Freshwater biodiversity loss is one of the greatest environmental threats in our changing world. Although declines have been reported extensively in the literature, much less attention has been ...devoted to solving the freshwater biodiversity crisis relative to other ecosystems. The recently proposed Emergency Recovery Plan for Freshwater Biodiversity (Tickner et al., 2020, BioScience, 70(4), 330–342) outlines an ambitious but necessary set of overarching actions that can help “bend the curve” for freshwater biodiversity declines. This plan is timely given the present opportunity to adjust freshwater biodiversity targets in international biodiversity agreements and to encourage meeting targets of relevant Sustainable Development Goals. Yet, relying solely on a trickle down from such agreements to national and local scales will likely take too long, given the immediate urgency of the situation. Here, we advocate for a broader, concerted effort from all actors to ensure the Emergency Recovery Plan meaningfully influences the actions of practitioners at a local scale. We outline the roles and responsibilities of actors involved with policy, research, professional bodies and societies, advocacy, and industry, as well as practitioners themselves, in achieving this goal. It is our hope that this overview facilitates the real‐world actions needed to execute the Emergency Recovery Plan so that we can indeed “bend the curve” for freshwater biodiversity.
The recently proposed Emergency Recovery Plan for Freshwater Biodiversity (Tickner et al., 2020, BioScience, 70(4), 330–342) outlines an ambitious but necessary set of overarching actions that can help “bend the curve” for freshwater biodiversity declines. It takes time for such plans to influence the small‐scale actions taken by practitioners working on the ground, but we do not have time to wait given the immediate urgency of the situation. Here, we advocate for a broader, concerted effort from all actors to ensure the Emergency Recovery Plan meaningfully influences the actions of practitioners at a local scale.
The surface detector array of the Telescope Array experiment Abu-Zayyad, T.; Aida, R.; Anderson, R. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
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Journal Article
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The Telescope Array (TA) experiment, located in the western desert of Utah, USA, is designed for the observation of extensive air showers from extremely high energy cosmic rays. The experiment has a ...surface detector array surrounded by three fluorescence detectors to enable simultaneous detection of shower particles at ground level and fluorescence photons along the shower track. The TA surface detectors and fluorescence detectors started full hybrid observation in March, 2008. In this article we describe the design and technical features of the TA surface detector.
Previous measurements of the composition of Ultra-High Energy Cosmic Rays (UHECRs) made by the High Resolution Fly’s Eye (HiRes) and Pierre Auger Observatory (PAO) are seemingly contradictory, but ...utilize different detection methods, as HiRes was a stereo detector and PAO is a hybrid detector. The five year Telescope Array (TA) Middle Drum hybrid composition measurement is similar in some, but not all, respects in methodology to PAO, and good agreement is evident between data and a light, largely protonic, composition when comparing the measurements to predictions obtained with the QGSJetII-03 and QGSJet-01c models. These models are also in agreement with previous HiRes stereo measurements, confirming the equivalence of the stereo and hybrid methods. The data is incompatible with a pure iron composition, for all models examined, over the available range of energies. The elongation rate and mean values of Xmax are in good agreement with Pierre Auger Observatory data. This analysis is presented using two methods: data cuts using simple geometrical variables and a new pattern recognition technique.
The incidence of neutropenia in metastatic castration‐resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors ...treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta‐analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta‐analysis was conducted of studies which reported areas under the plasma concentration‐time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta‐analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change 95% confidence interval (CI): 1.8 1.5‐2.2), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2‐fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio 95%CI: 0.46 0.31‐0.90). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel.
Patients with mCRPC have a significantly (1.8‐fold) lower docetaxel AUC compared to patients with other solid tumors, determined by our meta‐analysis. This could explain the lower incidence of neutropenia reported for this patient population, and confirmed by analysis of our clinical cohorts.
A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this ...intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.
For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D
, vitamin D
, or 25-hydroxyvitamin D (25OHD) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units IU vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.
We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 61·3% of 23 364 participants) than in the placebo group (14 217 62·3% of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I
=35·6%, p
=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 95% CI 0·65-0·94; 19 studies; I
=53·5%, p
=0·003), at daily dose equivalents of 400-1000 IU (0·70 0·55-0·89; ten studies; I
=31·2%, p
=0·16), for a duration of 12 months or less (0·82 0·72-0·93; 29 studies; I
=38·1%, p
=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 0·57-0·90; 15 studies; I
=46·0%, p
=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 0·86-1·07; 36 studies; I
=0·0%, p
=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.
Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.
None.
Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic ...approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended β-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained ‘extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.
Oral antiandrogen therapies are predominantly used in older men, but real-life studies evaluating the impact of age on pharmacokinetic exposure are lacking. This study aims to evaluate the impact of ...age on the pharmacokinetic profiles of abiraterone acetate and enzalutamide in clinical practice.
Retrospective observational study to evaluate the impact of age on the first steady-state sample of patients treated with abiraterone acetate or enzalutamide in routine daily clinical practice. The effect of age on target attainment was assessed.
For abiraterone acetate and enzalutamide, 71 and 64 patients were included, respectively. Baseline patients' characteristics and administered doses were not age-dependent. No age-related differences were observed in exposure to the main metabolites of abiraterone acetate, except for active metabolite Δ(4)-Abiraterone (D4A) with a median plasma concentration of 2.5 × 10
mg/L in the oldest versus 1.3 × 10
mg/L in the youngest age quartile (coefficient of variation, CV, 72%, p = 0.03). For enzalutamide, no significant differences in exposure were found, except for carboxylic acid enzalutamide, having a median plasma concentration of 5.8 mg/L versus 3.9 mg/L in the oldest versus the youngest age quartile (CV 66%, p = 0.03). However, this was driven by one patient aged 99 years old. Age had no significant influence on target attainment of either compound.
This study showed no significant impact of age on the pharmacokinetic profiles of abiraterone acetate and enzalutamide, except for the active metabolite D4A and the inactive metabolite carboxylic acid enzalutamide, both having significantly higher exposure in older males. Target attainments of abiraterone and enzalutamide were not significantly affected by age, which suggests that age has no clinically relevant impact on exposure to these oral antiandrogen therapies. However, the clinical impact of higher exposure to D4A in older males remains undetermined.
We present an upper limit on the flux of ultra-high-energy down-going neutrinos for
E
> 10
18
eV derived with the nine years of data collected by the Telescope Array surface detector (from November ...5, 2008 to October 5, 2017). The method is based on the multivariate analysis technique, so-called Boosted Decision Trees (BDT). Proton-neutrino classifier is built upon 16 observables related to both the properties of the shower front and the lateral distribution function.
We report on a measurement of the cosmic ray energy spectrum by the Telescope Array Low-Energy Extension (TALE) air fluorescence detector (FD). The TALE air FD is also sensitive to the Cherenkov ...light produced by shower particles. Low-energy cosmic rays, in the PeV energy range, are detectable by TALE as Cherenkov events. Using these events, we measure the energy spectrum from a low energy of ∼2 PeV to an energy greater than 100 PeV. Above 100 PeV, TALE can detect cosmic rays using air fluorescence. This allows for the extension of the measurement to energies greater than a few EeV. In this paper, we describe the detector, explain the technique, and present results from a measurement of the spectrum using ∼1000 hr of observation. The observed spectrum shows a clear steepening near 1017.1 eV, along with an ankle-like structure at 1016.2 eV. These features present important constraints on the origin of galactic cosmic rays and on propagation models. The feature at 1017.1 eV may also mark the end of the galactic cosmic ray flux and the start of the transition to extragalactic sources.
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