The associated risk of phthalate exposure, both parent compounds in the home and their metabolites in urine, to childhood allergic and respiratory morbidity, after adjusting for exposures of indoor ...pollutants, especially bioaerosols, was comprehensively assessed. Levels of five phthalates in settled dust from the homes of 101 children (3–9 years old) were measured, along with their corresponding urinary metabolites. Other environmental risk factors, including indoor CO2, PM2.5, formaldehyde, 1,3‐β‐d‐glucan, endotoxin, allergen and fungal levels, were concomitantly examined. Subject’s health status was verified by pediatricians, and parents recorded observed daily symptoms of their children for the week that the home investigation visit took place. Significantly increased level of benzylbutyl phthalate, in settled dust, was associated with test case subjects (allergic or asthmatic children). Higher levels of dibutyl phthalate and its metabolites, mono‐n‐butyl phthalate, and mono‐2‐ethylhexyl phthalate were found to be the potential risk factors for the health outcomes of interest. Similarly, indoor fungal exposure remained a significant risk factor, especially for reported respiratory symptoms. The relative contribution from exposure to phthalates and indoor biocontaminants in childhood allergic and respiratory morbidity is, for the first time, quantitatively assessed and characterized.
Practical Implications
For asthmatic and allergic children living in subtropical and highly developed environments like homes in Taiwan, controlling environmental exposure of phthalates may be viewed as equally important as avoiding indoor microbial burdens, for the management of allergy‐related diseases. It is also recognized that multidisciplinary efforts will be critical in realizing the true underlying mechanisms associated with these observations.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Some insects, such as dragonflies, have evolved nanoprotrusions on their wings that rupture bacteria on contact. This has inspired the design of antibacterial implant surfaces with insect-wing ...mimetic nanopillars made of synthetic materials. Here, we characterise the physiological and morphological effects of mimetic titanium nanopillars on bacteria. The nanopillars induce deformation and penetration of the Gram-positive and Gram-negative bacterial cell envelope, but do not rupture or lyse bacteria. They can also inhibit bacterial cell division, and trigger production of reactive oxygen species and increased abundance of oxidative stress proteins. Our results indicate that nanopillars' antibacterial activities may be mediated by oxidative stress, and do not necessarily require bacterial lysis.
Using data samples collected with the BESIII detector operating at the BEPCII storage ring, we measure the cross sections of the e + e − → π + π − D + D − process at center-of-mass energies from ...4.190 to 4.946 GeV with a partial reconstruction method. Resonance structures are seen and the cross section line shape can be described by the coherent sum of either two Breit-Wigner functions or a Breit-Wigner function and a phase space term. The mass and width of the resonance at about 4.4 GeV are determined to be (4371.6±2.5±9.2) MeV/c 2 and (167±4±29) MeV, respectively, which are in agreement with those of the ψ(4360) or Y(4390) state. The spin-3D-wave charmonium state X(3842) is searched for through the e + e − → π + π − X(3842) → π + π − D + D − process, and evidence with a significance of 4.2σ is found in the data samples with center-of-mass energies from 4.6 to 4.7 GeV.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Using a sample of about 10(10) J/Psi events collected at a center-of-mass energy root s = 3.097 GeV with the BESIII detector, the electromagnetic Dalitz decays J/Psi -> e(+)e(-) pi(+)pi(-) eta', ...with eta' -> gamma pi(+)pi(-) and eta' -> pi(+)pi(-) eta, have been studied. The decay J/Psi -> e(+)e(-) X(1835) is observed with a significance of 15 sigma, and also an e(+)e(-) invariant-mass dependent transition form factor of J/Psi -> e(+)e(-) X(1835) is presented for the first time. The intermediate states X(2120) and X(2370) are also observed in the pi(+)pi(-) eta' invariant-mass spectrum with significances of 5.3 sigma and 7.3 sigma. The corresponding product branching fractions for J/Psi -> e(+)e(-) X, X -> pi(+) pi(-) eta' X = X(1835), X(2120), and X(2370) are reported.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Summary
Background
The roles remain unclear of early on‐treatment quantitative serum HBsAg and hepatitis B virus (HBV) DNA levels in the prediction of a sustained response (SR) to peginterferon ...alfa‐2a therapy in HBeAg‐negative chronic hepatitis B (CHB) patients infected with genotype B or C.
Aims
To determine their roles in HBeAg‐negative CHB patients infected with genotype B or C.
Methods
Sixty‐one patients were treated with peginterferon alfa‐2a for 48 weeks. Serum HBsAg levels were quantified using the Abbott Architect HBsAg QT assay throughout treatment. Multiple regression analyses were performed to identify independent predictors of SR.
Results
Nineteen patients (31%) achieved SR with serum HBV DNA levels <312 copies/mL at 24 weeks post‐treatment. Serum HBsAg levels at 12 (OR 31.9; 95% CI 4.8–209.6; P = 0.0003) and 24 weeks of therapy (OR 8.8; 95% CI 2.0–38.0; P = 0.0035), and HBV DNA levels at baseline (OR 7.0; 95% CI 1.3–36.2; P = 0.0203), 12 (OR 7.9; 95% CI 1.2–48.4; P = 0.0249) and 24 weeks of therapy (OR 22.3; 95% CI 2.2–224.0; P = 0.0083) were early independent predictors of SR. A serum HBsAg cut‐off of 150 IU/mL at week 12 had an AUC, sensitivity, specificity and positive and negative predictive values of 0.75, 63%, 95%, 86% and 85% with respect to predicting SR respectively.
Conclusions
A quantitative serum HBsAg level at 12 weeks of therapy can be used for the early prediction of SR to peginterferon therapy in HBeAg‐negative CHB patients infected with genotype B or C.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:Tranexamic acid (TXA) reduces bleeding and the need for transfusion after total knee arthroplasty. Most literature has focused on intravenous (IV) administration of TXA, with less data ...available on the efficacy of topically administered TXA. This multicenter randomized clinical trial specifically assessed the efficacy of topical TXA compared with IV TXA as measured by calculated blood loss, drain output, and transfusion rates. Complications, including venous thromboembolism (VTE), were reported.
METHODS:A total of 640 patients who underwent primary unilateral total knee arthroplasty for osteoarthritis at 2 large academic centers were randomized to receive 1 g of IV TXA prior to tourniquet inflation and 1 g at closure, or 3 g of TXA diluted in 45 mL of normal saline solution (total volume of 75 mL) and topically applied after cementation. Age, sex, body mass index, American Society of Anesthesiologists (ASA) score, and preoperative hemoglobin level were similar between the groups. Univariate, multiple linear regression, and multiple logistic regression analyses were performed.
RESULTS:Patients who received topical TXA had significantly greater calculated blood loss compared with those who received IV TXA (mean of 324 compared with 271 mL; p = 0.005). Drain output was significantly higher in the topical TXA group compared with the IV TXA group (mean of 560 compared with 456 mL; p < 0.0001). The rate of transfusion was low in the topical and IV groups, with no significant difference on univariate analysis (1.6% compared with 0.6%, respectively; p = 0.45); however, on multiple logistic regression analysis, patients who received topical TXA were 2.2-fold more likely to receive a transfusion (p < 0.0001). The topical and IV TXA groups did not differ significantly with respect to the rate of thrombotic events (0.6% compared with 1.6%, respectively; p = 0.45).
CONCLUSIONS:In this large, randomized clinical trial involving patients undergoing total knee arthroplasty, both IV and topical TXA were associated with a low rate of transfusion. While IV TXA was associated with less calculated blood loss, lower drain output, and fewer transfusions, the small differences between the groups may not be clinically important. Given the low prevalence of thrombotic complications, the relative safety of one formulation of TXA over the other cannot be definitely established.
LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
InAs/GaAs quantum dot solar cell structures have been grown by metal organic vapor phase epitaxy, using partial capping of the quantum dots plus a subsequent thermal anneal. The optical ...characteristics of the InAs quantum dot layers have been studied as a function of the GaAs capping layer thickness and annealing temperature. We observe that a thinner capping layer and a higher annealing temperature result in lower non-radiative defect density and in improved quantum dot size homogeneity, leading to intense and sharp photoluminescence emission at low temperatures. We use an effective mass approximation model to correlate the photoluminescence emission characteristics to the quantum dot composition and dimensions. The resulting InAs/GaAs intermediate band solar cells show the best performance for the case of a 3 nm thick capping layer and annealing at 700 °C.
•Different capping techniques are analyzed using TEM and PL results.•QD composition and morphological evolution during capping procedure are described.•Theoretical calculations are employed to describe the obtained results.•A thin capping layer annealed at higher temperature provides interconnected QDs.•The optimized capping procedure improves PV performance by a factor higher than 3.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus ...letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.
A total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.
At the time of the second interim analysis, the median duration of follow-up was 26.4months. Median PFS was 25.3months 95% confidence interval (CI) 23.0–30.3 for ribociclib plus letrozole and 16.0months (95% CI 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457–0.704; log-rank P=9.63×10−8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.
The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.
NCT01958021
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging ...with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
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•Effective anti-PD-1 anti-tumor responses require IL-12-producing dendritic cells•Anti-PD-1 indirectly activates IL-12 through IFN-γ produced from CD8+ T cells•Agonizing the non-canonical NF-κB pathway enhances dendritic cell IL-12 production•Combining aPD-1 with non-canonical NF-κB agonism enhances checkpoint immunotherapy
Anti-PD-1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-γ released from drug-activated T cells. Furthermore, agonizing the non-canonical NF-κB pathway activates DCs and enhances aPD-1 therapy in an IL-12-dependent manner.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine platforms could ...address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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