Rapid COVID-19 vaccine development Graham, Barney S
Science (American Association for the Advancement of Science),
05/2020, Letnik:
368, Številka:
6494
Journal Article
Residential segregation by race and income are enduring features of urban America. Understanding the effects of residential segregation on educational attainment, labor market outcomes, criminal ...activity, and other outcomes has been a leading project of the social sciences for over half a century. This paper describes techniques for measuring the effects of neighborhood of residence on long-run life outcomes.
Metabolomics uses advanced analytical chemistry techniques to comprehensively measure large numbers of small molecule metabolites in cells, tissues and biofluids. The ability to rapidly detect and ...quantify hundreds or even thousands of metabolites within a single sample is helping scientists paint a far more complete picture of system-wide metabolism and biology. Metabolomics is also allowing researchers to focus on measuring the end-products of complex, hard-to-decipher genetic, epigenetic and environmental interactions. As a result, metabolomics has become an increasingly popular "omics" approach to assist with the robust phenotypic characterization of humans, crop plants and model organisms. Indeed, metabolomics is now routinely used in biomedical, nutritional and crop research. It is also being increasingly used in livestock research and livestock monitoring. The purpose of this systematic review is to quantitatively and objectively summarize the current status of livestock metabolomics and to identify emerging trends, preferred technologies and important gaps in the field. In conducting this review we also critically assessed the applications of livestock metabolomics in key areas such as animal health assessment, disease diagnosis, bioproduct characterization and biomarker discovery for highly desirable economic traits (i.e., feed efficiency, growth potential and milk production). A secondary goal of this critical review was to compile data on the known composition of the livestock metabolome (for 5 of the most common livestock species namely cattle, sheep, goats, horses and pigs). These data have been made available through an open access, comprehensive livestock metabolome database (LMDB, available at http://www.lmdb.ca). The LMDB should enable livestock researchers and producers to conduct more targeted metabolomic studies and to identify where further metabolome coverage is needed.
Summary
Endothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3–6 days after the onset of illness, which is known as ...the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24–48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor‐α, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin‐2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin‐1β through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down‐stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease.
Endothelial dysfunction leading to increased vascular permeability is a hallmark of severe dengue, leading to leakage of fluid into pleural and peritoneal cavities and shock. Although cytokines such as tumour necrosis factor‐α, which are highly elevated in dengue, and are likely to result in increased vascular permeability, the roles of DENV‐NS1 antigen and lipid mediators such as PAF in causing vascular leak are emerging. It may be that in practice, there are several pathways that contribute to vascular leak, but by understanding key mechanisms there may be opportunities for intervention.
Deuterated drugs: where are we now? Timmins, Graham S
Expert opinion on therapeutic patents,
10/2014, Letnik:
24, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium- carbon bond modifying their metabolism. There is great interest in ...the current state of development of this approach.
This review covers recent US patent applications and prosecutions in this area that are based on beneficial modifications in metabolism of deuterated versions of existing drugs. The current state of 35 U.S.C. §103 'obviousness' rejections are emphasized, as is the development of strategies to overcome such rejections. Current trials and market considerations are also discussed.
Deuterated drugs collectively are worth at least US$1 billion. It would seem that the likelihood of obviousness rejections is increasing in this area. However, careful elucidation of metabolic outcomes from deuteration that would not be anticipated from the prior art, and are instead unexpected and unobvious, has enabled allowance. Showing that drug deuteration alters pharmacokinetics by mechanisms not currently part of the prior art surrounding deuterated drugs has also been successful. Development of these and other strategies, combined with developing the extensive base of issued patents will enable the field to remain commercially attractive for some time.
The revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a ...public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met.
We developed a dynamic transmission model of the global HCV epidemic, calibrated to 190 countries, which incorporates data on demography, people who inject drugs (PWID), current coverage of treatment and prevention programmes, natural history of the disease, HCV prevalence, and HCV-attributable mortality. We estimated the worldwide impact of scaling up interventions that reduce risk of transmission, improve access to treatment, and increase screening for HCV infection by considering six scenarios: no change made to existing levels of diagnosis or treatment; sequentially adding the following interventions: blood safety and infection control, PWID harm reduction, offering of DAAs at diagnosis, and outreach screening to increase the number diagnosed; and a scenario in which DAAs are not introduced (ie, treatment is only with pegylated interferon and oral ribavirin) to investigate the effect of DAA use. We explored the effect of varying the coverage or impact of these interventions in sensitivity analyses and also assessed the impact on the global epidemic of removing certain key countries from the package of interventions.
By 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14·1 million (95% credible interval 13·0–15·2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640 000 deaths (620 000–670 000) from cirrhosis and liver cancer. A comprehensive package of prevention, screening, and treatment interventions could avert 15·1 million (13·8–16·1) new infections and 1·5 million (1·4–1·6) cirrhosis and liver cancer deaths, corresponding to an 81% (78–82) reduction in incidence and a 61% (60–62) reduction in mortality compared with 2015 baseline. This reaches the WHO HCV incidence reduction target of 80% but is just short of the mortality reduction target of 65%, which could be reached by 2032. Reducing global burden depends upon success of prevention interventions, implemention of outreach screening, and progress made in key high-burden countries including China, India, and Pakistan.
Further improvements in blood safety and infection control, expansion or creation of PWID harm reduction services, and extensive screening for HCV with concomitant treatment for all are necessary to reduce the burden of HCV. These findings should inform the ongoing global action to eliminate the HCV epidemic.
Wellcome Trust.
Summary Background Recent hypertension guidelines have reversed previous recommendations for lower blood pressure targets in high-risk patients, such as those with cardiovascular disease, renal ...disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies. Methods For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled trials with at least 6 months' follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes. Findings We identified 19 trials including 44 989 participants, in whom 2496 major cardiovascular events were recorded during a mean 3·8 years of follow-up (range 1·0–8·4 years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% 95% CI 4–22), myocardial infarction (13% 0–24), stroke (22% 10–32), albuminuria (10% 3–16), and retinopathy progression (19% 0–34). However, more intensive treatment had no clear effects on heart failure (15% 95% CI −11 to 34), cardiovascular death (9% –11 to 26), total mortality (9% –3 to 19), or end-stage kidney disease (10% –6 to 23). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1·2% per year in intensive blood pressure-lowering group participants, compared with 0·9% in the less intensive treatment group (RR 1·35 95% CI 0·93–1·97). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2·68 1·21–5·89, p=0·015), but the absolute excess was small (0·3% vs 0·1% per person-year for the duration of follow-up). Interpretation Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large. Funding National Health and Medical Research Council of Australia.
Respiratory syncytial virus (RSV) is an important cause of respiratory disease causing high rates of hospitalizations in infants, significant morbidity in children and adults, and excess mortality in ...the elderly. Major barriers to vaccine development include early age of RSV infection, capacity of RSV to evade innate immunity, failure of RSV‐induced adaptive immunity to prevent reinfection, history of RSV vaccine‐enhanced disease, and lack of an animal model fully permissive to human RSV infection. These biological challenges, safety concerns, and practical issues have significantly prolonged the RSV vaccine development process. One great advantage compared to other difficult viral vaccine targets is that passively administered neutralizing monoclonal antibody is known to protect infants from severe RSV disease. Therefore, the immunological goals for vaccine development are to induce effective neutralizing antibody to prevent infection and to avoid inducing T‐cell response patterns associated with enhanced disease. Live‐attenuated RSV and replication‐competent chimeric viruses are in advanced clinical trials. Gene‐based strategies, which can control the specificity and phenotypic properties of RSV‐specific T‐cell responses utilizing replication‐defective vectors and which may improve on immunity from natural infection, are progressing through preclinical testing. Atomic level structural information on RSV envelope glycoproteins in complex with neutralizing antibodies is guiding design of new vaccine antigens that may be able to elicit RSV‐specific antibody responses without induction of RSV‐specific T‐cell responses. These new technologies may allow development of vaccines that can protect against RSV‐mediated disease in infants and establish a new immunological paradigm in the host to achieve more durable protection against reinfection.
The Ensembl Variant Effect Predictor McLaren, William; Gil, Laurent; Hunt, Sarah E ...
Genome Biology,
06/2016, Letnik:
17, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive ...collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.
A Mediterranean dietary pattern is widely recommended for the prevention of chronic disease. We sought to define the most likely effects of the Mediterranean diet on vascular disease and mortality.
...We searched MEDLINE, EMBASE and the Cochrane Central Register without language restriction for randomized controlled trials comparing Mediterranean to control diets. Data on study design, patient characteristics, interventions, follow-up duration, outcomes and adverse events were sought. Individual study relative risks (RR) were pooled to create summary estimates.
Six studies with a total of 10950 participants were included. Effects on major vascular events (n = 477), death (n = 693) and vascular deaths (n = 315) were reported for 3, 5 and 4 studies respectively. For one large study (n = 1000) there were serious concerns about the integrity of the data. When data for all studies were combined there was evidence of protection against major vascular events (RR 0.63, 95% confidence interval 0.53-0.75), coronary events (0.65, 0.50-0.85), stroke (0.65, 0.48-0.88) and heart failure (0.30, 0.17-0.56) but not for all-cause mortality (1.00, 0.86-1.15) or cardiovascular mortality (0.90, 0.72-1.11). After the study of concern was excluded the benefit for vascular events (0.69, 0.55-0.86) and stroke (0.66, 0.48-0.92) persisted but apparently positive findings for coronary events (0.73, 0.51-1.05) and heart failure (0.25, 0.05-1.17) disappeared.
The Mediterranean diet may protect against vascular disease. However, both the quantity and quality of the available evidence is limited and highly variable. Results must be interpreted with caution.
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