Financial Analysis for Measuring and Comparing Risk in Grantmaking Portfolios

· Risk has not been treated in a systematic way that allows for a rich understanding of the extent to which foundations are, or should be, incorporating or evaluating risk in philanthropy. · In this article, we conceptualize and develop a tool to evaluate the levels of philanthropic risk that foundations maintain through their grant portfolios. · We create an index of aggregated risk at the portfolio level using several financial indicators based on previous theory and literature. Then, we test the index on a sample of foundations and their grantees in the state of Georgia and compare risk levels across community, corporate, family, independent, and operating foundations. · Our results show small differences in philanthropic risk levels when measured by financially oriented proxies between foundation types

New Insight Into Avian Papillomavirus Ecology and Evolution From Characterization of Novel Wild Bird Papillomaviruses

Viruses in the family Papillomaviridae have circular dsDNA genomes of approximately 5.7–8.6 kb that are packaged within non-enveloped, icosahedral capsids. The known papillomavirus (PV) representatives infect vertebrates, and there are currently more than 130 recognized PV species in more than 50 genera. We identified 12 novel avian papillomavirus (APV) types in wild birds that could represent five distinct species and two genera. Viruses were detected in paired oropharyngeal/cloacal swabs collected from six bird species, increasing the number of avian species known to harbor PVs by 40%. A new duck PV (DuPV-3) was found in mallard and American black duck (27.6% estimated prevalence) that was monophyletic with other known DuPVs. A single viral type was identified in Atlantic puffin (PuPV-1, 9.8% estimated prevalence), while a higher genetic diversity was found in other Charadriiformes. Specifically, three types [gull PV-1 (GuPV-1), -2, and -3] were identified in two gull species (estimated prevalence of 17% and 2.6% in American herring and great black-backed gull, respectively), and seven types [kittiwake PV-1 (KiPV-1) through -7] were found in black-legged kittiwake (81.3% estimated prevalence). Significantly higher DuPV-3 circulation was observed in spring compared to fall and in adults compared to juveniles. The studied host species’ tendencies to be in crowded environments likely affect infection rates and their migratory behaviors could explain the high viral diversity, illustrating how host behavior can influence viral ecology and distribution. For DuPV-3, GuPV-1, PuPV-1, and KiPV-2, we obtained the complete genomic sequences, which showed the same organization as other known APVs. Phylogenetic analyses showed evidence for virus–host co-divergence at the host taxonomic levels of family, order, and inter-order, but we also observed that host-specificity constraints are relaxed among highly related hosts as we found cross-species transmission within ducks and within gulls. Furthermore, the phylogeny of viruses infecting the Charadriiformes did not match the host phylogeny and gull viruses formed distinct monophyletic clades with kittiwake viruses, possibly reflecting past host-switching events. Considering the vast PV genotype diversity in other hosts and the large number of bird species, many more APVs likely remain to be discovered

Autism and autistic traits in those who died by suicide in England

Background: Autism and autistic traits are risk factors for suicidal behaviour. Aims: To explore the prevalence of autism (diagnosed and undiagnosed) in those who died by suicide, and identify risk factors for suicide in this group. Method: Stage 1: 372 coroners’ inquest records, covering the period 1 January 2014 to 31 December 2017 from two regions of England, were analysed for evidence that the person who died had diagnosed autism or undiagnosed possible autism (elevated autistic traits), and identified risk markers. Stage 2: 29 follow-up interviews with the next of kin of those who died gathered further evidence of autism and autistic traits using validated autism screening and diagnostic tools. Results: Stage 1: evidence of autism (10.8%) was significantly higher in those who died by suicide than the 1.1% prevalence expected in the UK general alive population (odds ratio (OR) = 11.08, 95% CI 3.92–31.31). Stage 2: 5 (17.2%) of the follow-up sample had evidence of autism identified from the coroners’ records in stage 1. We identified evidence of undiagnosed possible autism in an additional 7 (24.1%) individuals, giving a total of 12 (41.4%); significantly higher than expected in the general alive population (1.1%) (OR = 19.76, 95% CI 2.36–165.84). Characteristics of those who died were largely similar regardless of evidence of autism, with groups experiencing a comparably high number of multiple risk markers before they died. Conclusions: Elevated autistic traits are significantly over-represented in those who die by suicide

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. P. falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics

Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17//RAC1-mediated activation of NADPH oxidases

Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2–mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans

Public, private and personal: Qualitative research on policymakers' opinions on smokefree interventions to protect children in 'private' spaces

<p>Abstract</p> <p>Background</p> <p>Governments use law to constrain aspects of private activities for purposes of protecting health and social wellbeing. Policymakers have a range of perceptions and beliefs about what is public or private. An understanding of the possible drivers of policymaker decisions about where government can or should intervene for health is important, as one way to better guide appropriate policy formation. Our aim was to identify obstacles to, and opportunities for, government smokefree regulation of private and public spaces to protect children. In particular, to seek policymaker opinions on the regulation of smoking in homes, cars and public parks and playgrounds in a country with incomplete smokefree laws (New Zealand).</p> <p>Methods</p> <p>Case study, using structured interviews to ask policymakers (62 politicians and senior officials) about their opinions on new smokefree legislation for public and private places. Supplementary data was obtained from the Factiva media database, on the views of New Zealand local authority councillors about policies for smokefree outdoor public places.</p> <p>Results</p> <p>Overall, interviewees thought that government regulation of smoking in private places was impractical and unwise. However, there were some differences on what <it>was </it>defined as 'private', particularly for cars. Even in public parks, smoking was seen by some as a 'personal' decision, and unlikely to be amenable to regulation. Most participants believed that educative, supportive and community-based measures were better and more practical means of reducing smoking in private places, compared to regulation.</p> <p>Conclusions</p> <p>The constrained view of the role of regulation of smoking in public and private domains may be in keeping with current political discourse in New Zealand and similar Anglo-American countries. Policy and advocacy options to promote additional smokefree measures include providing a better voice for childrens' views, increasing information to policymakers about the harms to children from secondhand smoke and the example of adult smoking, and changing the culture for smoking around children.</p

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children