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Abstract Methane (CH4) emission reduction to limit warming to 1.5 °C can be tracked by analyzing CH4 concentration and its isotopic composition (δ 13C, δD) simultaneously. Based on reconstructions of the temporal trends, latitudinal, and vertical gradient of CH4 and δ13C from 1985 to 2020 using an atmospheric chemistry transport model, we show (1) emission reductions from oil and gas exploitation (ONG) since the 1990s stabilized the atmospheric CH4 growth rate in the late 1990s and early 2000s, and (2) emissions from farmed animals, waste management, and coal mining contributed to the increase in CH4 since 2006. Our findings support neither the increasing ONG emissions reported by the EDGARv6 inventory during 1990–2020 nor the large unconventional emissions increase reported by the GAINSv4 inventory since 2006. Total fossil fuel emissions remained stable from 2000 to 2020, most likely because the decrease in ONG emissions in some regions offset the increase in coal mining emissions in China.

We investigated low Earth orbit satellite (LEO) communications applying Multiple-Input/Multiple-Output (MIMO) technology to the feeder link transmission between a satellite and gateway antennas to improve the channel capacity. This paper calls LEO satellites using MIMO technology “LEO-MIMO” and considers satellite and gateway antenna configurations to improve the feeder link capacity. LEO-MIMO operates with a single LEO satellite equipped with multiple antenna elements and a gateway with multiple remotely located antennas. The conditions of the antenna configuration, such as the distances of satellite/gateway antenna elements and the number of antenna elements in the satellite and gateway, affect the channel capacity of LEO-MIMO. This paper reveals antenna configurations that improve the channel capacity for LEO-MIMO systems. Computer simulations show that the channel capacity of LEO-MIMO can achieve 4 bps/Hz at maximum higher than that of the conventional multi-beam system.

Abstract Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Abstract The dust direct radiative effect (DRE) depends strongly on the dust particle size distribution (PSD) and complex refractive index (CRI). Although recent studies constrained the dust PSD in the models, its CRI uncertainties are still large. As a result, whether dust warms or cools the climate system remains unclear. Here, we estimate the dust DRE by employing the regionally‐dependent dust CRI based on global measurements. We find that new dust CRI significantly enhances the scattering of dust in the shortwave while reduces its absorption in the longwave, which is opposite to that caused by increasing the coarse and giant dust fraction via constraining the PSD. Constraining both PSD and CRI ultimately leads to a net dust DRE of −0.68 W m−2, a cooling stronger than current model estimates.

IntroductionThe programmed death-1 (PD-1) immune checkpoint inhibitor pembrolizumab is currently approved in the US for the first-line (1L) treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), either alone or in combination with platinum and 5-fluorouracil (5-FU). However, the toxicity of 5-FU has motivated the study of alternate combinations that replace 5-FU with a taxane. The objective of the current study was to describe the baseline characteristics, treatment patterns and sequences, and real-world outcomes of individuals receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC in the US.MethodsThis was a retrospective study of US adults ≥18 years of age receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC, using electronic health record data from a nationwide de-identified database. Real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) outcomes were assessed using Kaplan–Meier analysis.ResultsThe study population comprised 83 individuals (80.7% male) with a median age of 64 years. The most common tumor site was the oropharynx (48.2%); 70.0% of these tumors were HPV-positive. A total of 71.1% of the study population had an Eastern Cooperative Oncology Group performance status of 0–1 at index date, 71.8% had a combined positive score for programmed death ligand-1 (PD-L1) expression of ≥1, and 30.8% had a score of ≥20. The median (95% CI) rwOS was 14.9 (8.8–23.3) months, rwToT was 5.3 (4.0–8.2) months, and rwTTNT was 8.7 (6.8–12.3) months. Among the 24 individuals who received a subsequent therapy, the most common second-line therapies were cetuximab-based (n = 9) or pembrolizumab-containing (n = 8) regimens.ConclusionsThe rwOS and other real-world outcomes observed for this study population further support pembrolizumab + platinum + taxane combination therapy as a potential 1L treatment option for R/M HNSCC.

In satellite Internet-of-Things (IoT) systems using the 920-MHz band Low Power Wide Area, available channels for each terminal are limited to avoid interference with terrestrial networks. Since this limitation depends on the location of the terminal, the available channels are different, resulting in throughput degradation. This paper proposes a transmission control scheme that reduces throughput degradation due to different available channels in the Contention Resolution Diversity Slotted ALOHA (CRDSA)/Irregular-Repetition Slotted ALOHA (IRSA) system. The proposed transmission control uses constraints that consider the characteristics of CRDSA/IRSA, as well as an objective function that considers fairness of throughput among terminals. Under these constraints and objective function, the transmission probability was calculated using an objective function that maximized the transmitting load. The computer simulation showed that it could achieve high throughput by preventing the influence of difference in the available channels.

Goal: To develop bending angle sensors based on double-layer capacitance for monitoring joint angles during cycling exercises. Methods: We develop a bending angle sensor based on double-layer capacitive and conducted three stretching, bending, and cycling tests to evaluate its validity. Results: We demonstrate that the bending angle sensor based on double-layer capacitance minimizes the change in the capacitance difference in the stretching test. The hysteresis and root mean square error (RMSE) compared with the optical motion capture show hysteresis: 8.0% RMSE and 3.1° in the bending test. Moreover, a cycling experiment for human joint angle measurements confirm the changes in accuracy. The RMSEs ranged from 4.7° to 7.0°, even when a human wears leggings fixed with the developed bending-angle sensor in the cycling test. Conclusion: The developed bending angle sensor provides a practical application of the quantitative and observational evaluation tool for knee joint angles.

BackgroundPembrolizumab, a PD-1 immune checkpoint inhibitor, is approved as first-line (1L) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) as monotherapy or in combination with platinum and 5-fluorouracil chemotherapy. Limited data exist on the use of these regimens in real-world settings.ObjectiveOur primary objectives were to describe baseline characteristics and real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) among individuals with R/M HNSCC receiving approved 1L pembrolizumab therapies. We also aimed to identify baseline factors associated with choice of 1L pembrolizumab therapy and with rwOS.MethodsThis was a retrospective cohort study of adults with R/M HNSCC receiving 1L pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We used Kaplan-Meier analyses to assess real-world outcomes, logistic regression modeling to identify factors associated with choice of 1L pembrolizumab therapy, and Cox proportional hazards models to identify factors associated with rwOS.ResultsThe study population included 431 individuals receiving 1L pembrolizumab monotherapy and 215 receiving 1L pembrolizumab plus chemotherapy. The use of 1L pembrolizumab monotherapy was associated with higher baseline combined positive score for PD-L1 expression, older age, higher Eastern Cooperative Oncology Group performance status (ECOG PS), laryngeal tumor site, and human papillomavirus (HPV)-positive tumor status. The pembrolizumab monotherapy group had a median (95% CI) rwOS of 12.1 (9.2–15.1) months, rwToT of 4.2 (3.5–4.6) months, and rwTTNT of 6.5 (5.4–7.4) months. Among this group, HPV-positive tumor status and lower ECOG PS were associated with longer rwOS, and oral cavity tumor site with shorter rwOS. The pembrolizumab plus chemotherapy cohort had a median (95% CI) rwOS of 11.9 (9.0–16.0) months, rwToT of 4.9 (3.8–5.6) months, and rwTTNT of 6.6 (5.8–8.3) months. In this group, HPV-positive tumor status was associated with longer rwOS.ConclusionsThis study adds to clinical trial data by summarizing real-world treatment outcomes with 1L pembrolizumab-containing therapies in a more heterogeneous population. Overall survival outcomes in both treatment groups were similar to those observed in the registration clinical trial. These findings support the use of pembrolizumab as standard of care for R/M HNSCC.

Abstract This study presents the results of the ERTDF S-12 project for searching an optimum reduction scenario of the short-lived climate pollutants (SLCPs) to simultaneously mitigate the global warming and environmental problems. The study utilized REAS emission inventory, Asia-Pacific Integrated Model-Enduse (AIM/Enduse), MIROC6 climate model, NICAM non-hydrostatic atmospheric model, and models for estimating environmental damages to health, agriculture, and flood risks. Results of various scenario search indicate that it is difficult to attain simultaneous reduction of global warming and environmental damages, unless a significant reduction of CO2 is combined with carefully designed SLCP reductions for CH4, SO2, black carbon (BC), NO x , CO, and VOCs. In this scenario design, it is important to take into account the impact of small BC reduction to the surface air temperature and complex atmospheric chemical interactions such as negative feedback between CH4 and NO x reduction. We identified two scenarios, i.e., B2a and B1c scenarios which combine the 2D-scenario with SLCP mitigation measures using End-of-Pipe (EoP) and new mitigation technologies, as promising to simultaneously mitigate the temperature rise by about 0.33 °C by 2050 and air pollution in most of the globe for reducing damages in health, agriculture, and flood risk. In Asia and other heavy air pollution areas, health-care measures have to be enhanced in order to suppress the mortality increase due to high temperature in hot spot areas caused by a significant cut of particulate matter. For this situation, the B1b scenario is better to reduce hot spot areas and high-temperature damage to the public health.

We have proposed a distributed array antenna (DAA) system for high-speed satellite communications. The DAA system uses multiple small tracking antennas and combines the transmission signals in-phase to increase the antenna gain. DAA system has a problem that the undesired radiation at the sidelobe direction increases as the antenna gain at the main lobe direction increases. In the mobile environment, the conventional technique can suppress the undesired radiation in the limited condition because of changing the direction of the undesired radiation according to the movement of the mobile station. This paper proposes a DAA technique that suppresses the undesired radiation by setting a transmission plate at each antenna aperture and moving them via adaptive control. The transmission plate consisting of a metal patch or slot retransmits electromagnetic waves and changes the amplitude and phase of the waves. To change the radiation patters of each antenna, the transmission plate rotates according to movement of the mobile station. After combining these changed signals, the adaptive control selects the rotate angle of the transmission plate to decrease the undesired radiation at the sidelobe direction. The antenna gain on the main lobe direction after combining is achieved with lower loss because the insertion loss through the transmission plate is smaller. The proposed technique offers more than $2.4$ dB improvement with three antennas and more than $3.5$ dB improvement with four antennas assuming each consists of $8 ¥times 8$ patches.

Abstract Uncertainty in risks posed by emerging stressors such as synthetic hormones impedes conservation efforts for threatened vertebrate populations. Synthetic hormones often induce sex‐biased perturbations in exposed animals by disrupting gonad development and early life‐history stage transitions, potentially diminishing per capita reproductive output of depleted populations and, in turn, being manifest as Allee effects. We use a spatially explicit biophysical model to evaluate how sex‐biased perturbation in life‐history traits of individuals (maternal investment in egg production and male‐skewed sex allocation in offspring) modulates density feedback control of year‐class strength and recovery trajectories of a long‐lived, migratory fish—shovelnose sturgeon (Scaphirhynchus platorynchus)—under spatially and temporally dynamic synthetic androgen exposure and habitat conditions. Simulations show that reduced efficiency of maternal investment in gonad development prolonged maturation time, increased the probability of skipped spawning, and, in turn, shrunk spawner abundance, weakening year‐class strength. However, positive density feedback disappeared (no Allee effect) once the exposure ceased. By contrast, responses to the demographic perturbation manifested as strong positive density feedback; an abrupt shift in year‐class strength and spawner abundance followed after more than two decades owing to persistent negative population growth (a strong Allee effect), reaching an alternative state without any sign of recovery. When combined with the energetic perturbation, positive density feedback of the demographic perturbation was dampened as extended maturation time reduced the frequency of producing male‐biased offspring, allowing the population to maintain positive growth rate (a weak Allee effect) and gradually recover. The emergent patterns in long‐term population projections illustrate that sex‐biased perturbation in life‐history traits can interactively regulate the strength of density feedback in depleted populations such as Scaphirhynchus sturgeon to further diminish reproductive capacity and abundance, posing increasingly greater conservation challenges in chemically altered riverscapes.

Abstract Background Translating pharmacogenetic research findings that have shown clinical efficacy into sustainable, routine clinical care at the institutional level requires strong evidence of improved patient outcomes bolstered by equitable reimbursement and a sound financial analysis. Although extensive research on the clinical value of pharmacogenetics has been completed, adoption into clinical practice lags due to a lack of evidence of clinical effectiveness and limited reimbursement. Methods The Sustainability Working Group within the NHGRI IGNITE I Network conducted an online survey of funded and non-funded IGNITE members to determine which genes they are researching, which have been translated into clinical practice, and how tests are billed. Data from the online surveys was consolidated and analyzed with results being tabulated for key findings. Due to the limited sample size, statistical analysis was forgone and results should be considered directional in nature. Results Fifteen out of twenty (75%) online survey responses were received and analyzed from IGNITE member sites delivering clinical care. Forty different genes were identified as being used for either research or clinical care. Thirty-two different genes were reported as being used clinically, an average of 6.9 genes were reported per site. Twenty-two and twenty-one genes were reported as being billed to third party payers or patients respectively. Although the survey did not ask whether sites submitting for reimbursement received payment, Medicare and Medicaid only reimburse for 6 of the 40 (15%) genes being tested. Of the 40 genes, 18 are rated by CPIC as having A/B level of evidence with the remainder being rated as C/D or having no rating. Approximately 32% more A/B rated genes were being reported clinically than non-A/B. Conclusion Adoption of pharmacogenetic testing continues to lag even at sites where leading experts conduct research and have the capability to report tests clinically. Clinical research that supports CPIC A level of evidence is important for provider and payer support. Adoption of pharmacogentic testing must also be justified financially, reimbursement is one key factor, and more health economic studies are needed in order to capture the value created by preventing drug-gene adverse events, emergency room visits, and hospitalizations.

Abstract The landscape of treatment for multiple myeloma (MM) has significantly changed over the last decade due to novel agents that have shown superiority in efficacy such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) over traditional therapies. However, the real‐world utilization of these new agents has not been studied well. This study evaluated year‐to‐year changes in treatment choices in a cohort of patients aged 66 or older in the Surveillance, Epidemiology, and End Results (SEER) registry linked with Medicare claims (SEER‐Medicare) data who were diagnosed with MM between 2007 and 2011. We identified 2477 symptomatic newly diagnosed patients who were followed for 6 months or more postdiagnosis and treated with systemic therapies but not with stem cell transplantation. Symptomatic patients were identified by evidence of hypercalcemia, renal failure, anemia, or bone lesions (CRAB criteria). The minimum follow‐up was imposed to ensure sufficient data to characterize treatment. Our analysis found that the proportion of treated patients increased from 75% in the 2007 cohort to 79% in the 2011 cohort. The share of PI‐based regimens including PI plus alkylating agents, PI plus IMiD, and PI‐only increased from 9% to 21%, 3% to 11%, and 16% to 22%, respectively, between 2007 and 2011. These findings translate to the share of PI‐based regimens having increased from 28% to 55% and that of IMiDs‐based regimens (excluding PI plus IMiD) having decreased from 43% to 27%. In conclusion, while the usage of PIs among elderly MM patients increased significantly replacing IMiD‐based regimens (with or without alkylating agents but not with PI) between 2007 and 2011, this significant shift did not increase the proportion of treated patients.

Abstract Biased estimates of population status are a pervasive conservation problem. This problem has plagued assessments of commercial exploitation of marine species and can threaten the sustainability of both populations and fisheries. We develop a computer‐intensive approach to minimize adverse effects of persistent estimation bias in assessments by optimizing operational harvest measures (harvest control rules) with closed‐loop simulation of resource‐management feedback systems: management strategy evaluation. Using saithe (Pollachius virens), a bottom water, apex predator in the North Sea, as a real‐world case study, we illustrate the approach by first diagnosing robustness of the existing harvest control rule and then optimizing it through propagation of biases (overestimated stock abundance and underestimated fishing pressure) along with select process and observation uncertainties. Analyses showed that severe biases lead to overly optimistic catch limits and then progressively magnify the amplitude of catch fluctuation, thereby posing unacceptably high overharvest risks. Consistent performance of management strategies to conserve the resource can be achieved by developing more robust control rules. These rules explicitly account for estimation bias through a computational grid search for a set of control parameters (threshold abundance that triggers management action, Btrigger, and target exploitation rate, Ftarget) that maximize yield while keeping stock abundance above a precautionary level. When the biases become too severe, optimized control parameters—for saithe, raising Btrigger and lowering Ftarget—would safeguard against a overharvest risk (

Wet deposition, including both in- and below-cloud scavenging, is critical for the atmospheric transport modeling of 137Cs following the Fukushima Daiichi Nuclear power plant (FDNPP) accident. Although intensively investigated, wet deposition simulation is still subject to uncertainties of meteorological inputs and wet scavenging modeling, leading to biased 137Cs transport prediction. To reduce the dual uncertainties, in- and below-cloud wet scavenging schemes of 137Cs were simultaneously integrated into Weather Research and Forecasting-Chemistry (WRF-Chem), yielding online coupled modeling of meteorology and the two wet scavenging processes. The integration was performed using 25 combinations of different in- and below-cloud schemes, covering most schemes in the literature. Two microphysics schemes were also tested to better reproduce the precipitation. The 25 models and the ensemble mean of 9 representative models were systematically compared with the below-cloud-only WRF-Chem model, using the cumulative deposition and atmospheric concentrations of 137Cs measurements. The results reveal that, with the Morrison's double moment cloud microphysics scheme, the developed models could better reproduce the rainfall and substantially improve the cumulative deposition simulation. The in-cloud scheme is influential to the model behaviors and those schemes considering cloud parameters also improve the atmospheric concentration simulations, whereas the others solely dependent on the rain intensity are sensitive to meteorology. The ensemble mean achieves satisfactory performance except one plume event, but still outperforms most models.

The third model intercomparison project (MIP) for investigating the atmospheric behavior of atmospheric caesium-137 (137Cs) emitted from Fukushima Daiichi Nuclear Power Plant (FDNPP) (3rd FDNPP-MIP), Japan, in March 2011, was conducted. A finer horizontal grid spacing (1 km) was used than in the previous FDNPP-MIP (2nd FDNPP-MIP, Sato et al., 2018; 3 km) to evaluate the models’ performance for high-concentration events measured near FDNPP. Nine of the models used in the 2nd FDNPP-MIP were also used in the 3rd FDNPP-MIP, and all models used identical source terms and meteorological fields. The performance of the models was evaluated through a comparison with observational data. Our analyses indicated that most of the observed high atmospheric 137Cs concentrations (plumes) were reasonably well simulated by the models, and the good performance of some models improved the performance of the multimodel, highlighting the advantage of using a multimodel ensemble. The analyses also confirmed that the use of a finer grid resolution resulted in the meteorological field near FDNPP being better reproduced in the 3rd FDNPP-MIP, and the performance of the models was better than that of the 2nd FDNPP MIP. The good representation of the wind field resulted in the reasonable simulation of the narrow distribution of high deposition amount to the northwest of FDNPP and the reduction of the overestimation in deposition amount over the area to the south of FDNPP compared to the 2nd FDNPP MIP. In contrast, the performance of the models in simulating plumes observed over the Nakadori area, the northern part of Gunma, and the Tokyo Metropolitan Area (TMA) was slightly worse than in the 2nd FDNPP-MIP.

Most global climate models overestimate the aerosol effect on cloud properties, but the reason for this is unclear. Here the authors show that using explicit representation of cloud microphysics, in global scale modelling, rather than parameterisations, reduces the overestimation.

Dust aerosols have great effects on global and regional climate systems. The Global Change Observation Mission-Climate (GCOM-C), also known as SHIKISAI, which was launched on 23 December 2017 by the Japan Aerospace Exploration Agency (JAXA), is a next-generation Earth observation satellite that is used for climate studies. The Second-Generation Global Imager (SGLI) aboard GCOM-C enables the retrieval of more precious global aerosols. Here, the first assimilation study of the aerosol optical thicknesses (AOTs) at 500 nm observed by this new satellite is performed to investigate a severe dust storm in spring over East Asia during 28–31 March 2018. The aerosol observation assimilation system is an integration of the four-dimensional local ensemble transform Kalman filter (4D-LETKF) and the Spectral Radiation Transport Model for Aerosol Species (SPRINTARS) coupled with the Non-Hydrostatic Icosahedral Atmospheric Model (NICAM). Through verification with the independent observations from the Aerosol Robotic Network (AERONET) and the Asian Dust and Aerosol Lidar Observation Network (AD-Net), the results demonstrate that the assimilation of the GCOM-C aerosol observations can significantly enhance Asian dust storm simulations. The dust characteristics over the regions without GCOM-C observations are better revealed from assimilating the adjacent observations within the localization length, suggesting the importance of the technical advances in observation and assimilation, which are helpful in clarifying the temporal–spatial structure of Asian dust and which could also improve the forecasting of dust storms, climate prediction models, and aerosol reanalysis.

Simultaneous observations of atmospheric potential oxygen (APO=O2+1.1×CO2) and air–sea O2 flux, derived from dissolved oxygen in surface seawater, were carried out onboard the research vessel MIRAI in the northern North Pacific and the Arctic Ocean in the autumns of 2012–2014. A simulation of the APO was also carried out using a three-dimensional atmospheric transport model that incorporated a monthly air–sea O2 flux climatology. By comparing the observed and simulated APO, as well as the observed and climatological air–sea O2 fluxes, it was found that the large day-to-day variation in the observed APO can be attributed to the day-to-day variation in the local air–sea O2 fluxes around the observation sites. It was also found that the average value of the observed air–sea O2 fluxes was systematically higher than that of the climatological O2 flux. This could explain the discrepancy between the observed and simulated seasonal APO cycles widely seen at various northern hemispheric observational sites in the fall season.

The effective radiative forcing (ERF) of anthropogenic aerosol can be more representative of the eventual climate response than other radiative forcing. We incorporate aerosol–cloud interaction into the Chinese Academy of Sciences Flexible Global Ocean–Atmosphere–Land System (CAS-FGOALS-f3-L) by coupling an existing aerosol module named the Spectral Radiation Transport Model for Aerosol Species (SPRINTARS) and quantified the ERF and its primary components (i.e., effective radiative forcing of aerosol-radiation interactions (ERFari) and aerosol-cloud interactions (ERFaci)) based on the protocol of current Coupled Model Intercomparison Project phase 6 (CMIP6). The spatial distribution of the shortwave ERFari and ERFaci in CAS-FGOALS-f3-L are comparable with that of most available CMIP6 models. The global mean 2014–1850 shortwave ERFari in CAS-FGOALS-f3-L (−0.27 W m−2) is close to the multi-model means in 4 available models (−0.29 W m−2), whereas the assessing shortwave ERFaci (−1.04 W m−2) and shortwave ERF (−1.36 W m−2) are slightly stronger than the multi-model means, illustrating that the CAS-FGOALS-f3-L can reproduce the aerosol radiation effect reasonably well. However, significant diversity exists in the ERF, especially in the dominated component ERFaci, implying that the uncertainty is still large.

Background. Diagnosis of non-alcoholic fatty liver disease (NAFLD) is limited by the need for liver biopsies. Serum cytokeratin 18 (CK-18) levels have been investigated as potential biomarkers for the presence of NAFLD and non-alcoholic steatohepatitis (NASH). Herein, we assessed the correlation between CK-18 levels and NAFLD progression.Material and methods. Serum CK-18 levels were estimated using the M30 antibody enzyme-linked immunosorbent assay in 147 patients diagnosed with NAFLD. In 72 patients, disease progression was evaluated by repeated liver biopsy, which was conducted after 4.3 ± 2.6 years. The relationship between the CK-18 levels and liver histological findings was assessed.Results. The CK-18 levels were useful for identifying NAFLD patients with NAFLD activity scores (NAS) ≥ 5 (NAS ≥ 5 vs. < 4: 675.1 U/L vs. 348.7 U/L; p < 0.0001). A cut-off value of 375 U/L was calculated using the receiver operating characteristic curve approach, with a specificity and sensitivity of 81.5 and 65%, respectively, for the diagnosis of NASH. Among the 72 patients who underwent repeated liver biopsy, 11 patients with a progressed NAS also had significantly increased serum CK-18 levels (p < 0.01); in 30 patients with an improved NAS, there was a significant improvement in the mean CK-18 levels (p < 0.0001). The 31 patients with static NAS had static CK-18 levels.Conclusions. In conclusion, serum CK-18 levels can predict NAS ≥ 5 in NAFLD patients. In NAFLD patients, serum CK-18 levels reflect NAS values and correlate with histological changes, and they appear to be useful indicators of progression and improvement.

The emissions from South Asia (SA) represent a critical source of aerosols on the Tibetan Plateau (TP), and aerosols can significantly reduce the surface solar energy. To enhance the precision of aerosol forecasting and its radiative effects in SA and TP, we employed a four-dimensional local ensemble transform Kalman filter (4D-LETKF) aerosol data assimilation (DA) system. This system was utilized to assimilate Himawari-8 aerosol optical thickness (AOT) into the Weather Research and Forecasting-Chemistry (WRF-Chem) model to depict one SA air pollution outbreak event in spring 2018. Sensitivity tests for the assimilation system have been conducted firstly to tune temporal localization lengths. Comparisons with independent Moderate Resolution Imaging Spectroradiometer (MODIS) and AErosol RObotic NETwork (AERONET) observations demonstrate that the AOT analysis and forecast fields have more reasonable diurnal variations by assimilating all the observations within 12h window, which are both better than assimilating the hourly observations in the current assimilation timeslot. Assimilation of the entire window of observations with aerosol radiative effect activation significantly improves the prediction of downward solar radiation compared to the free-run experiment. The assimilation of aerosol radiative effect activation led to a reduction in aerosol concentrations over SA, resulting in increased surface radiation, temperature, boundary layer height, and atmospheric instability. These changes facilitated air uplift, promoting aerosol transport from SA to the southeastern TP and leading to an increase in AOT in this region. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor, is approved as first-line (1L) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) as monotherapy or in combination with platinum and 5-fluorouracil chemotherapy. Limited data exist on the use of these regimens in real-world settings. Objective: Our primary objectives were to describe baseline characteristics and real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) among individuals with R/M HNSCC receiving approved 1L pembrolizumab therapies. We also aimed to identify baseline factors associated with choice of 1L pembrolizumab therapy and with rwOS. Methods: This was a retrospective cohort study of adults with R/M HNSCC receiving 1L pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We used Kaplan-Meier analyses to assess real-world outcomes, logistic regression modeling to identify factors associated with choice of 1L pembrolizumab therapy, and Cox proportional hazards models to identify factors associated with rwOS. Results: The study population included 431 individuals receiving 1L pembrolizumab monotherapy and 215 receiving 1L pembrolizumab plus chemotherapy. The use of 1L pembrolizumab monotherapy was associated with higher baseline combined positive score for PD-L1 expression, older age, higher Eastern Cooperative Oncology Group performance status (ECOG PS), laryngeal tumor site, and human papillomavirus (HPV)-positive tumor status. The pembrolizumab monotherapy group had a median (95% CI) rwOS of 12.1 (9.2-15.1) months, rwToT of 4.2 (3.5-4.6) months, and rwTTNT of 6.5 (5.4-7.4) months. Among this group, HPV-positive tumor status and lower ECOG PS were associated with longer rwOS, and oral cavity tumor site with shorter rwOS. The pembrolizumab plus chemotherapy cohort had a median (95% CI) rwOS of 11.9 (9.0-16.0) months, rwToT of 4.9 (3.8-5.6) months, and rwTTNT of 6.6 (5.8-8.3) months. In this group, HPV-positive tumor status was associated with longer rwOS. Conclusions: This study adds to clinical trial data by summarizing real-world treatment outcomes with 1L pembrolizumab-containing therapies in a more heterogeneous population. Overall survival outcomes in both treatment groups were similar to those observed in the registration clinical trial. These findings support the use of pembrolizumab as standard of care for R/M HNSCC. [ABSTRACT FROM AUTHOR]

Oxygen in the atmosphere undergoes variations and changes in response to biospheric activities, ocean–atmosphere exchange and fossil fuel combustion. Continuous in situ measurements of atmospheric δ(O2/N2) and CO2 mole fraction were started at Ny-Ålesund, Svalbard (78.93°N, 11.83°E, 40 m a.s.l.) in November 2012. Atmospheric potential oxygen (APO) calculated from the measured O2 and CO2 values during November 2012–January 2015 show a clear seasonal cycle with a peak-to-peak amplitude of approximately 50 per meg. The seasonal cycle of APO simulated using an atmospheric transport model, with prescribed oceanic O2, N2 and CO2 fluxes at monthly time intervals, is in excellent agreement with the observed APO. However, in spring and early summer, high values of APO are observed irregularly on a timescale of hours to days. By comparing backward trajectories of air parcels released from the site with distributions of marine net primary production (NPP), and tagged tracer experiments made using the atmospheric transport model for APO, it is found that these high APO fluctuations are primarily attributable to O2 emissions from the Greenland Sea, the Norwegian Sea and the Barents Sea, due to marine biological productivity. Marine net community production, estimated based on the sea-to-air O2 flux derived from observed APO fluctuations, agrees with NPP obtained from satellite observations within an order of magnitude. The results obtained in this study have still some uncertainties, but our continuous observations of atmospheric δ(O2/N2) and CO2 mole fraction at Ny-Ålesund can play an important role in detecting possible changes in the carbon cycle in the near future.

We have conducted systematic observations of the CH4 mole fraction and its carbon isotope ratio (δ13C) at Ny-Ålesund, Svalbard (78°55′N, 11°56′E) using air samples collected weekly since 1991 and 1996, respectively. The CH4 mole fraction showed long-term increase until 1999, stagnation between 2000 and 2006, followed by an increase after 2006. On the other hand, δ13C showed monotonous increase until 2006 and decrease after 2006. By comparing the rates of change in the CH4 mole fraction and δ13C under the assumption that the atmospheric CH4 lifetime is constant, it is suggested that the temporal pause of the CH4 mole fraction observed at Ny-Ålesund is attributed to reductions of CH4 release from the microbial and fossil fuel sectors. On the other hand, the increase in CH4 after 2006 could be ascribed to an increase in microbial CH4 release. The CH4 and δ13C data presented in this paper would be useful for clarifying their temporal variations in the Arctic atmosphere, as well as providing additional constraints on the global CH4 budget.

We present observations of CH4 concentrations from the lower to upper troposphere (LT and UT) over Japan during 1988–2010 based on aircraft measurements from the Tohoku University (TU). The analysis is aided by simulation results using an atmospheric chemistry transport model (i.e. ACTM). Tropospheric CH4 over Japan shows interannual and seasonal variations that are dependent on altitudes, primarily reflecting differences in air mass origins at different altitudes. The long-term trend and interannual variation of CH4 in the LT are consistent with previous reports of measurements at surface baseline stations in the northern hemisphere. However, those in the UT show slightly different features from those in the LT. In the UT, CH4 concentrations show a seasonal maximum in August due to efficient transport of air masses influenced by continental CH4 sources, while LT CH4 reaches its seasonal minimum during summer due to enhanced chemical loss. Vertical profiles of the CH4 concentrations also vary with season, reflecting the seasonal cycles at the respective altitudes. In summer, transport of CH4-rich air from Asian regions elevates UT CH4 levels, forming a uniform vertical profile above the mid-troposphere. On the other hand, CH4 decreases nearly monotonically with altitude in winter–spring. The ACTM simulations with different emission scenarios reproduce general features of the tropospheric CH4 variations over Japan. Tagged tracer simulations using the ACTM indicate substantial contributions of CH4 sources in South Asia and East Asia to the summertime high CH4 values observed in the UT. This suggests that our observations over Japan are highly sensitive to CH4 emission signals particularly from Asia.

We present the inversions (back-calculations or optimizations) of dust emissions for a severe winter dust event over East Asia in November 2016. The inversion system based on a fixed-lag ensemble Kalman smoother is newly implemented in the Weather Research and Forecasting model and is coupled with Chemistry (WRF-Chem). The assimilated observations are the hourly aerosol optical depths (AODs) from the next-generation geostationary satellite Himawari-8. The posterior total dust emissions (2.59 Tg) for this event are 3.8 times higher than the priori total dust emissions (0.68 Tg) during 25−27 November 2016. The net result is that the simulated aerosol horizontal and vertical distributions are both in better agreement with the assimilated Himawari-8 observations and independent observations from the ground-based AErosol RObotic NETwork (AERONET), the satellite-based Moderate Resolution Imaging Spectroradiometer (MODIS) and the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO). The developed emission inversion approach, combined with the geostationary satellite observations, can be very helpful for properly estimating the Asian dust emissions.

Detailed observations of O2:CO2 exchange ratios were conducted in a cool temperate deciduous forest located in central Japan. The exchange ratios of soil respiration and net assimilation were found to be 1.11±0.01 and 1.02±0.03 from soil chamber and branch bag measurements, respectively. Continuous measurements of the atmospheric O2/N2 ratio and the CO2 concentration, made inside the canopy during a summer season, indicated that the average exchange ratio was lower in the daytime (0.87±0.02) than in the nighttime (1.03±0.02) with a daily mean value of 0.94±0.01. The observed average daytime and nighttime exchange ratios were nearly consistent with the corresponding values obtained from a one-box canopy O2/CO2 budget model simulation of net turbulent O2 and CO2 fluxes between the atmosphere and the forest ecosystem. Our results suggest that the daily mean exchange ratios of the net turbulent O2 and CO2 fluxes depend sensitively on the forest ecosystem processes.

With the aim of carrying out detailed monitoring of temporal variations in the atmospheric O_2/N_2 ratio at Ny-Alesund, Svalbard, we have developed a new highprecision continuous measurement system, with a precision of better than ±4.0 per meg, using a fuel-cell O_2 analyzer. Considering the remoteness of the observation site, special attention was paid to the measurement system, in that: (1) the system can be controlled remotely from Japan using the Internet; (2) all of the data output from the system can be monitored and collected in Japan via the Internet; (3) a specially designed water trap based on a Stirling cooler is employed to automate the removal of water vapor from the sample air; (4) the CO_2 concentration can also be measured; and (5) it is possible to operate the system for one year without having to manually replace the high-pressure cylinders of standard gas and reference air. Systematic observation of the atmospheric O_2/N_2 ratio using the newly developed measurement system began at the site on November 8, 2012. By analyzing the observational results obtained over the first month, the effectiveness of the measurement system was verified, and the causes of cha acteristic temporal variations in the observed atmospheric O_2/N_2 ratio were examined.

In accordance with progression in current capabilities towards high-resolution approaches, applying a convective-permitting resolution to global aerosol models helps comprehend how complex cloud-precipitation systems interact with aerosols. This study investigates the impacts of a double-moment bulk cloud microphysics scheme, i.e., NICAM Double-moment bulk Water 6 developed in this study (NDW6-G23), on the spatiotemporal distribution of aerosols in the Nonhydrostatic Icosahedral Atmospheric Model as part of the version 19 series (NICAM.19) with 14 km grid spacing. The mass concentrations and optical thickness of the NICAM-simulated aerosols are generally comparable to those obtained from in situ measurements, but some aerosol species, especially dust and sulfate, have larger differences among the experiments with NDW6 and NSW6 compared to those among the experiments with different horizontal resolutions, i.e., 14 km and 56 km grid spacing, as shown in a previous study. The simulated aerosol burdens using NDW6 are generally lower than those using NSW6; the instantaneous radiative forcing due to aerosol-radiation interaction (IRFari) is estimated to be -1.57 Wm-2 (NDW6) and -1.86 Wm-2 (NSW6) in the global annual mean values of shortwave all-aerosol radiative forcing at the top of the atmosphere (TOA). This difference among the experiments using different cloud microphysics modules, e.g., 0.29 Wm-2 or 16% difference in IRFari values, is attributed to a different ratio of column precipitation to the sum of the column precipitation and column liquid cloud water, which strongly determines the magnitude of wet deposition in the simulated aerosols. Since the simulated ratios in the NDW6 experiment are larger than those of the NSW6 result, the scavenging effect of the simulated aerosols in the NDW6 experiment is larger than that in the NSW6 experiment. A large difference between the experiments is also found in the aerosol indirect effect (AIE), i.e., the shortwave effective radiative forcing due to aerosol-cloud interaction (ERFaci) from the present to preindustrial days, which is estimated to be -1.34 Wm-2 (NDW6) and -0.63 Wm-2 (NSW6) in global annual mean values. The magnitude of the ERFaci value in the NDW6 experiment is larger than that in the NSW6 result, probably due to the differences in the susceptibility of the simulated cloud water to the simulated aerosols and partly due to the nonlinear relationship between the ERFaci and AOT under different AOTs. Therefore, this study shows the importance of the impacts of the cloud microphysics module on aerosol distributions through both aerosol wet deposition and AIE. [ABSTRACT FROM AUTHOR]

Simultaneous measurements of the atmospheric O2/N2 ratio and CO2 concentration were made at Ny-Ålesund, Svalbard, and Syowa, Antarctica for the period 2001–2009. Based on these measurements, the observed atmospheric potential oxygen (APO) values were calculated. The APO variations produced by changes in the oceanic heat content were estimated using an atmospheric transport model and heat-driven air–sea O2 (N2) fluxes, and then subtracted from observed interannual variations of APO. The oceanic CO2 uptake derived from the resulting ‘corrected’ secular trend of APO showed interannual variability of less than ±0.6 GtC yr−1, significantly smaller than that derived from the ‘uncorrected’ trend of APO (±0.9 GtC yr−1). The average CO2 uptake during the period 2001–2009 was estimated to be 2.9±0.7 and 0.8±0.9 GtC yr−1 for the ocean and terrestrial biosphere, respectively. By excluding the influence of El Niño around 2002–2003, the terrestrial biospheric CO2 uptake for the period 2004–2009 increased to 1.5±0.9 GtC yr−1, while the oceanic uptake decreased slightly to 2.8±0.8 GtC yr−1.

Systematic measurements of the atmospheric O2/N2 ratio have been made using aircraft and ground-based stations in Japan since 1999. The observed seasonal cycles of the O2/N2 ratio and atmospheric potential oxygen (APO) vary almost in opposite phase to that of the CO2 concentration at all altitudes, and their amplitudes and phases are generally reduced and delayed, respectively, with increasing altitude. Simulations of APO using two atmospheric transport models reproduce general features of the observed seasonal cycle, but both models fail to reproduce the phase at an altitude ranging from 8 km to the tropopause. By analysing the observed secular trends of APO and CO2 concentration, and assuming a global net oceanic O2 outgassing of 0.2±0.5 GtC yr−1, we estimate global average terrestrial biospheric and oceanic CO2 uptake for the period 2000–2010 to be 1.0±0.8 and 2.5±0.7 GtC yr−1, respectively.