The World Health Organization was born as a normative agency: Seventy-five years of global health law under WHO governance

The World Health Organization (WHO) was born as a normative agency and has looked to global health law to structure collective action to realize global health with justice. Framed by its constitutional authority to act as the directing and coordinating authority on international health, WHO has long been seen as the central actor in the development and implementation of global health law. However, WHO has faced challenges in advancing law to prevent disease and promote health over the past 75 years, with global health law constrained by new health actors, shifting normative frameworks, and soft law diplomacy. These challenges were exacerbated amid the COVID-19 pandemic, as states neglected international legal commitments in national health responses. Yet, global health law reforms are now underway to strengthen WHO governance, signaling a return to lawmaking for global health. Looking back on WHO’s 75th anniversary, this article examines the central importance of global health law under WHO governance, reviewing the past successes, missed opportunities, and future hopes for WHO. For WHO to meet its constitutional authority to become the normative agency it was born to be, we offer five proposals to reestablish a WHO fit for purpose: normative instruments, equity and human rights mainstreaming, sustainable financing, One Health, and good governance. Drawing from past struggles, these reforms will require further efforts to revitalize hard law authorities in global health, strengthen WHO leadership across the global governance landscape, uphold equity and rights at the center of global health law, and expand negotiations in global health diplomacy

The World Health Organization was born as a normative agency: Seventy-five years of global health law under WHO governance

The World Health Organization (WHO) was born as a normative agency and has looked to global health law to structure collective action to realize global health with justice. Framed by its constitutional authority to act as the directing and coordinating authority on international health, WHO has long been seen as the central actor in the development and implementation of global health law. However, WHO has faced challenges in advancing law to prevent disease and promote health over the past 75 years, with global health law constrained by new health actors, shifting normative frameworks, and soft law diplomacy. These challenges were exacerbated amid the COVID-19 pandemic, as states neglected international legal commitments in national health responses. Yet, global health law reforms are now underway to strengthen WHO governance, signaling a return to lawmaking for global health. Looking back on WHO’s 75th anniversary, this article examines the central importance of global health law under WHO governance, reviewing the past successes, missed opportunities, and future hopes for WHO. For WHO to meet its constitutional authority to become the normative agency it was born to be, we offer five proposals to reestablish a WHO fit for purpose: normative instruments, equity and human rights mainstreaming, sustainable financing, One Health, and good governance. Drawing from past struggles, these reforms will require further efforts to revitalize hard law authorities in global health, strengthen WHO leadership across the global governance landscape, uphold equity and rights at the center of global health law, and expand negotiations in global health diplomacy

The Multiplanet System TOI-421: A Warm Neptune and a Super Puffy Mini-Neptune Transiting a G9 V Star in a Visual Binary

We report the discovery of a warm Neptune and a hot sub-Neptune transiting TOI-421 (BD-14 1137, TIC 94986319), a bright (V = 9.9) G9 dwarf star in a visual binary system observed by the Transiting Exoplanet Survey Satellite (TESS) space mission in Sectors 5 and 6. We performed ground-based follow-up observations—comprised of Las Cumbres Observatory Global Telescope transit photometry, NIRC2 adaptive optics imaging, and FIbre-fed Echellé Spectrograph, CORALIE, High Accuracy Radial velocity Planet Searcher, High Resolution Échelle Spectrometer, and Planet Finder Spectrograph high-precision Doppler measurements—and confirmed the planetary nature of the 16 day transiting candidate announced by the TESS team. We discovered an additional radial velocity signal with a period of five days induced by the presence of a second planet in the system, which we also found to transit its host star. We found that the inner mini-Neptune, TOI-421 b, has an orbital period of P_b = 5.19672 ± 0.00049 days, a mass of M_b = 7.17 ± 0.66 M⊕, and a radius of R_b = 2.68^(+0.19)_(-0.18) R⊕, whereas the outer warm Neptune, TOI-421 c, has a period of Pc = 16.06819 ± 0.00035 days, a mass of M_c = 16.42^(+1.06)_(-1.04) M⊕, a radius of R_c = 5.09^(+0.16)_(-0.15) R⊕ and a density of ρ_c = 0.685^(+0.080)_(-0.072) g cm⁻³. With its characteristics, the outer planet (ρ_c = 0.685^(+0.080)_(-0.072) g cm⁻³) is placed in the intriguing class of the super-puffy mini-Neptunes. TOI-421 b and TOI-421 c are found to be well-suited for atmospheric characterization. Our atmospheric simulations predict significant Lyα transit absorption, due to strong hydrogen escape in both planets, as well as the presence of detectable CH4 in the atmosphere of TOI-421 c if equilibrium chemistry is assumed

Recent Progress in Solar Atmospheric Neutrino Searches with IceCube

Cosmic-rays interacting with nucleons in the solar atmosphere produce a cascade of particles that give rise to a flux of high-energy neutrinos and gamma-rays. Fermi has observed this gamma-ray flux; however, the associated neutrino flux has escaped observation. In this contribution, we put forward two strategies to detect these neutrinos, which, if seen, would push forward our understanding of the solar atmosphere and provide a new testing ground of neutrino properties. First, we will extend the previous analysis, which used high-energy through-going muon events collected in the years of maximum solar activity and yielded only flux upper limits, to include data taken during the solar minima from 2018 to 2020. Extending the analysis to the solar minima is important as the gamma-ray data collected during past solar cycles indicates a possible enhancement in the high-energy neutrino flux. Second, we will incorporate sub-TeV events and include contributions from all neutrino flavors. These will improve our analysis sensitivity since the solar atmospheric spectrum is soft and, due to oscillation, contains significant contributions of all neutrino flavors. As we will present in this contribution, these complementary strategies yield a significant improvement in sensitivity, making substantial progress towards observing this flux

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer

Data de publicació electrònica: 12-04-2021Objective: Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including ΔNp63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme. Design: We combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO). Results: This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of ΔNp63 and the basal programme in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumours, we show that Gata6 inhibits tumour cell plasticity and immune evasion, consistent with patient-derived data, suggesting that GATA6 works as a barrier for acquiring the fully developed basal and metastatic phenotype. Conclusions: Our work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.Work in the lab of PM was supported by the grant P27361-B23 from the Austrian Science Grant (FWF) and by contributions from the Fellinger Krebsforschung foundation and the Ingrid Shaker-Nessmann Krebsforschungsvereinigung foundation. Patients were not involved in the design of this study. RAU and GAL were supported by The Linda T. and John A. Mellowes Endowed Innovation and Discovery Fund, the Theodore W. Batterman Family Foundation, Inc and NIH Grants: R01 DK52913 and R01 CA178627. Work in the lab of FXR was supported, in part, by grant RTI2018-101071-B-I00 (Ministerio de Ciencia, Innovación y Universidades, Madrid, Spain). CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510