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

Pre-compositional algorithms in compositions by Boulez, Cage and Xenakis in the 1950s.

In the 1950s, the idea of pre-compositional automation, or subjecting as many parameters as the composer desires to controls or formal plans other than the will/personality of the composer, was a theme that crossed over supposed stylistic divides, such as indeterminism versus serialism, or serialism versus stochasticism. I shall examine three crucial works from the period, Music of Changes, Structures 1a and Achorripsis by John Cage, Pierre Boulez and Iannis Xenakis respectively. The first section provides a context for discussion of these composers by the investigation of selected works by Schoenberg and Webern. The following three sections explore the works mentioned, aiming to show that these works upon scrutiny themselves typify a high-level of compositional automatism unprecedented for each composer up to that time My analyses draw upon other commentaries as well as observations of my own. Following this, I aim to uncover why pre-compositional automation was chosen as a valid strategy for composition, as well as exploring what common ground the composers occupied aesthetically and intellectually. My conclusion is that the relative degrees of control of the material were the chief division between Boulez, Cage and Xenakis. The last section ends by looking at developments in the use of pre-compositional algorithms taken by other composers after the 1950s

Controlling Lipid Micelle Stability Using Oligonucleotide Headgroups

Lipid-based micelles provide an attractive option for therapeutic and diagnostic applications because of their small size (<20 nm) and ability to self-assemble and improve the solubility of both hydrophobic drugs and dyes. Their use, however, has been challenged by the fact that these particles are inherently unstable in serum becaue of interactions with protein components, which drives the micelle equilibrium to the monomeric state. We have engineered serum stabilized micelles using short quadruplex forming oligonucleotide extensions as the lipid headgroup. Quadruplex formation on the surface of the particles, confirmed by ¹H NMR, results in slight distortion of the otherwise spherical micelles and renders them resistant to disassembly by serum proteins for >24 h. Using antisense oligonucleotides we demonstrated that disruption of the quadruplex leads to micelle destabilization and cargo release. The ability to use oligonucleotide interactions to control lipid particle stability represents a new approach in the design of programmed nanoscale devices

Responses to the COVID-19 Pandemic by the Biochemistry Authentic Scientific Inquiry Lab (BASIL) CURE Consortium: Reflections and a Case Study on the Switch to Remote Learning

Campus shutdowns during the SARS-CoV-2 pandemic posed unique challenges to faculty and students engaged in laboratory courses. Formerly hands-on experiments had to be quickly pivoted to emergency remote learning. While some resources existed prior to this period, many currently available online modules and/or simulations focus on a single technique. The Biochemistry Authentic Scientific Inquiry Lab (BASIL) curriculum has, for several years, provided a robust, linked, holistic inquiry experience that allows students to make connections between multiple techniques, both computational in nature as well as wet-lab-based. As a course-based undergraduate research experience (CURE), this flexible, module-based curriculum allows students to generate original hypotheses based on analysis of proteins of unknown function. We have taught this curriculum as the upper-level laboratory course on our campuses and were obliged to transition to remote instruction at various points in the course sequence. We report on the experiences of faculty and students over the transition period in this course. Additionally, we report as a case study results of one of our campus’ ongoing discipline-based education research (DBER) on the BASIL curriculum prior to and during remote delivery

Aptamer-Targeted Dendrimersomes Assembled from Azido-Modified Janus Dendrimers “Clicked” to DNA

Amphiphilic Janus dendrimers (JDs), synthetic alternatives to lipids, have the potential to expand the scope of nanocarrier delivery systems. JDs self-assemble into vesicles called dendrimersomes, encapsulate both hydrophobic cargo and nucleic acids, and demonstrate enhanced stability in comparison to lipid nanoparticles (LNPs). Here, we report the ability to enhance the cellular uptake of Janus dendrimersomes using DNA aptamers. Azido-modified JDs were synthesized and conjugated to alkyne-modified DNAs using copper-catalyzed azide alkyne cycloaddition. DNA-functionalized JDs form nanometer-sized dendrimersomes in aqueous solution via thin film hydration. These vesicles, now displaying short DNAs, are then hybridized to transferrin receptor binding DNA aptamers. Aptamer-targeted dendrimersomes show improved cellular uptake as compared to control vesicles via fluorescence microscopy and flow cytometry. This work demonstrates the versatility of using click chemistry to conjugate functionalized JDs with biologically relevant molecules and the feasibility of targeting DNA-modified dendrimersomes for drug delivery applications

Screening Libraries of Amphiphilic Janus Dendrimers Based on Natural Phenolic Acids to Discover Monodisperse Unilamellar Dendrimersomes

Natural, including plant, and synthetic phenolic acids are employed as building blocks for the synthesis of constitutional isomeric libraries of self-assembling dendrons and dendrimers that are the simplest examples of programmed synthetic macromolecules. Amphiphilic Janus dendrimers are synthesized from a diversity of building blocks including natural phenolic acids. They self-assemble in water or buffer into vesicular dendrimersomes employed as biological membrane mimics, hybrid and synthetic cells. These dendrimersomes are predominantly uni- or multilamellar vesicles with size and polydispersity that is predicted by their primary structure. However, in numerous cases, unilamellar dendrimersomes completely free of multilamellar assemblies are desirable. Here, we report the synthesis and structural analysis of a library containing 13 amphiphilic Janus dendrimers containing linear and branched alkyl chains on their hydrophobic part. They were prepared by an optimized iterative modular synthesis starting from natural phenolic acids. Monodisperse dendrimersomes were prepared by injection and giant polydisperse by hydration. Both were structurally characterized to select the molecular design principles that provide unilamellar dendrimersomes in higher yields and shorter reaction times than under previously used reaction conditions. These dendrimersomes are expected to provide important tools for synthetic cell biology, encapsulation, and delivery

Screening libraries of amphiphilic Janus dendrimers based on natural phenolic acids to discover monodisperse unilamellar dendrimersomes

Natural, including plant, and synthetic phenolic acids are employed as building blocks for the synthesis of constitutional isomeric libraries of self-assembling dendrons and dendrimers that are the simplest examples of programmed synthetic macromolecules. Amphiphilic Janus dendrimers are synthesized from a diversity of building blocks including natural phenolic acids. They self-assemble in water or buffer into vesicular dendrimersomes employed as biological membrane mimics, hybrid and synthetic cells. These dendrimersomes are predominantly uni- or multilamellar vesicles with size and polydispersity that is predicted by their primary structure. However, in numerous cases, unilamellar dendrimersomes completely free of multilamellar assemblies are desirable. Here, we report the synthesis and structural analysis of a library containing 13 amphiphilic Janus dendrimers containing linear and branched alkyl chains on their hydrophobic part. They were prepared by an optimized iterative modular synthesis starting from natural phenolic acids. Monodisperse dendrimersomes were prepared by injection and giant polydisperse by hydration. Both were structurally characterized to select the molecular design principles that provide unilamellar dendrimersomes in higher yields and shorter reaction times than under previously used reaction conditions. These dendrimersomes are expected to provide important tools for synthetic cell biology, encapsulation, and delivery

Self-Sorting and Coassembly of Fluorinated, Hydrogenated, and Hybrid Janus Dendrimers into Dendrimersomes

The modular synthesis of a library containing seven self-assembling amphiphilic Janus dendrimers is reported. Three of these molecules contain environmentally friendly chiral-racemic fluorinated dendrons in their hydrophobic part (<b>R</b>_<b>F</b>), one contains achiral hydrogenated dendrons (<b>R</b>_<b>H</b>), while one denoted hybrid Janus dendrimer, contains a combination of chiral-racemic fluorinated and achiral hydrogenated dendrons (<b>R</b>_<b>HF</b>) in its hydrophobic part. Two Janus dendrimers contain either chiral-racemic fluorinated dendrons and a green fluorescent dye conjugated to its hydrophilic part (<b>R</b>_<b>F</b><b>-NBD</b>) or achiral hydrogenated and a red fluorescent dye in its hydrophilic part (<b>R</b>_<b>H</b><b>-RhB</b>). These <b>R</b>_<b>F</b>, <b>R</b>_<b>H</b>, and <b>R</b>_<b>H</b>F Janus dendrimers self-assembled into unilamellar or onion-like soft vesicular dendrimersomes (DSs), with similar thicknesses to biological membranes by simple injection from ethanol solution into water or buffer. Since <b>R</b>_<b>F</b> and <b>R</b>_<b>H</b> dendrons are not miscible, <b>R</b>_<b>F</b><b>-NBD</b> and <b>R</b>_<b>H</b><b>-RhB</b> were employed to investigate by fluorescence microscopy the self-sorting and coassembly of <b>R</b>_<b>F</b> and <b>R</b>_<b>H</b> as well as of phospholipids into hybrid DSs mediated by the hybrid hydrogenated-fluorinated <b>R</b>_<b>HF</b> Janus dendrimer. The hybrid <b>R</b>_<b>HF</b> Janus dendrimer coassembled with both <b>R</b>_<b>F</b> and <b>R</b>_<b>H</b>. Three-component hybrid DSs containing <b>R</b>_<b>H</b>, <b>R</b>_<b>F</b>, and <b>R</b>_<b>HF</b> were formed when the proportion of <b>R</b>_<b>HF</b> was higher than 40%. With low concentration of <b>R</b>_<b>HF</b> and in its absence, <b>R</b>_<b>H</b> and <b>R</b>_<b>F</b> self-sorted into individual <b>R</b>_<b>H</b> or <b>R</b>_<b>F</b> DSs. Phospholipids were also coassembled with hybrid <b>R</b>_<b>HF</b> Janus dendrimers. The simple synthesis and self-assembly of DSs and hybrid DSs, their similar thickness with biological membranes and their imaging by fluorescence and ¹⁹F-MRI make them important tools for synthetic biology