A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma

SummaryBackgroundTo our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS).ObjectiveEvaluate the dose–response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS.MethodsIn this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg twice daily (BID), or placebo, administered for 14 days (12–14-day washout). Trough forced expiratory volume in one second (FEV1), 0–24-h weighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup.ResultsSubjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0–24-h WM FEV1 versus placebo (0.068–0.121 L [p ≤ 0.017] with no clear dose–response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9–21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters.ConclusionThe modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma.ClinicalTrials.govNCT01641692

Estimation of Length or Height in Infants and Young Children Using Ulnar and Lower Leg Length with Dual-energy X-ray Absorptiometry Validation

AIM: We compared the accuracy and reproducibility of using ulnar and lower leg length measurements to predict length and height in infants and children aged 0 to 6 years. METHOD: Length/height and ulnar and lower leg length were measured in 352 healthy preterm and term-born children (167 males, 185 females) (Mean age= 2.6±1.6 years). Ulna length was measured as the distance between the proximal olecranon process and the distal styloid process of the ulna. Tibia length was measured as the distance from the proximal aspect of the medial condyle and the most distal aspect of the medial malleolus of the tibia using a segmometer. Length measurements were taken using an infant length board in children less than 24 months of age, whereas a portable stadiometer was used to measure height in older children. Equations were developed using ulnar and lower leg length and age. Intra- and inter-examiner variability (n=167) was calculated, and dual-energy X-ray absorptiometry scans (n=126) were used to determine accuracy of limb lengths. RESULTS: Ulnar and lower leg length explained over 95% of the variability in length/height in term infants and children, but less in preterm infants (R(2) =0.80-0.87). In preterm infants, the limits of agreement (LOA) for males were -2.44 to 2.44cm and -2.88 to 2.88cm for the ulna and lower leg respectively, whereas the LOA for females were -1.90 to 1.90cm and -1.87 to 1.87cm respectively. In older children, the LOA for males were -5.53 to 4.48cm and -5.59 to 4.62cm for the ulna and lower leg respectively, whereas the LOA for females were -5.57 to 5.01cm and -6.02 to 5.02cm respectively. Intra- and inter-examiner variability was low for all measurements in both sexes and age groups. INTERPRETATION: Length and height measurements using infant length board or stadiometer are reproducible. Because of the wide limits of agreement, estimation of length and height in children using ulnar and lower leg length is not an acceptable alternative to traditional methods

Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC50 = 2.67–13.19 μM) compared to bicalutamide (IC50 = 20.44 μM) in LNCaP. Remarkably, novel double branched bicalutamide analogues (27 and 28) were isolated as major by-products and found to have the best activity across three human prostate cancer cell lines (LNCaP, VCaP and PC3). The most active compound 28 shows sub-micromolar activity (IC50 = 0.43 μM in LNCaP), which represents more than 40-fold improvement over the clinical anti-androgen bicalutamide (IC50 = 20.44 μM) and a more than 3 fold improvement over enzalutamide (IC50 = 1.36 μM). Moreover, strong reduction of PSA expression in LNCaP cells upon treatment with compounds 27, 28 and 33 was observed during qPCR analysis, confirming their AR antagonist activity. Molecular modelling studies revealed a novel binding mode of these structurally distinct double branched analogues within the ligand binding domain (LBD) of the androgen receptor

Single Versus Multi-Center Surgeons\u27 Risk-Adjusted Mitral Valve Repair Procedural Outcomes

The purpose of this study is to explore strategies to improve mitral valve repair (MVr) outcomes. This research explores postoperative outcomes of patients undergoing MVr surgery by single center surgeons versus patients of multicenter surgeons. Specific outcomes of interest include 30-day operative mortality, major operative complications (e.g., deep sternal wound infection, permanent stroke, renal dysfunction requiring dialysis, reoperation, and prolonged ventilation), length of stay, and 30-day readmissions. In brief, the serisk-adjusted outcome rates for surgeons that perform mitral valve repair procedures will be compared for surgeons that operate at a single center [i.e. SC surgeons] versus multiple centers [i.e. MC surgeons]. The overarching study hypothesis is: H(0) There will be no difference in the risk-adjusted outcome rates between surgeons that operate at a single center [i.e. SC surgeons] versus multiple centers [i.e. MC surgeons]. Based on prior research, however, it is anticipated that single center surgeons may have superior outcomes compared to multi-center surgeons

mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell-derived hematopoietic progenitors

Generation of functional hematopoietic stem and progenitor cells (HSPCs) from human pluripotent stem cells (PSCs) has been a long-sought-after goal for use in hematopoietic cell production, disease modeling, and eventually transplantation medicine. Homing of HSPCs from bloodstream to bone marrow (BM) is an important aspect of HSPC biology that has remained unaddressed in efforts to derive functional HSPCs from human PSCs. We have therefore examined the BM homing properties of human induced pluripotent stem cell-derived HSPCs (hiPS-HSPCs). We found that they express molecular effectors of BM extravasation, such as the chemokine receptor CXCR4 and the integrin dimer VLA-4, but lack expression of E-selectin ligands that program HSPC trafficking to BM. To overcome this deficiency, we expressed human fucosyltransferase 6 using modified mRNA. Expression of fucosyltransferase 6 resulted in marked increases in levels of cell surface E-selectin ligands. The glycoengineered cells exhibited enhanced tethering and rolling interactions on E-selectin-bearing endothelium under flow conditions in vitro as well as increased BM trafficking and extravasation when transplanted into mice. However, glycoengineered hiPS-HSPCs did not engraft long-term, indicating that additional functional deficiencies exist in these cells. Our results suggest that strategies toward increasing E-selectin ligand expression could be applicable as part of a multifaceted approach to optimize the production of HSPCs from human PSCs

The Astrophysical Distance Scale: V. A 2% Distance to the Local Group Spiral M33 via the JAGB Method, Tip of the Red Giant Branch, and Leavitt Law

The J-region asymptotic giant branch (JAGB) method is a new standard candle that is based on the stable intrinsic J-band magnitude of color-selected carbon stars, and has a precision comparable to other primary distance indicators such as Cepheids and the TRGB. We further test the accuracy of the JAGB method in the Local Group Galaxy M33. M33's moderate inclination, low metallicity, and nearby proximity make it an ideal laboratory for tests of systematics in local distance indicators. Using high-precision optical BVI and near-infrared JHK photometry, we explore the application of three independent distance indicators: the JAGB method, the Cepheid Leavitt Law, and the TRGB. We find: $\mu_0$ (TRGB I) = 24.72 +/- 0.02 (stat) +/- 0.07 (sys) mag, $\mu_0$ (TRGB NIR) = 24.72 +/- 0.04 (stat) +/- 0.10 (sys) mag, $\mu_0$ (JAGB) = 24.67 +/- 0.03 (stat) +/- 0.04 (sys) mag, $\mu_0$ (Cepheid) = 24.71 +/- 0.04 (stat) +/- 0.01 (sys) mag. For the first time, we also directly compare a JAGB distance using ground-based and space-based photometry. We measure: $\mu_0$ (JAGB F110W) = 24.71 +/- 0.06 (stat) +/- 0.05 (sys) mag using the (F814-F110W) color combination to effectively isolate the JAGB stars. In this paper, we measure a distance to M33 accurate to 2% and provide further evidence that the JAGB method is a powerful extragalactic distance indicator that can effectively probe a local measurement of the Hubble constant using spaced-based observations. We expect to measure the Hubble constant via the JAGB method in the near future, using observations from JWST.Comment: 23 pages, 14 figures, accepted to the ApJ. v2 is exactly the same as v1 except for a fixed minor typo found while looking at the proof

A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075

Association between food insecurity and depressive symptoms among adolescents aged 12-15 years from 22 low- and middle-income countries

Food insecurity may be a risk factor for depression in adolescents. However, data on this topic from low- and middle-income countries (LMICs) are scarce, despite food insecurity being most common in LMICs. Therefore, we aimed to examine the association between food-insecurity and depressive symptoms among school-going adolescents from 22 LMICs. Cross-sectional data from the Global school-based Student Health Survey were analyzed. Self-report measures assessed past 12-month depressive symptoms and past 30-day food insecurity (hunger). Multivariable logistic regression and meta-analysis were conducted to assess associations. Data on 48,401 adolescents aged 12–15 years were analyzed [mean (SD) age 13.8 (0.9) years; 51.4 % females]. The prevalence of depressive symptoms was 29.3 %, and those of moderate and severe food insecurity were 45.0 and 6.3 %, respectively. After adjustment for potential confounders, compared to no food insecurity, the pooled OR (95 %CI) of moderate and severe food insecurity were 1.36 (1.30–1.42) and 1.81 (1.67–1.97), respectively. The level of between-country heterogeneity was low. Food insecurity was associated with significantly higher odds for depressive symptoms among adolescents in LMICs. Policies to address food insecurity may also help prevent depression in this population, pending future longitudinal research.</p