Chemistry Parameters Research Articles

338 Laboratory safety from a 16-week phase 3 study of dupilumab in patients aged 6 months to 5 years with moderate-to-severe atopic dermatitis

Abstract Many systemic therapies used for moderate-to-severe atopic dermatitis (AD) have immunosuppressive properties and necessitate laboratory screening and monitoring, adding to the treatment burden. Previous dupilumab studies in adults, adolescents and children aged 6–11 years with moderate-to-severe AD showed no clinically meaningful adverse changes in laboratory parameters. Here we evaluate hematology and chemistry laboratory safety data for dupilumab-treated children aged 6 months to 5 years with moderate-to-severe atopic dermatitis. Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (NCT03346434 part B), a randomized, double-blind placebo-controlled phase 3 study. 162 patients were randomized to either dupilumab 200/300 mg every 4 weeks (q4w; N = 83; baseline weight ≥5 <15 kg: 200 mg; ≥15 to <30 kg: 300 mg) or placebo (N = 79) for 16 weeks. From Day –14, all patients initiated standardized treatment with low-potency topical corticosteroids. Laboratory data was collected at baseline, weeks 4 and 16. At baseline, mean (SD) counts of hematology parameters were similar in both treatment groups: haemoglobin (dupilumab: 129.4 gL−1 [12]; placebo: 127.2 gL−1 [11.4]), lymphocyte (dupilumab: 4.6 × 109 L−1 [1.8]; placebo: 4.5 × 109 L−1 [1.7]), basophil (dupilumab: 0.07 × 109 L−1 [0.03]; placebo: 0.07 × 109 L−1 [0.04]), platelet (dupilumab: 397.7 × 109 L−1 [103.2]; placebo: 385.6 × 109 L−1 [112.9]) and eosinophils (dupilumab: 1.1 × 109 L−1 [0.7]; placebo: 1.1 × 109 L−1 [0.7]). Mean (SD) haemoglobin count in the dupilumab (128.4 × gL−1 [11]) and placebo groups (128.2 × gL−1 [11.2]), lymphocyte count in the dupilumab (4.20 × 109 L−1 [2.06]) and placebo groups (4.29 × 109 L−1 [1.52]) and basophil count in the dupilumab (0.07 × 109 L−1 [0.04]) and placebo groups (0.06 × 109 L−1 [0.03]) remained with the normal reference range for this population at week 16. The mean change (SD) in platelet count at week 16 was −16.3 × 109 L−1 (78.5) in the dupilumab group and +17.4 × 109 L−1 (106.6) in the placebo group. In the dupilumab treatment group, the mean eosinophil count increased at week 4 (mean change from baseline [SD]; + 0.48 × 109 L−1 [1.8]) and trended downward by week 16 (+0.31 × 109 L−1 [1.4]) while minimal changes were noted in the placebo group at week 4 (0.1 × 109 L−1 [0.7]) and week 16 (−0.2 × 109 L−1 [0.7]). The values for creatine kinase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, albumin and protein at week 16 remained within the normal reference range in all treatment groups. Two patients in the dupilumab 200/300 mg q4w arm of this study reported treatment-emergent adverse events of severe and moderate eosinophilia. Neither event was associated with clinical symptoms nor led to the discontinuation of the study treatment. No clinically meaningful changes in hematology and chemistry parameters in children aged 6 months to 5 years with moderate-to-severe AD were seen with 16 weeks of dupilumab treatment. These data demonstrate that, as with adults, adolescents and older children, routine laboratory monitoring is unnecessary in this younger population. Dupilumab was generally well tolerated with an acceptable safety profile.

Unifying biological field observations to detect and compare ocean acidification impacts across marine species and ecosystems: what to monitor and why

Abstract. Approximately one-quarter of the CO2 emitted to the atmosphere annually from human activities is absorbed by the ocean, resulting in a reduction of seawater pH and shifts in seawater carbonate chemistry. This multi-decadal process, termed “anthropogenic ocean acidification” (OA), has been shown to have detrimental impacts on marine ecosystems. Recent years have seen a globally coordinated effort to measure the changes in seawater chemistry caused by OA, with best practices now available for these measurements. In contrast to these substantial advances in observing physicochemical changes due to OA, quantifying their biological consequences remains challenging, especially from in situ observations under real-world conditions. Results from 2 decades of controlled laboratory experiments on OA have given insight into the likely processes and mechanisms by which elevated CO2 levels affect biological process, but the manifestation of these process across a plethora of natural situations has yet to be fully explored. This challenge requires us to identify a set of fundamental biological and ecological indicators that are (i) relevant across all marine ecosystems, (ii) have a strongly demonstrated link to OA, and (iii) have implications for ocean health and the provision of ecosystem services with impacts on local marine management strategies and economies. This paper draws on the understanding of biological impacts provided by the wealth of previous experiments, as well as the findings of recent meta-analyses, to propose five broad classes of biological indicators that, when coupled with environmental observations including carbonate chemistry, would allow the rate and severity of biological change in response to OA to be observed and compared. These broad indicators are applicable to different ecological systems, and the methods for data analysis suggested here would allow researchers to combine biological response data across regional and global scales by correlating rates of biological change with the rate of change in carbonate chemistry parameters. Moreover, a method using laboratory observation to design an optimal observing strategy (frequency and duration) and observe meaningful biological rates of change highlights the factors that need to be considered when applying our proposed observation strategy. This innovative observing methodology allows inclusion of a wide diversity of marine ecosystems in regional and global assessments and has the potential to increase the contribution of OA observations from countries with developing OA science capacity.

Evaluation of the host immune response assay SeptiCyte RAPID for potential triage of COVID-19 patients

Tools for the evaluation of COVID-19 severity would help clinicians with triage decisions, especially the decision whether to admit to ICU. The aim of this study was to evaluate SeptiCyte RAPID, a host immune response assay (Immunexpress, Seattle USA) as a triaging tool for COVID-19 patients requiring hospitalization and potentially ICU care. SeptiCyte RAPID employs a host gene expression signature consisting of the ratio of expression levels of two immune related mRNAs, PLA2G7 and PLAC8, measured from whole blood samples. Blood samples from 146 adult SARS-CoV-2 (+) patients were collected within 48 h of hospital admission in PAXgene blood RNA tubes at Hospital del Mar, Barcelona, Spain, between July 28th and December 1st, 2020. Data on demographics, vital signs, clinical chemistry parameters, radiology, interventions, and SeptiCyte RAPID were collected and analyzed with bioinformatics methods. The performance of SeptiCyte RAPID for COVID-19 severity assessment and ICU admission was evaluated, relative to the comparator of retrospective clinical assessment by the Hospital del Mar clinical care team. In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity: critical vs. mild (AUC = 0.93, p < 0.0001), critical vs. moderate (AUC = 0.77, p = 0.002), severe vs. mild (AUC = 0.85, p = 0.0003), severe vs. moderate (AUC = 0.63, p = 0.05). This discrimination was significantly better (by AUC or p-value) than could be achieved by CRP, lactate, creatine, IL-6, or D-dimer. Some of the critical or severe cases had “early” blood draws (before ICU admission; n = 33). For these cases, when compared to moderate and mild cases not in ICU (n = 37), SeptiCyte RAPID had AUC = 0.78 (p = 0.00012). In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity as defined by the WHO COVID-19 Clinical Management Living Guidance of January 25th, 2021. Measurements taken early (before a patient is considered for ICU admission) suggest that high SeptiScores could aid in predicting the need for later ICU admission.

Evaluation of an Oral Supplemental Cannabidiol Product for Acceptability and Performance in Mature Horses.

Thirty stock type geldings (15 ± 3 years; 556 ± 63 kg BW) were used in a randomized complete design over 28 days to determine the influence of cannabidiol (CBD) oil supplementation levels on body weight, body condition, and blood chemistry. Horses were randomly assigned to one of three dietary treatments (n = 10 per treatment) formulated with canola oil to provide 1.50 mg CBD/kg BW (TRTA), 0.75 mg CBD/kg BW (TRTB), or 0.00 mg CBD/kg BW (canola oil; CTRL). Treatments were top-dressed onto concentrate and individually administered twice daily. Horses were maintained in adjacent dry lots and received coastal bermudagrass hay ad libitum. Body weight and body condition scores (BCS) were obtained every 14 days. On day 0 and 28, blood was collected via jugular venipuncture and serum was harvested to perform a blood chemistry panel and drugs of abuse screening at the Texas Veterinary Medical Diagnostic Laboratory. Data were analyzed using PROC MIXED of SAS (v9.4), and the model included treatment, time, and the treatment × time interaction, and linear and quadratic orthogonal polynomial contrasts to partition sum of squares. Analysis of composited treatment samples revealed lower CBD concentrations than indicated from initial testing by the manufacturer (0.13 mg CBD/kg in TRTA; 0.12 mg CBD/kg in TRTB). At this level of supplementation, canola-based CBD oil was well-accepted by mature horses, banned substances were not detectable in blood, and blood chemistry parameters were not adversely affected as a result of supplementation. More research is warranted to describe the discrepancy between formulated levels compared to tested levels of CBD in the canola-based supplement.

Use of dynamic adaptive chemistry and dynamic cell clustering in computational fluid dynamics to accelerate calculation of combustion simulation of diesel engine

Based on the theory of dynamic adaptive chemistry and dynamic cell clustering, a 3D model for fuel combustion in the cylinder is constructed to study the fast calculation algorithm to accelerate the engine combustion simulation and analyze the impacts of the basic structure and the main parameters of dynamic adaptive chemistry and dynamic cell clustering on diesel engine simulation. It is found that the error threshold value of the dynamic adaptive chemistry algorithm should be set appropriately to ensure the accuracy of the simulation, and the dynamic adaptive chemistry algorithm should employ different initial search species and threshold values to meet different research objectives. Regarding the dynamic cell clustering algorithm, the data accuracy in the overall spatial range can be guaranteed, but the local location information will be missing, which will have a great impact on the prediction of pollutants. Therefore, suitable cell clustering conditions should be selected to meet the requirements of different targets.

Sigma Metrics as a Valuable Tool for Effective Analytical Performance and Quality Control Planning in Clinical Laboratory: A Retrospective Study

Introduction: For the release of precise and accurate reports of routine tests, its necessary to follow a proper quality management system in the clinical laboratory. One of the most popular quality management system tools, for process improvement, six sigma has been accepted widely in the laboratory testing process. It gives an objective assessment of analytical methods and instrumentation. Six sigma measures the outcome of a process, on a scale of 0 to 6. The poor outcomes are measured in terms of defects per million opportunities (DPMO). Aim: To do the performance assessment of each analyte by six sigma analysis and to plan and chart out a better, customised, quality control plan for each analyte, according to its own sigma value. Materials and Methods: This was a retrospective observational study, conducted from January 2022 to June 2022, in the Department of Central Laboratory, KMCT Medical College, Kozhikode, Kerala, India. The precision and accuracy of 26 parameters in both haematology and biochemistry were assessed via Internal Quality Control (IQC) and External Quality Assurance (EQAS) Programme, analysis, and their performance was assessed by sigma analysis. Results: Clinical chemistry parameters showed an average percentage of Coefficient of Variation (CV%) of 2.65% and 2.3% for all the parameters in L2 (normal level) and L3 (abnormal levels) respectively. In haematology, the average CV% came out as, 1.3% (high level),1.82% (low level), and 1.35% (normal level). These values indicate excellent precision for all parameters in both clinical chemistry and haematology; with CV% below 3%. It was observed in the month of May, due to reconstitution errors, bias% showed a setback in a few chemistry parameters, due to which the sigma was lowered. Parameters with &lt;3 sigma metrics (poor performance) occupy 37%, 3-6 sigma metrics (good performance) occupy 29% and &gt;6 sigma metrics (world-class performance) occupy 34% of all the 26 parameters of clinical chemistry and haematology. Mean, Standard Deviation (SD) for biochemistry parameters were calculated using the daily IQC data. Conclusion: With the present study, sigma metric analysis provides a benchmark for the laboratory to design a protocol for IQC, address poor assay performance, and assess the efficiency of the existing laboratory processes. It is on the basis of strict quality control measures and sigma analysis, the present Institute, was able to achieve world-class performance in many analytes of clinical chemistry and haematology disciplines. However, a few analytes like alkaline phosphatase, alanine transaminase, aspartate transaminase, and total protein needed more stringent external quality assurance monitoring and modified quality control measures.

Discussion on Improvement of Teaching Contents about Common Evaluation Parameters in Analytical Chemistry

Discussion on Improvement of Teaching Contents about Common Evaluation Parameters in Analytical Chemistry

Que tipo de lençol prefere o peixe dorminhoco gordo? Efeito da cor do fundo do tanque no crescimento e na saúde dos Dormitator latifrons (Richardson, 1844)

Abstract A little-studied characteristic of the Mexican native fish Dormitator latifrons is the effect that the color of the bottom or lining of ponds or tubs can have on their growth and blood parameters under controlled conditions. After a quarantine period in prophylactic treatment, an initial assay was performed. The organisms were grouped into four treatments (white, yellow, blue, and black) in triplicate, with 30 individuals with an average weight of 34.7± 2.5 g and average size of 12.5 ± 1.5 cm per tank. The trial lasted 60 days, after which a final biometry to all specimens and blood extractions to six random organisms per tank were performed. The following hematological and blood chemistry parameters were evaluated: erythrocytes, cell counts, and differential counts, as well as glucose, albumin, a/g ratio, and total proteins. Final weight, weight gain, and specific growth rate presented statistical differences between treatments (p&lt;0.05), with dark bottoms (blue and black) above 80% of WG and above 1.0 of SGR. No statistically differences were found in hematological blood chemistry parameters (p&gt;0.05). The growth results suggest that dark pond bottoms promote the adaptation of Dormitator latifrons by allowing it to avoid detection by predators through the adoption of a cryptic coloration. However, the species shows a great capacity for crypsis, being able to change its pigmentation to adapt to different bottom colors.

Early Predictors of Severity in Newly Diagnosed COVID-19 Patients: A Cross-sectional study

Introduction: Corona virus disease 2019 (COVID-19) is a pandemic that has claimed many lives and consumed financial resources globally in the recent past. In this context, it is necessary to evaluate the role of different ‘low-cost’ and routine serum biochemistry markers in predicting the severity of illness in patients with COVID-19. There are many studies are available in this regard to assist clinicians to predict the severity of COVID-19, but were from high end laboratories which include costlier markers. Aim: To study the routinely done serum biochemistry markers which are of lower cost to determine their role individually and in combination in the early prediction of on-going severity of diagnosed COVID-19 patients. Materials and Methods: This was a descriptive and cross- sectional study,conducted in Department of Biochemistry and Microbiology at Mehdi Nawaz Jung Institute of Oncology and Regional Cancer Center (MNJIO &amp; RCC), a tertiary cancer care institute at Hyderabad, India for a period of three months during the pandemic second wave, from August to October 2021. A total of 100 subjects of 35 to 75 age group who were Reverse- Transcriptase-Polymerase Chain Reaction (RT-PCR) positive for SARS-COV2 were included in this study. At the same time of swab, venous blood collected for Lactate Dehydrogenase (LDH), Alanine Aminotransferase (ALT), Albumin, C-Reactive Protein (CRP) and Ferritin and electrolytes sodium, potassium were estimated. These subjects were followed for ten days to categorise the severity, whether home quarantined or hospitalised. The numerical data was recorded as master chart in MS Excel spread sheet, and was imported to the free trial software, IBM SPSS Statistics (version 28.0) and analysed. Results: Age and sex did not show any significance (p=0.12&amp;0.62) but smoking, alcoholism and co-morbidities had a significant association with the level of illness (p&lt;0.001). Serum LDH, CRP and Ferritin were qualified as significant (p&lt;0.001) markers to predict the ongoing severity. The relationship between the LDH, Ferritin and CRP and the severity is expressed as Odds Ratios (OR) with 95% confidence intervals. The combined use as markers for these three parameters had 0.99 area under curve with a best predictive efficacy at 100% sensitivity and 80.3% specificity with positive likelihood ratio of 5.07. Conclusion: Routine chemistry parameters are cost-effective as they are readily available, of lower cost and can be used in combination and also time saving investigations helpful in predicting the need for hospitalisation so as to assure the safety of COVID-19 patients.

Astragalus polysaccharide (APS) supplement in beagle dogs after castration: Effects on the haematology and serum chemistry profiles, immune response, and oxidative stress status.

Castration is one of the most common surgical procedures performed in dogs. However, based on increasing evidence, male animals experience significant pain after castration. Astragalus polysaccharide (APS), one of the main bioactive components in A. membranaceus bunge, has been widely used as part of Fu-Zheng therapy to enhance natural defense mechanisms. This study was carried out to determine the effects of supplementing different doses of Astragalus polysaccharide (APS; control, 0mg/kg; APSL, 400mg/kg; and APSH, 800mg/kg) for 8 weeks on the haematology and serum chemistry profiles, immune response, and oxidative stress status in weanling beagle dogs. After adapting to the experimental environment for 1 week, 18 male beagle dogs (Sichuan Institute of Musk Deer Breeding, China; average initial weight, 3.80± 0.43g; age, 3-month-old) were randomly allotted to diets supplemented with three doses of APS (Control, 0mg/kg; low, 400mg/kg; and high, 800mg/kg), referred to as control, APSL, and APSH, respectively; six dogs were assigned to each treatment. The dogs were fed the respective diets twice daily at 08:30 and 16:30h in sufficient quantity to supply the metabolizable energy requirements for 8 weeks. On day 43 (19 weeks old), the dogs were castrated. On days 42 (prior to castration, 19 weeks old), 50 (day 7 after castration, 20 weeks old), and 57 (day 14 after castration, 21 weeks old) to measure the haematology, blood chemistry, immune response, and oxidative stress status parameters. Based on our findings, the APSH diet decreased weight gain and increased the feed to gain ratio in dogs (P < 0.05). At 14 days after castration, the wound was almost closed, slightly swollen, dry, and clean in the groups supplemented with APS. In addition, optimal APS supplementation was found to decrease erythrocyte count (RBC), haematocrit (HCT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), C-reactive protein (CRP), interleukin 1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels, and cortisol and protein carbonyl (PC) concentrations (P < 0.05). Moreover, the mean corpuscular haemoglobin (MCH) and platelet (PLT) levels, interleukin 10 (IL-10) and glutathione (GSH) content, and Cu/Zn superoxide dismutase (SOD1), catalase (CAT), and glutathione peroxidase (Se-GPx) activities were increased in the APS supplemented groups (P < 0.05) CONCLUSION: This study demonstrated that supplementing weanling beagle dogs with optimum APS could positively affect wound healing by improving their haematological profile (decreased RBC and HCT content, increased MCH and PLT levels), serum biochemical parameters (decreased ALP and ALT content), immune status (decreased CRP, IL-1β, and TNF-α levels; increased IL-10 content), and antioxidant defense (decreased cortisol and PC content; increased GSH content, and SOD1, CAT, and Se-GPx activities). However, the detailed mechanism whereby APS regulates these changes requires further investigation. In addition, the results of this study suggest that 400mg/kg diet is the optimum APS dose for beagle dogs.

Effect of microstructure on tensile properties of quenched and partitioned martensitic stainless steels

Quenching and partitioning (Q&P) treatment has been proven effective in manufacturing advanced high strength steels with high content of retained austenite, showing the improved balance of high strength and sufficient ductility. This method has been very well elaborated for carbon steel processing over the last two decades. Though it can also be potentially applied for processing other steel families, this has been scarcely studied. This article focuses on the effect of chemistry and heat treatment parameters on the microstructure and properties of Q&P treated martensitic stainless steels. Three different martensitic stainless steels with different contents of alloying elements are subjected to Q&P processing with varying quenching temperature or partitioning temperature and partitioning time. The tensile behavior of the Q&P treated steels is studied. The effect of chemistry and Q&P treatment parameters on the microstructure and tensile properties is analyzed. The effect of plastic deformation on the microstructure of the Q&P treated steels is also investigated. It is demonstrated that the Q&P treated martensitic stainless steels can show a good combination of enhanced strength and sufficient tensile ductility. Their uniform elongation increases with the increasing volume fraction of retained austenite due to the transformation induced plasticity (TRIP) effect. The ability of the martensitic matrix to accumulate plastic deformation also plays an important role. The Q&P process - microstructure - property relationship is discussed.

Spatial distribution of seawater carbonate chemistry and hydrodynamic controls in a low-inflow estuary

Coastal and estuarine systems play an important role in the global carbon cycle and often have complex carbonate chemistry dynamics due to a multitude of biogeochemical and physical drivers. Compared to classic estuaries, mechanisms driving the distribution of carbonate parameters in low-inflow estuaries are understudied. The spatial distribution of carbonate chemistry and hydrodynamic parameters were characterized in Morro Bay, a short and seasonally hypersaline estuary on the Central California Coast, during the dry, low-inflow season to better understand in situ modifications. Sampling transects were completed in the main channel in June, August, and September of 2018, bracketing both a high and low tide on each date. Temperature, salinity, total alkalinity, and dissolved inorganic carbon all increased from the mouth to the back of the estuary, with larger values observed during the low tide. pH values decreased towards the back of the bay, and had little variation between high and low tide for June and August transects. Flushing times (estimated using a salt-budget model approach) also increased toward the back of the bay which led to hypersaline conditions. Salinity alone only explained 20–33% of observed changes in total alkalinity and 13–22% of observed changes in dissolved inorganic carbon throughout the bay. The remaining changes in total alkalinity and dissolved inorganic carbon were likely driven by biogeochemical modifications enhanced by extended flushing times, particularly in the back bay. Prior to this project, Morro Bay experienced a recent, rapid collapse of eelgrass, the major biogenic habitat. In the last four years eelgrass in Morro Bay appears to be on a recovery trajectory; therefore, this study provides a baseline whereby future studies can evaluate carbonate chemistry changes associated with potential eelgrass recovery and expansion. This study highlights the unique hydrodynamic exchange in seasonally low-inflow estuaries and its potentially large role in influencing local carbonate chemistry and ocean acidification.

Evaluation of genotoxicity and 13-week subchronic toxicity of root of Asarum heterotropoides var. seoulense (Nakai) Kitag

Ethnopharmacological relevanceAsarum heterotropoides var. seoulense (Nakai) Kitag is a traditional herbal medicine used in Korea and China. It is effective in aphthous stomatitis, local anesthesia, headache, toothache, gingivitis, and inflammatory diseases. However, information on the toxicity of the root of Asarum heterotropoides var. seoulense (Nakai) Kitag (AR) is limited. Therefore, preclinical toxicity studies on AR are needed to reduce the risk of excessive intake. Aim of the studyWe aimed to evaluate genotoxicity and the potential toxicity due to repeated administration of AR powder. Materials and methodsIn vitro bacterial reverse mutation assay (Ames), in vitro chromosomal aberration assay (CA), and in vivo micronucleus (MN) assay in ICR mice were conducted. As positive results were obtained in Ames and CA assays, alkaline comet assay and pig-a gene mutation test were conducted for confirmation. For evaluating the general toxicity of AR powder, a 13-week subchronic toxicity test was conducted, after determining the dose by performing a single and a 4-week dose range finding (DRF) test. A total of 152 Sprague-Dawley (SD) rats were orally administered AR powder at doses of 0, 150, 350, 500, 1000, and 2000 mg/kg/day in the 13-week subchronic toxicity test. Hematology, clinical chemistry, urinalysis, organ weight, macro-, and microscopic examination were conducted after rat necropsy. ResultsAR powder induced genotoxicity evidenced in the Ames test at 187.5, 750, 375, and 1500 μg/plate of TA100, TA98, TA1537, and E. coli WP2uvrA in the presence and absence of S9, respectively; CA test at 790 μg/mL for 6 h in the presence of S-9; 75 μg/mL for 6 h in the absence of S-9, and 70 μg/mL for 22 h in the absence of S-9 in the stomach in the comet assay but not in MN and pig-a assays. In the 13-week subchronic toxicity study, clinical signs including irregular respiration, noisy respiration, salivation, and decreased body weight or food consumption were observed in males and females in the 2000 mg/kg/day group. In hematology tests, clinical chemistry, urinalysis, organ weight, and macroscopic examination, changes were observed in the dose groups of 500 mg/kg/day and above. Microscopic examination revealed hyperplasia of the stomach as a test-related change. Hepatocellular adenoma and changes in liver-related clinical chemistry parameters were observed. The rat No Observed Adverse Effect Level (NOAEL) was 150 mg/kg/day in males and <150 mg/kg/day in females. ConclusionsAR powder is potentially toxic to the liver and stomach and should be used with caution in humans. A long-term study on carcinogenicity is necessitated because DNA damage or changes in tissue lesions were observed in SD rats.

Physical-Chemical Recovery of a Montane Stream After Remediation of Acid Mine Drainage: Timing and Extent After Turning off the Tap.

We monitored physical-chemical conditions in the North Fork of Clear Creek in Colorado (USA) before, during, and after the start of remediation (lime treatment) to remove metals from two major inputs of acid mine drainage (AMD) water. In addition, we analyzed historical monitoring data that extended back more than two decades. Concentration-discharge (C-D) and load-discharge (L-D) plots accounted for discharge dependence in concentrations and loads of metals, major ions, and other water chemistry parameters. Total and dissolved concentrations, and loads of the metals decreased after remediation began, with the largest decreases usually during low stream flow. However, postremediation concentrations and loads remained slightly to considerably higher than reference, probably because of unidentified groundwater seeps and/or small surface flows. Dissolved Cu concentrations decreased much less than total Cu concentrations, because the percentage of total Cu in the dissolved phase increased considerably as particulate Fe (PFe) concentration decreased. We conclude that 1) water chemistry can change to a new steady state or pseudo-steady state relatively quickly after major AMD inputs to a stream are remediated; 2) elevated flows during snowmelt and rainfall periods can mobilize additional amounts of major ions and metals, resulting in in-stream concentrations that are manifestations of both dilution and mobilization; 3) although lime treatment of AMD-related waters can decrease metal concentrations, it does not decrease elevated concentrations of major ions that might impair sensitive stream invertebrates; 4) although Fe is toxic to aquatic organisms, PFe adsorbs other metals and thereby provides protection against their toxicity; and 5) use of C-D and L-D plots and element ratios can indicate the presence of unidentified AMD inputs to a stream. Environ Toxicol Chem 2023;42:495-511. © 2022 SETAC.

Telomere length in Thai Buddhist monks and Thai males aged 40 years and above

Introduction: The daily lifestyles of Thai Buddhist monks and Thai males differ due to Buddhist practices, which potentially affect telomere length. Telomeres are DNA compounds located at the ends of chromosomes that shorten with each cell division. This study investigated the difference in telomere length between Thai Buddhist monks and Thai males aged ≥40 years. Method: This was a cross-sectional study involving 100 Thai Buddhist monks aged ≥40 years who had been ordained for more than five years and 100 Thai males aged ≥40 years. General information and health information were assessed by questionnaire. Nutritional status was determined by body composition and blood chemistry parameters. Telomere length was measured by Monochrome Multiplex RealTime Quantitative PCR and expressed as T/S ratio. Result: Mean telomere length of Thai Buddhist monks was longer than that of Thai males (1.08±0.18 vs. 1.02±0.17; p&lt;0.050). In both groups, the mean telomere length in subjects aged ≥60 years was shorter than that in subjects aged 40-59 years (p&lt;0.010). Alcohol consumption, which affected Thai males (p&lt;0.050), but meditation tend to slow down the shortening of telomeres (r=0.167; p&lt;0.050) in both groups. Conclusion: Age was the parameter that affected telomere length the most. Furthermore, various factors in the Buddhist monk group, such as a peaceful lifestyle, meditation, non-alcohol consumption, and fewer underlying diseases, could explain for the longer telomere lengths in this group.

In Vivo Analysis of Extract of Leaves of Mistletoe as a Benalu Duku: Clinical Chemical Value Associated with Histopathology, Liver, Kidneys, and Lethal Dose Determinate.

The active compounds from the leaves of Dendrophthoe pentandra L. Miq., also known as, Benalu Duku (in Indonesia), are known to contain progesterone-like compounds (PLCs). This study aims to determine the effect of giving a single dose of PLCs on liver and kidney function in rats and the dose limit that causes the death of experimental animals. The PLCs were analyzed for chemical and physical characterization and compared to a pure standard of progesterone using HPLC, IR spectrometry, thermogravimetry, and NMR. The research was carried out in two sections. In section one, thirty-five healthy adult male rats were divided into six experimental groups and a control group of five rats each. The groups received, respectively, 50 to 75 mg/kg of PLCs (i.p.). The control group was given a 0.5 mL Aqua Pro injection. Alanine aminotransferase, aspartate aminotransferase, creatinine, and blood urea nitrogen were assessed using the clinical chemistry of blood serum analysis. Cell disruptions were analyzed to determine the degeneration effects of PLCs on the liver and kidney in the experimental and control groups. In section two, thirty healthy adult male rats were divided into 6 groups, each group of 5 rats, and injected with PLCs at a dose of 0.9-2.1 g/kg BW, followed by a lethal dose test. The control groups were available for 5 individual rats at 0 g/kg BW of PLCs. Our findings indicated that PLCs have a similarity chemical and physical characterized each other compounds, then the following administration of 50 to 75 mg/kg of PLCs did not affect the parameters of clinical chemistry. Histopathology analysis of the liver and kidney revealed normal subcellular levels in the experimental group, with the nonlethal dose at 0.9 g/kg BW.

Natural organic matter source, concentration, and pH influences the toxicity of zinc to a freshwater microalga

Zinc is a contaminant of concern in aquatic environments and is a known toxicant to many aquatic organisms. Dissolved organic matter (DOM) is a toxicity modifying factor for zinc and is an important water chemistry parameter. This study investigated the influence of DOM concentration, source, and water pH on the chronic toxicity of zinc to a freshwater microalga, Chlorella sp. The influence of DOM on zinc toxicity was dependent on both concentration and source. In the absence of DOM, the 72-h EC50 was 112 μg Zn.L−1. In the presence of a DOM high in fulvic-like components, zinc toxicity was either slightly decreased (<4-fold increase in EC10s across 15 mg C.L−1 range) or unchanged (minimal difference in EC50s). In the presence of a DOM high in humic-like (aromatic and high molecular weight) components, zinc toxicity was slightly decreased at the EC10 level and strongly increased at the EC50 level. The influence of pH on zinc toxicity was dependent on the source of DOM present in the water. In the presence of DOM high in humic-like components pH did not influence toxicity. In the presence of DOM high in fulvic-like components, pH had a significant effect on EC50 values. Labile zinc (measured by diffusive gradients in thin-films) followed linear relationships with dissolved zinc but could not explain the changes in observed toxicity, with similar DGT-labile zinc relationships shown for the two DOMs despite each DOM influencing toxicity differently. This indicates changes in toxicity may be unrelated to changes in zinc lability. The results suggest that increased toxicity of zinc in the presence of DOM may be due to direct uptake of Zn-DOM complexes. This study highlights the importance of considering DOM source and characteristics when incorporating DOM into water quality guidelines through bioavailability models.

The impact of the secondary infections in ICU patients affected by COVID-19 during three different phases of the SARS-CoV-2 pandemic.

Microbial secondary infections can contribute to an increase in the risk of mortality in COVID-19 patients, particularly in case of severe diseases. In this study, we collected and evaluated the clinical, laboratory and microbiological data of COVID-19 critical ill patients requiring intensive care (ICU) to evaluate the significance and the prognostic value of these parameters. One hundred seventy-eight ICU patients with severe COVID-19, hospitalized at the S. Francesco Hospital of Nuoro (Italy) in the period from March 2020 to May 2021, were enrolled in this study. Clinical data and microbiological results were collected. Blood chemistry parameters, relative to three different time points, were analyzed through multivariate and univariate statistical approaches. Seventy-four percent of the ICU COVID-19 patients had a negative outcome, while 26% had a favorable prognosis. A correlation between the laboratory parameters and days of hospitalization of the patients was observed with significant differences between the two groups. Moreover, Staphylococcus aureus, Enterococcus faecalis, Candida spp, Pseudomonas aeruginosa and Klebsiella pneumoniae were the most frequently isolated microorganisms from all clinical specimens. Secondary infections play an important role in the clinical outcome. The analysis of the blood chemistry tests was found useful in monitoring the progression of COVID-19.

Abstract B010: A novel hybrid with anti-angiogenic and DNA crosslinking activities potently suppresses the growth of colorectal cancer cells and patient-derived organoids in mice

Abstract Background: Colorectal cancer (CRC) is the second-leading death of all cancers in the world. Metastasis is the basis for cause of death in patients with CRC. Currently, combination of anti-VEGF therapy and DNA damaging agents, such as Bevacizumab + FOLFOX, has become the first-line therapy in managing colorectal cancer progression. To mimic the first-line therapy, we have conjugated the angiogenesis inhibitory and the DNA damaging moieties to form a bifunctional hybrid molecule. The purpose of this study is to prove the efficacy and safety of the novel hybrid molecule in treatment of CRC cells in mouse models. Materials and methods: The novel hybrid molecule, designated as BO-2762, was synthesized as previously reported. The anti-proliferative activity was analyzed by PrestoBlue® assay in a variety of CRC cell lines and CRC patient derived organoids (PDO). DNA damage was analyzed by alkaline gel electrophoresis and comet assay. Antiangiogenic property was assessed using the docking model, in vitro tube formation, and in vivo angiogenesis methods. Anti-tumor efficacy of BO-2762 was determined using xenografts of CRC cell lines and PDOs at 20 mg/kg via tail vein injection. For safety profiling and toxicology study, the ICR mice model was adopted for various pathological analyses. Results: The values of anti-proliferative IC50 of BO-2762 against a panel of 11 CRC and 10 PDO cell lines were ranged between 0.5 to 4.5 µM. Subsequently, we demonstrated that BO-2762 induced DNA inter-strand cross-linking (ICL) by alkaline agarose gel electrophoresis. Apparently, ICLs caused significant cell cycle arrest at the S phase, and subsequently triggered apoptosis. The angiogenesis inhibition by BO-2762 was also confirmed by in vitro tube formation assay and Direct In Vivo Angiogenesis Assay. The anti-CRC activity of BO-2762 was assessed using xenografts of CRC cells, derived from metastatic sites (LoVo and SW620 cells) and from primary sites (LS1034 and HT-29 cells). Via tail vein injection of BO-2762 at 20 mg/kg for 10 times, the growth of LoVo, SW620, LS1034, and HT-29 cells was suppressed by 85.8%, 83.0%, 75.4%, and 44.8% respectively. In addition, BO-2762 also significantly suppressed the growth of metastatic PDOs (T53 and T112) by 90%. Biosafety analysis showed promising safety parameters in blood chemistry and major organs. Conclusions: Our present results have shown that conjugated hybrid molecule with DNA cross-linking and anti-angiogenic activity is likely a novel approach to treat patients with CRC. Citation Format: Vaikar Navakanth Rao, Kuo-Chu Lai, Chin-Hung Liu, Shung-Haur Yang, Jeou-Yuan Chang, Tsann-Long Su, Te-Chang Lee. A novel hybrid with anti-angiogenic and DNA crosslinking activities potently suppresses the growth of colorectal cancer cells and patient-derived organoids in mice [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B010.

Results From a Multiple Ascending Dose Study in Healthy Volunteers of ACD856, a Positive Modulator of Neurotrophin Trk‐Receptors

AbstractBackgroundACD856 is a novel positive allosteric modulator of Trk‐receptors in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired. The aim of this study was to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple ascending doses of ACD856.Method24 healthy volunteer subjects were administered ACD856 or placebo as a daily oral solution over 7 days in 3 cohorts of stepwise ascending doses. After each dose, the safety, tolerability, and pharmacokinetics of ACD856 were assessed by an internal Safety Review Committee to decide on the escalation of dose to the next cohort.ResultThere were no clinically significant changes from baseline in mean ECG, vital signs, physical examination findings, clinical chemistry, haematology, coagulation, or urinalysis parameters after receiving the 7 daily doses of ACD856. Occasional individual abnormal laboratory values were observed but all were assessed as not clinically significant. Most of the reported adverse events were of mild intensity, only a few were of moderate intensity and none of severe intensity. No serious adverse events were reported.The pharmacokinetic data confirmed the findings from the previously performed single ascending dose (SAD) study, including that ACD856 has a rapid absorption, long half‐life, high bioavailability, and a linear dose‐dependent exposure. The Cmax at steady state was approximately 1.6‐fold higher than the initial dose administration and no time‐dependent clearance was observed. Moreover, initial CSF data confirms CNS exposure of ACD856. Further PK, CSF and pharmacodynamic data will be shown at the time of presentation.ConclusionACD856 was shown to be safe and well tolerated in man at the tested dose levels and with a suitable pharmacokinetic profile for further clinical development. In the next step, ACD856 will be evaluated in a phase Ib study with the aim to further assess pharmacodynamic effects.