ABSTRACT The Murchison Widefield Array (MWA) has collected hundreds of hours of Epoch of Reionization (EoR) data and now faces the challenge of overcoming foreground and systematic contamination to ...reduce the data to a cosmological measurement. We introduce several novel analysis techniques, such as cable reflection calibration, hyper-resolution gridding kernels, diffuse foreground model subtraction, and quality control methods. Each change to the analysis pipeline is tested against a two-dimensional power spectrum figure of merit to demonstrate improvement. We incorporate the new techniques into a deep integration of 32 hours of MWA data. This data set is used to place a systematic-limited upper limit on the cosmological power spectrum of mK2 at k = 0.27 h Mpc−1 and z = 7.1, consistent with other published limits, and a modest improvement (factor of 1.4) over previous MWA results. From this deep analysis, we have identified a list of improvements to be made to our EoR data analysis strategies. These improvements will be implemented in the future and detailed in upcoming publications.
Summary
Background
Anti‐tumour necrosis factor‐α (TNFα) antibodies are efficacious in inflammatory bowel disease (IBD). These drugs carry the theoretical risk of malignancy, particularly lymphoma, ...but no systematic review and meta‐analysis has examined this issue.
Aim
To pool data from all available placebo‐controlled studies to estimate risk of malignancy with anti‐TNFα therapy in IBD.
Methods
MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to November 2013. Randomised controlled trials (RCTs) comparing anti‐TNFα therapy with placebo in adults with Crohn's disease (CD) or ulcerative colitis (UC) were eligible. Data were pooled to obtain a relative risk (RR) of malignancy with a 95% confidence interval (CI).
Results
The search strategy identified 25 338 citations, of which 22 RCTs were eligible (11 infliximab, six adalimumab, four certolizumab and one golimumab) involving 7054 patients (4566 CD and 2488 UC). In total, there were 16 (0.39%) malignancies in 4135 IBD patients allocated to anti‐TNFα, compared with 13 (0.45%) in 2919 patients randomised to placebo. There were no cases of lymphoma in the active treatment group, compared with three (0.1%) in the control group. The RR of malignancy for patients receiving anti‐TNFα therapy compared with placebo was 0.77 (95% CI 0.37–1.59). When seven individuals with nonmelanoma skin cancer were excluded from the analysis, the RR was 0.90 (95% CI 0.40–2.02).
Conclusions
Anti‐TNFα therapy was not associated with an increased risk of malignancy in patients with IBD. However, no trials provided data for risk of malignancy beyond 1 year of treatment, meaning that an increased risk in the longer term cannot be excluded.
Chronic non-cancer pain, a disabling and distressing condition, is common in adults. It is a global public health problem and economic burden on health and social care systems and on people with ...chronic pain. Psychological treatments aim to reduce pain, disability and distress. This review updates and extends its previous version, published in 2012.
To determine the clinical efficacy and safety of psychological interventions for chronic pain in adults (age > 18 years) compared with active controls, or waiting list/treatment as usual (TAU).
We identified randomised controlled trials (RCTs) of psychological therapies by searching CENTRAL, MEDLINE, Embase and PsycINFO to 16 April 2020. We also examined reference lists and trial registries, and searched for studies citing retrieved trials.
RCTs of psychological treatments compared with active control or TAU of face-to-face therapies for adults with chronic pain. We excluded studies of headache or malignant disease, and those with fewer than 20 participants in any arm at treatment end.
Two or more authors rated risk of bias, extracted data, and judged quality of evidence (GRADE). We compared cognitive behavioural therapy (CBT), behavioural therapy (BT), and acceptance and commitment therapy (ACT) with active control or TAU at treatment end, and at six month to 12 month follow-up. We did not analyse the few trials of other psychological treatments. We assessed treatment effectiveness for pain intensity, disability, and distress. We extracted data on adverse events (AEs) associated with treatment.
We added 41 studies (6255 participants) to 34 of the previous review's 42 studies, and now have 75 studies in total (9401 participants at treatment end). Most participants had fibromyalgia, chronic low back pain, rheumatoid arthritis, or mixed chronic pain. Most risk of bias domains were at high or unclear risk of bias, with selective reporting and treatment expectations mostly at unclear risk of bias. AEs were inadequately recorded and/or reported across studies. CBT The largest evidence base was for CBT (59 studies). CBT versus active control showed very small benefit at treatment end for pain (standardised mean difference (SMD) -0.09, 95% confidence interval (CI) -0.17 to -0.01; 3235 participants; 23 studies; moderate-quality evidence), disability (SMD -0.12, 95% CI -0.20 to -0.04; 2543 participants; 19 studies; moderate-quality evidence), and distress (SMD -0.09, 95% CI -0.18 to -0.00; 3297 participants; 24 studies; moderate-quality evidence). We found small benefits for CBT over TAU at treatment end for pain (SMD -0.22, 95% CI -0.33 to -0.10; 2572 participants; 29 studies; moderate-quality evidence), disability (SMD -0.32, 95% CI -0.45 to -0.19; 2524 participants; 28 studies; low-quality evidence), and distress (SMD -0.34, 95% CI -0.44 to -0.24; 2559 participants; 27 studies; moderate-quality evidence). Effects were largely maintained at follow-up for CBT versus TAU, but not for CBT versus active control. Evidence quality for CBT outcomes ranged from moderate to low. We rated evidence for AEs as very low quality for both comparisons. BT We analysed eight studies (647 participants). We found no evidence of difference between BT and active control at treatment end (pain SMD -0.67, 95% CI -2.54 to 1.20, very low-quality evidence; disability SMD -0.65, 95% CI -1.85 to 0.54, very low-quality evidence; or distress SMD -0.73, 95% CI -1.47 to 0.01, very low-quality evidence). At follow-up, effects were similar. We found no evidence of difference between BT and TAU (pain SMD -0.08, 95% CI -0.33 to 0.17, low-quality evidence; disability SMD -0.02, 95% CI -0.24 to 0.19, moderate-quality evidence; distress SMD 0.22, 95% CI -0.10 to 0.54, low-quality evidence) at treatment end. At follow-up, we found one to three studies with no evidence of difference between BT and TAU. We rated evidence for all BT versus active control outcomes as very low quality; for BT versus TAU. Evidence quality ranged from moderate to very low. We rated evidence for AEs as very low quality for BT versus active control. No studies of BT versus TAU reported AEs. ACT We analysed five studies (443 participants). There was no evidence of difference between ACT and active control for pain (SMD -0.54, 95% CI -1.20 to 0.11, very low-quality evidence), disability (SMD -1.51, 95% CI -3.05 to 0.03, very low-quality evidence) or distress (SMD -0.61, 95% CI -1.30 to 0.07, very low-quality evidence) at treatment end. At follow-up, there was no evidence of effect for pain or distress (both very low-quality evidence), but two studies showed a large benefit for reducing disability (SMD -2.56, 95% CI -4.22 to -0.89, very low-quality evidence). Two studies compared ACT to TAU at treatment end. Results should be interpreted with caution. We found large benefits of ACT for pain (SMD -0.83, 95% CI -1.57 to -0.09, very low-quality evidence), but none for disability (SMD -1.39, 95% CI -3.20 to 0.41, very low-quality evidence), or distress (SMD -1.16, 95% CI -2.51 to 0.20, very low-quality evidence). Lack of data precluded analysis at follow-up. We rated evidence quality for AEs to be very low. We encourage caution when interpreting very low-quality evidence because the estimates are uncertain and could be easily overturned.
We found sufficient evidence across a large evidence base (59 studies, over 5000 participants) that CBT has small or very small beneficial effects for reducing pain, disability, and distress in chronic pain, but we found insufficient evidence to assess AEs. Quality of evidence for CBT was mostly moderate, except for disability, which we rated as low quality. Further trials may provide more precise estimates of treatment effects, but to inform improvements, research should explore sources of variation in treatment effects. Evidence from trials of BT and ACT was of moderate to very low quality, so we are very uncertain about benefits or lack of benefits of these treatments for adults with chronic pain; other treatments were not analysed. These conclusions are similar to our 2012 review, apart from the separate analysis of ACT.
Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow ...failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.
ABSTRACT
We study the ionizing photon production efficiency at the end of the Epoch of Reionization (z ∼ 5.4 − 6.6) for a sample of 30 Ly α emitters. This is a crucial quantity to infer the ionizing ...photon budget of the universe. These objects were selected to have reliable spectroscopic redshifts, assigned based on the profile of their Ly α emission line, detected in the MUSE deep fields. We exploit medium-band observations from the JWST Extragalactic Medium-band Survey (JEMS) to find the flux excess corresponding to the redshifted Hα emission line. We estimate the ultraviolet (UV) luminosity by fitting the full JEMS photometry, along with several HST photometric points, with Prospector. We find a median UV continuum slope of $\beta = -2.09^{+0.23}_{-0.21}$, indicating young stellar populations with little-to-no dust attenuation. Supported by this, we derive ξion,0 with no dust attenuation and find a median value of log$\frac{\xi _{ion,0}}{\text{Hz erg}^{-1}} = 25.44^{+0.21}_{-0.15}$. If we perform dust attenuation corrections and assume a Calzetti attenuation law, our values are lowered by ∼0.1 dex. Our results suggest Ly α emitters at the Epoch of Reionization have slightly enhanced ξion,0 compared to previous estimations from literature, in particular, when compared to the non-Ly α emitting population. This initial study provides a promising outlook on the characterization of ionizing photon production in the early universe. In the future, a more extensive study will be performed on the entire data set provided by the JWST Advanced Deep Extragalactic Survey (JADES). Thus, for the first time, allowing us to place constraints on the wider galaxy populations driving reionization.
Before acquiring highest-resolution data of Ceres, questions remained about the emplacement mechanism and source of Occator crater’s bright faculae. Here we report that brine effusion emplaced the ...faculae in a brine-limited, impact-induced hydrothermal system. Impact-derived fracturing enabled brines to reach the surface. The central faculae, Cerealia and Pasola Facula, postdate the central pit, and were primarily sourced from an impact-induced melt chamber, with some contribution from a deeper, pre-existing brine reservoir. Vinalia Faculae, in the crater floor, were sourced from the laterally extensive deep reservoir only. Vinalia Faculae are comparatively thinner and display greater ballistic emplacement than the central faculae because the deep reservoir brines took a longer path to the surface and contained more gas than the shallower impact-induced melt chamber brines. Impact-derived fractures providing conduits, and mixing of impact-induced melt with deeper endogenic brines, could also allow oceanic material to reach the surfaces of other large icy bodies.
Culture and health Napier, A David, PhD; Ancarno, Clyde, PhD; Butler, Beverley, PhD ...
The Lancet (British edition),
11/2014, Letnik:
384, Številka:
9954
Journal Article
Recenzirano
Although culture can be considered as a set of subjective values that oppose scientific objectivity, we challenge this view in this Commission by claiming that all people have systems of value that ...are unexamined. Such systems are, at times, diffuse, and often taken for granted, but are always dynamic and changing. They produce novel and sometimes perplexing needs, to which established caregiving practices often adjust slowly.
The Apolipoprotein E (APOE) gene is a major genetic risk factor associated with Alzheimer's disease (AD). APOE encodes for three main isoforms in humans (E2, E3, and E4). Homozygous E4 individuals ...have more than a 10-fold higher risk for developing late-onset AD, while E2 carriers are protected. A hallmark of AD is a reduction in cerebral glucose metabolism, alluding to a strong metabolic component in disease onset and progression. Interestingly, E4 individuals display a similar regional pattern of cerebral glucose hypometabolism decades prior to disease onset. Mapping this metabolic landscape may help elucidate the underlying biological mechanism of APOE-associated risk for AD. Efficient metabolic coupling of neurons and glia is necessary for proper neuronal function, and disruption in glial energy distribution has been proposed to contribute to neuronal cell death and AD pathology. One important function of astrocytes – canonically the primary source of apolipoprotein E in the brain – is to provide metabolic substrates (lactate, lipids, amino acids and neurotransmitters) to neurons. Here we investigate the effects of APOE on astrocyte glucose metabolism in vitro utilizing scintillation proximity assays, stable isotope tracer metabolomics, and gene expression analyses. Glucose uptake is impaired in E4 astrocytes relative to E2 or E3 with specific alterations in central carbon metabolism. Using stable isotope labeled glucose U-13C allowed analyses of astrocyte-specific deep metabolic networks affected by APOE, and provided insight to the effects downstream of glucose uptake. Enrichment of 13C in early steps of glycolysis was lowest in E4 astrocytes (highest in E2), while synthesis of lactate from glucose was highest in E4 astrocytes (lowest in E2). We observed an increase in glucose flux through the pentose phosphate pathway (PPP), with downstream increases in gluconeogenesis, lipid, and de novo nucleotide biosynthesis in E4 astrocytes. There was also a marked increase in 13C enrichment in the TCA cycle of E4 astrocytes – whose substrates were also incorporated into biosynthetic pathways at a higher rate. Pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) are the two main enzymes controlling pyruvate entry to the TCA cycle. PC gene expression is increased in E4 astrocytes and the activity relative to PDH was also increased, compared to E2 or E3. Decreased enrichment in the TCA cycle of E2 and E3 astrocytes is suggestive of increased oxidation and non-glucose derived anaplerosis, which could be fueling mitochondrial ATP production. Conversely, E4 astrocytes appear to increase carbon flux into the TCA cycle to fuel cataplerosis. Together, these data demonstrate clear APOE isoform-specific effects on glucose utilization in astrocytes, including E4-associated increases in lactate synthesis, PPP flux, and de novo biosynthesis pathways.
Glucose utilization in astrocytes expressing either human E2 (green arrows) or E4 (red arrows) relative to E3. E2 astrocytes display increased flux through glycolysis, a more oxidative TCA cycle, and decreased pentose phosphate pathway (PPP) flux. E4 astrocytes display increased glucose flux through PPP, in both re-entry into glycolysis (gluconeogenesis), increased biosynthesis, and increased lactate synthesis, with a less oxidative TCA cycle. Display omitted
•Stable isotope tracing reveals APOE-specific changes in astrocyte glucose utilization•APOE alters glucose entry into the TCA cycle•E4 astrocytes increase glucose flux into PPP and de novo biosynthesis pathways
To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of ...nonresponders.
Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the
and
genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.
Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio HR 1.0, 95% confidence interval CI 0.7-1.4;
= 0.96). Both the
and
genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3;
= 0.006 and HR 2.5, 95% CI 1.1-5.2;
= 0.032, respectively). The effect of lithium was different for
carriers (
= 0.027), but not for
carriers (
= 0.22). The 12-month survival probability for
carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).
This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.
Abstract
Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within ...hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity.
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