished by their activity against numerous microorganisms, including P. falciparum, have become relevant. This study evaluated the antiplasmodial activity of imidazole derivatives of UA and BA against P. falciparum in vitro. Eight molecules were obtained by semisynthesis and tested against P. falciparum strains (NF54 and CQ-resistant 106/cand isolated in Porto Velho, Brazil); 2a and 2b showed activity against NF54 and 106/cand strains with IC50 <10µM. They presented high selectivity indexes (SI>25) and showed synergism when combined with artemisinin. 2b inhibited the parasite's ring and schizont forms regardless of when the treatment began. In silico analysis presented a tight bind of 2b in the topoisomerase II-DNA complex. This study demonstrates the importance of natural derivate compounds as new candidates for malarial treatment with new mechanisms of action. Semisynthesis led to new triterpenes that are active against P. falciparum and may represent new alternatives for malaria drug development.

Investigation of therapeutic potential of cerium oxide nanoparticles in Alzheimer's disease using transgenic Drosophila.

In the current study, the therapeutic potential of cerium oxide nanoparticles (nCeO2) was investigated in a human tau (htau) model of Alzheimer's disease (AD), using Drosophila melanogaster as an in vivo model. nCeO2 synthesised via the hydroxide-mediated approach were characterised using Fourier transform infrared (FTIR), transmission electron microscopy (TEM), X-ray diffraction (XRD) analyses and Raman spectroscopy. Characterisation studies confirmed the formation of pure cubic-structured nCeO2 and showed that the particles were spherically shaped, with an average size between 20 and 25nm. The synthesised nCeO2 were then administered as part of the diet to transgenic Drosophila for onemonth, at 0.1 and 1mM concentrations, and its effect on the biochemical levels of superoxide dismutase (SOD), acetylcholinesterase (AChE), and the climbing activity of flies were studied in a pan-neuronal model (elav; htau) of AD. Using an eye-specific model of htau expression (GMR; htau), the effect of nCeO2 on htau and autophagy-related (ATG) gene expression was also studied. Dietary administration of nCeO2 at a concentration of 1mM restored the activity of SOD similar to that of control, but both concentrations of nCeO2 failed to modulate the level of AChE, and did not elicit any significant improvements in the climbing activity of elav; htau flies. Moreover, nCeO2 at a concentration of 1mM significantly affected the climbing activity of elav; htau flies. nCeO2 also elicited a significant decrease in htau gene expression at both concentrations and increased the mRNA expression of key autophagy genes ATG1 and ATG18. The results therefore indicate that nCeO2 aids in replenishing the levels of SOD and tau clearance via the activation of autophagy.

Nonlinear Dynamics Analysis of a Rolling Bearing

A numerical analysis of the nonlinear bearing model about two degrees of freedom has been presented in this paper. The contact between a ball and ring by Hertz theory is described. Influence of the number of balls, shaft rotation and clearance on the acceleration were investigated in detail. Three numbers of balls from 11 to 16 were analyzed. The clearance level in the range of 0-71μm has been studied. It has been shown that the acceleration responses are different, depending on the vibration direction and are usually higher when the radial internal clearance and the shaft speed are increased. The higher ball number caused that the accelerations decreased in both directions. Moreover, two dynamic indicators that can be used for comparison bearing dynamics have been proposed. These obtained results are useful for understanding the vibration response mechanism from a practical point of view.