Determination and health risk assessment of carbamate pesticide residues in date palm fruits (Phoenix dactylifera) using QuEChERS method and UHPLC-MS/MS.

This study aimed to investigate carbamate pesticide residues in different varieties of date palm fruits in the UAE, utilizing UHPLC-MS/MS. For sample preparation and clean-up, the efficiency and performance of different QuEChERS dispersive solid-phase extraction kits were compared. Precision and recovery were assessed at 10 µg kg-1 for the three kits, revealing that Kit 2 demonstrated the best performance. The selected QuEChERS method was validated to detect 14 carbamate residues in 55 date samples. The method exhibited strong linearity with R2 > 0.999 and low LOD (0.01-0.005 µg kg-1) and LOQ (0.003-0.04 µg kg-1). Excellent accuracy (recovery: 88-106%) and precision (RSD: 1-11%) were observed, with negligible matrix effect (- 4.98-13.26%). All samples contained at least one carbamate residue. While most detected residues were below their MRLs, carbosulfan was found in 21 samples, propoxur in 2 samples, and carbofuran in 1 sample above their MRLs. The hazard index (HI) was calculated for carbosulfan, phenmedipham, carbaryl, propoxur, carbofuran, and methomyl to assess potential health risks for date consumers. All HI values were below the safety limit of 1.0, indicating that the consumption of dates does not pose a non-carcinogenic health risk for adults and children.

Targeted Quantification of Glutathione/Arginine Redox Metabolism Based on a Novel Paired Mass Spectrometry Probe Approach for the Functional Assessment of Redox Status.

Glutathione (GSH) redox control and arginine metabolism are critical in regulating the physiological response to injury and oxidative stress. Quantification assessment of the GSH/arginine redox metabolism supports monitoring metabolic pathway shifts during pathological processes and their linkages to redox regulation. However, assessing the redox status of organisms with complex matrices is challenging, and single redox molecule analysis may not be accurate for interrogating the redox status in cells and in vivo. Herein, guided by a paired derivatization strategy, we present a new ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based approach for the functional assessment of biological redox status. Two structurally analogous probes, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and newly synthesized 2-methyl-6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (MeAQC), were set for paired derivatization. The developed approach was successfully applied to LPS-stimulated RAW 264.7 cells and HDM-induced asthma mice to obtain quantitative information on GSH/arginine redox metabolism. The results suggest that the redox status was remarkably altered upon LPS and HDM stimulation. We expect that this approach will be of good use in a clinical biomarker assay and potential drug screening associated with redox metabolism, oxidative damage, and redox signaling.

Occurrence and risk assessment of pesticides and their transformation products related to olive groves in surface waters of the Guadalquivir river basin.

Pesticides are considered one of the main sources of contamination of surface waters, especially in rural areas highly influenced by traditional agricultural practices. The objective of this work was to evaluate the impact caused by pesticides and their transformation products (TPs) related to olive groves in surface waters with strong agricultural pressure. 11 streams were monitored during four sampling campaigns over 2 years. A solid-phase extraction, followed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) analysis was used in the quantitative target approach, with more than 70 validated compounds. Target method was combined with a suspect screening strategy involving more than 500 pesticides and TPs, using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) to identify additional pesticides and TPs out of the scope of analysis. A total of 43 different compounds were detected with the target method. The herbicide MCPA was present in all samples and at the highest concentration (1260 ng L-1), followed by the fungicide carbendazim (1110 ng L-1), and the herbicide chlorotoluron (706 ng L-1). The suspect screening strategy revealed the presence of 7 compounds out of the target analysis (1 pesticide and 6 TPs). 6 analytes were confirmed with the analytical standards. Semi-quantification results revealed that TPs exhibited higher concentrations than their corresponding parent compounds, indicating higher persistency. Some small streams showed a comparable number of pesticides and concentrations to the most polluted large river. The determined pesticide and TPs concentrations represented an estimated environmental hazard in almost all sampling sites under study. This work underscores the importance of including pesticide TPs and small streams impacted by extensive agricultural activities in water quality monitoring programs.

Distribution and risk assessment of pesticide pollution in small streams adjoining paddy fields.

The present investigation was planned to bridge the knowledge gap on spatiotemporal variations of pesticide pollution in small streams adjacent to paddy fields, and to visualize the associated risks in the aquatic ecosystems. We screened 106 pesticides using GCMSMS and LCMSMS from 10 small streams (n = 212, surface water samples) adjacent to paddy fields over seven months. Fifty-five pesticides were detected across different streams and months. The highest mean concentration was detected for fenobucarb (272 ng L-1), followed by thiamethoxam (199 ng L-1). The highest maximum concentration was detected for thiamethoxam ( 13,264 ng L-1), followed by triflumezopyrim ( 11,505 ng L-1). The highest detection frequency was recorded for fenobucarb (80.00%), followed by pretilachlor (79.00%). Out of the ten streams, Attabira stream had the highest mean number of pesticides detected in each sample. Maximum number of pesticides were detected in October followed by September. Pesticides namely, hexaconazole, pretilachlor, tricyclazole, fenobucarb and thiamethoxam were consistently detected across all streams. The risk assessment against the fishes, micro-invertebrates and algae were measured by risk quotient index (RQ). Twenty-five pesticides out of the detected pesticides (n = 55) had risk quotient values greater than 1. The highest RQmax values were observed in case of fenpropathrin followed by cyfluthrin-3. The highest RQmean value was observed in case of cyfluthrin, indicating its higher toxicity to fishes. The present study reveals that small streams are polluted with pesticides and there is a need to develop strategies and policy interventions in regularizing the pesticide uses for reducing the pesticide pollution in aquatic systems.

In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone-deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight-treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109 /L, WBC ≤10 × 109 /L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.

Risk assessment of pesticides used in the eastern Avocado Belt of Michoacan, Mexico: A survey and water monitoring approach.

Pesticides use raises concerns regarding environmental sustainability, as pesticides are closely linked to the decline of biodiversity and adverse human health outcomes. This study proposed a holistic approach for assessing the potential risks posed by pesticides for human health and the environment in the eastern region of Michoacan, where extensive agricultural lands, especially corn and avocado fields, surround the Monarch Butterfly Biosphere Reserve. We used a combination of qualitative (semi-structured interviews) and quantitative (chemical analysis) data. Fifty-five interviews with smallholder farmers allowed us to identify pesticide types, quantities, frequencies, and application methods. A robust and precise analytical method based on solid-phase extraction and LC-MS/MS was developed and validated to quantify 21 different pesticides in 16 water samples (rivers, wells, runoff areas). We assessed environmental and human health risks based on the pesticides detected in the water samples and reported in the interviews. The interviews revealed the use of 28 active ingredients, including glyphosate (29 % of respondents), imidacloprid (27 %), and benomyl (24 %). The pesticide analysis showed the presence of 13 different pesticides and degradation products in the water samples. The highest concentrations were found for imidacloprid (1195 ngL-1) and carbendazim (a degradation product of benomyl; 932 ngL-1), along with the metabolite of pyrethroid insecticides, 3-PBA (494 ngL-1). The risk assessment indicates that among the most used pesticides, the fungicide benomyl and carbendazim pose the highest risk to human health and aquatic ecosystems, respectively. This study unveils novel insights on agricultural practices for the avocado, a globally consumed crop that is undergoing rapid production expansion. It calls for the harmonisation of crop protection with environmental responsibility, safeguarding the health of the people involved and the surrounding ecosystems.

Analysis, residue behaviour and risk assessment of combination product of iprovalicarb + copper oxychloride in representative fruiting vegetables, cucurbit and in soil using LC-MS/MS and ICP-MS.

Combination product of two herbicides, i.e. iprovalicarb and copper oxychloride, is a new formulation. There is paucity of data on the dissipation pattern and risk assessment of this combination product in crops. To understand the dissipation behaviour/kinetics of this product, a supervised field trial was undertaken on cucumber and tomato. Method validation for a QuEChERS-based method for analysis of these pesticides from cucumber and tomato matrices reveals that all the parameters were within the acceptance range in accordance with SANTE. The limit of quantitation (LOQ) for iprovalicarb in cucumber and tomato fruits, and in soil matrices when analysed on LC-MS/MS was established at 0.01 mg kg-1. Similarly, the LOQ for copper oxychloride (as copper) on ICP-MS was established at 0.5 mg kg-1 in cucumber and tomato fruits and 5.0 mg kg-1 in soil. Dissipation of iprovalicarb was slower in tomato fruits as compared to cucumber fruits. The initial accumulation of the residues of iprovalicarb was 0.073 and 0.243 mg kg-1 in cucumber and 0.214 and 0.432 mg kg-1 in tomato fruits at standard and double dose, respectively. Similarly, copper oxychloride residues were 3.51 and 6.45 mg kg-1 in cucumber and 1.26 and 2.56 mg kg-1 in tomato fruits at standard and double dose, respectively. The residues were below LOQ in cucumber fruits, tomato fruits and soil at the time of harvest. The residues of copper oxychloride persisted till harvest time in cucumber fruits and in soil. A preharvest interval (PHI) of 3 day is recommended on safer side for the combination product of iprovalicarb + copper oxychloride. Theoretical maximum daily intake (TMDI) is less than maximum permissible intake (MPI) for iprovalicarb and copper oxychloride at both the doses from 0 day and onward. The results from the present study can be of immense importance for establishing label claims, maximum residue limits (MRLs) and risk assessment by national and international regulatory agencies.

A study of the pesticide residues in rapeseeds in China: Levels, distribution and health risk assessment.

The aim of this survey was to evaluate the residue levels, distribution and exposure risk of the 38 most commonly used pesticides in rapeseed samples collected from the main production areas in China over a two-year period. The sampling area covered 12 provinces, including Guizhou, Shaanxi, Yunnan, Hunan, Jiangxi, Sichuan, Chongqing, Anhui, Henan, Hubei, Zhejiang, and Jiangsu provinces. The pesticide residues were determined using a QuEChERS (Quick Easy Cheap Effective Rugged and Safe) method coupled with gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry. 8.4% of the rapeseed samples contained pesticides with a residue level ranging from 0.001 to 0.634 mg/kg. The detected analytes were imidacloprid, quizalofop-P-ethyl, thiamethoxam, paclobutrazol, prochloraz, tebuconazole, difenoconazole, s-metolachlor, carbofuran, and carbendazim. The concentrations of four analytes, including thiamethoxam, difenoconazole, carbendazim and prochloraz, exceeded the maximum residue level set by the Chinese government for rapeseed, with exceedance rates of 0.1%, 0.1%, 0.1%, and 1.1%, respectively. Based on the index of quality for residues (IqR) values, 91.6% of the total rapeseed samples had an IqR category of Excellent (IqR = 0). Only 1.5% of the tested samples were of inadequate quality. Furthermore, the assessment of chronic and acute exposure, as well as health risks associated with pesticide residues in rapeseed, was conducted for different age groups within the Chinese population, including adults (6-14 years), children (15-49 years), and the elderly (50-74 years). The results of this assessment indicated that pesticide residues in rapeseed cultivated in China are not expected to be of short- or long-term risks to the Chinese customers.

[Exposure Level and Risk Impact Assessment of Pesticides and Veterinary Drugs in Aquaculture Environment].

To explore the exposure level of pesticides and veterinary drugs in an aquaculture environment and its impact on the ecological environment, this study took the aquaculture environment in Shanghai as an example, and samples of water, sediment, and inputs from 40 major aquaculture farms were collected from July to September 2022. The types and contents of pesticides and veterinary drugs were screened using high-performance liquid chromatography-electrostatic field orbital ion trap mass spectrometry, and the risk quotient (RQ) method was used to assess the ecological risk of pesticide contamination in water and sediment. The results showed that 13 drugs were screened out from 204 samples (72 samples of water, 72 samples of mud, and 60 samples of input), namely, chlorpromazine, carbendazim, thiophanate, diazepam, florfenicol, simazine, amantidine, diazepam, trimethoprim, ciprofloxacin, ofloxacin, mebendazole, and enrofloxacin. Among them, 12 species were found in water samples with concentrations ranging from 0.016 µg·L-1 to 2.084 µg·L-1. The concentrations of seven species in the mud samples ranged from 0.018 µg·kg-1 to 23.101 µg·kg-1. The results showed that there were four types of inputs, ranging from 1.979 µg·kg-1 to 101.940 µg·kg-1. Seven drugs were found in both water and sediment. The risk quotient (RQ) results showed that there were some high and middle risks in both water and sediment samples of aquaculture farms, and the ecological risks of carbendazim were the highest in both water and sediment samples of aquaculture farms; the RQ values were 3.848 and 1.580, respectively, indicating high risk. It is suggested to strengthen the control and management of exogenous pesticides and veterinary drugs in aquaculture environments to protect the ecosystem health of the aquaculture environment.

Detection of 11 carbamate pesticide residues in raw and pasteurized camel milk samples using liquid chromatography tandem mass spectrometry: Method development, method validation, and health risk assessment.

This study aimed to use ultra-high-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer to detect 11 carbamate pesticide residues in raw and pasteurized camel milk samples collected from the United Arab Emirates. A method was developed and validated by evaluating limits of detection, limits of quantitation, linearity, extraction recovery, repeatability, intermediate precision, and matrix effect. Due to the high protein and fat content in camel milk, a sample preparation step was necessary to avoid potential interference during analysis. For this purpose, 5 different liquid-liquid extraction techniques were evaluated to determine their efficiency in extracting carbamate pesticides from camel milk. The established method demonstrated high accuracy and precision. The matrix effect for all carbamate pesticides was observed to fall within the soft range, indicating its negligible effect. Remarkably, detection limits for all carbamates were as low as 0.01 µg/kg. Additionally, the coefficients of determination were >0.998, demonstrating excellent linearity. A total of 17 camel milk samples were analyzed, and only one sample was found to be free from any carbamate residues. The remaining 16 samples contained at least one carbamate residue, yet all detected concentrations were below the recommended maximum residue limits set by Codex Alimentarius and the European Union pesticide databases. Nonetheless, it is worth noting that the detected levels of ethiofencarb in 3 samples were close to the borderline of the maximum residue limit. To assess the health risk for consumers of camel milk, the hazard index values of carbofuran, carbaryl, and propoxur were calculated. The hazard index values for these 3 carbamate pesticides were all below 1, indicating that camel milk consumers are not at risk from these residues.

Assessment of Contact Allergens in "Hypoallergenic" Athletic Shoes by Mass Spectrometry.

Background: Identification of athletic shoes for patients with contact allergy is difficult. Company reports of allergen content are often incorrect. Objectives: To determine whether chemical analysis of 4 athletic shoes, previously reported to be free of the most common contact allergens, contain quantifiable allergen levels. Methods: Samples from the uppers and insoles of 4 shoes believed to be free of common allergens were assessed by mass spectrometry. A total of 4 rubber accelerators and 2 adhesives were directly quantified and additional 7 rubber accelerators were assessed using semiquantitative measures. Results: Aside from carbamates (assayed as 59 ppm zinc in insoles) in SeaVee's Sixty-Six sneakers, para-tertiarybutylphenol formaldehyde resin (PTBFR) (assayed as 7.6 ppm paratertiary butylphenol or 4-tertiary butylphenol [4TBP] in uppers) in Allbirds Tree Runners and rosin (assayed as 628 ppm sodium abietate in uppers) and carbamates (24 ppm zinc in uppers) in Saucony Jazz sneakers, these shoes had low levels of all allergens assayed in this study. Tom's Carlo sneakers contained rosin (127 ppm sodium abietate in insoles), PTBFR (6.5 ppm 4TBP in uppers), and carbamates (112 ppm sodium abietate in insoles) but had low levels of all other assayed allergens. Conclusions: Although identifying allergen-free shoes is challenging, the results of this analysis will help patch testing physicians recommend athletic shoes to patients with specific allergies.

Validation of an SH-SY5Y Cell-Based Acetylcholinesterase Inhibition Assay for Water Quality Assessment.

The acetylcholinesterase (AChE) inhibition assay has been frequently applied for environmental monitoring to capture insecticides such as organothiophosphates (OTPs) and carbamates. However, natural organic matter such as dissolved organic carbon (DOC) co-extracted with solid-phase extraction from environmental samples can produce false-negative AChE inhibition in free enzyme-based AChE assays. We evaluated whether disturbance by DOC can be alleviated in a cell-based AChE assay using differentiated human neuroblastoma SH-SY5Y cells. The exposure duration was set at an optimum of 3 h considering the effects of OTPs and carbamates. Because loss to the airspace was expected for the more volatile OTPs (chlorpyrifos, diazinon, and parathion), the chemical loss in this bioassay setup was investigated using solid-phase microextraction followed by chemical analysis. The three OTPs were relatively well retained (loss <34%) during 3 h of exposure in the 384-well plate, but higher losses occurred on prolonged exposure, accompanied by slight cross-contamination of adjacent wells. Inhibition of AChE by paraoxon-ethyl was not altered in the presence of up to 68 mgc /L Aldrich humic acid used as surrogate for DOC. Binary mixtures of paraoxon-ethyl and water extracts showed concentration-additive effects. These experiments confirmed that the matrix in water extracts does not disturb the assay, unlike purified enzyme-based AChE assays. The cell-based AChE assay proved to be suitable for testing water samples with effect concentrations causing 50% inhibition of AChE at relative enrichments of 0.5-10 in river water samples, which were distinctly lower than corresponding cytotoxicity, confirming the high sensitivity of the cell-based AChE inhibition assay and its relevance for water quality monitoring. Environ Toxicol Chem 2022;41:3046-3057. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Determination of the economically justifiable price of cenobamate in the treatment of focal-onset seizures in adult patients with drug-resistant epilepsy in Spain.

OBJECTIVE: To determine the economically justifiable price (EJP) of cenobamate to become a cost-effective alternative compared with third-generation anti-seizure medications in the treatment of focal-onset seizures (FOS) in adult patients with drug-resistant epilepsy (DRE) in Spain. METHODS: Cost-effectiveness analysis compared cenobamate with brivaracetam, perampanel, eslicarbazepine acetate, and lacosamide. Markov model simulation of treatment pathway over a 60-year time horizon is presented. We determined the effectiveness and quality-adjusted life-years (QALYs) of health status and disutilities associated with treatment-related adverse events. Acquisition costs and use of medical resources were obtained from published literature and expert opinion. Base-case of cenobamate's EJP calculated applying a willingness-to-pay (WTP) threshold of €21,000/QALY. Analyses were performed at different thresholds, including dominant price scenario. Result robustness was assessed through sensitivity analyses. RESULTS: Base-case shows that cenobamate's daily EJP of €7.30 is cost-effective for a threshold of €21,000/QALY. At a daily price of €5.45, cenobamate becomes dominant over all treatment alternatives producing cost-savings for the national health system (NHS). Sensitivity analyses supported the robustness of base-case findings. CONCLUSIONS: Treatment with cenobamate produces incremental clinical benefit over third-generation ASMs, and at the base-case, EJP could represent a cost-effective option for the adjunctive treatment of FOS in adult patients with DRE in Spain.

Cost-Effectiveness of Elbasvir/Grazoprevir for the Treatment of Chronic Hepatitis C: A Systematic Review.

Objective: This study aims to systematically review recent economic evaluations of elbasvir/grazoprevir (EBR/GZR) for chronic hepatitis C (CHC), to critically appraise the reporting quality and to summarize the results. Methods: A literature search was undertaken using Medline, Embase, the Cochrane Library, EconLit, China National Knowledge Infrastructure, Wanfang Data, and Chongqing VIP to identify original articles containing economic evaluations of EBR/GZR for CHC published between 1 January 2000 and 31 December 2020. The Consolidated Health Economic Evaluation Reporting Standards statement was used to assess the quality of reporting of the articles. Results: Of 93 articles identified, 13 studies fulfilled the inclusion criteria. These studies were conducted in 4 countries, and 8 active interventions were assessed. The target population was patients infected with CHC genotype 1 infection in all studies. Eight out of 13 studies that compared EBR/GZR vs. other direct antiviral agents suggested that EBR/GZR was generally more cost-effective or dominant than daclatasvir/asunaprevir (DCV/ASV), sofosbuvir/velpatasvir (SOF/VEL), ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir (3D) but not more cost-effective than glecaprevir/pibrentasvir (GLE/PIB). Two studies from China and one study from the USA that compared EBR/GZR vs. pegylated interferon and ribavirin (PegIFN/RBV) consistently indicated that EBR/GZR was generally more cost-effective than PegIFN/RBV. One study from Italy compared EBR/GZR with SOF + PegIFN/RBV and suggested that EBR/GZR had a lower cost and higher effectiveness. One study from France and one study from the USA confirmed that compared with non-therapy for patients with chronic kidney disease, EBR/GZR was cost-effective at commonly accepted current standards. All included studies were of good quality of reporting, with an average score of 21.9 (range 19-23). Conclusion: EBR/GZR for CHC genotype 1 might be cost-effective or dominant compared with PegIFN/RBV and other direct antiviral agents (SOF/VEL, 3D, DCV/ASV, LDF/SOF) or non-therapy. However, under certain assumptions, EBR/GZR was not a cost-effective alternative for CHC patients vs. GLE/PIB.

Encorafenib in Combination With Cetuximab After Systemic Therapy in Patients With BRAFV600E Mutant Metastatic Colorectal Cancer: German Health Technology Assessment-Driven Analyses From the BEACON CRC Study.

BACKGROUND: Purpose of this analysis was to report data of the BEACON CRC trial used in the German Health Technology Assessment (HTA) and previously unpublished data focusing on the dual blockade (encorafenib + cetuximab) and appropriate comparative therapy (ACT/control: cetuximab + irinotecan-based chemotherapy) of patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: Analyses included overall survival (OS) and time-to-event analyses of morbidity and safety. RESULTS: A total of 220 patients received encorafenib + cetuximab and 221 patients ACT/control. Median OS was 9.3 (encorafenib + cetuximab) versus 5.9 months (ACT/control) (stratified hazard ratio (HRstrat): 0.61 [95% confidence interval: 0.48-0.77]). Time-to-response (TTR) showed a statistically significant advantage for encorafenib + cetuximab compared to ACT/control (HRstrat [95% CI]: 10.46 [3.75; 29.15]; P < .0001). Median progression-free survival 2, ie, PFS after initiation of subsequent treatment after completion of study treatment, was 8.3 (dual blockade) versus 5.3 months (ACT/control), representing a statistically significant benefit for the dual blockade (HRstrat [95% CI]: 0.62 [0.48; 0.78]; P < .0001). The statistically significant advantage for diarrhea (EORTC QLQ-C30) reached clinical relevance (LS-mean [95% CI]; P-value / Hedges'g [95% CI]: -12.61 [-17.75; -7.47]; P < .0001 / -0.53 [-0.74; -0.31]). The time-to-event analyses showed a statistically significant benefit for the dual blockade for serious adverse events (AE), severe AEs and AEs leading to discontinuation. CONCLUSION: In the HTA, the German G-BA granted a "hint for a considerable additional benefit" of encorafenib + cetuximab compared to the ACT in BRAFV600E-mutant mCRC patients. This treatment is considered the new standard of care for these patients.

Effect of carbendazim on honey bee health: Assessment of survival, pollen consumption, and gut microbiome composition.

Gut microbiota and nutrition play major roles in honey bee health. Recent reports have shown that pesticides can disrupt the gut microbiota and cause malnutrition in honey bees. Carbendazim is the most commonly used fungicide in China, but it is not clear whether carbendazim negatively affects the gut microbes and nutrient intake levels in honey bees. To address this research gap, we assessed the effects of carbendazim on the survival, pollen consumption, and sequenced 16 S rRNA gene to determine the bacterial composition in the midgut and hindgut. Our results suggest that carbendazim exposure does not cause acute death in honey bees even at high concentrations (5000 mg/L), which are extremely unlikely to exist under field conditions. Carbendazim does not disturb the microbiome composition in the gut of young worker bees during gut microbial colonization and adult worker bees with established gut communities in the mid and hindgut. However, carbendazim exposure significantly decreases pollen consumption in honey bees. Thus, exposure of bees to carbendazim can perturb their beneficial nutrition homeostasis, potentially reducing honey bee immunity and increasing their susceptibility to infection by pathogens, which influence effectiveness as pollinators, even colony health.

Residue distribution and risk assessment of bifenazate and its metabolite in garlic plant.

The dissipation, conversion and risk assessment of bifenazate and bifenazate-diazene in garlic plant were studied by a modified QuEChERS method coupled with UHPLC-MS/MS for the first time. Bifenazate dissipated rapidly in garlic chive and serpent garlic with the half-lives of 3.0-3.9 days and 6.1-6.9 days, respectively. Bifenazate residue on garlic (<0.01 mg/kg) was significantly lower than the other two matrices in the whole growing period, which meant residues in the above-ground part were not transferred to the garlic. Furthermore, garlic chive had higher residues than serpent garlic due to the differences in morphological characteristics. Bifenazate-diazene was easier to convert to bifenazate, with the conversion rates of 93%, 16% and 32% in garlic, serpent garlic and garlic chive extracts, respectively. Additionally, the dietary intake risk for bifenazate was acceptable with RQchronic < 100% according to the international and national assessments.

Cost-effectiveness of encorafenib plus cetuximab in BRAF V600E-mutated colorectal cancer.

Recently, the introduction of encorafenib in combination with cetuximab was considered as a practice changing in BRAFV600-mutated metastatic colorectal cancer. The aim of this paper was to assess the cost-effectiveness of encorafenib plus cetuximab in the second-line treatment of BRAFV600-mutated metastatic colorectal cancer. BEACON CRC Trail was considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (overall survival). Four hundred forty-one patients were included. Differences in costs between the two arms (encorafenib plus cetuximab vs FOLFIRI plus cetuximab) was 59 501 €, with a cost of 17 500 € per month of overall survival-gain. Combining pharmacological costs of drugs with the measure of efficacy represented by overall survival, at the actual prize encorafenib cannot be considered cost-effectiveness for second-line treatment of BRAFV600-mutated metastatic colorectal cancer.

Dissipation and dietary risk assessment of carbendazim and epoxiconazole in citrus fruits in China.

BACKGROUND: Carbendazim and epoxiconazole are widely applied to control anthracnose and sand bark fungal diseases in citrus. The residues of these two fungicides in citrus and their potential risk to consumers have generated much public concern. We therefore sought to investigate the dissipation, residue, and dietary risk assessment of carbendazim and epoxiconazole in citrus. RESULTS: The dissipation kinetics and residue levels of carbendazim and epoxiconazole in citrus under field conditions were measured using dispersive solid-phase extraction and ultra-high-performance liquid chromatography-tandem mass spectrometry. The citrus samples were extracted with acetonitrile and purified by primary secondary amine sorbent. The mean recoveries of carbendazim and epoxiconazole ranged from 86.2 to 105.6% and relative standard deviations were ≤9.8%. The half-lives of carbendazim and epoxiconazole in whole citrus ranged from 2.0 to 18.0 days. Hazard quotient (HQ) and risk quotient (RQ) models were applied to whole citrus for dietary exposure risk assessment based on the terminal residue test. Hazard quotients ranged from 0.066 to 0.134% and RQs from 18.48 to 82.12%. CONCLUSION: Carbendazim and epoxiconazole in citrus degraded rapidly following first-order kinetics models. The dietary risk of exposure to both carbendazim and epoxiconazole through citrus, based on HQ and RQ, was acceptable for human consumption. This study indicates scientifically validated maximum residue limits in citrus, which are currently lacking for epoxiconazole in China. © 2021 Society of Chemical Industry.