An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to ...progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.
We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval CI, 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).
This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
In this paper we present the results of optical high-resolution imaging and spectroscopy of the complex planetary nebula (PN) NGC 3242. Our study is based on the analysis of the narrow-band Hα λ6563, ...O iii λ5007, N ii λ6584, and S ii λ6724 Å images, and high-resolution spectroscopy using spectral ranges centred on the Hα λ6564, N ii λ6583, and O iii λ5007 Å. We detected and analysed morphological components beyond the multiple-shell structure of this PN, to investigate the small-scale morphological components aligned towards its major axis (such as knots and ansae, as well as the arc-like features) and its surroundings. Thus, we investigated the morpho-kinematical properties of NGC 3242, as well as their nature and formation. Our results regarding the elliptical double-shell structure and the distance to this nebula are in concordance with previous studies. Furthermore, we have used the software shape to construct a 3D model of NGC 3242, allowing us to successfully reproduce our observational data. We conclude that the prominent knots emitting in the N ii line are fast, low-ionization emission regions related to high-velocity jets and the so-called ansae-like features rather resemble bubbles. The disruptions immersed in the halo, whose emission was detected in the O iii high-excitation emission line, remarkably display high velocities and were formed likely in an earlier ejection event, in comparison to the innermost low-ionization structures and bubbles. Finally, according to our model, the kinematical ages of the structures in NGC 3242 range from 390 to 5400 yr.
An efficient monitoring and control system for solar photovoltaic modules, which combines the use of a non-linear MPPT backstepping controller with a custom wireless sensor network (WSN) has been ...developed. The infrastructure consists of a wireless smart photovoltaic system (WSPS) and a wireless centralized control system (WCC). The data of sensing, coordination and control is handled by using a WSN based on IEEE 802.15.4 technology in beacon enable mode and with guaranteed time slot. This assures the data transmission and a synchronous acquisition, which are critical elements in a wireless photovoltaic monitoring system. All measured data is gathered by an autonomous, compact and low-cost sensor node installed in each PV module, and it is transferred to the coordinator node. The power consumption of the sensor node represents only 0.25% of the power delivered by the photovoltaic module. A backstepping controller to track the Maximum Power Point (MPP) by means of a buck-boost converter derives the reference parameters to return to each PV module accordingly. The wireless solution uses low latency techniques to achieve a real-time monitoring and a stable performance of the controller. The centralized control identifies all the network nodes and significantly simplifies the maintenance operations. Experimental validation shows the robustness against interference and security in the wireless data transmission and confirms the feasibility of the proposed wireless sensor system in tracking the maximum power transfer under different weather conditions, achieving an efficiency over the 99% in the MPPT.
Summary
Type 1 diabetes results from destruction of insulin‐producing beta cells in pancreatic islets and is characterized by islet cell autoimmunity. Autoreactivity against non‐beta cell‐specific ...antigens has also been reported, including targeting of the calcium‐binding protein S100β. In preclinical models, reactivity of this type is a key component of the early development of insulitis. To examine the nature of this response in type 1 diabetes, we identified naturally processed and presented peptide epitopes derived from S100β, determined their affinity for the human leucocyte antigen (HLA)‐DRB1*04:01 molecule and studied T cell responses in patients, together with healthy donors. We found that S100β reactivity, characterized by interferon (IFN)‐γ secretion, is a characteristic of type 1 diabetes of varying duration. Our results confirm S100β as a target of the cellular autoimmune response in type 1 diabetes with the identification of new peptide epitopes targeted during the development of the disease, and support the preclinical findings that autoreactivity against non‐beta cell‐specific autoantigens may have a role in type 1 diabetes pathogenesis.
This paper presents a study of the effect of a combined biostimulation–bioaugmentation treatment applied to a silty-loam soil polluted with 60,600
mg
kg
−1 of a complex mixture of total petroleum ...hydrocarbons (TPH), which comprises 40% aliphatic hydrocarbons (AH) and 21% polycyclic aromatic hydrocarbons (PAH). The bioaugmentation was performed with
Rhizopus sp.,
Penicillium funiculosum and
Aspergillus sydowii strains isolated from two aged soils contaminated with 60,600 and 500,000
mg of TPH per kilogram of dried soil. The native fungi were able to grow in a complex solid mixture of hydrocarbons of high molecular weight, after previous acclimatization in liquid culture. The three fungi mentioned above were able to remove, respectively, 36%, 30% and 17% more PAH in comparison with biostimulation alone. In the bioaugmented systems with
Rhizopus sp. and
A. sydowii, a positive correlation of respirometric activity (CO
2 production) with hydrocarbon removal was obtained (
R
2=0.75;
p(
F)=0.001 and
R
2=0.78;
p(
F)=0.001, respectively); in contrast,
P. funiculosum did not show any correlation. An interesting finding from this work is that two of these species of fungi had not previously been reported as being PAH-degrading.
Background
Exposure to life-threatening drug-drug interactions (DDIs) occurs despite the widespread use of clinical decision support. The DDI between warfarin and nonsteroidal anti-inflammatory drugs ...is common and potentially life-threatening. Patients can play a substantial role in preventing harm from DDIs; however, the current model for DDI decision-making is clinician centric.
Objective
This study aims to design and study the usability of DDInteract, a tool to support shared decision-making (SDM) between a patient and provider for the DDI between warfarin and nonsteroidal anti-inflammatory drugs.
Methods
We used an SDM framework and user-centered design methods to guide the design and usability of DDInteract—an SDM electronic health record app to prevent harm from clinically significant DDIs. The design involved iterative prototypes, qualitative feedback from stakeholders, and a heuristic evaluation. The usability evaluation included patients and clinicians. Patients participated in a simulated SDM discussion using clinical vignettes. Clinicians were asked to complete eight tasks using DDInteract and to assess the tool using a survey adapted from the System Usability Scale.
Results
The designed DDInteract prototype includes the following features: a patient-specific risk profile, dynamic risk icon array, patient education section, and treatment decision tree. A total of 4 patients and 11 clinicians participated in the usability study. After an SDM session where patients and clinicians review the tool concurrently, patients generally favored pain treatments with less risk of gastrointestinal bleeding. Clinicians successfully completed the tasks with a mean of 144 (SD 74) seconds and rated the usability of DDInteract as 4.32 (SD 0.52) of 5.
Conclusions
This study expands the use of SDM to DDIs. The next steps are to determine if DDInteract can improve shared decision-making quality and to implement it across health systems using interoperable technology.
To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical ...atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1±3.9%; median: 5.7% at day 14, and mean ± SD: 7.4±2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5±4.0%; median: 3.6%; P=0.03 and P<0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69±0.21 mm) were compared with those found at day 0 (0.65±0.16 mm) (P=0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA.
Aims/hypothesis
Proinflammatory and proapoptotic cytokines such as TNF-
α
are upregulated in human obesity. We evaluated the association between ghrelin isoforms (acylated and desacyl ghrelin) and ...TNF-α in obesity and obesity-associated type 2 diabetes, as well as the potential role of ghrelin in the control of apoptosis and autophagy in human adipocytes.
Methods
Plasma concentrations of the ghrelin isoforms and TNF-α were measured in 194 participants. Ghrelin and ghrelin
O
-acyltransferase (GOAT) levels were analysed by western-blot, immunohistochemistry and real-time PCR in 53 biopsies of human omental adipose tissue. We also determined the effect of acylated and desacyl ghrelin (10 to 1,000 pmol/l) on TNF-α-induced apoptosis and autophagy-related molecules in omental adipocytes.
Results
Circulating concentrations of acylated ghrelin and TNF-α were increased, whereas desacyl ghrelin levels were decreased in obesity-associated type 2 diabetes. Ghrelin and GOAT were produced in omental and subcutaneous adipose tissue. Visceral adipose tissue from obese patients with type 2 diabetes showed higher levels of GOAT, increased adipocyte apoptosis and increased expression of the autophagy-related genes
ATG5
,
BECN1
and
ATG7
. In differentiating human omental adipocytes, incubation with acylated and desacyl ghrelin reduced TNF-α-induced activation of caspase-8 and caspase-3, and cell death. In addition, acylated ghrelin reduced the basal expression of the autophagy-related genes
ATG5
and
ATG7
, while desacyl ghrelin inhibited the TNF-α-induced increase of
ATG5
,
BECN1
and
ATG7
expression.
Conclusions/interpretation
Apoptosis and autophagy are upregulated in human visceral adipose tissue of patients with type 2 diabetes. Acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in human visceral adipocytes.
Pollution of coasts by toxic metals and metalloids is a worldwide problem for which phytoremediation using halophytes and associated microbiomes is becoming relevant. Metal(loid) excess is a ...constraint for plant establishment and development, and plant growth promoting rhizobacteria (PGPR) mitigate plant stress under these conditions. However, mechanisms underlying this effect remain elusive. The effect of toxic metal(loid)s on activity and gene expression of ROS-scavenging enzymes in roots of the halophyte Spartina densiflora grown on real polluted sediments in a greenhouse experiment was investigated. Sediments of the metal-polluted joint estuary of Tinto and Odiel rivers and control, unpollutred samples from the Piedras estuary were collected and submitted to ICP-OES. Seeds of S. densiflora were collected from the polluted Odiel marshes and grown in polluted and unpolluted sediments. Rhizophere biofilm-forming bacteria were selected based on metal tolerance and inoculated to S. densiflora and grown for 4 months. Fresh or frozen harvested plants were used for enzyme assays and gene expression studies, respectively. Metal excess induced SOD (five-fold increase), whereas CAT and ascorbate peroxidase displayed minor induction (twofold). A twofold increase of TBARs indicated membrane damage. Our results showed that metal-resistant PGPR (P. agglomerans RSO6 and RSO7 and B. aryabhattai RSO25) contributed to alleviate metal stress, as deduced from lower levels of all antioxidant enzymes to levels below those of non-exposed plants. The oxidative stress index (OSI) decreased between 50 and 75% upon inoculation. The results also evidenced the important role of PAL, involved in secondary metabolism and/or lignin synthesis, as a pathway for metal stress management in this halophyte upon inoculation with appropriate PGPR, since the different inoculation treatments enhanced PAL expression between 3.75- and five-fold. Our data confirm, at the molecular level, the role of PGPR in alleviating metal stress in S. densiflora and evidence the difficulty of working with halophytes for which little genetic information is available.
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