dataesr/scientific-paragraphs-categorization huggingface dataset:
Comparison of somatic mutations according to prognosis The average number of mutations per sample was not significantly different between tumors with relapse and Only top canonical pathways with predictive z-score ≥ 2 are presented, together with a p value. The overlapping ratio indicates the ratio of genes from the dataset that map to the pathway divided by the total number of genes that map to the same pathway tumors without relapse (2. 7 vs. 2. 6, p = 0. 9) and the mutation frequency was similar in the two groups (data not shown). After grouping into pathways, the PIK3CA/AKT/ mTOR pathway was altered significantly more frequently in tumors with relapse (90. 9 vs. 56. 4%, p = 0. 004). The association between PIK3CA/AKT/mTOR pathway status and RFS was assessed in 89 patients with a median follow-up of 65.
No study has yet investigated whether these genes are associated with resistance to endocrine therapy. ESR1 mutation drives acquired endocrine resistance. ESR1 mutation has been studied in metastatic breast cancer, as ESR1 mutations are a very rare event in primary breast cancers with only 0. 5% in a large TCGA dataset  [42] [43] [44]. However, the rare mutant ESR1 LBD cells may arise from a rare and undetectable pre-existing clone in primary treatment-naive tumors, conferring a selective advantage over other endocrine-sensitive clones in response to endocrine therapy  [45]. In our study, ESR1 hotspot mutations were detected in 3. 4% of treatment-naive tumors, and interestingly all of these tumors were non-responders to NET. Detection of ESR1 mutation as early as possible may therefore be useful for prognosis and clinical decision-making, but screening in early-stage disease would likely require very sensitive techniques.
Funding This work was supported by  le Comité d'Etude et de Suivi des projets de Transfert (CEST) de l'Institut Curie ,  Institut Carnot  and  Astra Zeneca. High -throughput sequencing was performed by the  Institut Curie ICGex NGS  platform supported by  ANR-10-EQPX-03  ( Equipex ) and  ANR-10-INBS-09-08  ( France Génomique Consortium ) grants from the  Agence Nationale de la Recherche  (" Investissements d'Avenir" program ), by the  Canceropole Ile-de-France  and by the  SiRIC-Curie program -SiRIC Grant INCa-DGOS-4654.
During dose finding, five of 12 (41. 7%) evaluable patients for MTD determination experienced dose-limiting toxicities: alpelisib 300 mg, Grade 2 hyperglycemia (n=1); alpelisib 250 mg, Grade 2 hyperglycemia (n=1), Grade 4 hyperglycemia and Grade 3 acute kidney injury (n=1); and alpelisib 150 mg, Grade 2 hyperglycemia (n=1) and Grade 4 leukopenia (n=1). The MTD of alpelisib when administered with paclitaxel was 150 mg QD. Most frequent all-grade AEs were diarrhea (73. 7%; Grade 3/4 10. 5%) and hyperglycemia (57. 9%; Grade 3/4 31. 6%). The planned dose-expansion phase was not initiated. Alpelisib plus paclitaxel has a challenging safety profile in patients with advanced solid tumors. This study was closed following the completion of the dosefinding phase. Clinical trial registration: ClinicalTrials.
Further, PIK3CA mutations are among the most frequently observed alterations in solid tumors  [8] [9] [10] [11] [12]. Therefore, administration of paclitaxel plus a PI3K p110α-specific inhibitor is a potential therapeutic strategy by which to delay disease progression in patients with advanced solid tumors. Alpelisib (BYL719) is an oral, selective inhibitor of class I PI3K p110α that has shown potent antitumor activity in preclinical studies  [13, 14]. In a Phase Ia study of single-agent alpelisib in patients with advanced solid tumors (NCT01219699), a tolerable safety profile and encouraging preliminary activity was observed in those with PIK3CA-altered (mutation/amplification) advanced solid tumors, with the maximum tolerated dose (MTD) declared as 400 mg once daily (QD)  [15, 16]. In addition, single-agent alpelisib was generally well tolerated, with the most frequent all-grade, treatmentrelated adverse events (AEs; ≥30% of patients) including hyperglycemia (51.
The present study was therefore closed following the completion of the dosefinding phase. In contrast to this study, the combination of alpelisib with nab-paclitaxel was well tolerated in a Phase I study (N=10)  [21]. The MTD of alpelisib was not reached and the recommended Phase II dose was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m 2 IV weekly  [21]. Although the results need to be verified in a larger cohort, this study indicates that adding alpelisib to a taxane may be possible. Finally, promising disease control and survival benefits, with a manageable safety profile, have been observed with alpelisib plus fulvestrant in a Phase Ib study (NCT01219699) in patients with PIK3CA-altered estrogen receptor-positive, HER2-advanced breast cancer (ABC)  [22, 23]. Accordingly, the Phase III SOLAR-1 study (NCT02437318) is investigating the efficacy and safety of alpelisib 300 mg QD plus fulvestrant in patients with PIK3CA-mutant and wildtype, aromatase inhibitor-resistant, hormone receptorpositive (HR+), HER2-ABC.
Further, the Phase II BYLieve study (NCT03056755) is investigating the efficacy and safety of alpelisib 300 mg QD plus fulvestrant or letrozole in patients with PIK3CA mutant, HR+, HER2-ABC, who have progressed on or after cyclin-dependent kinase 4/6 inhibitor treatment. The challenging safety profile of alpelisib plus paclitaxel from the present closed study will help inform ongoing studies of alpelisib in combination with other therapies. T max , median hours (.
ACKNOWLEDGMENTS We thank the patients who took part in this study and their families, as well as the investigators, research coordinators, and staff at each study site. We also thank  Nicholas Crabb ,  MSc , and  Cassandra Krone, PhD , ( Articulate Science ) for medical editorial assistance with this manuscript. During the course of the study,  Dr Rodon 's institution was  Vall d'Hebron University Hospital, Barcelona, Spain. His current institution is The  University of Texas MD Anderson Cancer Center, Houston, TX, USA , email address: JRodon@mdanderson. org.
Introduction Selective laser melting (SLM) is a form of powder-bed fusion additive manufacturing  [1]. It works by melting and bonding successive layers of powder metal to produce three-dimensional shapes with the use of a high-power laser  [2]. The process usually takes place under an inert gas. Computer-Aided Design (CAD) software is used in the SLM process, which converts the full three-dimensional geometry to a series of layers for each laser pass. The thickness of each layer and a tool path are also defined  [1]. A variety of complex and small shapes can be produced with SLM. The surface finish of parts built with SLM is generally better than other additive manufacturing processes  [3]. Titanium (Ti-6Al-4V) and Inconel 718 alloys both find applications with the aerospace industry. The cost of these materials is high, and conventional machining of parts can have high rates of scrap Selective laser melting is known to generate tensile residual stresses during the build process  [4, 5, 6].
The distance between the measurement points as well as from the sample perimeter was set as 0. 25 mm. The measurements were carried out in a temperature-controlled room. The displacement data from the cut surfaces of the samples were processed with Matlab data analysis routines for alignment, averaging, cleaning, flattening and smoothing  [28]. For data smoothing a cubic spline with a knot spacing of 4 mm was used. For finite element (FE) analysis the geometry of one cut half of the sample was modelled. An 8-node brick element in Abaqus software with a non-uniform mesh was used. The FE mesh converges to a distance of 0. 1 mm between adjacent nodes at the sample edges, and in the center region of the samples this distance was about 0. 5 mm. A linear-elastic FE analysis was performed. The following material properties were used: The contour cut location for the Inconel 718 sample is shown in Figure  2(c ).
Acknowledgements We are grateful to  Andreas Nick  from the  Airbus APWorks Germany , for facilitating the project and providing the samples. Further thanks to  Steve Damms  at  The Institute for Advanced Manufacturing and Engineering  for his help with the WEDM. M. E. Fitzpatrick is grateful for funding from the  Lloyd's Register Foundation , a charitable foundation helping to protect life and property by supporting engineering-related education, public engagement and the application of research.
Identified index cases were requested, either via telephone calls or through trained community health workers (CHWs), to bring children with whom they live with to their PHC on a specific day to coincide with visits to that PHC by data enumerators. Child contacts were defined as those contacts of less than 15 years who shared the same household with a selected index case within the 3 months prior to the diagnosis of the index case. Therefore, all child contacts born after the index cases had started treatment or were not leaving with the index cases prior to the diagnosis of the index cases were excluded. Eligible children were enrolled following written informed consent by the parent or caregiver and children of 7 years and older also signed an assent form.
Data collection and management: A structured questionnaire adapted from screening guidelines  [26, 27]  was pre-tested and modified during a pilot study in two selected sites. Twelve data enumerators were trained to conduct interviews with parents/caregivers of selected child contacts and to collect data from TB registers and index case folders, using standardised data collection forms. We also trained 20 CHWs to explain the study to the parents/caregivers, and sensitise them to bring child contacts for screening at the PHCs. Data of the index case included: result of smear microscopy, demographic data, address of residence and telephone number. The uptake of IPT among child contacts following diagnosis of the index case was also recorded. The recorded data were validated by the index case, parents or caregivers of selected children once they were identified in order to ensure the accuracy of the data.
The sediment was thereafter re-suspended in 2ml of sterile distilled water by 0. 5ml transfer pipette. At the end, 0. 2 ml of sediment was inoculated onto solid media, Lowenstein Jensen media as per standard protocols  [29]. The growth of Mycobacterium tuberculosis bacteria was checked every 7 days up to 8 weeks. For microscopy, a drop of sediment prepared for culture was used for fluorescent acid-fast smear microscopy following the standard procedure  [29]. Data analysis: Clinical case definition categories for TB in children considered the standardised case definition recently published  [30]  and were based on clinical screening, X-ray and microbiological investigations. Children were categorized as follows: bacteriologically confirmed TB, unconfirmed TB and unlikely TB (Table  1 ). Categorical data were interpreted through frequency table with median and interquartile range (IQR) for continuous data.
Results Figure The median age for symptomatic child contacts was 4 years (IQR: 2-13). Among those 37 children, 59% were under five years old, 54% were female, HIV test was done for 31(84%) of them, 3% were HIV positive, and 97% had the evidence of BCG vaccination recorded. IPT had previously been commenced in 84 (89%) of 94 young child contacts without active TB at the time of evaluation. Data of uptake and adherence to IPT will be presented separately once follow-up of the cohort is complete. The majority of child contacts selected in the study were asymptomatic at the time of screening: 179/216 or 83% (95% CI, 77%-87%). All symptomatic child contacts (100%) were exposed to air pollution (tobacco smoke or burning wood) and the majority (64%) had their parents as index cases with 81% in contact with index cases for more than 8 hours per day.
Acknowledgments We would like to express our sincere gratitude to study participants and their parents or caregivers,  TB diagnostic laboratory  staff, TB focal points, head of PHCs, Community health workers and data enumerators involved in this study. We thank also  Jino Bahemuka  and  Mary Nellima Ondiaka  for editing the manuscript. We also thank the  Swedish International Development +Agency (Sida)  that funded this study through  University of Rwanda Coordination office of Research Activities (UR-CRA ). We declare that the funder has no role in the study design, data collection and analysis, preparation of the manuscript and decision to publish.
Purpose: Baclofen is widely used off-label for alcohol use disorders (AUD) in France, despite its uncertain efficacy and safety, particularly at high doses. This study was designed to evaluate the safety of this off-label use compared to the main approved drugs for AUD (acamprosate, naltrexone, nalmefene). Methods: This cohort study from the French Health Insurance claims database included patients, aged 18 to 70 years, with no serious comorbidity (assessed by the Charlson score) initiating baclofen or approved drugs for AUD between 2009 and 2015. The risk of hospitalisation or death associated with baclofen, at variable doses over time (from low doses <30 mg/day to high doses ≥180 mg/day), compared to approved drugs, was evaluated by a Cox model adjusted to sociodemographic and medical characteristics.
KEYWORDS adverse effects, alcohol use disorders, baclofen, claims database, cohort study, pharmacoepidemiology 1 | INTRODUCTION Baclofen has been indicated for the treatment of painful involuntary muscle spasms since 1972. It is a GABA B receptor agonist that crosses the blood-brain barrier. [12]  About 120 000 people initiated drug for AUD each year between 2009 and 2015 in France, with an annual prevalence of 500 000 treated persons. 13  2014, the French National Agency for Medicines and Health Products Safety (ANSM) enacted a temporary authorization for use  14  to monitor this use while awaiting more convincing studies on the efficacy and safety of baclofen for AUD. 0] [21]  These studies were not designed to assess the safety of baclofen in terms of all-cause hospitalisation and death, particularly at doses much higher than those recommended for the approved indication.
The effect of complete adjustment for patient characteristics, especially history of hospitalisation for alcohol-related problems, resulted in a higher estimated risk of all-cause hospitalisation in the baclofen group. Similarly, adjustment also led to an increased risk of death among people exposed to baclofen vs approved drugs for AUD. This study also comprises several limitations. As is often the case in medical administrative database studies, exposure could only be evaluated based on medication dispensing data, which does not guarantee that the medication was actually taken. Similarly, SNIIRAM dispensing data cannot be used to precisely estimate the doses of medication, as the dosage and number of days of treatment are not directly available, but are calculated. Although the estimates necessary to calculate the mean daily dose are probably adequate to measure a dose effect, they cannot be used to precisely define risk levels.
The results presented according to the dose categories used in this study must therefore be interpreted with caution. Another limitation of SNIIRAM data concerns the absence of detailed socioeconomic variables and the absence of reliable measures of obesity and smoking, suggesting a possible risk of residual confounding related to these variables. The off-label indication for baclofen cannot be determined directly from the SNIIRAM database. Following mediatisation of the use of baclofen for AUD and in view of its central neurological action, the rare use of baclofen has also been reported in bulimia,  37  cocaine addiction and stuttering. 38 Some patients treated with baclofen may also have been included in the cohort for muscle contractures secondary to sciatica, despite the exclusion of private rheumatologist-initiated treatments, which could explain the increased risk of hospitalisation, mainly at low doses <30 mg/day, for dorsalgia (code: M54), or pain (code: R52).
However, the low frequency of these hospitalisations possibly not related to the consequences of AUD would have a negligible impact on estimation of the risks of all-cause hospitalisation and death. The risks associated with all-cause "hospitalisation" and "death" events are competitive risks. However, "death" events probably had very little impact on estimation of the risk of hospitalisation because of their respective frequencies: 16 226 hospitalisations vs 556 death. Deaths occurring during the 30 days after a hospitalisation were taken into account in the estimation of the risk of death. Analysis of the link between exposure to drugs for AUD and deaths more than 30 days after hospitalisation became less clinically relevant. The main limitation of this study is the lack of data about alcohol.
Data concerning the types and severity of alcoholism and alcohol consumption were not available in the SNIIRAM database (only hospital stays for alcohol-related problems were identified), and the indications for each drug for AUD, unknown, can range from abstinence to reduction of alcohol consumption or craving. Baclofen for AUD is an offlabel drug promoted by patients and prescribers, unlike approved drugs. AUD could differ depending on these drugs, as the medical care of patients could temper the strength of risk associations and, more specifically, the dose-response relationship. However, baclofen exposure increased the risks of hospitalisation or death, irrespective of the dose class, and the similarity of the main results in the more homogeneous population restricted to subjects with a history of hospitalisation for alcohol-related problems, supports the absence of major residual confounding in this population of patients, under the age of 70 years, with no major comorbidities.
The white beam was monochromatised (l ¼ 0. 8266 Å) by a Si double crystal and focused by a Kirk-Patrick-Baez mirror. The intensity of the scattered beam was measured with a two-dimensional CCD detector located at 0. 51 m from the sample. RT measurements enabled evaluation of the efficiency of the anionic exchange on the pristine LDH-DS, by measuring the peaks related to the basal distance of the LDH. Time-resolved monitoring of the intensities and positions of these peaks during heating at 10 C min À1 from RT to 450 C (using a LINKAM THM 600R cell) provided insights about the thermal decomposition of the layered edice. Quick-EXAFS and Raman measurements. X-ray absorption spectroscopy (XAS) data were recorded at the Fe, Cu, and Zn Kedges during thermal decomposition of the PMMA-LDH nanocomposites (with heating at 10 C min À1 ), at the SAMBA beamline of the SOLEIL synchrotron radiation facility, using the Quick-EXAFS mode.
22 The set-up used for the time-resolved XAS monitoring of the PMMA-LDH thermal decomposition was identical to the one described fully in previous work concerning the thermal decomposition of LDH-Cl. 19 Data recorded at the Zn and Cu K-edges were collected in a single experiment, while a second measurement was used for collection of Fe K-edge data for the PMMA-ZAF and PMMA-ZCAF nanocomposites. The time for collection of one Quick-EXAFS spectrum was 0. 5 s, and 12 spectra were merged in order to improve the signal/noise ratio. During the thermal decomposition at temperatures from RT to 450 C, 210 spectra were typically recorded at each edge, with one spectrum obtained every 2 C. The Quick-EXAFS measurements were performed simultaneously with Raman spectroscopy analyses performed using an RXN1 spectrometer (Kaiser Optical Systems, Inc.
In order to elucidate the contributions of the copper and iron atoms to the non-diffusional process of PMMA-LDH thermal decomposition, a systematic calorimetric study was carried out under a non-oxidizing atmosphere (N 2 ). Irrespective of the iron or copper content of the LDH, the three degradation steps (S 1 , S 2 , and S 3 ) were endothermic events (Fig. S2 , ESI †). At least two heat consumption events were involved during the rst (S 1 ) and third (S 3 ) decomposition steps, one necessary for the unzipping reaction giving rise to monomer formation, and another one corresponding to the evaporation of MMA (Fig. 2 ). Comparing PMMA-ZA with PMMA-ZAF, the data evidenced that for both events, the isovalent substitution of aluminium by iron led to an increase of the endothermic heat. In contrast, the energy required for the degradation decreased as the Cu content  increased from PMMA-ZA to PMMA-ZCA-0.
Acknowledgements The authors thank SOLEIL for providing access to the SAMBA and SWING beamlines, and  Dr Florian Meneau  for assistance during the SAXS experiments. This work was partially supported by the  Brazilian National Council for Scientic and Technological Development (CNPq/PVE , grant # 401679/2013-6 ) and the  São Paulo State Research Support Foundation  ( FAPESP , grant # 2008/05475-9 ).
net, between September 2015 and November 2015 (Table  1 ). It is important to note that for all the courses we studied, both the registration and certification were free. Most teams from French institutions whose MOOCs were launched during this period of time were contacted. All of those that agreed to deliver the survey were included in the study. The fact that most were organized on FUN, and only one on Canvas, reflects the predominance of FUN in the French MOOC ecosystem. We believe that the technological differences between these two Learning Management Systems have little impact on the interactions occurring outside of the boundaries of course forums. A total of 7,614 answers were collected. The details of these courses and the number of answers per course are provided in Table  1. The analysis of sociodemographic data shows that in most courses, a majority of learners work full-time or part-time and have at least a Master's degree (Table  2 )  a result consistent with published studies  (Christensen et al.
, 1999; Langlais et al. , 2004) , but no consensus has been reached as to the underlying magnetization mechanism. Additionally, the origin, strength, and temporal decline of the ancient dynamo field are poorly constrained. Paleomagnetic measurements of samples, selected by the Mars 2020 rover mission and subsequently returned by a downstream mission, could revolutionize our understanding of the ancient 10. 1029/2018EA000420 dynamo field, that in turn is coupled to the evolution of the planet's interior  (Kuang et al. , 2008) , tectonic history  (Stevenson, 2001) , and climate  (Jakosky & Phillips, 2001). Magnetic field data have primarily been collected by satellites, particularly the Mars Global Surveyor (MGS) and Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft. A further source of magnetic field information is the ancient and strongly magnetized Martian meteorite, ALH 84001, which suggests that a dynamo with an Earth-strength field was active at, or before, 4 Ga  (Weiss et al.
Due to the uniqueness of the solution, the inverse problem reduces to a simple conversion formula between the SH coefficients of the Earth and Space Science 10. 1029/2018EA000420   1b. We also solve for the magnetization (Figures  2d  and 3d ) required to explain magnetic field observations using equivalent source dipoles as introduced by  Mayhew (1979). The observed measurements at any point can be described by the sum of the fields due to regularly spaced dipoles (here every 115 km) placed within a constant thickness layer (here 40 km). The input data set is generated by subselecting MGS and quiet MAVEN data, as described in  Mittelholz et al. (2018). For a set of possible model solutions, we examine the L-curve to find a reasonable trade-off between model complexity and misfit  (Aster et al.