Pulsar Timing with the Fermi LAT

We present an overview of precise pulsar timing using data from the Large Area Telescope (LAT) on Fermi. We describe the analysis techniques including a maximum likelihood method for determining pulse times of arrival from unbinned photon data. In addition to determining the spindown behavior of the pulsars and detecting glitches and timing noise, such timing analyses allow the precise determination of the pulsar position, thus enabling detailed multiwavelength follow up.Comment: 6 page, 3 figures, to appear in AIP Conference Proceedings of Pulsar Conference 2010 "Radio Pulsars: a key to unlock the secrets of the Universe", Sardinia, October 201

Pulsar Emission Geometry and Accelerating Field Strength

The high-quality Fermi LAT observations of gamma-ray pulsars have opened a new window to understanding the generation mechanisms of high-energy emission from these systems, The high statistics allow for careful modeling of the light curve features as well as for phase resolved spectral modeling. We modeled the LAT light curves of the Vela and CTA I pulsars with simulated high-energy light curves generated from geometrical representations of the outer gap and slot gap emission models. within the vacuum retarded dipole and force-free fields. A Markov Chain Monte Carlo maximum likelihood method was used to explore the phase space of the magnetic inclination angle, viewing angle. maximum emission radius, and gap width. We also used the measured spectral cutoff energies to estimate the accelerating parallel electric field dependence on radius. under the assumptions that the high-energy emission is dominated by curvature radiation and the geometry (radius of emission and minimum radius of curvature of the magnetic field lines) is determined by the best fitting light curves for each model. We find that light curves from the vacuum field more closely match the observed light curves and multiwavelength constraints, and that the calculated parallel electric field can place additional constraints on the emission geometr

Pulsar Emission Geometry and Accelerating Field Strength

The high-quality Fermi LAT observations of gamma-ray pulsars have opened a new window to understanding the generation mechanisms of high-energy emission from these systems. The high statistics allow for careful modeling of the light curve features as well as for phase resolved spectral modeling. We modeled the LAT light curves of the Vela and CTA 1 pulsars with simulated high-energy light curves generated from geometrical representations of the outer gap and slot gap emission models, within the vacuum retarded dipole and force-free fields. A Markov Chain Monte Carlo maximum likelihood method was used to explore the phase space of the magnetic inclination angle, viewing angle, maximum emission radius, and gap width. We also used the measured spectral cutoff energies to estimate the accelerating parallel electric field dependence on radius, under the assumptions that the high-energy emission is dominated by curvature radiation and the geometry (radius of emission and minimum radius of curvature of the magnetic field lines) is determined by the best fitting light curves for each model. We find that light curves from the vacuum field more closely match the observed light curves and multiwavelength constraints, and that the calculated parallel electric field can place additional constraints on the emission geometry

BMC Med

BACKGROUND: Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). METHODS: We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan-Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman's correlation coefficient. Analyses were conducted by tumor subtype. RESULTS: 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8-6.2) for HR-/HER2 - subtype to 13.3 months (36% CI 12.7-14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR - /HER2 - mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. CONCLUSIONS: Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Pulsar Observations with the Fermi Gamma-ray Space Telescope

Le Large Area Telescope à bord du satellite Fermi, lancé le 11 juin 2008, est un télescope spatial observant l'univers des hautes énergies. L'instrument couvre l'intervalle en énergie de 20MeV à 300 GeV avec une sensibilité nettement améliorée et la capacité de localiser des sources ponctuelles. Il détecte les photons gamma par leur conversion en paire électron-positron, et mesure leur direction et leur énergie grâce à un trajectographe et un calorimètre. Cette thèse présente les courbes de lumières et les mesures spectrales résolues en phase des pulsars radio et gamma détectés par le LAT. La mesure des paramètres spectraux (flux, indice spectral, et énergie de coupure) dépend des fonctions de réponse de l'instrument (IRFs). Une méthode développée pour la validation en orbite de la surface ecace est présentée en utilisant le pulsar de Vela. Les efficacités des coupures entre les données du LAT et les données simulées sont comparées à chaque niveau de la rejection du fond. Les résultats de cette analyse sont propagés vers les IRFs pour évaluer les systématiques des mesures spectrales. La dernière partie de cette thèse présente les découvertes de nouveaux pulsars individuels tels que PSR J0205+6449, J2229+6114, et J1048-5832 à partir des données du LAT et des éphémérides radio et X. Des analyses temporelles et spectrales sont investies dans le but de contraindre les modèles d'émission gamma. Finalement, nous discutons les propriétés d'une large population de pulsars gamma détectés par le LAT, incluant les pulsars normaux et les pulsars milliseconde.The Large Area Telescope (LAT) on Fermi, launched on 2008 June 11, is a space telescope to explore the high energy gamma-ray universe. The instrument covers the energy range from 20 MeV to 300 GeV with greatly improved sensitivity and ability to localize gamma-ray point sources. It detects gamma-rays through conversion to electron-positron pairs and measurement of their direction in a tracker and their energy in a calorimeter. This thesis presents the gamma-ray light curves and the phase-resolved spectral measurements of radio-loud gamma-ray pulsars detected by the LAT. The measurement of pulsar spectral parameters (i.e. integrated flux, spectral index, and energy cut-off) depends on the instrument response functions (IRFs). A method developed for the on-orbit validation of the effective area is presented using the Vela pulsar. The cut efficiencies between the real data and the simulated data are compared at each stage of the background rejection. The results are then propagated to the IRFs, allowing the systematic uncertainties of the spectral parameters to be estimated. The last part of this thesis presents the discoveries, using both the LAT observations and the radio and X ephemeredes, of new individual gamma-ray pulsars such as PSR J0205+6449, and the Vela-like pulsars J2229+6114 and J1048-5832. Timing and spectral analysis are investigated in order to constrain the gamma-ray emission model. In addition, we discuss the properties of a large population of gamma-ray pulsars detected by the LAT, including normal pulsars, and millisecond pulsars

Observations de pulsars avec le Fermi gamma-ray space telescope

Le Large Area Telescope à bord du satellite Fermi, lancé le 11 juin 2008, est un télescope spatial observant l'univers des hautes énergies. L'instrument couvre l'intervalle en énergie de 20MeV à 300GeV avec une sensibilité nettement améliorée et la capacité de localiser des sources ponctuelles. Il détecte les photons ? par leur conversion en paire électron- positron, et mesure leur direction et leur énergie grâce à un trajectographe et un calorimètre. Cette thèse présente les courbes de lumières et les mesures spectrales résolues en phase des pulsars radio et gamma détectés par le LAT. La mesure des paramètres spectraux (flux, indice spectral, et énergie de coupure) dépend des fonctions de réponse de l'instrument (IRFs). Une méthode développée pour la validation en orbite de la surface efficace est présentée en utilisant le pulsar de Vela. Les efficacités des coupures entre les données du LAT et les données simulées sont comparées à chaque niveau de la rejection du fond. Les résultats de cette analyse sont propagés vers les IRFs pour évaluer les systématiques des mesures spectrales. La dernière partie de cette thèse présente les découvertes de nouveaux pulsars ? individuels tels que PSR J0205+6449, J2229+6114, et J1048-5832 à partir des données du LAT et des éphémérides radio et X. Des analyses temporelles et spectrales sont investies dans le but de contraindre les modèles d'émission gamma. Finalement, nous discutons les propriétés d'une large population de pulsars gamma détectés par le LAT, incluant les pulsars normaux et les pulsars milliseconde.The Large Area Telescope (LAT) on Fermi, launched on 2008 June 11, is a space telescope to explore the high energy ?-ray universe. The instrument covers the energy range from 20MeV to 300GeV with greatly improved sensitivity and ability to localize ?-ray point sources. It detects ?-rays through conversion to electron-positron pairs and measurement of their direction in a tracker and their energy in a calorimeter. This thesis presents the ?-ray light curves and the phase-resolved spectral measurements of radio-loud gamma-ray pulsars detected by the LAT. The measurement of pulsar spectral parameters (i.e. integrated flux, spectral index, and energy cut-off) depends on the instrument response functions (IRFs). A method developed for the on-orbit validation of the effective area is presented using the Vela pulsar. The cut efficiencies between the real data and the simulated data are compared at each stage of the background rejection. The results are then propagated to the IRFs, allowing the systematic uncertainties of the spectral parameters to be estimated. The last part of this thesis presents the discoveries, using both the LAT observations and the radio and X ephemeredes, of new individual ?-ray pulsars such as PSR J0205+6449, and the Vela-like pulsars J2229+6114 and J1048-5832. Timing and spectral analysis are investigated in order to constrain the ?-ray emission model. In addition, we discuss the properties of a large population of ?-ray pulsars detected by the LAT, including normal pulsars, and millisecond pulsars