Detailed Inventory of the Evaporative Emissions from Parked Gasoline Vehicles and an Evaluation of Their Atmospheric Impact in Japan.

A detailed inventory was taken of evaporative emissions from parked gasoline vehicles in the Kanto region of Japan, 2015, based on the theoretical model to evaluate the amount of evaporative emissions. The inventory showed that evaporative emissions were high in metropolitan and urban areas because of the large populations in these areas and the high vehicle parking frequency. Using the new inventory, the sensitivity of evaporative emissions to the concentration of tropospheric ozone and secondary organic aerosol was evaluated using the chemical transport modeling solver, the community multiscale air quality modeling system (CMAQ), coupled with the weather research and forecasting (WRF) model. The calculation results showed that the evaporative emissions from permeation through fuel related parts were more significant in the generation of the tropospheric ozone than those from fuel tank venting. This was because the permeation emissions included a high proportion of high maximum incremental reactivity value components, such as aromatics. Neither of the evaporative emission types were significant secondary organic aerosol generators. Whole reduction of the evaporative emissions contributed an approximate 3 ppb decrease in tropospheric ozone in urban areas during the daytime. This information will contribute to the volatile organic compound (VOC) management strategy employed by governments worldwide.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.

BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

Variable indoleamine 2,3-dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy.

Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti-programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti-programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti-CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti-PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti-PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti-PD-1 antibody from the perspective of IDO and PD-L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression-free survival (HR = 0.33, 95% CI = 0.13-0.81, P = 0.016), whereas PD-L1 expression on tumors was not associated with progression-free survival. Significantly lower expression of IDO in tumors was found in non-responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti-PD-1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.

Subcutaneous Nodule on the Right Palm of a Young Boy: A Quiz.

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Context-Dependent Regulation of Collagen XVII Ectodomain Shedding in Skin.

Pemphigoid is a common autoimmune blistering disorder in which autoantibodies target transmembrane collagen XVII (COL17), a component of hemidesmosomes in basal keratinocytes. The ectodomain of COL17 can be cleaved from the cell surface within the juxtamembranous extracellular NC16A domain, and, interestingly, certain autoantibodies of pemphigoid patients preferentially react with the shed ectodomain. These findings suggest that COL17 ectodomain shedding generates neoepitopes on the shed form; however, the regulatory mechanism of the shedding in in vivo skin and the pathogenicity of the neoepitope-targeting antibodies still are uncertain. To address these issues, we produced rabbit antibodies specifically reacting with N-terminal cleavage sites of the shed COL17 ectodomain. The antibodies showed that certain amounts of the human COL17 ectodomain are cleaved physiologically at Gln(525) in in vivo skin. In contrast, migrating human keratinocytes cleave COL17 at Leu(524) but not at Gln(525). The passive transfer of antibodies reacting with an N-terminal cleavage site of the mouse COL17 ectodomain into neonatal wild-type mice failed to induce blister formation, even though the antibodies bound to the dermal-epidermal junctions, indicating that cleavage site-specific antibodies have reduced or absent pathogenicity for blister formation. This study shows the ectodomain shedding of COL17 to be a physiological event in in vivo human skin that probably generates nonpathologic epitopes on the cleavage sites.

Kinetic study of isoprene hydroxy hydroperoxide radicals reacting with sulphur dioxide and their global-scale impact on sulphate formation.

Isoprene is the most relevant volatile organic compound emitted during the biosynthesis of metabolism processes. The oxidation of isoprene by a hydroxy radical (OH) is one of the main consumption schemes that generate six isomers of isoprene hydroxy hydroperoxide radicals (ISOPOOs). In this study, the rate constants of ISOPOOs + sulphur dioxide (SO2) reactions that eventually generate sulphur trioxide (SO3), the precursor of sulphate aerosol (SO42-(p)), are determined using microcanonical kinetic theories coupled with molecular structures and energies estimated by quantum chemical calculations. The results show that the reaction rates range from 10-27 to 10-20 cm3 molecule-1 s-1, depending on the atmospheric temperature and structure of the six ISOPOO isomers. The effect of SO3 formation from SO2 oxidation by ISOPOOs on the atmosphere is evaluated by a global chemical transport model, along with the rate constants obtained from microcanonical kinetic theories. The results show that SO3 formation is enhanced in regions with high SO2 or low nitrogen oxide (NO), such as China, the Middle East, and Amazon rainforests. However, the production rates of SO3 formation by ISOPOOs + SO2 reactions are eight orders of magnitude lower than that from the OH + SO2 reaction. This is indicative of SO42-(p) formation from the direct oxidation of SO2 by ISOPOOs, which is almost negligible in the atmosphere. The results of this study entail a detailed analysis of SO3 formation from gas-phase reactions of isoprene-derived products.

Ozone responses to reduced precursor emissions: A modeling analysis on how attainable goals can improve air quality in the Mexico City Metropolitan Area.

High tropospheric ozone (O3) concentrations prevent the improvement of the air quality in the Mexico City Metropolitan Area (MCMA). Although the problem has improved considerably since the 1990s, a rebound in O3 levels in recent years has raised concerns about the deteriorating air quality. The nonlinear relationship between O3 formation and the emissions of its main precursors, i.e., volatile organic compounds (VOCs) and nitrogen oxides (NOx), is a challenge when measures are enacted for effective mitigation of the O3 problem. This study evaluated the reduction in precursors, VOCs and NOx, using an up-to-date regional air quality model (HERMES-Mex-WRF-CMAQ). For evaluating realizable scenarios, the decline in VOC achieved in Japan after policy implementation was the targeted VOC reduction (40 % from area sources), and the NOx reduction observed in the MCMA during the COVID-19 pandemic was the targeted NOx reduction (40 % from mobile sources). The analysis evaluated the O3 responses to changes in a single precursor and a combination of both during a period of high O3 concentrations (April 2019). The results showed that 40 % reduction in VOC emissions would decrease the O3 8-h maximum concentrations by 16 %. However, 40 % reduction in NOx emissions would increase O3 by >15 %. The simultaneous reduction of both precursors did not significantly affect O3 levels. The diagnosis of ozone sensitivity using the H2O2/HNO3 ratios reinforced the simulation findings, indicating that VOC emissions limited ozone formation in most MCMA areas. As the simulated scenarios were based on factual case studies, our research offers insights into the realistic aims of MCMA policies to reduce O3 levels.

Impact of introducing net-zero carbon strategies on tropospheric ozone (O3) and fine particulate matter (PM2.5) concentrations in Japanese region in 2050.

In this study, we estimated the future emission inventory of primary air pollutants in Japan in 2050 after introducing low-carbon technology based on the results of the socio-economic model provided by the Japanese government. The results suggested that introducing net-zero carbon technology would contribute to a 50-60 % decrease in primary NOx, SO2, and CO emissions and a ~30 % decrease in primary emissions of volatile organic compounds (VOCs) and PM2.5. The estimated emission inventory and future meteorological conditions in 2050 were applied as inputs to a chemical transport model. A scenario involving the application of future reduction strategies with relatively moderate global warming (RCP4.5) was evaluated. The results showed that the concentration of tropospheric ozone (O3) was highly reduced compared with that in 2015 after applying net-zero carbon reduction strategies. On the other hand, the fine particulate matter (PM2.5) concentration under the 2050 scenario was expected to be equal or higher because of the growth in secondary aerosol formation caused by the increase in short-wave radiation. Finally, the premature mortality change from 2015 to 2050 was analyzed, and the change in air quality contributed by net-zero carbon technology will contribute to a ~4000 decrease in premature deaths in Japan.

Sequential local injection of low-dose interferon-beta for maintenance therapy in stage II and III melanoma: a single-institution matched case-control study.

OBJECTIVE: To determine the beneficial effect of maintenance therapy in stage II and III melanoma by sequential local injection of low-dose interferon-ß. METHODS: We reviewed 46 patients with stage II and III primary melanoma at our institution from 2004 through 2009. Twenty-one patients were treated with interferon-ß maintenance therapy consisting of subcutaneous injection of natural interferon-ß at a dose of 3 × 10(6) IU/day for 10 consecutive days, and 25 patients underwent observation alone. RESULTS: Compared with all patients, overall survival and relapse-free survival were significantly worse in the observation group than in the interferon-ß group (p = 0.024 and 0.029, respectively). In stage II, a significant difference in overall survival, but not in relapse-free survival, was seen between the two groups (p = 0.041). When the interferon-ß group was stratified by subgroup, there was a statistical difference only between dosage and duration (p = 0.027 and p < 0.001, respectively). CONCLUSIONS: This study demonstrates that maintenance therapy by interferon-ß is beneficial in the outcome of the disease without substantial toxic effects, especially in patients with stage II melanoma. Extension of the duration of treatment beyond 2 years could further improve the therapeutic efficacy of interferon-ß.

Improvement of the Theoretical Model for Evaluating Evaporative Emissions in Parking and Refueling Events of Gasoline Fleets Based on Thermodynamics.

Evaporative emissions from gasoline vehicles are known as an emission source of volatile organic compounds that are the precursors of tropospheric ozone and secondary organic aerosols. We formulated new estimation models based on thermodynamics for two main evaporation processes, namely diurnal breathing loss (DBL) and refueling loss (RFL) from gasoline vehicles. The models enable us to evaluate real-world evaporative emissions using the fuel composition and environmental temperature as input parameters. The proposed models well replicated the experimental results of the canister breakthrough emission from DBL (DBLb) and RFL obtained in previous experimental studies. The evaporative DBLb and RFL emissions in Japan in 2015 were then estimated using the new models. The evaporative emission from DBLb was approximately 8800 t/y, and that from RFL was 73,300 t/y. In addition, we estimated the variation in fuel evaporative emissions due to the market penetration of zero-emission vehicles. Even if the sale of gasoline vehicles is banned from 2035, the evaporative emissions of DBLb and RFL from gasoline vehicles will only be halved after 2040. The two models proposed for estimating the DBLb and RFL in this study are expected to be applied in the evaluation of the emission inventories of volatile organic compounds in future work.

Exhaust emissions from gasoline vehicles after parking events evaluated by chassis dynamometer experiment and chemical kinetic model of three-way catalytic converter.

Despite the worldwide trend of introducing of zero-fuel-based vehicles to the market, the emissions of air pollutants and greenhouse gases from passenger vehicles are likely to remain a concern for the coming 20 to 30 years. In this study, exhaust emissions of gasoline engines running after varying parking durations were measured using a chassis dynamometer. The experimental results showed that exhaust emissions of hydrocarbons, nitrogen oxides, and carbon monoxide from most vehicles increased dramatically following 60 to 120 min of parking, and were higher than cold-start (1040 + min parking) emissions, indicating the impact of parking duration on atmospheric pollutant emissions. The after-treatment capacity of the three-way catalytic converter was evaluated by chemical kinetic modeling of the chemical reactions on the catalyst coupled with a time-dependent energy conservation equation. The results of the model calculation indicated that both the initial temperature of the three-way catalytic converter and the inlet engine gas temperature are critical factors impacting exhaust pollutants after parking; therefore, proper management to reduce the emissions after middle-term parking durations should be developed to mitigate air pollution.

Carotenoderma due to lycopenemia: A case report and evaluation of lycopene deposition in the skin.

Carotenoderma is a yellow-orange coloration of the skin caused by high levels of serum carotenoids, mostly due to the excessive intake of carotenoid-rich foods. The yellowish coloration is typically observed on the palms, soles, and nasolabial folds. Although the physical appearance is prominent, the condition itself is benign and harmless. Diagnosing carotenoderma is not difficult because of its unique manifestations, but its pathophysiology remains unclear. We report a relatively rare case of carotenoderma due to lycopenemia caused by the excessive intake of lycopene-rich vegetables and fruits. Lycopene is a carotenoid component that is distinguished by the high absorption of light around 488 nm. Given these characteristics, we examined a hematoxylin-eosin-stained specimen from the patient and tape-stripped samples by fluorescent microscopy with 488 nm wavelength emission and compared them with normal skin samples. Notably, the patient's samples showed a weaker autofluorescence in the stratum corneum and sweat glands. Furthermore, we measured carotenoid concentrations in the patient's skin noninvasively with Vegecheck® and found a higher score than the average of 24 healthy volunteers. These results support the long-held hypothesis that carotenoids are secreted in sweat and are deposited in the stratum corneum. To the best of our knowledge, no previous reports have measured skin carotenoid levels nor detailed the pathological findings of carotenoderma patients. This case further highlights that the excessive intake of lycopene causes carotenoderma and demonstrates that carotenoid deposition is particularly pronounced in the stratum corneum of the skin.