Search

Abstract Objective We investigated the relationship between prehospital systolic blood pressure (SBP) and pulse rate (PR) with stroke in patients with impaired consciousness. Methods We included adult patients with impaired consciousness admitted to the emergency department, categorizing them into nine groups based on SBP (≤99, 100–139, and ≥140 mmHg) and PR (≤59, 60–99, and ≥100/min). We analyzed the association between these groups and stroke and compared with the reference group (SBP 100–139 mmHg and PR 60–99/min) using logistic regression models. Results 837 patients were eligible (132 [16%] patients had a stroke). Groups with SBP ≥140 mmHg had a significantly higher risk of stroke regardless of PR (the adjusted odds ratio and 95% confidence interval in the group with PR ≤ 59/min, PR 60–99/min, and PR ≥ 100/min were 4.64 [1.63–13.20], 5.61 [3.24–9.70], and 2.84 [1.45–5.58], respectively). Similarly, among patients with severely impaired consciousness (≥Japan Coma scale III‐100), those with SBP ≥ 140 mmHg were at a significantly higher risk of stroke; within these groups, the group with SBP ≥ 140 mmHg and PR ≤ 59/min had the highest risk of stroke (the odds ratio and 95% confidence interval in the group with PR ≤ 59/min, PR 60–99/min and PR ≥ 100/min were 11.00 [1.70–72.90], 9.29 [3.34–26.00], and 4.83 [1.62–14.40], respectively). Conclusions Prehospital hypertension in patients with impaired consciousness was associated with a significantly higher risk of stroke. In patients with severely impaired consciousness, prehospital hypertension with bradycardia was significantly associated with the highest risk of stroke.

ABSTRACT Introduction Eudaimonic well‐being (EWB), which refers to optimal human functioning, is associated with psychophysiological outcomes, such as reduced inflammation and a lower risk of depression. Although physical activity (PA) and mindfulness have been shown to be predictive factors for EWB, potential mediators of the relationships of PA or mindfulness with EWB have yet to be identified. PA, mindfulness‐related psychophysiological factors (including serotonin [5‐HT], oxytocin [OXT]), and dopamine [DA] levels), and heart rate variability (HRV) have been shown to be associated with mental disorders or emotion regulation capacity. Purpose The purpose of this study is to explore the potential psychophysiological factors associated with PA, mindfulness and EWB. Methods A total of 49 young adults (25 males, 24 females) were included with an average age of 25 years (± 5). Plasma 5‐HT, OXT, and DA levels were obtained via blood samples from the brachial vein and were analyzed with enzyme‐linked immunosorbent assays (ELISAs), and HRV was obtained via 5‐min electrocardiograms (ECGs), with participants in the supine position. Spearman's correlation analyses were performed, followed by partial correlation analyses controlling for age, sex, and social status (i.e., student or working professional). Results HRV was found to be positively correlated with both moderate‐intensity PA (r = 0.47, p = 0.04) and EWB (purpose in life; r = 0.50, p = 0.03), even after controlling for relevant variables. On the other hand, neither 5‐HT, OXT, nor DA was correlated with PA, mindfulness, and EWB. Conclusion These results suggest that HRV may mediate the relationship between PA and EWB. Additional intervention studies are needed to elucidate the causal relationships among PA, HRV, and EWB.

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.

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.

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.

This case report demonstrates the use of a video laryngoscope to aid in the incision and drainage of a peritonsillar abscess in a 30-year-old male. This technique, which has not been widely discussed in the literature, provided enhanced visualization, overcoming challenges like poor access due to trismus and poor lighting. The video laryngoscope improved safety, offered clearer guidance, and provided valuable teaching opportunities, particularly for less experienced physicians and residents. This case contributes to the literature by illustrating how the video laryngoscope can function as both a therapeutic tool and an educational resource, improving the management of peritonsillar abscesses and potentially reducing complications. [ABSTRACT FROM AUTHOR]

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 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.

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.

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.