Individual and Collective Responsiveness to Climate Change: A Response to Dwyer

Commentaire / CommentaryL’histoire de James Dwyer au sujet d’une Commission GAIA fictive met en évidence les préoccupations concernant la portée de la bioéthique, en particulier en ce qui concerne la répartition de la responsabilité au niveau international face aux impacts des changements climatiques sur la santé. Ce commentaire traite de l’impact potentiel d’un individu sur les émissions de gaz à effet de serre et l’importance des réponses institutionnelles afin d’avoir un impact significatif.James Dwyer’s story about a fictional GAIA Commission highlighted unresolved concerns about the scope of bioethics, specifically regarding the global distribution of, and responsibility for, the health impacts of climate change. This commentary discusses the potential impact of an individual on greenhouse gas emissions and the importance of engaging institutional responses in order to have meaningful impacts

Caribbean Heat Threatens Health, Well-Being, and the Future of Humanity

Climate change has substantial impacts on public health and safety, disease risks and the provision of health care, with the poor being particularly disadvantaged. Management of the associated health risks and changing health service requirements requires adequate responses at local levels. Health-care providers are central to these responses. While climate change raises ethical questions about its causes, impacts and social justice, medicine and bioethics typically focus on individual patients and research participants rather than these broader issues. We broaden this focus by examining awareness among health-care providers in the Caribbean region, where geographic and socioeconomic features pose particular vulnerabilities to climate change. In focus groups, Caribbean providers described rises in mosquito-borne, flood-related, heat-related, respiratory and mental illnesses, and attributed these to local impacts of climate change. Their discussions showed that the significance of these impacts differs in different Caribbean nations, raising policy and social justice questions. Bioethics and public health ethics are situated to frame, inform and initiate public and policy dialog about values and scientific evidence associated with climate change. We urge readers to initiate such dialog within their own institutions about the context-dependent nature of the burdens of climate change, and values and policies that permit it to worsen

Re-reading of OraQuick HIV-1/2 rapid antibody test results: quality assurance implications for HIV self-testing programmes.

INTRODUCTION: Scale-up of HIV self-testing (HIVST) will play a key role in meeting the United Nation's 90-90-90 targets. Delayed re-reading of used HIVST devices has been used by early implementation studies to validate the performance of self-test kits and to estimate HIV positivity among self-testers. We investigated the stability of results on used devices under controlled conditions to assess its potential as a quality assurance approach for HIVST scale-up. METHODS: 444 OraQuick® HIV-1/2 rapid antibody tests were conducted using commercial plasma from two HIV-positive donors and HIV-negative plasma (high-reactive n = 148, weak-reactive n = 148 and non-reactive n = 148) and incubated them for six months under four conditions (combinations of high and low temperatures and humidity). Devices were re-read daily for one week, weekly for one subsequent month and then once a month by independent readers unaware of the previous results. We used multistage transition models to investigate rates of change in device results, and between storage conditions. RESULTS AND DISCUSSION: There was a high incidence of device instability. Forty-three (29%) of 148 initially non-reactive results became false weak-reactive results. These changes were observed across all incubation conditions, the earliest on Day 4 (n = 9 kits). No initially HIV-reactive results changed to a non-reactive result. There were no significant associations between storage conditions and hazard of results transition. We observed substantial statistical agreement between independent re-readers over time (agreement range: 0.74 to 0.96). CONCLUSIONS: Delayed re-reading of used OraQuick® HIV-1/2 rapid antibody tests is not currently a valid methodological approach to quality assurance and monitoring as we observed a high incidence (29%) of true non-reactive tests changing to false weak-reactive and therefore its use may overestimate true HIV positivity

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Background: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. Methods: We used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. Results: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. Conclusions: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease

Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis

Medical end-of-life decision-making in a small resource-poor Caribbean country : a mortality follow-back study of home deaths

Background: In resource-poor countries, including in Latin American and the Caribbean, empirical information about the characteristics and incidence of medical end-of-life decisions (MELDs)-withholding or withdrawing potentially life-prolonging medical treatments-is largely absent. Methods: The aim was to describe the incidence and decision-making characteristics of MELDs taken prior to the death of people who died at home in Trinidad and Tobago (T&T). A mortality follow-back study was used where a representative sample of deaths occurring at home in 2018 was drawn from death certificates at the national death registry. The general practitioners who certified the deaths were sent a questionnaire. Results: The sample consisted of 309 adult deaths and the response rate was 31% (N=96). Physicians were: mostly male (79.2%), practiced medicine for more than twenty-years (63.5%), had no formal palliative care training (69.8%). Non-sudden deaths represented 76% (N=73), of these, medications to alleviate pain and symptoms in the last 7 days of life were administered in 65.8%, including opioids 21%. Potentially life-prolonging treatments were withheld in 9.6% but none withdrawn. No physician/patient discussions about various end-of-life treatment options occurred in 61.6%. Compared to physicians with no formal training in palliative care, those with training more often: prescribed or administered opioids in the last 7 days of life (35.7% vs. 11.1%, P=0.01), had discussions with patients about end-of-life treatment options (60.7% vs. 24.4%, P=0.002), and discussed medication use to alleviate pain and other symptoms with patients (50% vs. 17.8%, P=0.004). Conclusions: Differences in the care and treatment general practitioners provided to their patients could be associated with them having been formally trained in palliative care. The necessary support to further develop palliative care in T&T is needed

Researching complementary and alternative treatments – the gatekeepers are not at home

Background: To explore the strengths and weaknesses of conventional biomedical research strategies and methods as applied to complementary and alternative medicine (CAM), and to suggest a new research framework for assessing these treatment modalities. Discussion: There appears to be a gap between published studies showing little or no efficacy of CAM, and reports of substantial clinical benefit from patients and CAM practitioners. This "gap" might be partially due to the current focus on placebo-controlled randomized trials, which are appropriately designed to answer questions about the efficacy and safety of pharmaceutical agents. In an attempt to fit this assessment strategy, complex CAM treatment approaches have been dissected into standardized and often simplified treatment methods, and outcomes have been limited. Unlike conventional medicine, CAM has no regulatory or financial gatekeeper controlling their therapeutic "agents" before they are marketed. Treatments may thus be in widespread use before researchers know of their existence. In addition, the treatments are often provided as an integrated 'whole system' of care, without careful consideration of the safety issue. We propose a five-phase strategy for assessing CAM built on the acknowledgement of the inherent, unique aspects of CAM treatments and their regulatory status in most Western countries. These phases comprise: 1. Context, paradigms, philosophical understanding and utilization 2. Safety status 3. Comparative effectiveness. 4. Component efficacy 5. Biological mechanisms. Summary: Using the proposed strategy will generate evidence relevant to clinical practice, while acknowledging the absence of regulatory and financial gatekeepers for CAM. It will also emphasize the important but subtle differences between CAM and conventional medical practic