Why Economics Does Not An Ethics Make: A Case Study

This essay is a multidisciplinary case study of environmental injustice. It demonstrates that misuse of the environment can ultimately impact humans unjustly and further that attempts to remediate injustice in one area merely shifts the burden of injustice to others. After providing the historical, sociological and scientific facts surrounding the 50-acre site, an ethical assessment is presented. It was determined that the actors in this case study were not employing any ethical valuing in their decision making process, but rather relied upon economic values to make their choices. The authors then suggest that judging them from within their own economic valuing system that the actors’ decisions had failed to meet their own values, i.e. good economics

Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma1 and have surveyed exons of protein-coding genes for mutations in 11 affected individuals2,3. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin4 in colorectal carcinogenesis5,6, the fusion lacks the TCF4 β-catenin–binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Enrichment of Bruch’s membrane from human donor eyes

Age-related macular degeneration (AMD) is a leading cause of visual impairment in the developed world. The disease manifests itself by the destruction of the center of the retina, called the macula, resulting in the loss of central vision. Early AMD is characterised by the presence of small, yellowish lesions called soft drusen that can progress onto late AMD such as geographic atrophy (dry AMD) or neovascularisation (wet AMD). Although the clinical changes are well described, and the understanding of genetic influences on conferring AMD risk are getting ever more detailed, one area lacking major progress is an understanding of the biochemical consequences of genetic risk. This is partly due to difficulties in understanding the biochemistry of Bruch’s membrane, a very thin extracellular matrix that acts as a biological filter of material from the blood supply and a scaffold on which the retinal pigment epithelial (RPE) cell monolayer resides. Drusen form within Bruch’s membrane and their presence disrupts nutrient flow to the RPE cells. Only by investigating the protein composition of Bruch’s membrane, and indeed how other proteins interact with it, can researchers hope to unravel the biochemical mechanisms underpinning drusen formation, development of AMD and subsequent vision loss. This paper details methodologies for enriching either whole Bruch’s membrane, or just from the macula region, so that it can be used for downstream biochemical analysis, and provide examples of how this is already changing the understanding of Bruch’s membrane biochemistry

SILAC-based quantitative proteomics to investigate the eicosanoid associated inflammatory response in activated macrophages

Background: Macrophages play a central role in inflammation by phagocytosing invading pathogens, apoptotic cells and debris, as well as mediating repair of tissues damaged by trauma. In order to do this, these dynamic cells generate a variety of inflammatory mediators including eicosanoids such as prostaglandins, leukotrienes and hydroxyeicosatraenoic acids (HETEs) that are formed through the cyclooxygenase, lipoxygenase and cytochrome P450 pathways. The ability to examine the effects of eicosanoid production at the protein level is therefore critical to understanding the mechanisms associated with macrophage activation. Results: This study presents a stable isotope labelling with amino acids in cell culture (SILAC) -based proteomics strategy to quantify the changes in macrophage protein abundance following inflammatory stimulation with Kdo2-lipid A and ATP, with a focus on eicosanoid metabolism and regulation. Detailed gene ontology analysis, at the protein level, revealed several key pathways with a decrease in expression in response to macrophage activation, which included a promotion of macrophage polarisation and dynamic changes to energy requirements, transcription and translation. These findings suggest that, whilst there is evidence for the induction of a pro-inflammatory response in the form of prostaglandin secretion, there is also metabolic reprogramming along with a change in cell polarisation towards a reduced pro-inflammatory phenotype. Conclusions: Advanced quantitative proteomics in conjunction with functional pathway network analysis is a useful tool to investigate the molecular pathways involved in inflammation

Bruch's membrane compartmentalises complement regulation in the eye with implications for therapeutic design in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world and affects nearly 200 million people globally. Local inflammation driven by complement system dysregulation is currently a therapeutic target. Bruch’s membrane (BrM) is a sheet of extracellular matrix that separates the retina from the underlying choroid, a highly vascularized layer that supplies oxygen and nutrition to the outer retina. Here, we show that most complement proteins are unable to diffuse through BrM, although FHL-1, factor D and C5a can. AMD-associated lipid deposition in BrM decreases FHL-1 diffusion. We show that this impermeability of BrM creates two separate semi-independent compartments with respect to complement activation and regulation. Complement proteins synthesized locally on either side of BrM, or on the choroidal side if derived from the circulation, predominantly remain on their side of origin. As previous studies suggest that complement activation in AMD is confined to the choroidal side of BrM, we propose a model whereby complement activation in the choriocapillaris layer of the choroid generates C5a, which crosses BrM to interact with its specific receptor on RPE cells to initiate an inflammatory response in the retina. Understanding mechanisms underpinning AMD is essential for developing therapeutics that target the right molecule in the right anatomical compartment

What predicts community members' intentions to take action to protect koalas?

Context: Without urgent action, koalas could be extinct in New South Wales (NSW), Australia by 2050. Despite the key role that community members could play in koala protection, we know little about what might motivate them to engage in these actions. Aims: This study surveyed residents (n = 585) of local government areas of far north east NSW to identify demographic and social-psychological factors associated with likelihood of engaging in actions that could help to protect koalas. Methods: A survey using a multi-pronged recruitment process was administered to relevant participants. Key results: Binary logistic regression analyses revealed that the likelihood of joining a community conservation group was greater in the Byron shire and for those with a stronger environmental identity, more positive attitudes toward koalas and who perceived that others who are important to them take action to protect koalas. Byron residents, those with a stronger environmental identity and those with more knowledge about koalas were also more likely to advocate government for koala protection. Positive attitudes towards koalas and perceptions that others who are important to them take action to protect koalas significantly predicted likelihood of restoring native vegetation on respondents' properties. Gender emerged as the only significant predictor of likelihood of joining council conservation initiatives. Conclusions: These findings provide insights that could help guide the efforts of government and non-government agencies in engaging community members with koala protection. Implications: This study identified which factors to target when focusing on koala protection behaviours, and can be used to help guide efforts to build community support for koala protection actions.</p

Off-target effects of bacillus Calmette-Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19

Background and objectives: Because of its beneficial off-target effects against non-mycobacterial infectious diseases, bacillus Calmette-Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID-19). Using samples from participants in a placebo-controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID-19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS-CoV-2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID-19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ-irradiated SARS-CoV-2-infected or mock-infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single-cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS-CoV-2-induced secretion of cytokines known to be associated with severe COVID-19, including IL-6, TNF-α and IL-10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS-CoV-2. Conclusions: The immunomodulatory signature of BCG's off-target effects on SARS-CoV-2 is consistent with a protective immune response against severe COVID-19.</p