Blood Concentrations Research Articles

Associations of Cord Blood Concentrations of Perfluoroalkyl Substances and Benzophenones with Autistic Traits at Age Seven in Singaporean Children

Associations of Cord Blood Concentrations of Perfluoroalkyl Substances and Benzophenones with Autistic Traits at Age Seven in Singaporean Children

Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients.

Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients. This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed. A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug-drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation. This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.

PBPK model-based gender-specific risk assessment of N-nitrosodimethylamine (NDMA) using human biomonitoring data.

Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95μg/day/kg for men and 10.60μg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.

The relationship between clinical impairment and blood drug concentration: Comparison between the most prevalent traffic relevant drug groups

AimThe aim of the present study was to investigate the relationship between blood concentrations of four different drug classes; ethanol, benzodiazepines, amphetamines and tetrahydrocannabinol (THC) and driver impairment as assessed by a clinical test of impairment (CTI). MethodsData was retrieved from a national database on CTI assessments and accompanying blood drug concentrations from apprehended drivers. All drug concentrations in blood were quantified using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), and compared to the results of the CTI which were categorized as either “not impaired”, “mildly impaired”, “moderately impaired”, or “considerably impaired”. ResultsA total number of 15 514 individual mono drug-cases collected over 9 years was included. 89% were men and the median age was 34 years. In addition, 3 684 individual cases with similar age and gender distribution where no drugs were detected, were included as a reference group. For ethanol and benzodiazepines the percentage of clinically impaired cases increased markedly from lower to higher concentration windows, from 60 to 97% for ethanol and from 38 to 76% for benzodiazepines. The corresponding increase for amphetamines and THC was modest, from 43 to 58% for amphetamines and from 41 to 55% for THC. The correlation between drug concentration and degree of impairment was high for ethanol (Spearman´s rho=0.548, p<0.001) and relatively high for benzodiazepines (Spearman´s rho=0.377, p<0.001), but low for amphetamines (Spearman´s rho=0.078, p<0.001) and THC (Spearman´s rho=0.100, p<0.001). ConclusionThe percentage of impaired drivers increased with increasing blood drug concentration for all four drug classes, most pronounced for ethanol and benzodiazepines and much less for amphetamines and THC. The median blood drug concentration increased with increasing magnitude of impairment for ethanol and benzodiazepines, while this was much less pronounced for amphetamines and THC. The ranges of drug concentrations, however, were wide for all four drug classes in all impairment categories as assessed by individual clinical examination.

Ghrelin induced by ultraviolet B exposure promotes the restoration of diabetic cutaneous wound healing.

Diabetes mellitus (DM) presents impediment to wound healing. While ultraviolet B (UVB) exposure showed therapeutic potential in various skin conditions, its capacity to mediate diabetic wound healing remains unclear. To investigate the efficacy of UVB on wound healing and its underlying basis. Male C57BL/6 mice were subjected to the high-fat diet followed by streptozotocin administration to establish the diabetic model. Upon confirmation of diabetes, full-thickness wounds were inflicted and the treatment group received UVB radiation at 50 mJ/cm2 for 5min every alternate day for 2 weeks. Wound healing rate was then assessed, accompanied by evaluations of blood glucose, lipid profiles, CD31 expression, and concentrations of ghrelin and leptin. Concurrently, in vitro studies were executed to evaluate the protective role of ghrelin on human umbilical vein endothelial cells (HUVEC) under high glucose (HG) conditions. Post UVB exposure, there was a marked acceleration in wound healing in DM mice without alterations in hyperglycemia and lipid profiles. Compared to non-UVB-exposed mice, the UVB group showed enhanced angiogenesis manifested by a surge in CD31 expression. This trend appeared to be in harmony with the elevated ghrelin levels. In vitro experiments indicated that ghrelin significantly enhanced the migratory pace and angiogenic properties of HUVEC under HG-induced stress, potentially mediated by an upregulation in vascular endothelial growth factor expression. UVB exposure bolstered wound healing in diabetic mice, plausibly mediated through augmented angiogenesis induced by ghrelin secretion. Such findings underscore the vast potential of UVB-induced ghrelin in therapeutic strategies targeting diabetic wound healing.

Production Responses of Multiparous Dairy Cattle with Differing Prepartum Muscle Reserves and Supplementation of Branched-Chain Volatile Fatty Acids

Periparturient dairy cattle undergo physiological adaptations to support fetal growth and colostrum synthesis in late gestation and milk production in early lactation. To support energy and protein demands dairy cattle mobilize body tissue reserves. The objective of this study was to determine the effects of prepartum skeletal muscle reserves and supplementation of branched-chain volatile fatty acids (BCVFA) on body composition measurements, metabolic markers related to health, protein, and energy status, and subsequent milk yield in multiparous dairy cows. Skeletal muscle reserves were assessed by 3 ultrasounds of the longissimus dorsi muscle depth (LDD) measured 42 d before expected calving (BEC), and cows (n = 48) were assigned to either high muscle (HM; > 4.6 cm) or low muscle (LM; ≤ 4.6 cm) groups. Cows were then randomly assigned to either control (CON) of soyhull pellets (80 g/d) or BCVFA treatment which contained isobutyrate (40 g/d), isovalerate (20 g/d), and 2-methylbutyrate (20 g/d) calcium salt products. Treatments were top dressed from 42 BEC until parturition, resulting in 4 combinations of muscle groups and treatments: HM-CON (n = 13), HM-BCVFA (n = 13), LM-CON (n = 11), and LM-BCVFA (n = 11). Measurements of the LDD, BW, and BCS were taken on the following days relative to calving -42, -35, -21, -7, 0, 7, 14, 21, 28. Weekly blood samples were taken to measure glucose, BHB, and insulin concentrations, and 5 of the blood sample time points were utilized to determine 3-methylhistidine and creatinine blood concentrations. Milk yield was recorded daily for the first 28 d of lactation, and samples were taken from both milkings once a wk for the first 4 wk to determine components. The statistical model included the fixed effects of treatment, group, time, their interactions, and the random effect of cow nested within group and treatment. Prepartum muscle mobilization varied between muscle groups, as LM cows accreted muscle prepartum, and HM cows mobilized muscle. The HM cows had higher milk fat, protein, lactose, and energy corrected milk yields. The BCVFA supplementation tended to increase blood glucose concentrations both prepartum and postpartum and decreased milk urea nitrogen concentrations. Higher prepartum skeletal muscle reserves improve productivity of early lactation cows likely due to differences in muscle mobilization, and BCVFA supplementation improves glucose dynamics during the transition period, which may improve the metabolic health of the periparturient dairy cow.

Predicting clearance with simple and permeability-limited PBPK frameworks: comparison of well-stirred, dispersion and parallel tube liver models.

One-compartment (1C) and permeability-limited models were used to evaluate the ability of microsomal and hepatocyte intrinsic clearances to predict hepatic clearance. Well-stirred (WSM), parallel tube (PTM), and dispersion (DM) models were evaluated within the liver as well as within whole-body physiologically based pharmacokinetic frameworks. It was shown that a linear combination of well-stirred and parallel-tube average liver blood concentrations accurately approximates dispersion model blood concentrations. Using a flow/permeability-limited model, a large systematic error was observed for acids and no systematic error for bases. A scaling factor that reduced interstitial fluid (ISF) plasma protein binding could greatly decrease the absolute average-fold error (AAFE) for acids. Using a 1C model, a scalar to reduce plasma protein binding decreased the microsomal clearance AAFE for both acids and bases. With a permeability-limited model, only acids required this scalar. The mechanism of the apparent increased cytosolic concentrations for acids remains unknown. We also show that for hepatocyte intrinsic clearance in vitro-in vivo correlations (IVIVCs), a 1C model is mechanistically appropriate since hepatocyte clearance should represent the net clearance from ISF to elimination. A relationship was derived that uses microsomal and hepatocyte intrinsic clearance to solve for an active hepatic uptake clearance, but the results were inconclusive. Finally, the PTM model generally performed better than the WSM or DM models, with no clear advantage between microsomes and hepatocytes. Significance Statement Prediction of drug clearance from microsomes or hepatocytes remains challenging. Various liver models (e.g. WSM, PTM, and DM) have been mathematically incorporated into liver as well as whole-body PBPK frameworks. Although the resulting models allow incorporation of pH partitioning, permeability, and active uptake for prediction of drug clearance, including these processes did not improve clearance predictions for both microsomes and hepatocytes.

A Novel Formulation of Ketorolac Tromethamine (NTM-001) in Continuous Infusion in Adults with and without Renal Impairment: A Randomized Controlled Pharmacologic Study.

There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment. Participants (≥ 65years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60-89mL/min for mild and 30-59mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75mg/h continuous intravenous (IV) infusion over 24h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15mg every 6h. There were four treatment periods of 24h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration-time profiles against target profiles. Adverse events were monitored. Thirty-nine subjects enrolled. Concentration-time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred. NTM-001 was considered safe and well tolerated in this population of participants ≥ 65years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects.

Protonitazene detection in two cases of opioid toxicity following the use of tetrahydrocannabinol vape products in Australia

Introduction Protonitazene is an opioid belonging to the 2-benzylbenzimidazole structural class. We describe two cases of opioid toxicity involving the reported inhalation of a delta-9-tetrahydrocannabinol vape product in which protonitazene was detected. Case reports Case 1 was a young male found unconscious after the reported use of a delta-9-tetrahydrocannabinol vape. He suffered two subsequent apnoeic episodes requiring bag-valve-mask ventilation before eventual recovery. Only protonitazene was detected in blood at a concentration of 0.74 µg/L. Case 2 was a young male who died shortly after being found unresponsive. The postmortem femoral blood concentrations of protonitazene and delta-9-tetrahydrocannabinol were 0.33 µg/L and 2 µg/L, respectively. Analysis of a pod vaping device found in the decedent’s hand and a separate e-liquid bottle labelled as delta-9-tetrahydrocannabinol showed a mixture of protonitazene and delta-9-tetrahydrocannabinol. Discussion The opioid effects of protonitazene are mediated through β-arrestin2 and mu opioid receptor signalling pathways. Benzimidazole opioids are lipophilic and, when mixed with a suitable solvent, can be used in a vape device. It is anticipated that naloxone would have provided effective reversal of toxicity in our cases. Conclusions Novel routes of opioid administration, like vaping, may appear relatively innocuous in comparison to intravenous administration, but opioids may still be absorbed at high concentrations, resulting in severe opioid toxicity or death.

Effects of adding antibiotics to an inactivated oil-adjuvant avian influenza vaccine on vaccine characteristics and chick health

During poultry immunization, antibiotics are typically added to inactivated oil-adjuvant avian influenza (AI) vaccines. Here, we evaluated the effects of adding ceftiofur, a third-generation cephalosporin, to an AI vaccine on vaccine stability and structure and on chick growth, immune efficacy, blood concentrations, biochemical and immunological indices, and gut microbiota. The results demonstrated that neither aqueous ceftiofur sodium nor ceftiofur hydrochloride oil emulsion formed a stable mixture with the vaccine. Adding ceftiofur formulations, particularly ceftiofur hydrochloride, at >4% significantly destabilized the vaccine's water-in-oil structures. Adding ceftiofur also increased vaccine malabsorption at the injection site; specifically, adding ceftiofur hydrochloride reduced H5N8 and H7N9 antibody titers after the first immunization (P < 0.05) and H7N9 antibody titers after the second immunization (P < 0.01). Serum drug concentrations did not differ significantly between the groups with ceftiofur sodium and hydrochloride addition. Ceftiofur addition increased postvaccination chick weight loss; compared with the vaccine alone, ceftiofur sodium-vaccine mixture increased chick weight significantly (P < 0.05). Ceftiofur addition also increased stress indices and reduced antioxidant capacity significantly (P < 0.05 or P < 0.01). Vaccination-related immune stress reduced gut microbiota diversity in chicks; ceftiofur addition reversed this change. AI vaccine immunization significantly reduced the relative abundance of Lactobacillus and Muribaculaceae but significantly increased that of Bacteroides and Eubacterium coprostanoligenes group. Ceftiofur addition restored the gut microbiota structure; in particular, ceftiofur hydrochloride addition significantly increased the abundance of the harmful gut microbes Escherichia-Shigella and Enterococcus, whereas ceftiofur sodium addition significantly reduced it. The changes in gut microbiota led to alterations in metabolic pathways related to membrane transport, amino acids, and carbohydrates. In conclusion, adding ceftiofur to the AI vaccine had positive effects on chick growth and gut microbiota modulation; however, different antibiotic concentrations and formulations may disrupt vaccine structure, possibly affecting vaccine safety and immunization efficacy. Thus, the addition of antibiotics to oil-adjuvant vaccines is associated with a risk of immunization failure and should be applied to poultry with caution.

Computational approach for drug discovery against Gardnerella vaginalis in quest for safer and effective treatments for bacterial vaginosis

Bacterial vaginosis (BV), primarily attributed to Gardnerella vaginalis, poses significant challenges due to antibiotic resistance and suboptimal treatment outcomes. This study presents an integrated approach to identify potential drug targets and screen compounds against this bacterium by leveraging a computational methodology. Subtractive proteomics of the reference strain ASM286196v1/UMB0386 (assembly accession: GCA_002861965.1) facilitated the prioritization of proteins with essential bacterial functions and pathways as potential drug targets. We selected 3-deoxy-7-phosphoheptulonate synthase (aroG gene product; also known as DAHP synthase) for downstream analysis. Molecular docking was employed in PyRx (AutoDock Vina) to predict binding affinities between aroG inhibitors from the ZINC database and 3-deoxy-7-phosphoheptulonate synthase. Molecular dynamics simulations of 100 ns, using GROMACS, validated the stability of drug-target interactions. Additionally, ADMET profiling aided in the selection of compounds with favorable pharmacokinetic properties and safety profile for human hosts. PBPK profiling showed that ZINC98088375 had the highest bioavailability and efficient systemic circulation. Conversely, ZINC5113880 demonstrated the lowest absorption rate (39.661%). Moreover, cirrhosis, steatosis, and renal impairment appeared to influence blood concentration of the drug, impacting bioavailability. The integrative –omics approach utilized in this study underscores the potential of computer-aided drug design and offers a rational strategy for targeted inhibitor discovery against G. vaginalis. The strategy is an attempt to address the limitations of current BV treatments, including antibiotic resistance, and pave way for the development of safer and more effective therapeutics.

Dexamethasone Long-Term Controlled Release from Injectable Dual-Network Hydrogels with Porous Microspheres Immunomodulation Promotes Bone Regeneration.

Long-lasting, controlled-release, and minimally invasive injectable platforms that provide a stable blood concentration to promote bone regeneration are less well developed. Using hexagonal mesoporous silica (HMS) loaded with dexamethasone (DEX) and poly(lactic-co-glycolic acid) (PLGA), we prepared porous DEX/HMS/PLGA microspheres (PDHP). In contrast to HMS/PLGA microspheres (HP), porous HMS/PLGA microspheres (PHP), DEX/PLGA microspheres (DP), and DEX/HMS/PLGA microspheres (DHP), PDHP showed notable immuno-coordinated osteogenic capabilities and were best at promoting bone mesenchymal stem cell proliferation and osteogenic differentiation. PDHP were combined with methacrylated silk (SilMA) and sodium alginate (SA) to form an injectable photocurable dual-network hydrogel platform that could continuously release the drug for more than 4 months. By adjusting the content of the microspheres in the hydrogel, a zero-order release hydrogel platform was obtained in vitro for 48 days. When the microsphere content was 1%, the hydrogel platform exhibited the best biocompatibility and osteogenic effects. The expression levels of the osteogenic gene alkaline phosphatases, BMP-2 and OPN were 10 to 15 times higher in the 1% group than in the 0% group, respectively. In addition, the 1% microsphere hydrogel strongly stimulated macrophage polarization to the M2 phenotype, establishing an immunological milieu that supports bone regrowth. The aforementioned outcomes were also observed in vivo. The most successful method for correcting cranial bone abnormalities in SD rats was to use a hydrogel called SilMA/SA containing 1% drug-loaded porous microspheres (PDHP/SS). The angiogenic and osteogenic effects of this treatment were also noticeably greater in the PDHP/SS group than in the control and blank groups. In addition, PDHP/SS polarized M2 macrophages and suppressed M1 macrophages in vivo, which reduced the local immune-inflammatory response, promoted angiogenesis, and cooperatively aided in situ bone healing. This work highlights the potential application of an advanced hydrogel platform for long-term, on-demand, controlled release for bone tissue engineering.

Resource partitioning influences levels of toxic trace elements in sympatric tropical seabirds

Morphologically similar species that occupy resource-limited environments tend to differ in their ecological traits in order to coexist, which may result in differential exposure to environmental threats. For instance, partitioning of feeding resources may influence contaminant exposure and bioaccumulation in marine predators through different diets or foraging habitats. Here, we sampled three tropical seabird species breeding in sympatry in the southwestern Atlantic Ocean for blood and feather trace element concentrations (As, Hg, Cd, Pb), and assessed their foraging ecology with bio-logging (GPS tracks and time-depth recorders), analysis of regurgitated prey, and carbon and nitrogen stable isotope mixing models. Red-billed tropicbirds (Phaethon aethereus), brown (Sula leucogaster) and masked (S. dactylatra) boobies differed in their preferred foraging locations, the range of foraging trips, diving parameters and diets. In addition, interspecific differences were detected in blood or feathers for all trace elements analyzed, suggesting influence of the differences observed in diet and space use. Red-billed tropicbirds had the largest foraging range over the continental shelf and over the slope, suggesting lower exposure to continental sources of metals. Brown and masked boobies had higher Hg concentrations than tropicbirds, higher δ15N values (a proxy for trophic level), and δ15N correlated with Hg levels, suggesting biomagnification of Hg along the food chain. Nonetheless, red-billed tropicbirds showed comparable levels of As and Cd in blood or feathers, and higher levels of Pb in both tissues in comparison to boobies, which may suggest overall exposure of seabirds in the region, through their diets and foraging areas. Resource partitioning is critical for allowing coexistence of different seabird species in shared breeding sites where they act as central-place foragers. Nonetheless, in scenarios of environmental pollution, these species-specific strategies lead to differential bioaccumulation, and thus distinct effects of pollution on populations are expected.

Diagnostic accuracy of the anion gap to identify toxic lithium concentrations: a single-center retrospective observational study

Introduction Lithium exhibits a narrow margin between therapeutic doses and toxic blood concentrations, which can pose a substantial risk of toxic effects. Reportedly, lithium toxicity may be associated with a reduced anion gap; however, the precise relationship remains unclear. This study examined several different anion gap calculation methods to detect toxic lithium concentrations without directly measuring blood lithium concentrations. Methods Our retrospective study analyzed blood samples collected for lithium concentration measurements. The anion gap was determined using three different methods, both with and without albumin and lactate concentration corrections. Samples were categorized into two groups based on lithium concentration (<1.5 or ≥1.5 mmol/L), and anion gap values were compared. Correlation and logistic regression analyses were used to assess the relationship between each anion gap indicator and lithium concentration. Receiver operating characteristic curves were used for diagnostic analysis. Results Overall, 24 measurements were collected, with 41.7% of samples falling within the toxic range. The high-lithium concentration group exhibited significantly smaller anion gaps. Correlation and logistic regression analyses revealed a significant association between anion gap values and lithium concentrations. Areas under the receiver operating characteristic curve were: conventional anion gap 0.77 (95% CI: 0.55–0.94); albumin-corrected anion gap 0.85 (95% CI: 0.66–1.00); and both albumin- and lactate-corrected anion gap 0.86 (95% CI: 0.66–1.00). Discussion The anion gap is calculated as the difference between measured cations and anions. Accumulation of lithium (a cation) may decrease measured cations and decrease the calculated anion gap. Abnormal albumin and lactate concentrations may also alter the anion gap and affect its usefulness as a diagnostic marker for elevated serum lithium concentrations. A negative likelihood ratio of 0.1 suggests that the anion gap might be valuable in excluding toxicity. Conclusions The corrected anion gap, accounting for albumin and lactate concentrations, may be beneficial in suggesting the possibility of toxic lithium concentrations.

Electrochemical sensor based on mesoporous g-C3N4/N-CNO/gold nanoparticles for measuring oxycodone

Oxycodone, often used as an analgesic, is a potent opioid. While its effectiveness has been proven in the control of moderate to acute pain, excessive use of oxycodone imposes heart failure, heart palpitations, reduction of red blood cells, bone pain, and even death. Therefore, monitoring the oxycodone concentration in blood is vital for emergency care. For this purpose, a novel electrochemical sensor was designed based on a glassy carbon electrode modified with mesoporous g-C3N4 (M-C3N4), carbon nano-onions doped with nitrogen (N-CNO), and gold nanoparticles. At first, the SEM and XRD techniques were employed to characterize prepared M-C3N4 and N-CNO samples. The electro-oxidation behavior of the oxycodone was evaluated by cyclic and differential pulse voltammetric methods. Based on the influence of the potential scanning rate and solution pH on the voltammetric response of oxycodone oxidation, a redox mechanism was proposed. A 16 nM detection limit was acquired for the oxycodone analysis with a linear response in the 0.05–150 µM range. This sensor showed a remarkable ability for oxycodone detection in plasma samples. The long-term stability, superior selectivity, and reproducibility of this sensor prove its ability to measure oxycodone accurately and precisely in authentic spices.

Time Scale Calculus: a new approach to multi-dose pharmacokinetic modeling.

In this paper, we use Time Scale Calculus (TSC) to formulate and solve pharmacokinetic models exploring multiple dose dynamics. TSC is a mathematical framework that allows the modeling of dynamical systems comprising continuous and discrete processes. This characteristic makes TSC particularly suited for multi-dose pharmacokinetic problems, which inherently feature a blend of continuous processes (such as absorption, metabolization, and elimination) and discrete events (drug intake). We use this toolkit to derive analytical expressions for blood concentration trajectories under various multi-dose regimens across several flagship pharmacokinetic models. We demonstrate that this mathematical framework furnishes an alternative and simplified way to model and retrieve analytical solutions for multi-dose dynamics. For instance, it enables the study of blood concentration responses to arbitrary dose regimens and facilitates the characterization of the long-term behavior of the solutions, such as their steady state.

Effects of weaning and inactivated Lactobacillus helveticus supplementation on dairy calf behavioral and physiological indicators of affective state

The objectives of this study were to determine if weaning would induce behavioral and physiological indicators of a negative affective state, and if supplementation of inactivated Lactobacillus helveticus (ILH) to dairy calves would reduce those indicators of negative affect during weaning. Male Holstein calves (n = 23) were enrolled in the study on d 1 of life. The calves were housed in individual pens in 1 of 4 rooms for the 42 d study. Calves began a stepdown weaning from 9 L/d of milk replacer (MR), at 150 g of MR powder/L, on d 35 and received 6 L/d on d 35 - 36, 3 L/d on d 37 - 38, and 0.4 L/d on d 39 - 42. The MR was divided between 3 meals/d until the last 0.4 L/d phase which was divided between 2 meals/d. Calves had ad libitum water access throughout the study and calf starter from d 28 onwards. Within room, calves were assigned to 1 of 2 treatments: 1) control (CON; n = 11) and 2) 5 g of ILH/d split over and mixed into the 0800 h and 2000 h milk feedings from d 3-42 (ILH; n = 12). Lying behavior was recorded using HOBO data loggers from d 21-41. On d 33, 37 and 41, infrared eye images were taken to determine maximum eye temperature (MET), saliva samples were collected to determine cortisol concentration, and play assessments were conducted to quantify play behavior. On d 34, 38, and 42, blood samples were collected to determine blood serotonin concentration, whereas on d 38 and 39, calves were tested with a cognitive task. A subset of calves (n = 5/treatment) were euthanized to collect gut and brain tissue samples for serotonin concentration on d 43. Weaning resulted in fewer (d 37-41, tendency: d 36), but longer (d 38-41, tendency: d 37), lying bouts and reduced play (d 41), although no changes in lying time, MET, saliva cortisol, nor blood serotonin were detected with initiation of weaning. Supplementation of ILH was associated with lower lying time throughout the study, and reduced play duration and higher salivary cortisol and MET during weaning. No differences in lying bouts, play count, blood and tissue (colon, ileum, prefrontal cortex and brain stem) serotonin concentration, and time to complete the cognitive task were detected between the treatments. Overall, weaning induced behavioral changes indicative of negative affective state, and some behavioral differences were observed with ILH supplementation both before and during weaning, with some physiological changes observed during weaning.

Hydroxychloroquine blood concentrations and effects in Chinese patients with IgA nephropathy.

Hydroxychloroquine (HCQ) is recommended for Chinese patients with immunoglobulin A nephropathy (IgAN). However, the relationship between HCQ blood concentration and the therapeutic effect for IgAN has not yet been defined. This study investigates the optimal and efficacious range of HCQ blood concentrations in Chinese patients with IgAN. Seventy-three patients with biopsy-proven IgAN who were at risk of progression were included in this study. Thirty-eight patients with IgAN were treated with HCQ plus an optimized renin-angiotensin-aldosterone system inhibitor (RAASi), and thirty-five patients received only RAASi. Blood HCQ concentration and 24-h proteinuria were examined at three and six months after treatment. The baseline proteinuria levels were comparable between the RAASi and HCQ groups. The HCQ group had lower 24-h proteinuria than the RAASi group three months after treatment, though the difference was not significant (p = 0.38). After six months, the median proteinuria level was significantly lower in the HCQ group than in the RAASi group (p < 0.05). The percentage reduction in 24-h proteinuria in the HCQ group was greater than that in the RAASi group at three (p < 0.05) and six months (p < 0.05). Hydroxychlorquine blood concentration and efficacy were positively correlated at three months (r = 0.428, p < 0.05) and six months (r = 0.48, p < 0.05). Moreover, the optimal blood concentration of HCQ for three-month efficacy was 418.96ng/mL and that for six-month efficacy was 582.48ng/mL. No serious adverse events were reported during HCQ treatment. Hydroxyhloroquine safely reduces proteinuria in Chinese patients with IgAN. The efficacy of HCQ is positively correlated with its blood concentration.

Physiological Features of the Response of the Respiratory and Circulation Systems to Physical Load in Students Engaged in Winter Football

Adaptive changes in the circulatory and respiratory systems under the influence of winter football training were studied. 50 men aged 21-25 years — 3rd-4th year students — were examined: control group — 25 people specializing in “soccer” (S), main group — 25 people studying in the specialization “winter football” (WF). The examination was performed twice — before and after physical activity. Running (average pace, 180 steps/min) for 15 minutes was used as dosed physical activity. The loads were performed either indoors at a temperature of plus 22–24°C, or in winter outside at a temperature of minus 18–20°C. Indoor and outdoor surveys were carried out on different days. Assessment of peripheral blood flow in the lower extremities was performed using rheography; to assess the main blood flow in the femoral artery, Doppler ultrasound was used. The study of external respiration functions was carried out using pneumotachography. The lactate concentration in capillary blood was determined photometrically. It has been shown that physical activity performed in the cold in adapted athletes (WF group) promotes increased integration between the respiratory and circulatory systems, ensuring the formation of a functional system characterized by stronger connections for optimal adaptation to the combined effects of physical activity and cold. In athletes training indoors (group S) under conditions of a combination of physical activity and cold exposure, on the contrary, desynchronization of the interaction of the respiratory and circulatory systems occurs, which leads to a decrease in adaptive reserves. Thus, sports training in winter football triggers phenotypic adaptive changes and creates a number of physiological mechanisms that promote increased integration between the respiratory and circulatory systems, providing optimal adaptation to the combined effects of physical activity and cold. The obtained facts will be useful for the development of special training programs aimed at increasing the functional reserve of the cardiorespiratory system of athletes training in cold conditions.

Mercury concentrations in Seaside Sparrows and Marsh Rice Rats differ across the Mississippi River Estuary.

Mercury (Hg) concentrations and their associated toxicological effects in terrestrial ecosystems of the Gulf of Mexico are largely unknown. Compounding this uncertainty, a large input of organic matter from the 2010 Deepwater Horizon oil spill may have altered Hg cycling and bioaccumulation dynamics. To test this idea, we quantified blood concentrations of total mercury (THg) in Seaside Sparrows (Ammospiza maritima) and Marsh Rice Rats (Oryzomys palustris) in marshes west and east of the Mississippi River in 2015 and 2016. We also tested for a difference in THg concentrations between oiled and non-oiled sites. To address the potential confounding effect of diet variation on Hg transfer, we used stable nitrogen (δ15N) and carbon (δ13C) isotope values as proxies of trophic position and the source of primary production, respectively. Our results revealed that five to six years after the spill, THg concentrations were not higher in sites oiled by the spill compared to non-oiled sites. In both species, THg was higher at sites east of the Mississippi River compared to control and oiled sites, located west. In Seaside Sparrows but not in Marsh Rice Rats, THg increased with δ15N values, suggesting Hg trophic biomagnification. Overall, even in sites with the most elevated THg, concentrations were generally low. In Seaside Sparrows, THg concentrations were also lower than previously reported in this and other closely related passerines, with only 7% of tested birds exceeding the lowest observed effect concentration associated with toxic effects across bird species (0.2 µg/g ww). The factors associated with geographic heterogeneity in Hg exposure remain uncertain. Clarification could inform risk assessment and future restoration and management actions in a region facing vast anthropogenic changes.