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There is currently limited data on the potential effects of tire and road wear particles (TRWP) on human health. TRWP include tire fragments, but also road wear materials, dust, adsorbed gaseous pollutants and different types of inclusions that could affect their hazard profiles. Due to their availability and lower complexity, ground tire particles (TP) are often used in toxicological studies. However, this makes it difficult to draw firm conclusions about the potential hazard of actual TRWP. Here, we compared the in vitro toxicological profile of ground TP and actual TRWP emissions of similar size collected from road traffic. For this purpose, TP and TRWP were separately incubated with alveolar macrophages for 24 h, and the cellular response was evaluated in terms of cytotoxicity, proinflammatory response and oxidative stress. Both TP and TRWP induced neither significant cytotoxicity nor oxidative stress, but triggered a concentration-dependent proinflammatory response, as evidenced by increased TNF-α production. The level of TNF-α production was slightly higher with TRWP than with TP, independent of the particle dose. All in all, the pulmonary toxicity of TRWP could be due primarily to the tire tread inclusions and only marginally to other particle components (i.e. road wear materials, dust …). Although these preliminary results need to be confirmed by further analysis, they could be useful for tire manufacturers in the production of safer-by-design tires., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Poor adherence to asthma and chronic obstructive pulmonary disease maintenance therapies impairs health outcomes. Proven and cost-effective programs to promote adherence and persistence are not yet in regular widespread use. Implementation costs are a potential barrier to uptake of such programs., Objective: We undertook a systematic literature review and narrative synthesis of studies investigating the cost-effectiveness of treatment adherence-promoting programs or that determined their impact on health care budget directly or via health care resource use (HCRU)., Methods: We identified relevant publications using Medline and PreMEDLINE (PubMed), Embase (Embase.com, Elsevier), and EconLit for publications between January 2000 and July 2021. We also searched clinical trial databases and selected conference proceedings., Results: Of 1,910 potentially relevant articles, 26 met prespecified inclusion criteria and underwent data extraction. Eleven reported a direct assessment of adherence, 15 included economic evaluations, and 17 described HCRU. None included an analysis of biologic medication use. When they were studied, interventions were often found to be highly cost-effective, with dominant incremental cost-effectiveness ratios in some cases. Reductions in direct costs and HCRU (health care visits, hospital admissions, and/or the use of medications, including add-on/reliever treatment and antibiotics) were frequently reported. Reported use of maintenance treatments improved in some studies. Counseling and/or digitally informed programs were used in all cases in which favorable outcomes were observed., Conclusions: Adherence-promoting interventions are mostly cost-effective and often result in reduced HCRU and associated costs. Multidisciplinary care involving one-to-one advice and digitally enhanced communications appear to offer the greatest benefit., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to examine tire and road wear particle (TRWP) emissions under realistic conditions in order to provide some valuable insights into understanding their sources and fate in the environment. TRWP emissions were evaluated with a fully instrumented vehicle driving on five representative road types: urban, ring road, suburban, highway, and rural. Multiple vehicle dynamic variables were recorded to assess the factors influencing these emissions. For the first time, emitted particles were collected on filters and analyzed by means of pyrolysis coupled with gas chromatography-mass spectrometry to determine the polymeric content of tires, in specifically quantifying styrene-butadiene rubber (SBR) and butadiene rubber (BR) pyrolytic markers. The measurements obtained from the five road types revealed similar size distributions for SBR + BR emissions, with maxima found in the (ultra)fine fraction (< 0.39 µm). Upon applying an SBR + BR-to-TRWP conversion factor, (ultra)fine fraction TRWP emissions proved to be the highest for suburban (64 ± 5 µg/km), followed by highway, urban, ring road and rural routes. The output represents up to 480 tons of TRWP per year emitted in the EU 27 , thus suggesting a widely impregnated atmospheric compartment capable of threatening human health. Furthermore, an analysis of variables revealed that acceleration, tire constraints, and constant sustained driving factors had specific impacts on TRWP emissions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Non-exhaust emissions are now recognized as a significant source of atmospheric particulate matter and the trend towards a reduction of conventionally fueled internal combustion engine vehicles on the road is increasing their contribution to air pollution due to lower exhaust emissions. These particles include brake wear particles (BWP) and tire-road contact particles (TRCP), which are composed of tire wear particles (TWP), road wear particles (RWP) and resuspended road dust (RRD). The goal of this study has therefore been to design an original experimental approach to provide insight into the chemical composition of particles emitted at the tire-road contact, focusing on the micron (PM 10-1μm ) and submicron (PM 1-0.1μm ) fractions. Through this characterization, an examination of the different TRCP generated by different materials (tire, road surface, brake system) was conducted. To achieve this, TRCP were collected at the rear of the wheel of an instrumented vehicle during road and track tests, and a SEM-EDX analysis was performed. Our experimental conditions have allowed us to demonstrate that, at the individual particle scale, TRCP are consistently associated with road dust materials and particles solely composed of tire or road materials are practically non-existent. The contribution of BWP to TRCP is marked by the emission of Fe-rich particles, including heavy metals like Ba, Mn and Cr. TWP, which result from rubber abrasion, consist of C-rich particles abundant in Si, Zn, and S. RWP, mainly composed of Al, Si, Fe, and Ca, can be either part of RRD or internally mixed with emitted TWP. The findings of this study highlight the substantial role of RRD to TRCP emissions under real driving conditions. Consequently, it underscores the importance of examining them simultaneously to achieve a more accurate estimation of on-road traffic emissions beyond the vehicle exhaust., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Inflammatory bowel disease poses significant social and economic burdens. We assessed the budget impact of including the recently approved subcutaneous (SC) formulation of vedolizumab as maintenance therapy (MT) in patients with ulcerative colitis (UC) in France., Methods: A decision-analytic model was developed from a French payer's perspective over 5 years to assess budget impact of including vedolizumab SC as MT for UC following induction therapy with vedolizumab intravenous (IV), by subtracting outcomes of a 'world without vedolizumab SC' from a 'world with vedolizumab SC.' Comparators included approved therapies: infliximab (branded/biosimilar), adalimumab (branded/biosimilar), golimumab, ustekinumab, and vedolizumab IV. The model predicts drug, medical, and total costs, including indirect costs in a scenario analysis. A one-way sensitivity analysis explored the impact of varying individual parameters., Results: Including vedolizumab SC as MT following vedolizumab IV induction yielded total cost savings of €59,176,842 (biologic-naïve) and €22,004,135 (biologic-experienced) versus a world without vedolizumab SC. Including indirect costs yielded cost savings in biologic-naïve (€62,600,716) and biologic-experienced (€24,314,915) populations in a world with vedolizumab SC., Conclusions: Introducing vedolizumab SC as MT after IV induction is expected to have substantial cost savings to a health plan from a French payer's perspective versus a world without vedolizumab SC.

Aim: De novo relapsed and/or refractory acute myeloid leukemia (rrAML) has limited treatment options for patients not eligible ('unfit') to receive intensive chemotherapy-based interventions. The authors aimed to summarize outcomes for licensed therapies in this setting. Materials & methods: A systematic literature review identified licensed therapies in this setting. A feasibility assessment was made to conduct a network meta-analysis to evaluate comparative efficacy. Results: Seven unique trials were identified. Median survival months were 13.8 for gemtuzumab ozogamicin (GO), 9.3 for gilteritinib (FLT3 mutated rrAML), 5.6 for low-dose cytarabine and 3.2 for best supportive care; transplant rates with gilteritinib and GO were 25.5 and 19%, respectively. A network meta-analysis was not feasible. Conclusion: There remains a high unmet need in de novo rrAML patients not eligible for intensive therapy, with GO and gilteritinib (only FLT3-mutated AML) providing the best current options.

Aim: To evaluate adherence, healthcare resource utilization (HRU) and costs for glatiramer acetate (GA; injectable), dimethyl fumarate (oral) and teriflunomide (oral) in relapsing multiple sclerosis. Patients & methods: Retrospective analyses of a claims database. Results: Teriflunomide patients were older with more co-morbidities and fewer relapses versus GA and dimethyl fumarate. GA patients were mostly disease-modifying therapies (DMTs)-treatment naive. Treatment adherence was 61-70%. All DMTs reduced HRU versus pre-index. Costs were comparable across cohorts. High adherence reduced hospitalizations and several costs versus low adherers. Conclusion: Adherence rates were high and comparable with all DMTs. Similar (and high) reductions in HRU and costs occurred with all DMTs. High adherence improved economic outcomes versus low adherence. Thus, investing in adherence improvement is beneficial to improve outcomes in relapsing multiple sclerosis.

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed., (© Individual authors.)

Aim: Assess the suitability of standard parametric, piecewise and mixture cure models (MCMs) for modeling long-term survival of acute myeloid leukemia patients achieving remission following treatment with gemtuzumab ozogamicin (GO) + standard chemotherapy (SC) or SC alone. MCMs can model survival data comprising of statistically cured (patients in long-term remission) and uncured patients. Materials & methods: Models were fit to patient-level data corresponding to individual treatment arms. Results: Visual inspection showed that MCMs fit the clinical data best. Survival modeling with MCMs showed that treatment with GO + SC versus SC alone results in higher statistical cure rates for event-free survival (rates: 26-35% vs 21-23%) and overall survival (rates: 48-52% vs 38-44%). Conclusion: MCMs are well suited to modeling long-term survival in acute myeloid leukemia patients. Clinical trial registration: NCT00927498 (ClinicalTrials.gov).

Objective: Bosutinib, nilotinib and dasatinib are approved for the treatment of patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). In the absence of head-to-head comparisons between second-generation tyrosine kinase inhibitors (TKIs), the objective of this study was to indirectly compare the efficacy of bosutinib with nilotinib and dasatinib in first-line (1L) CP-CML., Methods: Cross-trial heterogeneity in terms of patient baseline characteristics and imatinib dose escalation are difficult to adjust for in network meta-analyses and anchored matching-adjusted indirect treatment comparisons (MAICs). Therefore, an unanchored MAIC was performed using patient level data from bosutinib (BFORE trial) and published aggregated data from nilotinib (ENESTnd) and dasatinib (DASISION) trials. After matching, cytogenetic and molecular responses, and disease progression, after a minimum follow-up of 24 months were compared between nilotinib versus bosutinb and dasatinib versus bosutinib., Results: The comparison of nilotinib versus bosutinib resulted in no statistically significant differences for MMR at and by 24 months, MR4 by 24 months, MR4.5 at and by 24 months, CCyR by 24 months, and disease progression, however, a decreased odds of MR4 at 24 months in favor of bosutinib versus nilotinib was observed. The comparison of dasatinib versus bosutinib by 24 months resulted in no statistically significant differences for MMR, disease progression, and CCyR, however a decreased odds of MR4.5 in favor of bosutinib versus dasatinib was observed., Conclusions: Overall, in these analyses bosutinib demonstrates equivalent efficacy to nilotinib and dasatinib in the treatment of patients with newly diagnosed CP-CML.

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m 2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m 2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients. Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures). Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44-0.90, p  < .05) and 0.82 (0.54-1.26, p  = .37) respectively, and resulted in an OR for MCyR of 0.78 (0.53-1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38-0.76, p  < .01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46-1.13, p  = .16) for OS and a non-significant OR of 0.98 (0.71-1.35) for MCyR. Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically in favor of dasatinib and nilotinib, but not statistically significant.

The classic features of molar pregnancy are irregular vaginal bleeding, hyperemesis, enlarged uterus for gestational age and early failed pregnancy. Less common presentations include hyperthyroidism, early onset pre-eclampsia or abdominal distension due to theca lutein cysts. Here, we present a case of molar pregnancy where a woman presented to the emergency department with symptoms of acute abdomen and was treated as ruptured ectopic pregnancy. The woman underwent laparoscopy and evacuation of retained products of conception. Histological examination of uterine curettage confirmed the diagnosis of a complete hydatidiform mole. The woman was discharged home in good general condition with a plan for serial beta-human chorionic gonadotropin (beta-hCG) follow-up. Complete follow-up includes use of contraception and follow-up after beta-hCG is negative for a year., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Soils are playing a central role in the transfer and accumulation of anthropogenic pollutants in urbanized regions. Hence, this study aimed at examining the contamination levels of selected soils collected within and around the Paris conurbation (France). This also evaluated factors controlling contamination. Twenty-three trace and major elements as well as 82 organic micropollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), phthalates (PAEs), polybrominated diphenyl ethers (PBDEs), alkylphenols (APs), and perfluoroalkylated substances (PFASs) were analyzed. Results reinforced the concern raised by the occurrence and levels of metals such as Zn, Pb, Cu, and Hg, identified as metallic markers of anthropogenic activities, but also pointed out the ubiquitous contamination of soils by organic micropollutants in the 0.2-55,000-μg/kg dw range. For well-documented compounds like PAHs, PCBs, and to a lesser extent PBDEs, contents were in the range of background levels worldwide. The pollutant stock in tested soil was compared to the annual atmospheric input. For PAHs; Pb; and to a lesser extent Zn, Cu, Cd, Hg, Sb, PAEs, and APs, a significant stock was observed, far more important than the recent annual atmospheric fluxes. This resulted from both (i) the persistence of a fraction of pollutants in surface soils and (ii) the cumulative atmospheric inputs over several decades. Regarding PBDEs and PFASs, stronger atmospheric input contributions were observed, thereby highlighting their recent dispersal into the environment.

This study investigated, on both metric and centimetric scales, mercury (Hg) transformations and dynamics within a water column chemocline of a tropical reservoir. Data collected included conventional measurement of Hg in water samples, diffusive gradients in thin-films (DGT) assessments, and thermodynamic speciation modeling in order to portray the biogeochemical processes that control elemental Hg (EM) and dissolved monomethylated Hg (MeHg D ) production. The primary contribution of this study is demonstration that the DGT technique can be successfully implemented to examine labile Hg compound mobilization, and estimation of how local substratum facilitates Hg reduction and methylation reactions. DGT profiles with a resolution of 1cm revealed a fine sequence of prominent Hg reduction/oxidation reactions at the chemocline level. This is interpreted as a manifestation of both: i) kinetic effects capable of arising inside the diffusive layer of DGT devices, and ii) extremely localized production or consumption of reducible and methylable Hg. Another key result obtained at the metric scale is that EM and MeHg D production at a water column chemocline are intricately linked, as both are fueled by nutrients episodically released during the decomposition of falling epilimnetic organic particles or inhibited by dissolved organic matter and inorganic compounds continuously transported from the deeper monimolimnion. Finally, it is worth noting that the chemocline acts as an accumulation and recycling domain for falling MeHg-loaded organic particles, whereas the high primary productivity layer in the epilimnion represents the principal reactor with respect to Hg methylation and reduction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Roadside contamination (of air, soils and organisms) by polycyclic aromatic hydrocarbons (PAHs) was examined in an arable field and a mature forest (central France). Measured contents accounted for minute fractions of the cumulative vehicular exhaust emissions. The fate of vehicular PAHs was affected by many factors, including: atmospheric load dispersal, deposition on soils and vegetation, incorporation into water and organic matter cycles, and accumulation in species. Given these empirical results, we evaluated the consistency of a set of well-known diagnostic ratios. This effort has revealed that: i) most diagnostic ratio values vary considerably across roadside samples, including exhaust emissions; and ii) the first few meters from the carriageway or the road verge/forest interface or remote areas where surface water accumulates actually define turning or inflection points in the ratio profiles. These variations constitute a major obstacle to delimitating the extent of roadside contamination due to PAHs, in addition to raising questions over the applicability of ratios routinely used to designate sources. New ratios, namely (Flt+BkF)/(Pyr+BbF) and (Flt+BkF+BghiP)/Σ10PAH, have been specifically developed to address this challenge. The higher consistencies exhibited among environmental compartments as well as between surface soil and exhaust emissions still yield differentiated values relative to several industrial sources., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Elemental mercury (Hg(o)) for gold amalgamation is the main process applied by artisanal gold miners in South America, leading to important discharges into freshwater ecosystems. Through a 28-day experimental approach based on indoor microcosms, we simulated the chemical fate and bioavailability of Hg(o) droplets in the presence or absence of sediment collected from a typical forest creek that is unaffected by gold mining activities. Our results clearly showed significant mercury transfers in the water column in both the dissolved gaseous Hg(o) and oxidized (Hg(II)) forms, with a marked effect of the presence of sediment. After 28 days, Hg total (HgT) concentration in the water column was 25 times higher in sediment-free units (108 +/- 17 vs. 4 +/- 0.4 nM). Methylmercury (MeHg) determinations in the dissolved fraction showed a significant increase only in the presence of sediment after 7 and 14 days. Zebrafish (Danio rerio) were used as indicators for mercury bioavailability. The HgT determinations in four organs revealed significant accumulation levels as early as 7 days exposure, with marked differences in favor of fish collected from the sediment-free units. Significant MeHg increases were observed in the four organs only when sediment was present. Genomic tools applied to estimate sulfate-reducing bacteria communities showed mercury impacts on their diversity and distribution in the different compartments (water, sediment, biofilm, fish gut).

The Petit-Saut hydroelectric reservoir was filled in 1994 on the Sinnamary River in French Guiana (Amazonian basin). Flooding of the equatorial rain forest led to anoxia in most of the water column and enhanced mercury methylation in the reservoir hypolimnion. We selected the benthivorous/omnivorous fish species Curimata cyprinoides to investigate total mercury and methylmercury (MeHg) bioavailability and bioaccumulation capacities in the reservoir and downstream in the Sinnamary River. Mercury concentrations in the dorsal skeletal muscle were 10-fold higher in fish from the downstream zone. Stomach contents and stable nitrogen and carbon isotope ratios showed that biofilms and the associated invertebrate communities represented important food sources at the two sites. The delta 13C measurements indicated that biofilms in the flooded forest zone of the reservoir consist of endogenous primary producers; downstream, they are based on exogenous organic matter and microorganisms, mainly from the anoxic layers of the reservoir. Total mercury and MeHg concentrations in the biofilms and associated invertebrates were much higher at the downstream site compared to concentrations at the reservoir. Our results clearly show the importance of MeHg export from the anoxic layers of this tropical reservoir. We conclude that differences between biofilm composition and MeHg concentrations in the ingested food could explain the marked differences observed between mercury levels in fish.