There is an urgent need for drugs, therapies and vaccines to be available to protect the human population against COVID-19. One of the first approaches taken in the COVID-19 global response was to ...consider repurposing licensed drugs. This commentary highlights an extraordinary international collaborative effort of independent researchers who have recently all come to the same conclusion—that chloroquine or hydroxchloroquine are unlikely to provide clinical benefit against COVID-19.
The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a ...novel class of small molecules (1,2,3triazolo4,5-dpyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis ...and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.
Recently, new daphnane, tigliane, and jatrophane diterpenoids have been isolated from various Euphorbiaceae species, of which some have been shown to be potent inhibitors of chikungunya virus (CHIKV) ...replication. To further explore this type of compound, the antiviral activity of a series of 29 commercially available natural diterpenoids was evaluated. Phorbol-12,13-didecanoate (11) proved to be the most potent inhibitor, with an EC50 value of 6.0 ± 0.9 nM and a selectivity index (SI) of 686, which is in line with the previously reported anti-CHIKV potency for the structurally related 12-O-tetradecanoylphorbol-13-acetate (13). Most of the other compounds exhibited low to moderate activity, including an ingenane-type diterpene ester, compound 28, with an EC50 value of 1.2 ± 0.1 μM and SI = 6.4. Diterpene compounds are known also to inhibit HIV replication, so the antiviral activities of compounds 1−29 were evaluated also against HIV-1 and HIV-2. Tigliane- (4β-hydroxyphorbol analogues 10, 11, 13, 15, 16, and 18) and ingenane-type (27 and 28) diterpene esters were shown to inhibit HIV replication in vitro at the nanomolar level. A Pearson analysis performed with the anti-CHIKV and anti-HIV data sets demonstrated a linear relationship, which supported the hypothesis made that PKC may be an important target in CHIKV replication.
Estimates of ground-level ozone concentrations are necessary to determine the human health burden of ozone. To support the Global Burden of Disease Study, we produce yearly fine resolution global ...surface ozone estimates from 1990 to 2017 through a data fusion of observations and models. As ozone observations are sparse in many populated regions, we use a novel combination of the M3Fusion and Bayesian Maximum Entropy (BME) methods. With M3Fusion, we create a multimodel composite by bias-correcting and weighting nine global atmospheric chemistry models based on their ability to predict observations (8834 sites globally) in each region and year. BME is then used to integrate observations, such that estimates match observations at each monitoring site with the observational influence decreasing smoothly across space and time until the output matches the multimodel composite. After estimating at 0.5° resolution using BME, we add fine spatial detail from an additional model, yielding estimates at 0.1° resolution. Observed ozone is predicted more accurately (R 2 = 0.81 at the test point, 0.63 at 0.1°, and 0.62 at 0.5°) than the multimodel mean (R 2 = 0.28 at 0.5°). Global ozone exposure is estimated to be increasing, driven by highly populated regions of Asia and Africa, despite decreases in the United States and Russia.
Abstract
City-level estimates of ambient ozone concentrations and associated disease burdens are sparsely available, especially for low and middle-income countries. Recently available high-resolution ...gridded global ozone concentration estimates allow for estimating ozone concentrations and mortality at urban scales and for urban-rural catchment areas worldwide. We applied existing fine resolution global surface ozone estimates, developed by integrating observations (8834 sites globally) with nine atmospheric chemistry models, in an epidemiologically-derived health impact function to estimate chronic respiratory disease mortality worldwide in 2019. We compared ozone season daily maximum 8 h mixing ratio concentrations and ozone-attributable mortality for urban areas worldwide (including cities and densely-populated towns), and their surrounding peri-urban, peri-rural, and rural areas. In 2019, population-weighted mean ozone among all urban-rural catchment areas was greatest in peri-urban areas (52 ppb), followed by urban areas (cities and towns; 49 ppb). Of 423 100 estimated global ozone-attributable deaths, 37% (147 100) occurred in urban areas, where 40% of the world’s population resides, and 56% (254 000) occurred in peri-urban areas (<1 h from an urban area), where 47% of the world’s population resides. Across 12 946 cities (excluding towns), average population-weighted mean ozone was 51 ppb (sd = 13 ppb, range = 10–78 ppb). Three quarters of the ozone-attributable deaths worldwide (77%; 112 700) occurred in cities of South and East Asia. City-level ozone-attributable mortality rates varied by a factor of 10 across world regions. Ozone levels and attributable mortality were greatest in Asian and African cities; however, cities of higher-income regions, like high-income Asia Pacific and North America, continue to experience high ozone concentrations and attributable mortality rates, despite successful national air quality measures for reducing ozone precursor emissions. The disproportionate magnitude of ozone mortality compared with population size in peri-urban areas indicates that reducing ozone precursor emissions in places that influence peri-urban concentrations can yield substantial health benefits in these areas.
The aim of this study was to systematically review prior research investigating the effects of contact/collision sport participation on neurometabolite levels in the absence of concussion. Four ...online databases were searched to identify studies that measured neurometabolite levels in contact/collision sport athletes (without concussion) using proton (1H) or phosphorus (31P) magnetic resonance spectroscopy (MRS). All study designs were acceptable for inclusion. Meta‐analytic procedures were used to quantify the effect of contact/collision sport participation on neurometabolite levels and explore the impact of specific moderating factors (where sufficient data were available). Narrative synthesis was used to describe outcomes that could not be meta‐analysed. Nine observational studies involving 300 contact/collision sport athletes were identified. Six studies (providing 112 effect estimates) employed longitudinal (cohort) designs and three (that could not be meta‐analysed) employed case–control designs. N‐acetylaspartate (NAA; g = −0.331, p = 0.013) and total creatine (tCr; creatine + phosphocreatine; g = −0.524, p = 0.029), but not glutamate–glutamine (Glx), myo‐inositol (mI) or total choline (tCho; choline‐containing compounds; p's > 0.05), decreased between the pre‐season and mid−/post‐season period. Several moderators were statistically significant, including: sex (Glx: 6 female/23 male, g = −0.549, p = 0.013), sport played (Glx: 22 American football/4 association football soccer, g = 0.724, p = 0.031), brain region (mI: 2 corpus callosum/9 motor cortex, g = −0.804, p = 0.015), and the MRS quantification approach (mI: 18 absolute/3 tCr‐referenced, g = 0.619, p = 0.003; and tCho: 18 absolute/3 tCr‐referenced, g = 0.554, p = 0.005). In case–control studies, contact/collision sport athletes had higher levels of mI, but not NAA or tCr compared to non‐contact sport athletes and non‐athlete controls. Overall, this review suggests that contact/collision sport participation has the potential to alter neurometabolites measured via 1H MRS in the absence of concussion. However, further research employing more rigorous and consistent methodologies (e.g. interventional studies with consistent 1H MRS pulse sequences and quantifications) is required to confirm and better understand the clinical relevance of observed effects.
Our review examined neurometabolite levels assessed via magnetic resonance spectroscopy (MRS) in athletes undertaking contact/collision sport without concussion. Only studies employing proton (1H) MRS were found. In longitudinal studies (i.e. pre‐ vs. mid−/post‐ season), a reduction in N‐acetylaspartate (NAA) and total creatine (tCr; creatine and phosphocreatine), but not glutamate–glutamine (Glx), myo‐inositol (mI) or total choline (tCho; choline‐containing compounds) was found. In case–control studies, contact/collision sport athletes had higher mI, but not NAA or tCr compared to non‐contact sport athletes and non‐athlete controls. Overall, this review suggests that contact/collision sport participation can alter 1H MRS neurometabolites in the absence of concussion.
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