In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free ...DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected.
Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%.
Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.
Soybean is considered one of today’s most important crops. Planted on millions of hectares worldwide, the management of soybean pests usually requires large amounts of chemicals. However, a key ...component to meet the increasing demand for food due to the rapidly growing global population is protecting crops from pests while maintaining environmental quality through ecologically and economically sound integrated pest management (IPM) practices. Not only can IPM result in more profitable agriculture due to the reduction of pest control costs but also assures equitable, secure, sufficient, and stable flows of both food and ecosystem services. Despite those ecological and economic benefits, the vast areas of cultivated soybean as well as the convenience of spraying insecticides are encouraging the adoption of prophylactic pest control as a relatively inexpensive safeguard compared to IPM practices. Thus, in this forum, we discuss the reasons for soybean IPM not reaching its potential. We give examples of how we can revive this once successful pest management program with a focus on experiences in Brazil and the USA. We analyze IPM case studies to illustrate the need for growers to have easy and fast access to IPM information on its medium- and long-term benefits. Overall, this forum highlights the importance of IPM for agricultural sustainability including ecological and financial benefits.
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•Duplex hydrogenated Diamond-like Carbon was produced and characterised.•Friction and wear under dry condition of H-DLC/steel tribopair was assessed.•Adhesive strength of the coating ...was 80N after the scratch tests under dry condition.•Maximum and minimum values of average coefficient of friction were 0.21 and 0.13.•A protective transferred layer on the counterpart produced a carbon-carbon contact.
Carbon-based coatings are of wide interest due to their application in machine elements subjected to continuous contact where fluid lubricant films are not permitted. This paper describes the tribological performance under dry conditions of duplex layered H-DLC coating sequentially deposited by microwave excited plasma enhanced chemical vapour deposition on AISI 52100 steel. The architecture of the coating comprised Cr, WC, and DLC (a-C:H) with a total thickness of 2.8μm and compressive residual stress very close to 1GPa. Surface hardness was approximately 22GPa and its reduced elastic modulus around 180GPa. Scratch tests indicated a well adhered coating achieving a critical load of 80N. The effect of normal load on the friction and wear behaviours were investigated with steel pins sliding against the actual coating under dry conditions at room temperature (20±2°C) and 35–50% RH. The results show that coefficient of friction of the coating decreased from 0.21 to 0.13 values with the increase in the applied loads (10–50N). Specific wear rates of the surface coating also decrease with the increase in the same range of applied loads. Maximum and minimum values were 14×10−8 and 5.5×10−8mm−3/Nm, respectively. Through Raman spectroscopy and electron microscopy it was confirmed the carbon-carbon contact, due to the tribolayer formation on the wear scars of the coating and pin. In order to further corroborate the experimental observations regarding the graphitisation behaviour, the existing mathematical relationships to determine the graphitisation temperature of the coating/steel contact as well as the flash temperature were used.
An emerging source of information to recognize individuals' characteristics are the walking pattern-related parameters. The elderly can be one of the populations that can benefit most from ...recognition-based applications, which may help to increase their possibilities of living independently at home. Approaches have been mostly focused on gait events' identification or assessment; nonetheless, such information can also be used to obtain seniors' characteristics that depend on physiological or environmental factors. These factors can be useful to provide a customized assistance based on contextual information. In this paper, we propose a method focused on seniors, to detect steps, and to recognize gender and type of shoes by using only the initial foot contact (IC) data obtained from inertial sensors during semi-controlled walking. Data were collected from 20 older adults who walked at self-speed in a natural environment. The method consists of first clustering the IC using
-means; then, a trained recurrent neural network recognizes gender, type of shoes, and the step phases (IC and other phases); to finally conduct step detection (SD) using a ruled-based method. The method recognizes gender and the type of shoes with an accuracy of 93% and 83.07%, respectively, whereas there were not misrecognitions of the step phases. SD achieved a mean absolute percentage error equal to
. The good results show that the method is appropriate for users' characteristics recognition applications without depending on assumptions based on individualities. Likewise, the method can be useful to monitor physical activity or systems aimed to keep safe older adults.
In Spain, two synoptic-scale conditions influence heat wave formation. The first involves advection of warm and dry air masses carrying dust of Saharan origin (North African Dust (NAF) = 1). The ...second entails anticyclonic stagnation with high insolation and stability (NAF) = 0). Some studies show that the meteorological origin of these heat waves may affect their impact on morbidity and mortality.
To determine whether the impact of heat waves on health outcomes in Madrid (Spain) during 2013–2018 varied by synoptic-scale condition.
Outcome data consist of daily mortality and daily hospital emergency admissions (morbidity) for natural, circulatory, and respiratory causes. Predictors include daily maximum and minimum temperatures and daily mean concentrations of NO2, PM10, PM2.5, NO2, and O3. Analyses adjust for insolation, relative humidity, and wind speed. Generalized linear models were performed with Poisson link between the variables controlling for trend, seasonality, and auto-regression in the series. Relative Risks (RR) and Attributable Risks (AR) were determined. The RRs for mortality attributable to high temperatures were similar regardless of NAF status. For hospital admissions, however, the RRs for hot days with NAF = 0 are higher than for days with NAF = 1. We also found that atmospheric pollutants worsen morbidity and mortality, especially PM10 concentrations when NAF = 1 and O3 concentrations when NAF = 0.
The effect of heat waves on morbidity and mortality depends on the synoptic situation. The impact is greater under anticyclonic stagnation conditions than under Saharan dust advection. Further, the health impact of pollutants such as PM10 and O3 varies according to the synoptic situation.
Based on these findings, we strongly recommend prevention plans to include data on the meteorological situation originating the heat wave, on a synoptic-scale, as well as comprehensive preventive measures against the compounding effect of high temperatures and pollution.
Relative risks (RR) with their respective 95 % CIs of the significant independent variables for mortality due to the different causes. In brackets, the lag at which the statistical significant association occurs. Red colour when Saharan advection occurs, blue colour when there is an anticyclonic stagnation at the origin of the heat wave. Display omitted
•The effect of heat waves on morbid mortality depends on the synoptic situation.•Temperature has a greater effect in heat waves due to stable atmospheric conditions.•The health impact of PM10 and O3 varies according to the synoptic situation.
Deserts are stressful environments where the living beings must acquire different strategies to survive due to the water stress conditions. From the late Albian to the early Cenomanian, the northern ...and eastern parts of Iberia were the location of the desert system represented by deposits assigned to the Utrillas Group, which bear abundant amber with numerous bioinclusions, including diverse arthropods and vertebrate remains. In the Maestrazgo Basin (E Spain), the late Albian to early Cenomanian sedimentary succession represents the most distal part of the desert system (fore-erg) that was characterised by an alternation of aeolian and shallow marine sedimentary environments in the proximity of the Western Tethys palaeo-coast, with rare to frequent dinoflagellate cysts. The terrestrial ecosystems from this area were biodiverse, and comprised plant communities whose fossils are associated with sedimentological indicators of aridity. The palynoflora dominated by wind-transported conifer pollen is interpreted to reflect various types of xerophytic woodlands from the hinterlands and the coastal settings. Therefore, fern and angiosperm communities abundantly grew in wet interdunes and coastal wetlands (temporary to semi-permanent freshwater/salt marshes and water bodies). In addition, the occurrence of low-diversity megafloral assemblages reflects the existence of coastal salt-influenced settings. The palaeobotanical study carried out in this paper which is an integrative work on palynology and palaeobotany, does not only allow the reconstruction of the vegetation that developed in the mid-Cretaceous fore-erg from the eastern Iberia, in addition, provides new biostratigraphic and palaeogeographic data considering the context of angiosperm radiation as well as the biota inferred in the amber-bearing outcrops of San Just, Arroyo de la Pascueta and La Hoya (within Cortes de Arenoso succesion). Importantly, the studied assemblages include Afropollis, Dichastopollenites, Cretacaeiporites together with pollen produced by Ephedraceae (known for its tolerance to arid conditions). The presence of these pollen grains, typical for northern Gondwana, associates the Iberian ecosystems with those characterising the mentioned region.
The objective of this study was to analyze at the level of Spain's 52 provinces province level the temporal evolution of minimum mortality temperatures (MMT) from 1983 to 2018, in order to determine ...whether the increase in MMT would be sufficient to compensate for the increase in environmental temperatures in Spain for the period. It also aimed to analyze whether the rate of evolution of MMT would be sufficient, were it to remain constant, to compensate for the predicted increase in temperatures in an unfavorable (RCP 8.5) emissions scenario for the time horizon 2051–2100.
The independent variable was made up of maximum daily temperature data (Tmax) for the summer months in the reference observatories of each province for the 1983–2018 period. The dependent variable was daily mortality rate due to natural causes (ICD 10: A00-R99). For each year and province, MMT was determined using a quadratic or cubic fit (p < 0.05). Based on the annual MMT values, a linear fit was carried out that allowed for determining the time evolution of MMT. These values were compared with the evolution of Tmax registered in each observatory during the 1983–2018 analyzed period and with the predicted values of Tmax obtained for an RCP8.5 scenario for the period 2051–2100.
The rate of global variance in Tmax in the summer months in Spain during the 1983–2018 period was 0.41 °C/decade, while MMT across the whole country increased at a rate of 0.64 °C/decade. Variations in the provinces were heterogeneous. For the 2051–2100 time horizon, there was predicted increase in Tmax values of 0.66 °C/decade, with marked geographical differences. Although at the global level it is possible to speak of adaptation, the heterogeneities among the provinces suggest that the local level measures are needed in order to facilitate adaptation in those areas where it is not occurring.
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•Spain's global variance rate of Tmax during 1983–2018 was 0.41 °C/decade.•The MMT across the whole country increased at a rate of 0.64 °C/decade.•Considering predicted values for 2051–2100 (RCP 8.5) the rate would be 0.66 °C/decade.•Geographical heterogeneities suggest the need to articulate local level measures.
Abstract Background Although sleep disturbances are common during female mid-life, few studies have described in detail the prevalence of this problem and related risk factors. Objective To determine ...the prevalence of sleep disturbances in mid-aged women using validated tools. Assessment of determinants capable of influencing the prevalence of insomnia and poor sleep quality was also performed. Methods A total of 6079 women aged 40–59 of 11 Latin American countries were invited to fill out the Athens Insomnia Scale (AIS), the Pittsburgh Sleep Quality Index (PSQI), the Goldberg Anxiety and Depression Scale, the Menopause Rating Scale (MRS), the Brief Scale of Abnormal Drinking and a general socio-demographic questionnaire. Results Overall, 56.6% of surveyed women suffered of either insomnia, poor sleep quality, or both. Specifically, 43.6% and 46.2% presented insomnia and poor sleep quality in accordance to the AIS and the PSQI respectively. The prevalence of insomnia increased with female age (from 39.7% in those aged 40–44 to 45.2% in those aged 55–59, p < 0.0001) and menopausal stage (from 39.5% in premenopausal aged 40–44 to 46.3% in late postmenopausal ones, p < 0.0001). “Awakening during the night” (AIS: Item 2) was the most highly rated of all items and contributing in a higher degree (mean 16%) to the total score of the scale in all menopausal phases. Sleep quality also worsened with age and menopausal status, impairment particularly affecting sleep efficiency and latency and the increased use of hypnotics. Vasomotor symptoms (VMS), depressive mood and anxiety were associated to sleep disturbances. Women presenting sleep disturbances displayed a 2-fold increase in the severity of menopausal symptoms (higher total MRS scores) which was translated into a 6–8 times higher risk of impaired quality of life. Logistic regression analysis determined that female age, the presence of chronic disease, troublesome drinking, anxiety, depression, VMS, drug use (hypnotics and hormone therapy) were significant risk factors related to the presence of sleep disturbances. Higher educational level related to less insomnia and better sleep quality. Conclusion Insomnia and poor sleep quality were highly prevalent in this mid-aged female sample in which the influence of age and the menopause was only modest and rather linked to menopausal symptoms already occurring since the premenopause.
Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology ...regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
Abstract Light competition increases and plants’ growth pattern change to optimize light utilization when the leaf area index increases. It has been previously shown that using 95% canopy light ...interception (LI) as a grazing frequency criterion resulted in a greater proportion of leaves and a lower proportion of stem. The objective of the study was to characterize the forage production, morphological composition and nutritive value of Panicum maximum cv Mombaça. The experiment was carried out during summer, autumn–winter and spring. Treatments corresponded to combinations of two pre-grazing conditions (95% and maximum LI at pre-grazing; LI 95% and LI Max , respectively) and two post-grazing heights (PGHs; 30 and 50 cm). The statistical design was a randomized complete block, with a 2 × 2 factorial arrangement. Swards managed with LI 95% had greater proportions of leaves and lower proportions of stems compared to LI Max . Leaf proportion was lower during autumn–winter compared to summer and spring. The LI 95% had greater crude protein (CP) and digestibility (IVOMD), and lower acid detergent fibre (ADF) concentrations than LI Max . The 50 cm PGH pastures had greater CP content and IVOMD, and lower ADF content than 30 cm PGH pastures. Lower IVOMD was observed during autumn–winter than summer and spring. The variability observed on morphological characteristics was primarily associated with seasonality, whilst the nutritive value was primarily affected by grazing management. The pre-grazing target of LI 95% combined with 50 cm PGH was the combination that resulted in an increased proportion of leaves, decreased stems in basal stratum and the greatest nutritive value of the produced forage.
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