Abstract
The CHIME/FRB Project has recently released its first catalog of fast radio bursts (FRBs), containing 492 unique sources. We present results from angular cross-correlations of CHIME/FRB ...sources with galaxy catalogs. We find a statistically significant (
p
-value ∼ 10
−4
, accounting for look-elsewhere factors) cross-correlation between CHIME FRBs and galaxies in the redshift range 0.3 ≲
z
≲ 0.5, in three photometric galaxy surveys: WISE × SCOS, DESI-BGS, and DESI-LRG. The level of cross-correlation is consistent with an order-one fraction of the CHIME FRBs being in the same dark matter halos as survey galaxies in this redshift range. We find statistical evidence for a population of FRBs with large host dispersion measure (∼400 pc cm
−3
) and show that this can plausibly arise from gas in large halos (
M
∼ 10
14
M
⊙
), for FRBs near the halo center (
r
≲ 100 kpc). These results will improve in future CHIME/FRB catalogs, with more FRBs and better angular resolution.
In this review, we discuss the opportunity for repurposing drugs for use in l-DOPA-induced dyskinesia (LID) in Parkinson's disease. LID is a particularly suitable indication for drug repurposing ...given its pharmacological diversity, translatability of animal-models, availability of Phase II proof-of-concept (PoC) methodologies and the indication-specific regulatory environment. A compound fit for repurposing is defined as one with appropriate human safety-data as well as animal safety, toxicology and pharmacokinetic data as found in an Investigational New Drug (IND) package for another indication. We first focus on how such repurposing candidates can be identified and then discuss development strategies that might progress such a candidate towards a Phase II clinical PoC. We discuss traditional means for identifying repurposing candidates and contrast these with newer approaches, especially focussing on the use of computational and artificial intelligence (AI) platforms. We discuss strategies that can be categorised broadly as: in vivo phenotypic screening in a hypothesis-free manner; in vivo phenotypic screening based on analogy to a related disorder; hypothesis-driven evaluation of candidates in vivo and in silico screening with a hypothesis-agnostic component to the selection. To highlight the power of AI approaches, we describe a case study using IBM Watson where a training set of compounds, with demonstrated ability to reduce LID, were employed to identify novel repurposing candidates. Using the approaches discussed, many diverse candidates for repurposing in LID, originally envisaged for other indications, will be described that have already been evaluated for efficacy in non-human primate models of LID and/or clinically.
This article is part of the Special Issue entitled ‘Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders’.
•LID remains a largely unmet need but represents an opportune indication for drug repurposing.•Alongside traditional discovery methods, novel AI-driven approaches are being explored.•LID repurposing efforts benefit from excellent animal models with proven predictive validity.•The regulatory climate is increasingly receptive with programs able to gain orphan drug designation for the treatment of LID.
The Canadian Hydrogen Intensity Mapping Experiment (CHIME) is a novel transit radio telescope operating across the 400-800 MHz band. CHIME is composed of four 20 m × 100 m semicylindrical paraboloid ...reflectors, each of which has 256 dual-polarization feeds suspended along its axis, giving it a 200 deg2 field of view. This, combined with wide bandwidth, high sensitivity, and a powerful correlator, makes CHIME an excellent instrument for the detection of fast radio bursts (FRBs). The CHIME Fast Radio Burst Project (CHIME/FRB) will search beam-formed, high time and frequency resolution data in real time for FRBs in the CHIME field of view. Here we describe the CHIME/FRB back end, including the real-time FRB search and detection software pipeline, as well as the planned offline analyses. We estimate a CHIME/FRB detection rate of 2-42 FRBs sky-1 day-1 normalizing to the rate estimated at 1.4 GHz by Vander Wiel et al. Likely science outcomes of CHIME/FRB are also discussed. CHIME/FRB is currently operational in a commissioning phase, with science operations expected to commence in the latter half of 2018.
In Germany, deaths of SARS-CoV-2–positive persons are reported as ‘death related to SARS-CoV-2/COVID-19’ to the Robert Koch Institute, Germany's main infectious disease institution. In 177 ...COVID-19–associated deaths reported in Regensburg, Germany, from October 2020 to January 2021, we investigated how deaths following SARS-CoV-2 infection were reported and whether cases with a death attributed to SARS-CoV-2 (COVID-19 death CD) differed from cases with a reported death from other causes (non–COVID-19 death NCD).
This was an observational retrospective cohort study.
We analysed descriptive data on the numbers of cases, deaths, age, sex, symptoms and hospitalizations. We calculated odds ratios (ORs) with 95% confidence intervals (95% CIs) and performed Chi-squared/Fisher's exact test for categorical variables and the Wilcoxon rank-sum test for comparison of medians.
Deaths attributed to COVID-19 occurred primarily in elderly patients. The mortality rate and the case fatality ratio (CFR) increased with age. The median age and the prevalence of risk factors were similar between CD and NCD. Respiratory symptoms and pneumonia at the time of diagnosis were associated with death reported as CD. The odds of CD attribution in cases hospitalized because of COVID-19 were 6-fold higher than the odds of NCD (OR: 6.00; 95% CI: 1.32 to 27.22).
Respiratory symptoms/pneumonia at the time of diagnosis and hospitalization due to COVID-19 were associated with attributing a death to COVID-19. Numbers of COVID deaths need to be interpreted with caution. Criteria that facilitate attributing the cause of death among SARS-CoV-2 cases more uniformly could make these figures more comparable.
Objectives The aim of this study was to examine whether biomarkers can identify silent cardiac target organ damage (cTOD) in a primary prevention population. Background One possible way to improve ...primary prevention of cardiovascular events is to identify those patients who already harbor silent cTOD (i.e., myocardial ischemia, left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, or left atrial enlargement). This might be possible by screening with a biomarker (e.g. high sensitivity cardiac troponin T hs-cTnT or B-type natriuretic peptide BNP). Methods We prospectively recruited 300 asymptomatic individuals already receiving primary prevention therapy. Transthoracic echocardiography, stress echocardiography, and/or myocardial perfusion imaging were performed to identify silent cTOD. Results One hundred two (34%) patients had evidence of cTOD. Left ventricular hypertrophy was the most prevalent (29.7%) form of cTOD, followed by diastolic dysfunction (21.3%), left atrial enlargement (15.3%), systolic dysfunction (6.3%), and ischemia (6.3%). The area under the curve (AUC) for BNP to identify any form of silent cTOD was 0.78 overall and 0.82 in men. The equivalent figures for hs-cTnT were 0.70 and 0.75 in women. The AUC for BNP and hs-cTnT together was 0.81 and 0.82 in men. However, the discrimination power of other markers was poor, with AUCs of 0.61 for microalbuminuria, 0.49 for uric acid, and 0.58 for eGFR. Conclusions In asymptomatic treated primary prevention patients, BNP screening is able to identify existing silent cTOD. The performance of hs-cTnT was not as good as that of BNP. B-type natriuretic peptide plus hs-cTnT together performed best. Prescreening with BNP ± cTnT followed by targeted phenotyping is worth exploring further as a possible way to improve primary prevention.
Although CAD/CAM ceramics present a promising alternative to metal-ceramic fixed dental prostheses, little is known about their mid- and long-term clinical performance. This systematic review aims to ...estimate the survival and success rates and describes the underlying complication characteristics for CAD/CAM tooth-supported zirconia- and lithium disilicate-based fixed dental prostheses (FDPs). We systematically searched MEDLINE and Web of Science to find relevant prospective studies with a follow-up of at least one year. We estimated pooled 1-, 5-, and 10-year survival and success rates by combining the collected data in a Poisson regression model. Descriptive statistics were conducted to evaluate the distribution of failures and complications in the included studies. Risk of bias for the included studies was assessed with an adapted checklist for single-arm trials. Pooled estimated 1-, 5-, and 10-year survival rates ranged from 93.80% to 94.66%, 89.67% to 91.1%, and 79.33% to 82.20%, respectively. The corresponding success rates excluding failures, but including any other types of intervention were 94.53% to 96.77%, 90.89% to 94.62%, and 81.78% to 89.25%. Secondary caries was the most frequent cause of failure, followed by chipping of the veneering. The most common cause of complication excluding failures but requiring intervention was chipping of the veneering. Risk of bias was generally acceptable for the included studies, with seven studies associated with low risk of bias, eight studies with a moderate risk of bias, and three studies with serious risk of bias. The current meta-analysis on CAD/CAM-supported FDPs revealed satisfying survival and success rates for up to 10 years of exposure. More prospective studies focusing on long-term performance are needed to strengthen the evidence currently available in the literature.
The metal-insulator transition (MIT) is one of the most dramatic manifestations of electron correlations in materials. Various mechanisms producing MITs have been extensively considered, including ...the Mott (electron localization via Coulomb repulsion), Anderson (localization via disorder), and Peierls (localization via distortion of a periodic one-dimensional lattice) mechanisms. One additional route to a MIT proposed by Slater, in which long-range magnetic order in a three dimensional system drives the MIT, has received relatively little attention. Using neutron and x-ray scattering we show that the MIT in NaOsO(3) is coincident with the onset of long-range commensurate three dimensional magnetic order. While candidate materials have been suggested, our experimental methodology allows the first definitive demonstration of the long predicted Slater MIT.
Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs ...predicted by an in silico screen as having the potential to treat l-DOPA-induced dyskinesia (LID) in Parkinson's disease.
We analysed ∼1.3 million Medline abstracts using natural language processing and ranked 3539 existing drugs based on predicted ability to reduce LID. 3 drugs from the top 5% of the 3539 candidates; lorcaserin, acamprosate and ganaxolone, were prioritized for preclinical testing based on i) having a novel mechanism of action, ii) having not been previously validated for the treatment of LID, iii) being blood-brain-barrier penetrant and orally bioavailable and iv) being clinical trial ready.
We assessed the efficacy of acamprosate, ganaxolone and lorcaserin in a rodent model of l-DOPA-induced hyperactivity, with lorcaserin affording a 58% reduction in rotational asymmetry (P < 0.05) compared to vehicle. Acamprosate and ganaxolone failed to demonstrate efficacy. Lorcaserin, a 5HT2C agonist, was then further tested in MPTP lesioned dyskinetic macaques where it afforded an 82% reduction in LID (P < 0.05), unfortunately accompanied by a significant increase in parkinsonian disability.
In conclusion, although our data do not support the repurposing of lorcaserin, acamprosate or ganaxolone per se for LID, we demonstrate value of an in silico approach to identify candidate molecules which, in combination with an in vivo screen, can facilitate clinical development decisions. The present study adds to a growing literature in support of this paradigm shifting approach in the repurposing pipeline.
•Novel treatments are needed for l-DOPA-induced dyskinesia in Parkinson's disease.•Natural language processing of published abstracts to identify drugs to repurpose.•5HT2C agonism is a potential novel mechanism to reduce l-DOPA-induced dyskinesia.•Study supports use of in silico methods in identification of drugs to repurpose.
We report on the discovery of eight repeating fast radio burst (FRB) sources found using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope. These sources span a dispersion measure ...(DM) range of 103.5-1281 pc cm−3. They display varying degrees of activity: six sources were detected twice, another three times, and one 10 times. These eight repeating FRBs likely represent the bright and/or high-rate end of a distribution of infrequently repeating sources. For all sources, we determine sky coordinates with uncertainties of ∼10′. FRB 180916.J0158+65 has a burst-averaged DM = 349.2 0.3 pc cm−3 and a low DM excess over the modeled Galactic maximum (as low as ∼20 pc cm−3); this source also has a Faraday rotation measure (RM) of −114.6 0.6 rad m−2, which is much lower than the RM measured for FRB 121102. FRB 181030.J1054+73 has the lowest DM for a repeater, 103.5 0.3 pc cm−3, with a DM excess of ∼70 pc cm−3. Both sources are interesting targets for multi-wavelength follow-up due to their apparent proximity. The DM distribution of our repeater sample is statistically indistinguishable from that of the first 12 CHIME/FRB sources that have not yet repeated. We find, with 4 significance, that repeater bursts are generally wider than those of CHIME/FRB bursts that have not repeated, suggesting different emission mechanisms. Many of our repeater events show complex morphologies that are reminiscent of the first two discovered repeating FRBs. The repetitive behavior of these sources will enable interferometric localizations and subsequent host galaxy identifications.
We wished to determine the prevalence of, potential mechanistic associations of, and clinical outcomes related to anemia in patients with heart failure and a broad spectrum of left ventricular ...ejection fraction (LVEF).
In multivariable analyses, we examined the associations between hemoglobin and baseline characteristics, laboratory variables, and outcomes in 2653 patients randomized in the CHARM Program in the United States and Canada. Anemia was equally common in patients with preserved (27%) and reduced (25%) LVEF but was more common in black and older patients. Anemia was associated with ethnicity, diabetes, low body mass index, higher systolic and lower diastolic blood pressure, and recent heart failure hospitalization. More than 50% of anemic patients had a glomerular filtration rate <60 mL.min(-1).1.73 m(-2) compared with <30% of nonanemic patients. Despite an inverse relationship between hemoglobin and LVEF, anemia was associated with an increased risk of death and hospitalization, a relationship observed in patients with both reduced and preserved LVEF. There were 133 versus 69 deaths and 527 versus 352 hospitalizations per 1000 patient-years of follow-up in anemic versus nonanemic patients (both P<0.001). The effect of candesartan in reducing outcomes was independent of hemoglobin.
Anemia was common in heart failure, regardless of LVEF. Lower hemoglobin was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In heart failure, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex.
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