Low-cost pyrolysis of biomass-derived nitrogen-doped porous carbon: Chlorella vulgaris replaces melamine as a nitrogen source.

Porous carbon generated from biomass has a rich pore structure, is inexpensive, and has a lot of promise for use as a carbon material for energy storage devices. In this work, nitrogen-doped porous carbon was prepared by co-pyrolysis using bagasse as the precursor and chlorella as the nitrogen source. ZnCl2 acts as both an activator and a nitrogen fixer during activation to generate pores and reduce nitrogen loss. The thermal weight loss experiments showed that the pyrolysis temperatures of bagasse and chlorella overlap, which created the possibility for the synthesis of nitrogen-rich biochar. The optimum sample (ZBC@C-5) possessed a surface area of 1508 m2g-1 with abundant nitrogen-containing functional groups. ZBC@C-5 in the three-electrode system exhibited 244.1F/g at 0.5A/g, which was extremely close to ZBC@M made with melamine as the nitrogen source. This provides new opportunities for the use of low-cost nitrogen sources. Furthermore, the devices exhibit better voltage retention (39%) and capacitance retention (96.3%). The goal of this research is to find a low cost, and effective method for creating nitrogen-doped porous carbon materials with better electrochemical performance for highly valuable applications using bagasse and chlorella.

Assessment of CYP-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.

Toxicity assessment of commercial herbicide formulations to Eisenia andrei (Bouché, 1972) in oxisols.

The use of long-residual herbicides can have adverse effects on terrestrial ecosystems. This study assessed the acute and chronic toxicity and avoidance behavior of Eisenia andrei earthworms exposed to nominal concentrations of clomazone, indaziflam, and sulfentrazone, using recommended commercial formulations for sugarcane cultivation. The formulations included Gamit® 360 CS (360 g L-1 of the active ingredient - a.i. - clomazone), Boral® 500 SC (500 g L-1 of a.i. sulfentrazone), and Alion® (500 g L-1 of a.i. indaziflam). Boral® 500 SC induced avoidance at concentrations as low as 1 mg kg-1, while Gamit® 360 CS and Alion® exhibited higher avoidance at 50-75 mg kg-1 and 75-100 mg a.i. kg-1, respectively. Reproduction tests showed significant impacts from Gamit® 360 CS (EC50: 0.572 mg kg-1, EC10: 0.2144 mg kg-1) and Boral® 500 SC (EC50: 0.3941 mg kg-1, EC10: 0.134 mg kg-1). Acute toxicity tests indicated moderate toxicity for Gamit® 360 CS (LC50: 184.12 mg kg-1) and Boral® 500 SC (LC50: 1000 mg kg-1). Gamit® 360 CS reduced biomass at all concentrations, while Boral® 500 SC influenced only at higher levels (500 and 1000 mg kg-1). Results suggest significant acute risks with Gamit® 360 CS, while chronic exposure raises concerns for both Gamit® 360 CS and Boral® 500 SC, indicating potential long-term risks. Alion®'s acute effects were inconclusive, but chronic exposure hints at a possible risk. These findings provide crucial insights for environmental agencies establishing protective limits against herbicide exposure to non-target soil invertebrates.

Occurrence, distribution, and risk assessment of pesticides in surface water and sediment in Jiangsu Province, China.

The occurrence and distribution of 157 pesticides were investigated in surface water and sediment in Jiangsu Province, China. Gas chromatography-mass spectrometry was used to analyze and quantify these pesticides, and the risk quotient method was used to evaluate their respective environmental risk. The results showed that 91 pesticides were detected in surface water. The organophosphates (OPPs), fungicides, and amide herbicides were predominant. The total concentration in surface water ranged from 63.7 to 22,463 ng/L, 3.90 to 7262 ng/L, and ND to 34,120 ng/L, respectively. The mean concentration was 3479 ng/L, 1644 ng/L, and 1878 ng/L, respectively. The concentration range of detected pesticides in the Yangtze River Basin was generally lower than that in the Huai River Basin. In sediment samples, a total of 63 pesticides were detected. OPPs and amide herbicides were also ranked highest; the total concentration in sediment samples ranged from 2951 to 47,739 ng/g and 106 to 12,996 ng/g, respectively. And the mean concentrations was 6971 ng/g and 5130 ng/g, respectively. Suqian City had the highest concentration for OPPs and amide herbicides in the Huai River Basin, followed by Huai'an City, while Nanjing City and Yangzhou City ranked highest in the Yangtze River Basin. The spatial distribution of pesticides in Jiangsu Province indicated a concentration significantly higher in the western and northern regions than in the eastern and southern regions, and a concentration generally higher in lakes than in rivers. The risk assessment results showed that OPPs, fungicides, amide herbicides, organochlorines, and triazine herbicides in most surface water samples posed a high risk and had regional pollution characteristics. In sediment samples, organochlorines, carbamates, other herbicides, and other insecticides posed a high risk in northern Jiangsu Province, whereas OPPs, amide herbicides, and triazine herbicides posed high risks everywhere in Jiangsu Province.

Melamine in Iranian foodstuffs: A systematic review, meta-analysis, and health risk assessment of infant formula.

The presence of melamine in food is one of the most significant threats to consumer health and food safety now confronting the communities. The goal of this systematic review and meta-analysis was to determine the melamine content of different food products available on the Iranian market. The pooled melamine concentration (95% confidence interval) on 484 samples of animal-based foodstuffs was as follows: 0.22 (0.08, 0.36 mg kg-1) for milk, 0.39 (0.25, 0.53 mg kg-1) for coffee mate, 1.45 (1.36, 1.54 mg kg-1) for dairy cream, 0.90 (0.50, 1.29 mg kg-1) for yoghurt, 1.25 (1.20, 1.29 mg kg-1) for cheese, 0.81 (-0.16, 1.78 mg kg-1) for hen eggs, 1.28 (1.25, 1.31 mg kg-1) for poultry meat, 0.58 (0.35, 0.80 mg kg-1) for chocolates, and 0.98 (0.18, 1.78 mg kg-1) for infant formula. Based on the results of health risk assessment study on toddlers under 2 years old who ingested infant formula (as a melamine-sensitive group), all groups of toddlers are at an acceptable level of non-carcinogenic risk (THQ ≤ 1). Toddlers were classified according to their ILCR (carcinogenic risk) levels due to infant formula consumption as follows: under 6 months (0.0000056), 6-12 months (0.0000077), 12-18 months (0.0000102), and 18-24 months (0.0000117). The melamine carcinogenicity in infant formula for children had an ILCR value of 0.000001-0.0001 in the investigation, which was considerable risk. According to the findings, Iranian food products (notably infant formula) should be analyzed for melamine contamination on a regular basis.

Triazine Herbicides Risk Management Strategies on Environmental and Human Health Aspects Using In-Silico Methods.

As an effective herbicide, 1, 3, 5-Triazine herbicides (S-THs) are used widely in the pesticide market. However, due to their chemical properties, S-THs severely threaten the environment and human health (e.g., human lung cytotoxicity). In this study, molecular docking, Analytic Hierarchy Process-Technique for Order Preference by Similarity to the Ideal Solution (AHP-TOPSIS), and a three-dimensional quantitative structure-active relationship (3D-QSAR) model were used to design S-TH substitutes with high herbicidal functionality, high microbial degradability, and low human lung cytotoxicity. We discovered a substitute, Derivative-5, with excellent overall performance. Furthermore, Taguchi orthogonal experiments, full factorial design of experiments, and the molecular dynamics method were used to identify three chemicals (namely, the coexistence of aspartic acid, alanine, and glycine) that could promote the degradation of S-THs in maize cropping fields. Finally, density functional theory (DFT), Estimation Programs Interface (EPI), pharmacokinetic, and toxicokinetic methods were used to further verify the high microbial degradability, favorable aquatic environment, and human health friendliness of Derivative 5. This study provided a new direction for further optimizations of novel pesticide chemicals.

Occurrence, fate, seasonal variability, and risk assessment of twelve triazine herbicides and eight related derivatives in source, treated, and tap water of Wuhan, Central China.

Triazine herbicides have been widely used, are frequently detected in aqueous environments and soils, and can cause acute or chronic toxicity to living organisms. We collected source water samples (n = 20) originating from the Hanshui River and the Yangtze River of Wuhan section, treated water samples (n = 20), and tap water samples (n = 169) in Wuhan, Central China during 2019 for determination of twelve triazine herbicides and their eight derivatives (collectively defined as TZs) and characterizing their fate during water treatment. Eighteen of the twenty TZs were detected in the source water. Atrazine (ATZ) had the highest concentrations (median: 22.4 ng/L) in the source water samples while DACT had the highest concentrations (median: 31.4 ng/L) in the treated water. "Tryns" (ametryn, prometryn, simetryn, terbutryn) were efficiently removed by conventional water treatment, while other target analytes were not; interestingly, hydroxypropazine and prometon increased significantly accompanied by prometryn disappearance, which implicated potential transformation pathways. In addition, "tryns" might be transformed into "tons" (atraton, prometon, secbumeton, terbumeton) by ozonation. In the tap water samples, diaminochlorotriazine had the highest concentrations (median: 34.9 ng/L) among the target analytes, followed by ATZ (18.3 ng/L), hydroxyatrazine (5.17 ng/L), deethylatrazine (5.00 ng/L), hydroxypropazine (3.20 ng/L), deisopropylatrazine (2.05 ng/L), hydroxydesethylatrazine (1.68 ng/L), and others. The TZs had the highest cumulative concentration in July in the tap water samples (median: 89.7 ng/L). This study found that ozonation in combination with activated carbon was more efficient in removing triazine herbicides, although "tryns" could also be transformed during conventional treatment. Ecological risk assessment showed moderate risks posed by hydroxyterbuthylazine, prometryn, and simetryn; the Hanshui River had higher risks than the Yangtze River, and July had higher risks than February. Human exposure to the TZs via water ingestion was low compared to the reference doses. This study characterized the occurrence of some new emerging TZs in the source water, their fate during drinking water treatment, and their seasonal variability in the tap water.

Assessment of the bioaccessibility of PAHs and other hazardous compounds present in recycled tire rubber employed in synthetic football fields.

Recycled tire crumb rubber (RTCR) surfaces contain harmful and carcinogenic substances, which can be ingested by the users of these facilities, mainly athletes and children. In this work, the potential in-vitro oral bioaccessibility of eighteen polycyclic aromatic hydrocarbons (PAHs) from RTCR employed as infill in synthetic football fields was studied in human synthetic body fluids (saliva, gastric, duodenal and bile), prepared according the Unified Bioaccessibility Method. Solid-phase extraction (SPE) using commercial sorbents and a new green material based on cork (cork industry by-product) were used to isolate the bioaccessible PAHs before gas chromatography-tandem mass spectrometry analysis. The method was optimized and validated attending the analytical figures of merit. The feasibility of cork biosorbent for the extraction of the compounds was demonstrated, as well as the suitability of the UBM method to perform the digestion with good precision. The application to real samples collected from football fields demonstrated the presence of 17 of the 18 target PAHs in the biofluids. Most volatile PAHs such as NAP, ACY, ACE, FLU, PHN and ANC, achieved the highest bioaccessibility percentage levels. The carcinogenic B[a]P was detected in 75 % of the samples at concentrations up to 2.5 ng g-1 (bioaccessible fraction). Children exposure assessment was carried out to identify potential risk. Other hazardous and environmentally problematic compounds such as N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone), recently related with the dead of coho salmon, and hexamethoxymethylmelamine (HMMM), among others, were also detected. This is the first study in which the bioaccesibility from real crumb rubber samples of 15 out of the 16 PAHs considered as priority pollutants by the United States Environmental Protection Agency (EPA) and the presence of 6PPD-quinone and HMMM in the bioaccessible fractions is reported.

In vivo assessment of triazine lipid nanoparticles as transfection agents for plasmid DNA.

Non-viral vectors for in vivo delivery of plasmid DNA rely on optimized formulations to achieve robust transgene expression. Several cationic lipids have been developed to deliver nucleic acids, but most recent literature has focused on mRNA due to its increased expression profile and excluded plasmid DNA, which may have the advantage of being less immunogenic. In this study, we describe the in vivo evaluation of cationic triazine based lipids, previously prepared by our group. We identify one lipid with limited in vivo toxicity for studies to optimize the lipid formulations, which include an evaluation of the influence of PEG and helper lipids on transgene expression. We then demonstrate that lipoplexes, but not lipid nanoparticles, formed from triazine lipids achieve similar transgene expression levels as AAV vectors and offer enhanced expression as compared to a commercially available cationic lipid, DOTAP. Importantly, the lipid nanoparticles and lipoplexes induce minimal antibody profiles toward the expressed protein, while serving as a platform to induce robust antibody responses when directly delivering the protein. Collectively, these data demonstrate the potential for triazine based lipids as non-viral vectors for gene delivery, and highlights the need to optimize each formulation based on the exact contents to achieve enhanced transgene expression with plasmid DNA constructs.

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Exposure to melamine and its derivatives in Chinese adults: The cumulative risk assessment and the effect on routine blood parameters.

Melamine (MEL) and its derivatives, ammeline (AMN), ammelide (AMD), cyanuric acid (CYA) are widely existed in environmental media. Animal studies have reported the cumulative risk assessment (CRA) of simultaneous exposure to MEL and its derivatives and explored the associations between exposure and routine blood parameters. Such information is largely unknown in human studies. In this study, we detected the urinary concentrations of MEL and its derivatives in 239 Chinese adults to conduct the CRA by evaluating their hazard quotients (HQ) and hazard Index (HI), and also explored the possible associations between exposure and measured routine blood parameters in study population. The detectable frequencies of MEL, AMN, AMD and CYA were 96.65%, 41.00%, 97.91% and 97.07%, respectively. The median values of creatinine (Cr)-adjusted MEL, AMN, AMD, CYA and the total concentrations of MEL and its derivatives (∑MEL) were 11.41 µg/g Cr, not detected (ND), 2.64 µg/g Cr, 15.30 µg/g Cr, 35.02 µg/g Cr, respectively. There were 9 (3.77%) participants with estimated daily intakes (EDIs) of CYA exceeding the tolerable daily intake (TDI) of 2500 ng/kg bw/day, and 12 (5.02%) participants with HI of ∑MEL exposure exceeding 1 based on the strictest TDI value. Urinary concentrations of MEL and its derivatives were positively associated with specific routine blood parameters, including hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, white blood cell, neutrophil count (P < 0.05). Meanwhile, exposure to MEL and its derivatives increased the risk of red blood cell abnormality (P < 0.05). Our study is the first study to provide evidence-based data on the CRA of exposure to MEL and its derivatives in Chinese adults, and to propose a possible association between such exposure and routine blood parameters in human.

Monitoring, cross-resistance, inheritance, and fitness costs of brown planthoppers, Nilaparvata lugens, resistance to pymetrozine in China.

BACKGROUND: The brown planthopper, Nilaparvata lugens, is considered the most destructive pest of rice in many Asian countries including China. Use of pymetrozine in insect resistance management (IRM) has been one strategy to control this pest. In this study, we reported the status of pymetrozine resistance in Nilaparvata lugens (Stål) collected from China over the period 2017-2021 and selected a strain of N. lugens resistant to pymetrozine and evaluated the cross-resistance, inheritance and fitness costs of the resistance. RESULTS: Monitoring data (2017-2021) showed that field populations of N. lugens in China developed moderate- to high-level pymetrozine resistance during these 5 years. By continuous selection with pymetrozine in the lab, the pymetrozine selected N. lugens strain (Pym-R98 ) developed a 225.2-fold resistance compared to a susceptible strain. The Pym-R98 strain showed high cross-resistance to dinotefuran (66.6-fold) and low cross-resistance to nitenpyram (5.2-fold) and sulfoxaflor (5.8-fold). Inheritance pattern analysis of Pym-R93 revealed that resistance to pymetrozine was polygenic, autosomal and incompletely dominant. Fitness costs of pymetrozine resistance were present in Pym-R90 and WA2020 strains with a relative fitness of 0.72 and 0.60, respectively. The developmental duration of Pym-R90 and WA2020 was significantly longer and hatchability was significantly lower compared to pymetrozine-susceptible strain (Pym-S). CONCLUSIONS: N. lugens has developed high level of resistance to pymetrozine. Pymetrozine-resistance brown planthopper had cross-resistance with some of neonicotinoids such as dinotefuran, nitenpyram and sulfoxaflor. The autosomal, incompletely dominant and polygenic resistance to pymetrozine in N. lugens and the fitness costs associated with this resistance can be exploited in IRM strategies to preserve the lifetime of pymetrozine for control of N. lugens in China. © 2022 Society of Chemical Industry.

Environmental monitoring and potential health risk assessment from Pymetrozine exposure among communities in typical rice-growing areas of China.

Pymetrozine is one of the most commonly used insecticides in China. This study was conducted to analyse Pymetrozine's potential exposures through various environmental routes beyond the treatment areas. The aim was to estimate the potential health risk for communities due to non-dietary exposures to Pymetrozine in soil and paddy water. Data on registration of pesticides in China, government reports, questionnaires, interviews and literature reviews as well as toxicological health investigations were evaluated to determine the hazard and dose-response characteristics of Pymetrozine. These were based on the US EPA exposure and human health risk assessment methods and exposure data from soil and paddy water samples collected between 10 and 20 m around the resident's location. The exposure doses from dermal contact through soil and paddy water were estimated. The potential cancer risk from the following exposure routes was evaluated: ingestion through soil; dermal contact exposure through soil; dermal contact exposure through paddy water. The potential total cancer risk for residents was estimated to be less than 1 × 10-6. These were relatively low and within the acceptable risk levels. The potential hazard quotient (HQ) from acute and lifetime exposure by dermal contact through paddy water and soil and acute and lifetime exposure by soil ingestion for residents was less than 1, indicating an acceptable risk level. This study suggested that there were negligible cancer risk and non-cancer risks based on ingestion and dermal contact routes of exposure to residents.

Baloxavir vs oseltamivir: reduced utilization and costs in influenza.

OBJECTIVES: To determine whether baloxavir use is associated with lower health care resource utilization (HCRU) and costs for secondary influenza complications post treatment compared with oseltamivir. STUDY DESIGN: Retrospective cohort study. METHODS: Patients filling a prescription for baloxavir or oseltamivir within 48 hours following an influenza-related outpatient visit were identified in the 2018-2019 influenza season from the US Truven MarketScan Research Databases and propensity matched 1:2 (baloxavir:oseltamivir). Outcomes were assessed 15 and 30 days after antiviral treatment and included all-cause, all respiratory-related, and select respiratory-related (influenza, asthma, chronic obstructive pulmonary disease, or infection) HCRU and costs. RESULTS: The study included 5080 baloxavir-treated and 10,160 matched oseltamivir-treated patients. All-cause emergency department (ED) visits and inpatient hospitalizations were lower in baloxavir-treated patients, with a statistically significant difference in the percentage hospitalized at 30 days (0.3% vs 0.5%; P = .04). ED visits for all or select respiratory-related conditions were significantly reduced with baloxavir (P < .01 for all comparisons). Mean per-patient cost savings at day 30 for all-cause, all respiratory-related, and select respiratory-related conditions were $79, $50, and $51, respectively, despite slightly higher prescription costs for baloxavir. In high-risk patients (baloxavir: n = 1958; oseltamivir: n = 3949), the incidence of ED visits was significantly lower for all respiratory-related and select respiratory-related conditions (P < .01); cost savings with baloxavir in the high-risk cohort were substantially greater than in the overall cohort. CONCLUSIONS: Treatment of patients with influenza with single-dose baloxavir was generally associated with lower HCRU and costs post treatment compared with oseltamivir, particularly in high-risk patients.

Risk assessment of cyromazine and methoxyfenozide resistance suggests higher additive genetic but lower environmental variation supporting quick resistance development in non-target Chrysoperla carnea (Stephens).

Insecticides are effective against economic pests, but these pose serious threats to the environment and ecosystem components such as natural enemies. Resistance risk assessment forecasts insecticide resistance development in target pests and non-target biological control agents under special conditions. Field-collected Chrysoperla carnea was selected with two Insect Growth Regulators (IGRs) viz. cyromazine and methoxyfenozide for 15 generations to determine the resistance development potential of this natural enemy. Selection to cyromazine and methoxyfenozide induced 759.08-fold and 3531.67-fold resistance with realized heritability of 0.37 and 0.62 in C. carnea, respectively, suggesting higher additive genetic variations in first half of selection (h2 = 0.46 for cyromazine and h2 = 0.75 for methoxyfenozide) than in second half (h2 = 0.18 and 0.25, respectively). Estimates of projected rate of resistance development indicate C. carnea will take only 6 to 2 generations at h2 = 0.37, 8 to 2 at h2 = 0.27, and 5 to 2 at h2 = 0.27, at constant slope = 1.81 for a tenfold increase in cyromazine resistance. At h2 = 0.37, 3-1, and 10-8 generations would be needed for this increase in LC50 if slope = 0.82 and 2.82, respectively. Similarly, it may take 3 to 1 generations at h2 = 0.62 and 0.72, but 4 to 1 at h2 = 0.52, at constant slope = 1.62, for a tenfold increase in methoxyfenozide resistance. On the same h2 = 0.62, 1-0, and 5-1 generations would be required for increase if slope = 0.62 and 2.62, respectively. Selection and resistance to both insecticides induced an insignificant difference in the sex ratio of C. carnea. These results confirm that this natural enemy has tremendous potential for resistance development under selection pressure.

Comparison of Intra-Familial Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Oseltamivir Using an Influenza Transmission Model and a Health Insurance Claims Database.

BACKGROUND: Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. METHODS: Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018-19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. RESULTS: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th-97.5th percentiles, 1.68-1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs' age category, virus type, and month of onset revealed similar trends favoring BXM. CONCLUSIONS: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan.

PURPOSE: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti-influenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients. METHODS: This retrospective cohort study used a large-scale Japanese employment-based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. RESULTS: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti-influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti-influenza treatments (odds ratios for baloxavir were 0.90-0.99 compared to other therapies). CONCLUSIONS: Based on real-world observation using a large-scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti-influenza drugs.

Assessment of Transporter-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients. METHODS: In PIONEER, a Phase 2 trial evaluating safety and efficacy of selective kinase inhibitor avapritinib in patients with ISM, the 12-item ISM-SAF was administered daily. Psychometric evaluation of score reliability, validity, and clinical interpretation was conducted using the trial data. RESULTS: Thirty-eight patients contributed to analyses (78.9% female; mean age = 49). Baseline internal consistency reliability (α) for bi-weekly TSS, GSS, and SSS was 0.86, 0.83, and 0.82, respectively. Test-retest reliability among patients exhibiting no change in Patient Global Impression of Symptom Severity (PGIS) between Baseline and Day 15 exceeded 0.74 universally. Construct validity and known-groups analysis showed moderate to strong ISM-SAF score correlation (r = 0.382-0.881) to supportive patient-reported questionnaires (e.g., PGIS and Mastocytosis Quality of Life Questionnaire) symptom and skin scores, and ability to distinguish among clinically unique groups. Correlations of ISM-SAF and other assessment change scores reflect evidence of score sensitivity. Clinically important difference and response estimates were 7-10 and 19, respectively. DISCUSSION: ISM-SAF produced reliable, construct-valid, sensitive scores when administered in PIONEER to patients in the target population. Results of this study support the use of the ISM-SAF as a reliable and valid measure to evaluate disease symptomology in ISM patients. Trial registration ClinicalTrials.gov, NCT03731260. Registered 10 October 2018, https://clinicaltrials.gov/ct2/show/study/NCT03731260 .

Influenza polymerase inhibitor resistance: Assessment of the current state of the art - A report of the isirv Antiviral group.

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2.