The VORTEX project: first results and perspectives

(abridged) Vortex coronagraphs are among the most promising solutions to perform high contrast imaging at small angular separations. They feature a very small inner working angle, a clear 360 degree discovery space, have demonstrated very high contrast capabilities, are easy to implement on high-contrast imaging instruments, and have already been extensively tested on the sky. Since 2005, we have been designing, developing and testing an implementation of the charge-2 vector vortex phase mask based on concentric subwavelength gratings, referred to as the Annular Groove Phase Mask (AGPM). Science-grade mid-infrared AGPMs were produced in 2012 for the first time, using plasma etching on synthetic diamond substrates. They have been validated on a coronagraphic test bench, showing broadband peak rejection up to 500:1 in the L band, which translates into a raw contrast of about $6\times 10^{-5}$ at $2 \lambda/D$. Three of them have now been installed on world-leading diffraction-limited infrared cameras (VLT/NACO, VLT/VISIR and LBT/LMIRCam). During the science verification observations with our L-band AGPM on NACO, we observed the beta Pictoris system and obtained unprecedented sensitivity limits to planetary companions down to the diffraction limit ($0.1''$). More recently, we obtained new images of the HR 8799 system at L band during the AGPM first light on LMIRCam. After reviewing these first results obtained with mid-infrared AGPMs, we will discuss the short- and mid-term goals of the on-going VORTEX project, which aims to improve the performance of our vortex phase masks for future applications on second-generation high-contrast imagers and on future extremely large telescopes (ELTs).Comment: To appear in SPIE proceedings vol. 914

Three years of harvest with the vector vortex coronagraph in the thermal infrared

For several years, we have been developing vortex phase masks based on sub-wavelength gratings, known as Annular Groove Phase Masks. Etched onto diamond substrates, these AGPMs are currently designed to be used in the thermal infrared (ranging from 3 to 13 {\mu}m). Our AGPMs were first installed on VLT/NACO and VLT/VISIR in 2012, followed by LBT/LMIRCam in 2013 and Keck/NIRC2 in 2015. In this paper, we review the development, commissioning, on-sky performance, and early scientific results of these new coronagraphic modes and report on the lessons learned. We conclude with perspectives for future developments and applications.Comment: To appear in SPIE proceedings vol. 990

LEMUR: Large European Module for solar Ultraviolet Research. European contribution to JAXA's Solar-C mission

Understanding the solar outer atmosphere requires concerted, simultaneous solar observations from the visible to the vacuum ultraviolet (VUV) and soft X-rays, at high spatial resolution (between 0.1" and 0.3"), at high temporal resolution (on the order of 10 s, i.e., the time scale of chromospheric dynamics), with a wide temperature coverage (0.01 MK to 20 MK, from the chromosphere to the flaring corona), and the capability of measuring magnetic fields through spectropolarimetry at visible and near-infrared wavelengths. Simultaneous spectroscopic measurements sampling the entire temperature range are particularly important. These requirements are fulfilled by the Japanese Solar-C mission (Plan B), composed of a spacecraft in a geosynchronous orbit with a payload providing a significant improvement of imaging and spectropolarimetric capabilities in the UV, visible, and near-infrared with respect to what is available today and foreseen in the near future. The Large European Module for solar Ultraviolet Research (LEMUR), described in this paper, is a large VUV telescope feeding a scientific payload of high-resolution imaging spectrographs and cameras. LEMUR consists of two major components: a VUV solar telescope with a 30 cm diameter mirror and a focal length of 3.6 m, and a focal-plane package composed of VUV spectrometers covering six carefully chosen wavelength ranges between 17 and 127 nm. The LEMUR slit covers 280" on the Sun with 0.14" per pixel sampling. In addition, LEMUR is capable of measuring mass flows velocities (line shifts) down to 2 km/s or better. LEMUR has been proposed to ESA as the European contribution to the Solar C mission.Comment: 35 pages, 14 figures. To appear on Experimental Astronom

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins

Early markers for myocardial ischemia and sudden cardiac death.

The post-mortem diagnosis of acute myocardial ischemia remains a challenge for both clinical and forensic pathologists. We performed an experimental study (ligation of left anterior descending coronary artery in rats) in order to identify early markers of myocardial ischemia, to further apply to forensic and clinical pathology in cases of sudden cardiac death. Using immunohistochemistry, Western blots, and gene expression analyses, we investigated a number of markers, selected among those which are currently used in emergency departments to diagnose myocardial infarction and those which are under investigation in basic research and autopsy pathology studies on cardiovascular diseases. The study was performed on 44 adult male Lewis rats, assigned to three experimental groups: control, sham-operated, and operated. The durations of ischemia ranged between 5 min and 24 h. The investigated markers were troponins I and T, myoglobin, fibronectin, C5b-9, connexin 43 (dephosphorylated), JunB, cytochrome c, and TUNEL staining. The earliest expressions (≤30 min) were observed for connexin 43, JunB, and cytochrome c, followed by fibronectin (≤1 h), myoglobin (≤1 h), troponins I and T (≤1 h), TUNEL (≤1 h), and C5b-9 (≤2 h). By this investigation, we identified a panel of true early markers of myocardial ischemia and delineated their temporal evolution in expression by employing new technologies for gene expression analysis, in addition to traditional and routine methods (such as histology and immunohistochemistry). Moreover, for the first time in the autopsy pathology field, we identified, by immunohistochemistry, two very early markers of myocardial ischemia: dephosphorylated connexin 43 and JunB

LEMUR: Large European Module for Solar Ultraviolet Research

The solar outer atmosphere is an extremely dynamic environment characterized by the continuous interplay between the plasma and the magnetic field that generates and permeates it. Such interactions play a fundamental role in hugely diverse astrophysical systems, but occur at scales that cannot be studied outside the solar system. Understanding this complex system requires concerted, simultaneous solar observations from the visible to the vacuum ultraviolet (VUV) and soft X-rays, at high spatial resolution (between 0.1 and 0.3), at high temporal resolution (on the order of 10 s, i.e., the time scale of chromospheric dynamics), with a wide temperature coverage (0.01 MK to 20 MK, from the chromosphere to the flaring corona), and the capability of measuring magnetic fields through spectropolarimetry at visible and near-infrared wavelengths. Simultaneous spectroscopic measurements sampling the entire temperature range are particularly important. These requirements are fulfilled by the Japanese Solar-C mission (Plan B), composed of a spacecraft in a geosynchronous orbit with a payload providing a significant improvement of imaging and spectropolarimetric capabilities in the UV, visible, and near-infrared with respect to what is available today and foreseen in the near future. The Large European Module for solar Ultraviolet Research (LEMUR), described in this paper, is a large VUV telescope feeding a scientific payload of high-resolution imaging spectrographs and cameras. LEMUR consists of two major components: a VUV solar telescope with a 30 cm diameter mirror and a focal length of 3.6 m, and a focal-plane package composed of VUV spectrometers covering six carefully chosen wavelength ranges between 170 Angstrom and 1270 Angstrom. The LEMUR slit covers 280 on the Sun with 0.14 per pixel sampling. In addition, LEMUR is capable of measuring mass flows velocities (line shifts) down to 2 km s 1 or better. LEMUR has been proposed to ESA as the European contribution to the Solar C mission

Guía de práctica clínica para el tratamiento farmacológico inicial de nefritis lúpica en el Seguro Social del Perú (EsSalud)

Background: This article summarizes the clinical practice guideline (CPG) for the initial pharmacological treatment of lupus nephritis in the Social Security of Peru (EsSalud). Objective: To provide evidence-based clinical recommendations for initial pharmacological treatment of non-refractory adults with class I to V lupus nephritis in EsSalud. Material and Methods: A guideline development group (GDG) was formed, which included specialist physicians and methodologists, who formulated clinical questions. Systematic searches were conducted for systematic reviews and - when deemed relevant - primary studies in PubMed during 2021. Evidence was selected to answer each of the clinical questions posed. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. In periodic working meetings, the GEG used the GRADE methodology to review the evidence and formulate recommendations. The CPG was reviewed by external experts before its approval. Results: The CPG addressed 6 clinical questions, divided into 2 topics: initial treatment of the induction and maintenance phase. Based on these questions, 11 recommendations were formulated (all conditional), 22 points of good clinical practice, and 2 flow charts. Conclusion: Evidence-based recommendations were issued for the management of patients with this pathology.Introducción: El presente artículo resume la guía de práctica clínica (GPC) para el tratamiento farmacológico inicial nefritis lúpica en el Seguro Social del Perú (EsSalud). Objetivo: Proveer recomendaciones clínicas basadas en evidencia para tratamiento farmacológico inicial de adultos con nefritis lúpica clase I a V no refractarios en EsSalud. Material y Métodos: Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos, el cual formuló preguntas clínicas. Se realizaron búsquedas sistemáticas de revisiones sistemáticas y –cuando fue considerado pertinente– estudios primarios en PubMed durante el 2021. Se seleccionó la evidencia para responder cada una de las preguntas clínicas planteadas. Se evaluó la certeza de evidencia usando la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). En reuniones de trabajo periódicas, el GEG usó la metodología GRADE para revisar la evidencia y formular las recomendaciones. La GPC fue revisada por expertos externos antes de su aprobación. Resultados: La GPC abordó 6 preguntas clínicas, divididas en 2 temas: tratamiento inicial de la fase de inducción y mantenimiento. En base a dichas preguntas se formularon 11 recomendaciones (todas condicionales), 22 puntos de buena práctica clínica, y 2 flujogramas. Conclusión: Se emitieron recomendaciones basadas en evidencia para el manejo de pacientes con esta patología

Multi-Center Fetal Brain Tissue Annotation (FeTA) Challenge 2022 Results

Segmentation is a critical step in analyzing the developing human fetal brain. There have been vast improvements in automatic segmentation methods in the past several years, and the Fetal Brain Tissue Annotation (FeTA) Challenge 2021 helped to establish an excellent standard of fetal brain segmentation. However, FeTA 2021 was a single center study, and the generalizability of algorithms across different imaging centers remains unsolved, limiting real-world clinical applicability. The multi-center FeTA Challenge 2022 focuses on advancing the generalizability of fetal brain segmentation algorithms for magnetic resonance imaging (MRI). In FeTA 2022, the training dataset contained images and corresponding manually annotated multi-class labels from two imaging centers, and the testing data contained images from these two imaging centers as well as two additional unseen centers. The data from different centers varied in many aspects, including scanners used, imaging parameters, and fetal brain super-resolution algorithms applied. 16 teams participated in the challenge, and 17 algorithms were evaluated. Here, a detailed overview and analysis of the challenge results are provided, focusing on the generalizability of the submissions. Both in- and out of domain, the white matter and ventricles were segmented with the highest accuracy, while the most challenging structure remains the cerebral cortex due to anatomical complexity. The FeTA Challenge 2022 was able to successfully evaluate and advance generalizability of multi-class fetal brain tissue segmentation algorithms for MRI and it continues to benchmark new algorithms. The resulting new methods contribute to improving the analysis of brain development in utero.Comment: Results from FeTA Challenge 2022, held at MICCAI; Manuscript submitted. Supplementary Info (including submission methods descriptions) available here: https://zenodo.org/records/1062864

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so