MeerKAT’s large number (64) of 13.5 m diameter antennas, spanning 8 km with a densely packed 1 km core, create a powerful instrument for wide-area surveys, with high sensitivity over a wide range of ...angular scales. The MeerKAT Galaxy Cluster Legacy Survey (MGCLS) is a programme of long-track MeerKAT L-band (900−1670 MHz) observations of 115 galaxy clusters, observed for ∼6−10 h each in full polarisation. The first legacy product data release (DR1), made available with this paper, includes the MeerKAT visibilities, basic image cubes at ∼8″ resolution, and enhanced spectral and polarisation image cubes at ∼8″ and 15″ resolutions. Typical sensitivities for the full-resolution MGCLS image products range from ∼3−5 μJy beam−1. The basic cubes are full-field and span 2° × 2°. The enhanced products consist of the inner 1.2° × 1.2° field of view, corrected for the primary beam. The survey is fully sensitive to structures up to ∼10′ scales, and the wide bandwidth allows spectral and Faraday rotation mapping. Relatively narrow frequency channels (209 kHz) are also used to provide H I mapping in windows of 0 < z < 0.09 and 0.19 < z < 0.48. In this paper, we provide an overview of the survey and the DR1 products, including caveats for usage. We present some initial results from the survey, both for their intrinsic scientific value and to highlight the capabilities for further exploration with these data. These include a primary-beam-corrected compact source catalogue of ∼626 000 sources for the full survey and an optical and infrared cross-matched catalogue for compact sources in the primary-beam-corrected areas of Abell 209 and Abell S295. We examine dust unbiased star-formation rates as a function of cluster-centric radius in Abell 209, extending out to 3.5 R 200. We find no dependence of the star-formation rate on distance from the cluster centre, and we observe a small excess of the radio-to-100 μm flux ratio towards the centre of Abell 209 that may reflect a ram pressure enhancement in the denser environment. We detect diffuse cluster radio emission in 62 of the surveyed systems and present a catalogue of the 99 diffuse cluster emission structures, of which 56 are new. These include mini-halos, halos, relics, and other diffuse structures for which no suitable characterisation currently exists. We highlight some of the radio galaxies that challenge current paradigms, such as trident-shaped structures, jets that remain well collimated far beyond their bending radius, and filamentary features linked to radio galaxies that likely illuminate magnetic flux tubes in the intracluster medium. We also present early results from the H I analysis of four clusters, which show a wide variety of H I mass distributions that reflect both sensitivity and intrinsic cluster effects, and the serendipitous discovery of a group in the foreground of Abell 3365.
Monoacylglycerol lipase (MAGL), a serine hydrolase extensively expressed throughout the brain, serves as a key gatekeeper regulating the tone of endocannabinoid signaling. Preclinically, inhibition ...of MAGL is known to provide therapeutic benefits for a number of neurological disorders. The availability of a MAGL-specific positron emission tomography (PET) ligand would considerably facilitate the development and clinical characterization of MAGL inhibitors via noninvasive and quantitative PET imaging. Herein, we report the identification of the potent and selective irreversible MAGL inhibitor 7 (PF-06809247) as a suitable radioligand lead, which upon radiolabeling was found to exhibit a high level of MAGL specificity; this enabled cross-species measurement of MAGL brain expression (B max), assessment of in vivo binding in the rat, and nonhuman primate PET imaging.
Position sensitivity enables the correction of response non-uniformities in room-temperature semiconductor detectors caused by crystal defects and other factors. It can also be used to pinpoint the ...exact location of crystal defects responsible for the response variations. This work describes a technique for revealing and visualizing the detector regions affecting the charge collection efficiency in CdZnTe (CZT), TlBr, and CsPbBr3 detectors configured as position-sensitive virtual Frisch-grid (VFG) devices. The technique correlates the photopeak events in energy spectra with their spatial distributions inside the detectors using the position information. By selecting the events from narrow energy intervals within a photopeak, we can visualize the detector volumes with particular charge collection efficiencies, which, in turn, correlate with the locations of electrode and crystal defects. We demonstrate this technique in several examples. Columnar structures in the volume plots (position distribution maps) are consistent with signal losses near or at the anode in selected samples of CZT and TlBr. Structures exhibiting a distinct depth dependence are consistent with grain boundaries or other crystal defects.
Sickle cell anemia is one of the commonest causes of stroke in children. It is usually, but not always, associated with intracranial vasculopathy. We have assessed the value of ultrasound screening ...for extracranial internal carotid artery disease.
Using Doppler ultrasound scanning, we assessed peak systolic blood velocity, tortuosity and stenosis in the extracranial internal carotid arteries of 236 children with sickle cell anemia. Seventeen of the children had previously had a stroke. All measurements were performed as part of routine clinical care.
The median extracranial internal carotid artery velocity was 148cm/s (5(th) centile 84, 95(th) centile 236). Higher velocities were significantly correlated with younger age, higher white blood cell counts and higher rates of hemolysis. Fourteen (5.9%) had tortuous extracranial internal carotid arteries and 13 (5.4%) had stenosis or occlusion. None of the children with tortuous vessels but 8 of those with stenosis had previously had a stroke; the presence of stenosis was strongly associated with overt clinical stroke (OR 35.9, 95% C.I. 9.77-132, P<0.001). In 6 children, extracranial stenosis was part of extensive intracranial vasculopathy, but in 2 there was no evidence of intracranial disease. Stenosis seemed to be more common in older children.
Extracranial internal carotid artery stenosis is strongly associated with stroke in children with sickle cell anemia, and may explain some cases of stroke without overt intracranial vasculopathy. Doppler ultrasound scanning of extracranial internal carotid arteries is non-invasive and fairly quick to perform and may identify children at increased risk of stroke who would otherwise be missed. The value of extracranial internal carotid artery scanning should be studied prospectively.
Background
Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous ...system. To develop
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CPF-06809247 into a clinically usable MAGL positron emission tomography (PET) radioligand, we assessed the occupancy of MAGL by an inhibitor in the non-human primate (NHP) brain. Additionally, we measured the whole-body distribution of
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CPF-06809247 in NHP and estimated human effective radiation doses.
Methods
Seven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements along with arterial blood sampling were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a pro-drug of a selective MAGL inhibitor (total of seven doses between 0.01 and 1.27 mg/kg). Kinetic parameters
K
1
,
k
2
and
k
3
were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function.
k
4
was set as 0 according to the irreversible binding of
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CPF-06809247.
K
i
by 2TC and Patlak analysis were calculated as the influx constant. The target occupancy was calculated using
K
i
at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model.
Results
Radioactivity retention was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4–100.5% in a dose dependent manner. Whole-body PET showed high radioactivity uptake values in the liver, small intestine, kidney, and brain. The effective dose of
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CPF-06809247 was calculated as 4.3 μSv/MBq.
Conclusions
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CPF-06809247 is a promising PET ligand for further studies of MAGL in the human brain.
Abstract We present the rationale, design features, and protocol of the Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) Family Study (ClinicalTrials.gov NCT02046005). The PRE-RA Family ...Study is an NIH-funded prospective, randomized controlled trial designed to compare the willingness to change behaviors in first-degree relatives of rheumatoid arthritis (RA) patients without RA after exposure to RA risk educational programs. Consented subjects are randomized to receive education concerning their personalized RA risk based on demographics, RA-associated behaviors, genetics, and biomarkers or to receive standard RA information. Four behavioral factors associated with RA risk were identified from prior studies for inclusion in the risk estimate: cigarette smoking, excess body weight, poor oral health, and low fish intake. Personalized RA risk information is presented through an online tool that collects data on an individual's specific age, gender, family history, and risk-related behaviors; presents genetic and biomarker results; displays relative and absolute risk of RA; and provides personalized feedback and education. The trial outcomes will be changes in willingness to alter behaviors from baseline to 6 weeks, 6 months, and 12 months in the three intervention groups. The design and the execution of this trial that targets a special population at risk for RA, while incorporating varied risk factors into a single risk tool, offer distinct challenges. We provide the theoretical rationale for the PRE-RA Family Study and highlight particular design features of this trial that utilize personalized risk education as an intervention.
BACKGROUND In mammals, oocyte activation at fertilization is thought to be induced by the sperm-specific phospholipase C zeta (PLCζ). However, it still remains to be conclusively shown that PLCζ is ...the endogenous agent of oocyte activation. Some types of human infertility appear to be caused by failure of the sperm to activate and this may be due to specific defects in PLCζ. METHODS AND RESULTS Immunofluorescence studies showed PLCζ to be localized in the equatorial region of sperm from fertile men, but sperm deficient in oocyte activation exhibited no specific signal in this same region. Immunoblot analysis revealed reduced amounts of PLCζ in sperm from infertile men, and in some cases, the presence of an abnormally low molecular weight form of PLCζ. In one non-globozoospermic case, DNA analysis identified a point mutation in the PLCζ gene that leads to a significant amino acid change in the catalytic region of the protein. Structural modelling suggested that this defect may have important effects upon the structure and function of the PLCζ protein. cRNA corresponding to mutant PLCζ failed to induce calcium oscillations when microinjected into mouse oocytes. Injection of infertile human sperm into mouse oocytes failed to activate the oocyte or trigger calcium oscillations. Injection of such infertile sperm followed by two calcium pulses, induced by assisted oocyte activation, activated the oocytes without inducing the typical pattern of calcium oscillations. CONCLUSIONS Our findings illustrate the importance of PLCζ during fertilization and suggest that mutant forms of PLCζ may underlie certain types of human male infertility.
Purpose
To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness.
Methods
We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We ...defined “early” EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds.
Results
We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion.
Conclusions
We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access.
Objective To assess the effectiveness of physiotherapy compared with no intervention in patients with Parkinson’s disease.Design Systematic review and meta-analysis of randomised controlled ...trials.Data sources Literature databases, trial registries, journals, abstract books, and conference proceedings, and reference lists, searched up to the end of January 2012.Review methods Randomised controlled trials comparing physiotherapy with no intervention in patients with Parkinson’s disease were eligible. Two authors independently abstracted data from each trial. Standard meta-analysis methods were used to assess the effectiveness of physiotherapy compared with no intervention. Tests for heterogeneity were used to assess for differences in treatment effect across different physiotherapy interventions used. Outcome measures were gait, functional mobility and balance, falls, clinician rated impairment and disability measures, patient rated quality of life, adverse events, compliance, and economic analysis outcomes.Results 39 trials of 1827 participants met the inclusion criteria, of which 29 trials provided data for the meta-analyses. Significant benefit from physiotherapy was reported for nine of 18 outcomes assessed. Outcomes which may be clinically significant were speed (0.04 m/s, 95% confidence interval 0.02 to 0.06, P<0.001), Berg balance scale (3.71 points, 2.30 to 5.11, P<0.001), and scores on the unified Parkinson’s disease rating scale (total score −6.15 points, −8.57 to −3.73, P<0.001; activities of daily living subscore −1.36, −2.41 to −0.30, P=0.01; motor subscore −5.01, −6.30 to −3.72, P<0.001). Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the interventions for any outcomes assessed, apart from motor subscores on the unified Parkinson’s disease rating scale (in which one trial was found to be the cause of the heterogeneity).Conclusions Physiotherapy has short term benefits in Parkinson’s disease. A wide range of physiotherapy techniques are currently used to treat Parkinson’s disease, with little difference in treatment effects. Large, well designed, randomised controlled trials with improved methodology and reporting are needed to assess the efficacy and cost effectiveness of physiotherapy for treating Parkinson’s disease in the longer term.
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