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Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA

Abstract To evaluate national epidemiologic data on infants treated for patent ductus arteriosus (PDA) in Korea and analyze outcomes associated with different PDA treatments. We retrospectively evaluated data on 12,336 patients diagnosed with PDA (International Classification of Diseases-10 code: Q250) between 2015 and 2018 from the Health Insurance Review and Assessment database. Among them, 1623 patients underwent surgical ligation (code: O1671). We used birth certificate data from Statistics Korea to estimate the prevalence, diagnosis, and treatment of PDA. The prevalence of infants with PDA was 81 infants per 10,000 live births and 45.2% in very low birth weight (VLBW) infants, which increased from 2015 to 2018. PDA ligation was performed in 2571 infants and 22% VLBW infants. Medical treatment was administered to 4202 infants, which decreased significantly, especially in VLBW infants (62% to 53%). The proportion of treatment was as follows: conservative treatment (53.1%), intravenous ibuprofen (24.4%), surgery (20.4%), and oral ibuprofen (10.7%); that among 4854 VLBW infants was as follows: intravenous ibuprofen (46.3%), conservative treatment (33.2%), surgery (22.2%), and oral ibuprofen (14.2%). Surgical treatment had a significantly higher risk (odds ratio 1.36) of mortality than conservative treatment. Surgical and/or medical treatments were associated with a higher risk of morbidity. Recently, increased use of conservative management of PDA has contributed to improved neonatal outcomes in VLBW infants. Select patients may still benefit from surgical ligation following careful consideration.

Abstract Background and Aim Tenofovir disoproxil fumarate (TDF) has been efficacious in treating chronic hepatitis B (CHB), but long‐term use is accompanied by a decline in renal function and bone mineral density (BMD). Tenofovir alefanamide (TAF) is a prodrug of tenofovir, with similar efficacy in CHB but with fewer side effects than TDF. Recent studies on patients who underwent the switch from TDF to TAF have shown improved bone and renal profiles from 24 to 48 weeks of follow‐up. Methods This study provides follow‐up at 72 weeks in a real‐world cohort of 61 Asian CHB patients who were switched from TDF to TAF. All patients had been treated with TDF for at least 12 months with hepatitis B virus DNA

Courtney Crim,1 Michael L Watkins,1 Eric D Bateman,2 Gregory J Feldman,3 Isabelle Schenkenberger,4 Edward M Kerwin,5 Catriona Crawford,6 Krishna Pudi,7 Shuyen Ho,8 Charlotte Baidoo,9 Ramiro Castro-Santamaria10 1GSK, Research and Development, Research Triangle Park, NC, USA; 2Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa; 3S. Carolina Pharmaceutical Research, Spartanburg, SC, USA; 4Klinische Forschung Berlin GbR, Berlin, Germany; 5Clinical Trials Division, Crisor LLC, Clinical Research Institute, Medford OR, USA; 6GSK, Global Medical, Stockley Park, Uxbridge, Middlesex, UK; 7Upstate Pharmaceutical Research, Greenville, SC, USA; 8PAREXEL International, Durham, NC, USA; 9GSK, Clinical Statistics, Stockley Park, Uxbridge, Middlesex, UK; 10GSK, Research and Development, Collegeville, PA, USA Background: Batefenterol is a novel bifunctional muscarinic antagonist β2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose–response of batefenterol and select a dose for Phase III development.Patients and methods: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0–6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose–response modeling, respectively, on day 42.Results: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1–292.8 and 182.2–244.8 mL, respectively), with a relatively flat dose–response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed.Conclusion: Batefenterol 300 µg may represent the optimal dose for Phase III studies. Keywords: bifunctional, bronchodilator, dual-pharmacophore, dose–response, muscarinic antagonist β2-agonist

Engineered T cells with chimeric antigen receptor (CAR) are emerging as an effective cancer therapy. Here the authors show that CAR T cells recognizing self-MHC can be ‘tuned’ ex vivo via CAR downregulation and CAR T cell death to generate a CAR T pool specifically targeting tumor cells with high MHC expression.

Michelle Cheng,1,* Samantha Ho,1,* Jun Hwan Yoo,1,2,* Deanna Hoang-Yen Tran,1,* Kyriaki Bakirtzi,1 Bowei Su,1 Diana Hoang-Ngoc Tran,1 Yuzu Kubota,1 Ryan Ichikawa,1 Hon Wai Koon1 1Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Republic of Korea *These authors share co-first authorship Background: Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion: Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation. Keywords: colon cancer, epithelial–mesenchymal transition, fibroblasts

The Orange (Or) protein regulates carotenoid biosynthesis and environmental stress in plants. Previously, we reported that overexpression of the sweetpotato [Ipomoea batatas (L.) Lam] Or gene (IbOr) in transgenic Arabidopsis (referred to as IbOr-OX/At) increased the efficiency of photosystem II (PSII) and chlorophyll content after heat shock. However, little is known about the role of IbOr in PSII-mediated protection against abiotic stress. In this study, comparative proteomics revealed that expression of PsbP (an extrinsic subunit of PSII) is up-regulated in heat-treated IbOr-OX/At plants. We then identified and functionally characterized the PsbP-like gene (IbPsbP) from sweetpotato. IbPsbP is predominantly localized in chloroplast, and its transcripts are tissue-specifically expressed and up-regulated in response to abiotic stress. In addition, IbOr interacts with IbPsbP and protects it from heat-induced denaturation, consistent with the observation that transgenic sweetpotato overexpressing IbOr maintained higher PSII efficiency and chlorophyll content upon exposure to heat stress. These results indicate that IbOr can protect plants from environmental stress not only by controlling carotenoid biosynthesis but also by directly stabilizing PSII.

An experiment was conducted to investigate the effect of monochromatic and mixed light color on performance, bone, meat quality, blood properties and immunity of broiler chicks. In experiment 1, 1,200 Ross×Ross 1-day old chicks were equally allotted to the following 8 light treatments with 3 replications: red (R), yellow (Y) green (G), blue (B), mixed R×Y, Y×G, and G×B light colors. Fluorescent white light was the control. Experiment 2 considered similar treatments (6 treatments with 4 replications) except R and R×Y were not tested. Light (24 L: 0 D) and intensity (0.1 watts/m2) was maintained at the bird’s head level. Weight gain during weeks 2-3 increased in the G and G×B groups (P

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is primarily expressed on activated T cells and is known to enhance proliferation of T cells, prevent activation-induced cell death, and promote memory formation of CD8+ T cells. In particular, it is well acknowledged that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells rather than CD4+ T cells, but the underlying mechanism remains unclear. Here we found that 4-1BB triggering markedly increased IL-2Rα (CD25) and IL-2 expressions of CD8+ T cells but minimally for CD4+ T cells. Proliferation of CD8+ T cells was moderately enhanced by direct 4-1BB triggering in the absence of signaling through IL-2Rα/IL-2 interactions, but further promoted in the presence of IL-2Rα/IL-2 interactions. Among the TNFRSF members including OX40, GITR, CD30, and CD27, 4-1BB was superior in the ability to induce IL-2Rα expression on CD8+ T cells. When the primary and secondary expansions of CD8+ T cells in vivo were examined by adoptively transferring OVA-specific CD8+ T cells along with the treatment with agonistic anti-4-1BB and/or antagonistic anti-CD25 F(ab')2 mAb, 4-1BB triggering enhanced both primary and secondary expansion of CD8+ T cells in vivo, and the 4-1BB effects were moderately suppressed in primary expansion while completely abolished in secondary expansion of OVA-specific CD8+ T cells by blocking IL-2Rα. These results suggest that 4-1BB-mediated increases of IL-2Rα and IL-2 prolong the effects of transient TCR- and 4-1BB-mediated signaling in CD8+ T cells, and that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells through the amplification of autocrine IL-2/IL-2R signaling loop.

C11H25AuNPS2, monoclinic, P121/c1 (no. 14), a = 11.1101(5) Å, b = 13.5725(6) Å, c = 21.945(1) Å, β = 90.057(1)°, V = 3309.2 Å3, Z = 8, Rgt(F) = 0.040, wRref(F2) = 0.080, T = 223 K.

An experiment was conducted to evaluate the effect of dietary metabolizable energy (ME) and crude protein (CP) on the performance, egg quality, blood properties, bone characteristics and yolk fatty acid composition of organic laying hens. At 23 weeks, a total of 600 Brown nick laying hens were randomly distributed into 24 outdoor pens (4 replicate pens/treatment; 25 birds/pen) and were given (2750, 2775 and 2800 kcal of ME/kg) and CP (16 and 17%) resulting in a 3×2 factorial arrangement of organic dietary treatments. The experiment lasted 23 weeks. The performance of laying hens were not affected by the dietary treatment while the egg weight was increased with energy and CP levels in the diet (P

Brief G, Lammich T, Nagel E, Pfennigsdorf S, Spraul CW, Ho S. Fixed combination of bimatoprost and timolol in patients with primary open-angle glaucoma or ocular hypertension with inadequate IOP adjustment. Clin Ophthalmol. 2010:4 1125–1129.Dr Stefan Pfennigsdorf was incorrectly identified as Dr Sabine Pfennigsdorf in this work.Read the original article

C52H56Au2N2O6P2S2, monoclinic, P121/n1 (no. 14), a = 10.501(2) Å, b = 10.145(2) Å, c = 24.085(4) Å, β = 92.546(4)°, V = 2563.3 Å3, Z = 2, Rgt(F) = 0.045, wRref(F2) = 0.146, T = 223 K.

Abstract Background Myocardial disarray is an important histological feature of hypertrophic cardiomyopathy (HCM) which has been studied post-mortem, but its in-vivo prevalence and extent is unknown. Cardiac Diffusion Tensor Imaging (cDTI) provides information on mean intravoxel myocyte orientation and potentially myocardial disarray. Recent technical advances have improved in-vivo cDTI, and the aim of this study was to assess the interstudy reproducibility of quantitative in-vivo cDTI in patients with HCM. Methods and results A stimulated-echo single-shot-EPI sequence with zonal excitation and parallel imaging was implemented. Ten patients with HCM were each scanned on 2 different days. For each scan 3 short axis mid-ventricular slices were acquired with cDTI at end systole. Fractional anisotropy (FA), mean diffusivity (MD), and helix angle (HA) maps were created using a cDTI post-processing platform developed in-house. The mean ± SD global FA was 0.613 ± 0.044, MD was 0.750 ± 0.154 × 10-3 mm2/s and HA was epicardium −34.3 ± 7.6°, mesocardium 3.5 ± 6.9° and endocardium 38.9 ± 8.1°. Comparison of initial and repeat studies showed global interstudy reproducibility for FA (SD = ± 0.045, Coefficient of Variation (CoV) = 7.2%), MD (SD = ± 0.135 × 10-3 mm2/s, CoV = 18.6%) and HA (epicardium SD = ± 4.8°; mesocardium SD = ± 3.4°; endocardium SD = ± 2.9°). Reproducibility of FA was superior to MD (p = 0.003). Global MD was significantly higher in the septum than the reference lateral wall (0.784 ± 0.188 vs 0.750 ± 0.154 x10-3 mm2/s, p Conclusions To the best of our knowledge, this is the first study to assess the interstudy reproducibility of DTI in the human HCM heart in-vivo and the largest cDTI study in HCM to date. Our results show good reproducibility of FA, MD and HA which indicates that current technology yields robust in-vivo measurements that have potential clinical value. The interpretation of regional differences in the septum requires further investigation.

We present a catalog of 4195 optically confirmed Sunyaev–Zel’dovich (SZ) selected galaxy clusters detected with signal-to-noise ratio >4 in 13,211 deg2 of sky surveyed by the Atacama Cosmology Telescope (ACT). Cluster candidates were selected by applying a multifrequency matched filter to 98 and 150 GHz maps constructed from ACT observations obtained from 2008 to 2018 and confirmed using deep, wide-area optical surveys. The clusters span the redshift range 0.04 < z < 1.91 (median z = 0.52). The catalog contains 222 z > 1 clusters, and a total of 868 systems are new discoveries. Assuming an SZ signal versus mass-scaling relation calibrated from X-ray observations, the sample has a 90% completeness mass limit of M500c > 3.8 × 1014 Me, evaluated at z = 0.5, for clusters detected at signal-to-noise ratio >5 in maps filtered at an angular scale of 2 4. The survey has a large overlap with deep optical weak-lensing surveys that are being used to calibrate the SZ signal mass-scaling relation, such as the Dark Energy Survey (4566 deg2), the Hyper Suprime-Cam Subaru Strategic Program (469 deg2), and the Kilo Degree Survey (825 deg2). We highlight some noteworthy objects in the sample, including potentially projected systems, clusters with strong lensing features, clusters with active central galaxies or star formation, and systems of multiple clusters that may be physically associated. The cluster catalog will be a useful resource for future cosmological analyses and studying the evolution of the intracluster medium and galaxies in massive clusters over the past 10 Gyr.

Abstract Background We aimed to assess the impact of inconsistent responses on the internal reliability of a multi-item scale by developing a procedure to adjust Cronbach's alpha. Methods A procedure for adjusting Cronbach's alpha when there are inconsistent responses was developed and used to assess the impact of inconsistent responses on internal reliability by evaluating the standard Chinese 12-item Short Form Health Survey in adolescents. Results Contrary to common belief, random responses may inflate Cronbach's alpha when their mean differ from that of the true responses. Fixed responses inflate Cronbach's alpha except in scales with both positive and negative polarity items. In general, the bias in Cronbach's alpha due to inconsistent responses may change from negative to positive with an increasing number of items in a scale, but the effect of additional items beyond around 10 becomes small. The number of response categories does not have much influence on the impact of inconsistent responses. Conclusions Cronbach's alpha can be biased when there are inconsistent responses, and an adjustment is recommended for better assessment of the internal reliability of a multi-item scale.

We study the cross-correlation between the Planck cosmic microwave background (CMB) lensing convergence map and the extended-Baryon Oscillation Spectroscopic Survey (e-BOSS) quasar overdensity obtained from the Sloan Digital Sky Survey (SDSS) IV, in the redshift range 0.9 < z < 2.2. We detect the CMB lensing convergence–quasar cross-power spectrum at 5.4σ significance. The cross-power spectrum provides a quasar clustering bias measurement that is expected to be particularly robust against systematic effects. The redshift distribution of the quasar sample has a median redshift z ≈ 1.55, and an effective redshift about 1.51. The best-fitting bias of the quasar sample is b q = 2.43 ± 0.45, corresponding to a host halo mass of log 10 h − 1MM = 12.54 +−00 .. 2536 . This is broadly consistent with the previous literature on quasars with a similar redshift range and selection. Since our constraint on the bias comes from the cross-correlation between quasars and CMB lensing, we expect it to be robust to a wide range of possible systematic effects that may contaminate the autocorrelation of quasars. We checked for a number of systematic effects from both CMB lensing and quasar overdensity, and found that all systematics are consistent with null within 2σ. The data are not sensitive to a possible scale dependence of the bias at present, but we expect that as the number of quasars increases [in future surveys such as Dark Energy Spectroscopic Instrument (DESI)], it is likely that strong constraints on the scale dependence of the bias can be obtained.

One of the most powerful cosmological data sets when it comes to constraining neutrino masses is represented by galaxy power spectrum measurements, Pgg(k). The constraining power of Pgg(k) is however severely limited by uncertainties in the modeling of the scale-dependent galaxy bias b(k). In this work we present a new proof-of-principle for a method to constrain b(k) by using the cross-correlation between the cosmic microwave background (CMB) lensing signal and galaxy maps (C κg) using a simple but theoretically well-motivated parametrization for b(k). We apply the method using C κg measured by cross-correlating Planck lensing maps and the Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 11 (DR11) CMASS galaxy sample, and Pgg(k) measured from the BOSS DR12 CMASS sample. We detect a nonzero scale-dependence at moderate significance, which suggests that a proper modeling of b(k) is necessary in order to reduce the impact of nonlinearities and minimize the corresponding systematics. The accomplished increase in constraining power of Pgg(k) is demonstrated by determining a 95% confidence level upper bound on the sum of the three active neutrino masses Mν of Mν