Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436

Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis

Objectives To investigate, in anti-cyclic citrullinated peptide antibody positive (CCP+) at-risk individuals without clinical synovitis, the prevalence and distribution of ultrasound (US) bone erosions (BE), their correlation with subclinical synovitis and their association with the development of inflammatory arthritis (IA). Methods Baseline US scans of 419 CCP+ at-risk individuals were analysed. BE were evaluated in the classical sites for rheumatoid arthritis damage: the second and fifth metacarpophalangeal (MCP2 and MCP5) joints, and the fifth metatarsophalangeal (MTP5) joints. US synovitis was defined as synovial hypertrophy (SH) ≥2 or SH ≥1+power Doppler signal ≥1. Subjects with ≥1 follow-up visit were included in the progression analysis (n=400). Results BE were found in ≥1 joint in 41/419 subjects (9.8%), and in 55/2514 joints (2.2%). The prevalence of BE was significantly higher in the MTP5 joints than in the MCP joints (p1 joint 10.6 (95% CI 1.9 to 60.4, p<0.01) and BE and synovitis in ≥1 MTP5 joint 5.1 (95% CI 1.4 to 18.9, p=0.02). In high titre CCP+ at-risk individuals, with positive rheumatoid factor and BE in ≥1 joint, the OR increased to 16.9 (95% CI 2.1–132.8, p<0.01). Conclusions In CCP+ at-risk individuals, BE in the feet appear to precede the onset of clinical synovitis. BE in >1 joint, and BE in combination with US synovitis in the MTP5 joints, are the most predictive for the development of clinical arthritis

Fasting and nutrient-stimulated plasma peptide-YY levels are elevated in critical illness and associated with feed intolerance: an observational, controlled study

INTRODUCTION: Delayed gastric emptying and feed intolerance occur frequently in the critically ill. In these patients, gastric motor responses to nutrients are disturbed. Peptide YY (PYY) slows gastric emptying. The aim of this study was to determine fasting and nutrient-stimulated plasma PYY concentrations and their relationship to cholecystokinin (CCK) in critically ill patients. METHODS: Studies were performed in 19 unselected mechanically ventilated critically ill patients (12 males; 48 ± 7 years old) in a randomised, single-blind fashion. Subjects received a 60-minute duodenal infusion of Ensure(® )at either 1 or 2 kcal/minute. Blood samples were collected at baseline and at 20, 40, 60, and 180 minutes following commencement of the nutrient infusion for the measurement of plasma PYY and CCK concentrations (using radioimmunoassay). Patient data were compared to 24 healthy subjects (17 males; 43 ± 2 years old). RESULTS: Fasting PYY concentration was higher in patients (P < 0.05), particularly in those with feed intolerance (P < 0.05). Plasma PYY concentrations were higher in patients during nutrient infusion (area under the curve [AUC] at 1 kcal/minute: 2,265 ± 718 versus 1,125 ± 138 pmol/l.min, P < 0.05; at 2 kcal/minute: 2,276 ± 303 versus 1,378 ± 210 pmol/l.min, P = 0.01) compared to healthy subjects. The magnitude of PYY elevation was greater in patients during the 1 kcal/minute infusion (AUC: 441 ± 153 versus 186 ± 58 pmol/l.min, P < 0.05), but not the 2 kcal/minute infusion. Fasting and nutrient-stimulated plasma CCK concentrations were higher in patients (P < 0.05). There was a relationship between plasma PYY and CCK concentrations during fasting (r = 0.52, P < 0.05) and nutrient infusion (r = 0.98, P < 0.0001). CONCLUSION: In critical illness, both fasting and nutrient-stimulated plasma PYY concentrations are elevated, particularly in patients with feed intolerance, in conjunction with increased CCK concentrations

Probing spin dynamics of ultra-thin van der Waals magnets via photon-magnon coupling

Layered van der Waals (vdW) magnets can maintain a magnetic order even down to the single-layer regime and hold promise for integrated spintronic devices. While the magnetic ground state of vdW magnets was extensively studied, key parameters of spin dynamics, like the Gilbert damping, crucial for designing ultra-fast spintronic devices, remains largely unexplored. Despite recent studies by optical excitation and detection, achieving spin wave control with microwaves is highly desirable, as modern integrated information technologies predominantly are operated with these. The intrinsically small numbers of spins, however, poses a major challenge to this. Here, we present a hybrid approach to detect spin dynamics mediated by photon-magnon coupling between high-Q superconducting resonators and ultra-thin flakes of Cr2Ge2Te6 (CGT) as thin as 11 nm. We test and benchmark our technique with 23 individual CGT flakes and extract an upper limit for the Gilbert damping parameter. These results are crucial in designing on-chip integrated circuits using vdW magnets and offer prospects for probing spin dynamics of monolayer vdW magnets

AdS Black Hole Solutions in the Extended New Massive Gravity

We have obtained (warped) AdS black hole solutions in the three dimensional extended new massive gravity. We investigate some properties of black holes and obtain central charges of the two dimensional dual CFT. To obtain the central charges, we use the relation between entropy and temperature according to the AdS/CFT dictionary. For AdS black holes, one can also use the central charge function formalism which leads to the same results.Comment: 24pages, some organization corrected, minor corrections, references added, final published versio

The anomalous U(1) global symmetry and flavors from an SU(5) x SU(5)′' GUT in Z12−IZ_{12-I} orbifold compactification

In string compactifications, frequently there appears the anomalous U(1) gauge symmetry which belonged to E8$\times$E8 of the heterotic string. This anomalous U(1) gauge boson obtains mass at the compactification scale, just below $10^{18\,}$GeV, by absorbing one pseudoscalar (corresponding to the model-independent axion) from the second rank anti-symmetric tensor field $B_{MN}$. Below the compactification scale, there results a global symmetry U(1)$_{\rm anom}$ whose charge $Q_{\rm anom}$ is the original gauge U(1) charge. This is the most natural global symmetry, realizing the "invisible" axion. This global symmetry U(1)$_{\rm anom}$ is suitable for a flavor symmetry. In the simplest compactification model with the flipped SU(5) grand unification, we calculate all the low energy parameters in terms of the vacuum expectation values of the standard model singlets.Comment: 18 pages, 4 figur

Comorbidities in Anti-Cyclic Citrullinated Peptide Positive At-Risk Individuals Do Not Differ from Those Patients with Early Inflammatory Arthritis

Objectives: To compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of inflammatory arthritis (IA) to those in patients with early IA. Methods: Baseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n = 296). The second cohort [the Inflammatory Arthritis CONtinuum study (IACON)] recruited patients with early IA (n = 725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status, and body mass index. Results: Patients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid-lowering agent, ischemic heart disease, cerebrovascular disease, lung disease, and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p = 0.037). Conclusion: There was no significant difference in comorbidities among people with CCP antibodies but without IA, compared to those of patients with established IA

Prioritising referrals of individuals at-risk of RA: guidance based on results of a 10-year national primary care observational study

Background Musculoskeletal (MSK) symptoms are among the commonest reasons for primary care assessments; however, few individuals will be diagnosed with an inflammatory arthritis (IA) within the following year. The purpose of this study was to investigate, in individuals with new MSK symptoms, the association between patient factors and risk of progression to IA, in order to optimise primary care referrals to rheumatology. Methods Individuals ≥16 years old with new non-specific MSK symptoms and no clinical synovitis were recruited by primary care across the UK from July 2007 until May 2019. Those testing positive for the anti-CCP2 assay (anti-CCP+) were invited to Leeds for follow-up. Subjects with a negative result (anti-CCP−) were sent a 1-year questionnaire, and general practitioners were contacted to confirm whether the individual had been diagnosed with an IA by a rheumatologist. Predictors for progression were assessed using multivariable regression analysis. Results Six thousand seven hundred eighty individuals were recruited: 3% were anti-CCP+, of whom 45% progressed to IA, predominantly rheumatoid arthritis. Anti-CCP+ participants with high antibody levels had an odds ratio (OR) for progression to IA of 9.42 [P < 0.001, 95% CI (3.13–28.30)], hand pain, OR 2.74 [P = 0.043, 95% CI (1.03–7.27)] and foot pain, OR 4.10 [P = 0.003, 95% CI (1.59–10.54)]. In low-level anti-CCP+ individuals, absence of pain in hands or feet had a negative predictive value of 96% for progression to IA. One-year follow-up data were available for 5640 anti-CCP− individuals, of whom 53 were diagnosed with IA (0.93%). Pain in hands, OR 2.51 [P = 0.018, 95% CI (1.17–5.39)] or knees, OR 3.03 [P = 0.003, 95% CI (1.47–6.25)] were associated with development of IA within 12 months. Conclusions This is the largest prospective primary care study of individuals at risk of IA, and the first one to prospectively investigate the outcome of MSK symptoms in a large anti-CCP− cohort. High anti-CCP levels and pain in hands/feet indicated an increased likelihood of progression to IA. In patients with low anti-CCP level and no pain in the hands/feet, progression is unlikely. In anti-CCP− patients, those with hand or knee pain were at increased risk of progression. This study demonstrates that routinely available tests and joint symptoms provide useful discrimination that may be used to prioritise referrals to rheumatology and avoid a delayed diagnosis. Trial registration NCT, NCT02012764. Registered 25 January 2007

Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis

Background: Individuals at risk of rheumatoid arthritis (RA) demonstrate systemic autoimmunity in the form of anti-citrullinated peptide antibodies (ACPA). MicroRNAs (miRNAs) are implicated in established RA. This study aimed to (1) compare miRNA expression between healthy individuals and those at risk of and those that develop RA, (2) evaluate the change in expression of miRNA from "at-risk" to early RA and (3) explore whether these miRNAs could inform a signature predictive of progression from "at-risk" to RA. Methods: We performed global profiling of 754 miRNAs per patient on a matched serum sample cohort of 12 anti-cyclic citrullinated peptide (CCP) + "at-risk" individuals that progressed to RA. Each individual had a serum sample from baseline and at time of detection of synovitis, forming the matched element. Healthy controls were also studied. miRNAs with a fold difference/fold change of four in expression level met our primary criterion for selection as candidate miRNAs. Validation of the miRNAs of interest was conducted using custom miRNA array cards on matched samples (baseline and follow up) in 24 CCP+ individuals; 12 RA progressors and 12 RA non-progressors. Results: We report on the first study to use matched serum samples and a comprehensive miRNA array approach to identify in particular, three miRNAs (miR-22, miR-486-3p, and miR-382) associated with progression from systemic autoimmunity to RA inflammation. MiR-22 demonstrated significant fold difference between progressors and non-progressors indicating a potential biomarker role for at-risk individuals. Conclusions: This first study using a cohort with matched serum samples provides important mechanistic insights in the transition from systemic autoimmunity to inflammatory disease for future investigation, and with further evaluation, might also serve as a predictive biomarker

Hydroxyapatite Mineralization on the Calcium Chloride Blended Polyurethane Nanofiber via Biomimetic Method

Polyurethane nanofibers containing calcium chloride (CaCl2) were prepared via an electrospinning technique for the biomedical applications. Polyurethane nanofibers with different concentration of CaCl2 were electrospun, and their bioactivity evaluation was conducted by incubating in biomimetic simulated body fluid (SBF) solution. The morphology, structure and thermal properties of the polyurethane/CaCl2 composite nanofibers were characterized by means of scanning electron microscopy (SEM), field-emission scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy and thermogravimetry. SEM images revealed that the CaCl2 salt incorporated homogeneously to form well-oriented nanofibers with smooth surface and uniform diameters along their lengths. The SBF incubation test confirmed the formation of apatite-like materials, exhibiting enhanced bioactive behavior of the polyurethane/CaCl2 composite nanofibers. This study demonstrated that the electrospun polyurethane containing CaCl2 composite nanofibers enhanced the in vitro bioactivity and supports the growth of apatite-like materials