Neuropathic pain (NeP), redefined as pain caused by a lesion or a disease of the somatosensory system, is a disabling condition that affects approximately two million Canadians.
To review the ...randomized controlled trials (RCTs) and systematic reviews related to the pharmacological management of NeP to develop a revised evidence-based consensus statement on its management.
RCTs, systematic reviews and existing guidelines on the pharmacological management of NeP were evaluated at a consensus meeting in May 2012 and updated until September 2013. Medications were recommended in the consensus statement if their analgesic efficacy was supported by at least one methodologically sound RCT (class I or class II) showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment were based on the degree of evidence of analgesic efficacy, safety and ease of use.
Analgesic agents recommended for first-line treatments are gabapentinoids (gabapentin and pregabalin), tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors. Tramadol and controlled-release opioid analgesics are recommended as second-line treatments for moderate to severe pain. Cannabinoids are now recommended as third-line treatments. Recommended fourth-line treatments include methadone, anticonvulsants with lesser evidence of efficacy (eg, lamotrigine, lacosamide), tapentadol and botulinum toxin. There is support for some analgesic combinations in selected NeP conditions.
These guidelines provide an updated, stepwise approach to the pharmacological management of NeP. Treatment should be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Additional studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes and treatment of pediatric, geriatric and central NeP.
Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. We developed an immunodeficient mouse model to test the tumorigenic ...potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. We show that a minority population of CD44⁺ cancer cells, which typically comprise <10% of the cells in a HNSCC tumor, but not the CD44⁻ cancer cells, gave rise to new tumors in vivo. Immunohistochemistry revealed that the CD44⁺ cancer cells have a primitive cellular morphology and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44⁻ cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. The tumors that arose from purified CD44⁺ cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. Furthermore, the tumorigenic CD44⁺ cells differentially express the BMI1 gene, at both the RNA and protein levels. By immunohistochemical analysis, the CD44⁺ cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. Taken together, these data demonstrate that cells within the CD44⁺ population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis.
We present Atacama Large Millimeter/submillimeter Array and Multi-Unit Spectroscopic Explorer observations of the brightest cluster galaxy in Abell 2597, a nearby (z = 0.0821) cool core cluster of ...galaxies. The data map the kinematics of a three billion solar mass filamentary nebula that spans the innermost 30 kpc of the galaxy's core. Its warm ionized and cold molecular components are both cospatial and comoving, consistent with the hypothesis that the optical nebula traces the warm envelopes of many cold molecular clouds that drift in the velocity field of the hot X-ray atmosphere. The clouds are not in dynamical equilibrium, and instead show evidence for inflow toward the central supermassive black hole, outflow along the jets it launches, and uplift by the buoyant hot bubbles those jets inflate. The entire scenario is therefore consistent with a galaxy-spanning "fountain," wherein cold gas clouds drain into the black hole accretion reservoir, powering jets and bubbles that uplift a cooling plume of low-entropy multiphase gas, which may stimulate additional cooling and accretion as part of a self-regulating feedback loop. All velocities are below the escape speed from the galaxy, and so these clouds should rain back toward the galaxy center from which they came, keeping the fountain long lived. The data are consistent with major predictions of chaotic cold accretion, precipitation, and stimulated feedback models, and may trace processes fundamental to galaxy evolution at effectively all mass scales.
Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show ...mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.
Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.
FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).
FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
ABSTRACT We present results from a very deep (650 ks) Chandra X-ray observation of the galaxy group NGC 5813, the deepest Chandra observation of a galaxy group to date. This system uniquely shows ...three pairs of collinear cavities, with each pair associated with an unambiguous active galactic nucleus (AGN) outburst shock front. The implied mean kinetic power is roughly the same for each outburst, demonstrating that the average AGN kinetic luminosity can remain stable over long timescales (∼50 Myr). The two older outbursts have larger, roughly equal total energies as compared with the youngest outburst, implying that the youngest outburst is ongoing. We find that the gas radiative cooling rate and mean shock heating rate are well balanced at each shock front, suggesting that shock heating alone is sufficient to offset cooling and establish AGN/intracluster medium (ICM) feedback within at least the central 30 kpc. This heating takes place roughly isotropically and most strongly at small radii, as is required for feedback to operate. We suggest that shock heating may play a significant role in AGN feedback at smaller radii in other systems, where weak shocks are more difficult to detect. We find non-zero shock front widths that are too large to be explained by particle diffusion. Instead, all measured widths are consistent with shock broadening due to propagation through a turbulent ICM with a mean turbulent speed of ∼70 km s−1. Finally, we place lower limits on the temperature of any volume-filling thermal gas within the cavities that would balance the internal cavity pressure with the external ICM.
We present a catalogue of ~3000 submillimetre sources detected ( greater than or equal to 3.5...) at 850 ...m over ~5 deg super( 2) surveyed as part of the James Clerk Maxwell Telescope (JCMT) ...SCUBA-2 Cosmology Legacy Survey (S2CLS). This is the largest survey of its kind at 850 ...m, increasing the sample size of 850 ...m selected submillimetre galaxies by an order of magnitude. The wide 850 ...m survey component of S2CLS covers the extragalactic fields: UKIDSS-UDS, COSMOS, Akari-NEP, Extended Groth Strip, Lockman Hole North, SSA22 and GOODS-North. The average 1... depth of S2CLS is 1.2 mJy beam super( -1), approaching the SCUBA-2 850 ...m confusion limit, which we determine to be ... 0.8 mJy beam super( -1). We measure the 850 ...m number counts, reducing the Poisson errors on the differential counts to approximately 4 per cent at S sub( 850) ... 3 mJy. With several independent fields, we investigate field-to-field variance, finding that the number counts on 0.5...-1... scales are generally within 50 per cent of the S2CLS mean for S sub( 850) > 3 mJy, with scatter consistent with the Poisson and estimated cosmic variance uncertainties, although there is a marginal (2...) density enhancement in GOODS-North. The observed counts are in reasonable agreement with recent phenomenological and semi-analytic models, although determining the shape of the faint-end slope (S sub( 850) < 3 mJy) remains a key test. The large solid angle of S2CLS allows us to measure the bright-end counts: at S sub( 850) > 10 mJy there are approximately 10 sources per square degree, and we detect the distinctive up-turn in the number counts indicative of the detection of local sources of 850 ...m emission, and strongly lensed high-redshift galaxies. All calibrated maps and the catalogue are made publicly available. (ProQuest: ... denotes formulae/symbols omitted.)
Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were ...quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.
Exciton-polaritons in semiconductor microcavities form a highly nonlinear platform to study a variety of effects interfacing optical, condensed matter, quantum and statistical physics. We show that ...the complex polariton patterns generated by picosecond pulses in microcavity wire waveguides can be understood as the Cherenkov radiation emitted by bright polariton solitons, which is enabled by the unique microcavity polariton dispersion, which has momentum intervals with positive and negative group velocities. Unlike in optical fibres and semiconductor waveguides, we observe that the microcavity wire Cherenkov radiation is predominantly emitted with negative group velocity and therefore propagates backwards relative to the propagation direction of the emitting soliton. We have developed a theory of the microcavity wire polariton solitons and of their Cherenkov radiation and conducted a series of experiments, where we have measured polariton-soliton pulse compression, pulse breaking and emission of the backward Cherenkov radiation.
Several recent studies have emphasised the need for a more integrated process in which researchers, policy makers and practitioners interact to identify research priorities. This paper discusses such ...a process with respect to the UK water sector, detailing how questions were developed through inter-disciplinary collaboration using online questionnaires and a stakeholder workshop. The paper details the 94 key questions arising, and provides commentary on their scale and scope. Prioritisation voting divided the nine research themes into three categories: (1) extreme events (primarily flooding), valuing freshwater services, and water supply, treatment and distribution each >
150/1109 votes; (2) freshwater pollution and integrated catchment management 100–150 votes and; (3) freshwater biodiversity, water industry governance, understanding and managing demand and communicating water research 50–100 votes. The biggest demand was for research to improve understanding of intervention impacts in the water environment, while a need for improved understanding of basic processes was also clearly expressed, particularly with respect to impacts of pollution and aquatic ecosystems. Questions that addressed aspects of appraisal, particularly incorporation of ecological service values into decision making, were also strongly represented. The findings revealed that sustainability has entered the lexicon of the UK water sector, but much remains to be done to embed the concept operationally, with key sustainability issues such as resilience and interaction with related key sectors, such as energy and agriculture, relatively poorly addressed. However, the exercise also revealed that a necessary condition for sustainable development, effective communication between scientists, practitioners and policy makers, already appears to be relatively well established in the UK water sector.
We report the discovery of three very late T dwarfs in the UKIRT Infrared Deep Sky Survey (UKIDSS) Third Data Release: ULAS J101721.40+011817.9 (ULAS1017), ULAS J123828.51+095351.3 (ULAS1238) and ...ULAS J133553.45+113005.2 (ULAS1335). We detail optical and near-infrared (NIR) photometry for all three sources, and mid-IR photometry for ULAS1335. We use NIR spectra of each source to assign spectral types T8p (ULAS1017), T8.5 (ULAS1238) and T9 (ULAS1335) to these objects. ULAS1017 is classed as a peculiar T8 (T8p) due to appearing as a T8 dwarf in the J band, whilst exhibiting H- and K-band flux ratios consistent with a T6 classification. Through comparison to BT-Settl model spectra we estimate that ULAS1017 has 750 K ≲Teff≲ 850 K, and 5.0 ≲ log g(cm s−2) ≲ 5.5, assuming solar metallicity. This estimate for gravity is degenerate with varying metallicity. We estimate that ULAS1017 has an age of 1.6–15 Gyr, a mass of 33–70MJ and lies at a distance of 31–54 pc. We do not estimate atmospheric parameters for ULAS1238 due to a lack of K-band photometry. We extend the unified scheme of Burgasser et al. to the type T9 and suggest the inclusion of the WJ index to replace the now saturated J-band indices. We propose ULAS1335 as the T9 spectral type standard. ULAS1335 is the same spectral type as ULAS J003402.77−005206.7 and CFBDS J005910.90−011401.3. We argue that given the similarity of the currently known >T8 dwarfs to the rest of the T dwarf sequence, the suggestion of the Y0 spectral class for these objects is premature. Comparison of model spectra with that of ULAS1335 suggest a temperature below 600 K, possibly combined with low gravity and/or high metallicity. We find ULAS1335 to be extremely red in NIR to mid-IR colours, with H−4.49= 4.34 ± 0.04. This is the reddest NIR to mid-IR colour yet observed for a T dwarf. The NIR to mid-IR spectral energy distribution of ULAS1335 further supports Teff < 600 K, and we estimate Teff∼ 550–600 K for ULAS1335. We estimate that ULAS1335 has an age of 0.6–5.3 Gyr, a mass of 15–31MJ and lies at a distance of 8–12 pc.
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