What Do Core Obligations under the Right to Health Bring to Universal Health Coverage?

Can the right to health, and particularly the core obligations of states specified under this right, assist in formulating and implementing universal health coverage (UHC), now included in the post-2015 Sustainable Development Goals? In this paper, we examine how core obligations under the right to health could lead to a version of UHC that is likely to advance equity and rights. We first address the affinity between the right to health and UHC as evinced through changing definitions of UHC and the health domains that UHC explicitly covers. We then engage with relevant interpretations of the right to health, including core obligations. We turn to analyze what core obligations might bring to UHC, particularly in defining what and who is covered. Finally, we acknowledge some of the risks associated with both UHC and core obligations and consider potential avenues for mitigating these risks

Dynamic telomerase gene suppression via network effects of GSK3 inhibition

<b>Background</b>: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression. <b>Methodology/Principal Findings</b>: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3′-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFκB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc. <b>Conclusions/Significance</b>: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting

The right to health of non-nationals and displaced persons in the sustainable development goals era: challenges for equity in universal health care

Introduction: Under the Millennium Development Goals (MDGs), United Nations (UN) Member States reported progress on the targets toward their general citizenry. This focus repeatedly excluded marginalized ethnic and linguistic minorities, including people of refugee backgrounds and other vulnerable non-nationals that resided within a States’ borders. The Sustainable Development Goals (SDGs) aim to be truly transformative by being made operational in all countries, and applied to all, nationals and non-nationals alike. Global migration and its diffuse impact has intensified due to escalating conflicts and the growing violence in war-torn Syria, as well as in many countries in Africa and in Central America. This massive migration and the thousands of refugees crossing borders in search for safety led to the creation of two-tiered, ad hoc, refugee health care systems that have added to the sidelining of non-nationals in MDG-reporting frameworks. Conclusion: We have identified four ways to promote the protection of vulnerable non-nationals’ health and well being in States’ application of the post-2015 SDG framework: In setting their own post-2015 indicators the UN Member States should explicitly identify vulnerable migrants, refugees, displaced persons and other marginalized groups in the content of such indicators. Our second recommendation is that statisticians from different agencies, including the World Health Organization’s Gender, Equity and Human Rights programme should be actively involved in the formulation of SDG indicators at both the global and country level. In addition, communities, civil society and health justice advocates should also vigorously engage in country’s formulation of post-2015 indicators. Finally, we advocate that the inclusion of non-nationals be anchored in the international human right to health, which in turn requires appropriate financing allocations as well as robust monitoring and evaluation processes that can hold technocratic decision-makers accountable for progress.publishedVersio

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

“Counting Care Work: The Empirical and Policy Implications of Care Theory

The provision of adequate and quality care to the elderly, children, and those who are ill or disabled is one of the pressing social problems of our time. Despite the far-reaching formulations of care in the theoretical realm, advocacy and policymaking efforts around care work remain largely atomized. Translating the wide-ranging insights of care scholarship into tools for public policy solutions requires a practical application of the concept as well as empirical measurement. In this study we integrate the insights of care theory with feminist economic analysis to conceptualize care as a single sector at the foundation of the state’s human infrastructure. We then measure the scope of care work across paid work, unpaid labor and government investment in one US state. We find that the care sector in Massachusetts is substantial in its scope and human and economic impact: 22 percent of the paid labor force, 20 percent of the average resident’s daily time, and 57 percent of state and local government spending. Data such as this gives policymakers and advocates an empirical foundation to build on in framing a broader vision of care policy. Strengthening the human infrastructure in Massachusetts and elsewhere is an economic and ethical imperative, and our goal has been to provide both empirical data and a practically useful conceptual frame that can be used as tools by those working towards the social transformation of care