Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study

Background To evaluate the long-term efficacy, safety and immunogenicity of continuing LBEC0101; the etanercept (ETN) biosimilar; or switching from the ETN reference product (RP) to LBEC0101 in patients with rheumatoid arthritis (RA). Methods This multicentre, single-arm, open-label extension study enrolled patients who had completed a 52-week randomised, double-blind, parallel phase III trial of LBEC0101 vs ETN-RP. Patients treated with ETN-RP during the randomised controlled trial switched to LBEC0101; those treated with LBEC0101 continued to receive LBEC0101 in this study. LBEC0101 (50 mg) was administered subcutaneously once per week for 48 weeks with a stable dose of methotrexate. Efficacy, safety and immunogenicity of LBEC0101 were assessed up to week 100. Results A total of 148 patients entered this extension study (70 in the maintenance group and 78 in the switch group). The 28-joint disease activity scores (DAS28)-erythrocyte sedimentation rate (ESR) were maintained in both groups from week 52 to week 100 (from 3.068 to 3.103 in the maintenance group vs. from 3.161 to 3.079 in the switch group). ACR response rates at week 100 for the maintenance vs. switch groups were 79.7% vs. 83.3% for ACR20, 65.2% vs. 66.7% for ACR50 and 44.9% vs. 42.3% for ACR70. The incidence of adverse events and the proportion of patients with newly developed antidrug antibodies were similar in the maintenance and switch groups (70.0% and 70.5%, 1.4% and 1.3%, respectively). Conclusions Administration of LBEC0101 showed sustained efficacy and acceptable safety in patients with RA after continued therapy or after switching from ETN-RP to LBEC0101. Trial registration ClinicalTrials.gov, NCT02715908. Registered 22 March 2016.This extension study was funded by LG Chem, Ltd. (formerly, LG Life Sciences, Ltd), Mochida Pharmaceutical Co., Ltd. and Korea Health Industry Development Institute

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Cloud Observation and Cloud Cover Calculation at Nighttime Using the Automatic Cloud Observation System (ACOS) Package

An Automatic Cloud Observation System (ACOS) and cloud cover calculation algorithm were developed to calculate the cloud cover at night, and the calculation results were compared with the cloud cover data of a manned observatory (Daejeon Regional Office of Meteorology, DROM) that records human observations. Annual and seasonal analyses were conducted using the 1900&ndash;0600 local standard time (LST) hourly data from January to December 2019. Prior to calculating the cloud cover of ACOS, pre-processing was performed by removing surrounding obstacles and correcting the distortion caused by the fish-eye lens. In addition, the red&ndash;blue ratio (RBR) threshold was determined, according to the image characteristics (RBR and luminance) using the red, green, and blue (RGB) brightness value of the area in which the solar zenith angle (SZA) was less than 80&deg;, to calculate the cloud cover. The calculated cloud cover exhibited a bias of &minus;0.28 tenths, root mean square error (RMSE) of 1.78 tenths, and a correlation coefficient of 0.91 for DROM across all cases. The frequency of the cases that exhibited differences less than 1 tenth between the observed and calculated cloud cover was 46.82%, while the frequency of cases that exhibited differences less than 2 tenths was 87.79%

Compositional Characteristics of Atmospheric Aerosols during a Consecutive High Concentration Episode in Seoul, Korea

This study focuses on the temporal variation in the compositional characteristics of atmospheric aerosols in Seoul, South Korea, during the consecutive high aerosol concentration episode from 30 December 2013 to 2 January 2014. The temporal variations in the observed physical, optical, and chemical properties show that there were three distinct episodes during the period: haze, mixed haze/Asian dust, and Asian dust episodes. For the haze period, the concentration of secondary inorganic aerosols increased and both secondary inorganic aerosols and calcium species exhibited simultaneously high concentrations during the mixed haze/Asian dust period. The neutralization factors by ammonia in the haze periods were higher as 1.03 than the other periods, meanwhile the neutralization contribution by calcium carbonate was relatively higher as 1.39 during the Asian dust episode. The backward trajectory analysis showed that concentrations of SO42&minus;, NO3&minus;, and NH4+ were relatively high when air masses moved over East China. Principal component analysis showed that water-soluble components originated from soil dust/incineration, secondary aerosols/biomass burning, and road dust from the haze aerosol. For the mixed haze/Asian dust episode, the major source of aerosols was estimated to have originated from soil dust, pollutants from fossil fuel combustion, biomass burning, and sea-salt emissions. Furthermore, the main sources of ionic species in the Asian dust aerosols were estimated to be sea-salt/soil dust, secondary aerosols/coal combustion, and road dust

Therapeutic Effect of Repetitive Transcranial Magnetic Stimulation for Post-stroke Vascular Cognitive Impairment: A Prospective Pilot Study

ObjectivePost-stroke cognitive impairment (PSCI) is resistant to treatment. Recent studies have widely applied repetitive transcranial magnetic stimulation (rTMS) to treat various brain dysfunctions, such as post-stroke syndromes. Nonetheless, a protocol for PSCI has not been established. Therefore, this study is aimed to evaluate the therapeutic effect of our high-frequency rTMS protocol for PSCI during the chronic phase of stroke. MethodsIn this prospective study, ten patients with PSCI were enrolled and received high-frequency rTMS on the ipsilesional dorsolateral prefrontal cortex (DLPFC) for 10 sessions (5 days per week for 2 weeks). Cognitive and affective abilities were assessed at baseline and 2 and 14 weeks after rTMS initiation. To investigate the therapeutic mechanism of rTMS, the mRNA levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-1 beta, transforming growth factor beta [TGF-beta], and tumor necrosis factor alpha [TNF-alpha]) in peripheral blood samples were quantified using reverse transcription polymerase chain reaction, and cognitive functional magnetic resonance imaging (fMRI) was conducted at baseline and 14 weeks in two randomly selected patients after rTMS treatment. ResultsThe scores of several cognitive evaluations, i.e., the Intelligence Quotient (IQ) of Wechsler Adult Intelligence Scale, auditory verbal learning test (AVLT), and complex figure copy test (CFT), were increased after completion of the rTMS session. After 3 months, these improvements were sustained, and scores on the Mini-Mental Status Examination and Montreal Cognitive Assessment (MoCA) were also increased (p &lt; 0.05). While the Geriatric Depression Scale (GeDS) did not show change among all patients, those with moderate-to-severe depression showed amelioration of the score, with marginal significance. Expression of pro-inflammatory cytokines was decreased immediately after the ten treatment sessions, among which, IL-1 beta remained at a lower level after 3 months. Furthermore, strong correlations between the decrease in IL-6 and increments in AVLT (r = 0.928) and CFT (r = 0.886) were found immediately after the rTMS treatment (p &lt; 0.05). Follow-up fMRI revealed significant activation in several brain regions, such as the medial frontal lobe, hippocampus, and angular area. ConclusionsHigh-frequency rTMS on the ipsilesional DLPFC may exert immediate efficacy on cognition with the anti-inflammatory response and changes in brain network in PSCI, lasting at least 3 months.N

Analysis of the Occurrence Frequency of Seedable Clouds on the Korean Peninsula for Precipitation Enhancement Experiments

Our study analyzed the occurrence frequency and distribution of seedable clouds around the Korean Peninsula in order to better secure water resources. Cloud products from the Communication, Ocean, and Meteorological Satellite (COMS), including cloud fraction, cloud top height, cloud top temperature, cloud phase, cloud top pressure, cloud optical thickness, and rainfall intensity, were used. Daytime hourly data between 0900 and 1800 local standard time (LST) observed from December 2016 to November 2019 was used. Seedable clouds occurring within this period were evaluated based on seasonal cloud phases, occurrence frequency, and cloud characteristics according to land, sea, and cloud type. These clouds exhibited varying average occurrence frequencies in different seasons. Sc (stratocumulus) clouds exhibited the highest occurrence frequency for all seasons, with an average of 63%, followed by Cu (cumulus) at 15%, As (altostratus) at 13%, and Ac (altocumulus) at 6%. We determined that low-level clouds primarily occurred around the Korean Peninsula, and the occurrence frequency of stratiform clouds was highest for water phase seedable clouds, while the occurrence frequency of cumuliform clouds was highest for ice phase seedable clouds. We believe that precipitation enhancement experiments could be suitable for western and eastern seas around the Korean Peninsula as well as for mountainous regions on land

Influence of Quasi-Periodic Oscillation of Atmospheric Variables on Radiation Fog over A Mountainous Region of Korea

To enhance our understanding of fog processes over complex terrain, various fog events that occurred during the International Collaborative Experiments for Pyeongchang 2018 Winter Olympics and Paralympics (ICE-POP) campaign were selected. Investigation of thermodynamic, dynamic, and microphysical conditions within fog layers affected by quasi-periodic oscillation of atmospheric variables was conducted using observations from a Fog Monitor-120 (FM-120) and other in-situ meteorological instruments. A total of nine radiation fog cases that occurred in the autumn and winter seasons during the campaign over the mountainous region of Pyeongchang, Korea were selected. The wavelet analysis was used to study quasi-period oscillations of dynamic, microphysical, and thermodynamic variables. By decomposing the time series into the time-frequency space, we can determine both dominant periods and how these dominant periods change in time. Quasi-period oscillations of liquid water content (LWC), pressure, temperature, and horizontal/vertical velocity, which have periods of 15&ndash;40 min, were observed during the fog formation stages. We hypothesize that these quasi-periodic oscillations were induced by Kelvin&ndash;Helmholtz instability. The results suggest that Kelvin&ndash;Helmholtz instability events near the surface can be explained by an increase in the vertical shear of horizontal wind and by a simultaneous increase in wind speed when fog forms. In the mature stages, fluctuations of the variables did not appear near the surface anymore

Primary Gastric Small Cell Carcinoma (Presenting as Linitis Plastica) Diagnosed Using Endoscopic Ultrasound-Guided Biopsy: A Case Report

Small cell carcinomas are the most aggressive, highly malignant neuroendocrine tumors; among these, gastric small cell carcinoma (GSCC) is extremely rare. Here we report a case of a patient with primary GSCC, presenting as linitis plastic, who was diagnosed using endoscopic ultrasound (EUS)-guided biopsy. With undiagnosed linitis plastica, an 80-year-old woman was referred to our institution. Abdominal computed tomography revealed irregular wall thickening extending from the gastric body to the antrum. Endoscopy suspected to have Borrmann type IV advanced gastric cancer. EUS of the stomach showed diffuse submucosal thickening of the gastric wall, mainly the antrum. EUS-guided bite-on-bite biopsy confirmed the diagnosis of GSCC. In general, GSCC is difficult to diagnose and careful examination is necessary to determine the therapeutic strategy; however, EUS is particularly helpful in the differential diagnosis of a lesion presenting as linitis plastica

Theoretical Calculations of Directional Scattering Intensities of Small Nonspherical Ice Crystals: Implications for Forward Scattering Probes

In situ aircraft measurements of the sizes and concentrations of liquid cloud droplets and ice crystals with maximum dimensions (D-max) less than similar to 50 mu m have been measured mainly using forward scattering probes over the past half century. The operating principle of forward scattering probes is that the measured intensity of light scattered by a cloud particle at specific forward scattering angles can be related to the size of that particle assuming the shape and thermodynamic phase of the target are known. Current forward-scattering probes assume spherical liquid cloud droplets and use the Lorenz-Mie theory to convert the scattered light to particle size. Uncertainties in sizing ice crystals using forward scattering probes are unavoidable since the single-scattering properties of ice crystals differ from those of spherical liquid cloud droplets and because their shapes can vary. In this study, directional scattering intensities of four different aspect ratios (ARs = 0.25, 0.50, 1.00, and 2.00) of hexagonal ice crystals with random orientations and of spherical liquid cloud droplets were calculated using the discrete dipole approximation (i.e., ADDA) and Lorenz-Mie code, respectively, to quantify the errors in sizing small ice crystals and cloud droplets using current forward scattering probes and to determine the ranges of optimal scattering angles that would be used in future forward scattering probes. The calculations showed that current forward scattering probes have average 5.0% and 17.4% errors in sizing liquid cloud droplets in the forward (4-12 degrees) and backward (168-176 degrees) direction, respectively. For measurements of hexagonal ice crystals, average sizing errors were 42.1% (23.9%) in the forward (backward) direction and depended on the ARs of hexagonal ice crystals, which are larger than those for liquid cloud droplets. A newly developed size conversion table based on the calculated single-scattering properties of hexagonal ice crystals using the ADDA reduced the sizing errors for the hexagonal ice crystals down to 14.2% (21.9%) in the forward (backward) direction. This study is a purely theoretical examination of the operating principle of forward scattering probes and there are several limitations, such as assumed hexagonal ice crystals with smooth surfaces and random orientations