We have evaluated the energetics of 38 solar eruptive events observed by a variety of spacecraft instruments between 2002 February and 2006 December, as accurately as the observations allow. The ...measured energetic components include: (1) the radiated energy in the Geostationary Operational Environmental Satellite 1-8 A band, (2) the total energy radiated from the soft X-ray (SXR) emitting plasma, (3) the peak energy in the SXR-emitting plasma, (4) the bolometric radiated energy over the full duration of the event, (5) the energy in flare-accelerated electrons above 20 keV and in flare-accelerated ions above 1 MeV, (6) the kinetic and potential energies of the coronal mass ejection (CME), (7) the energy in solar energetic particles (SEPs) observed in interplanetary space, and (8) the amount of free (non-potential) magnetic energy estimated to be available in the pertinent active region. Major conclusions include: (1) the energy radiated by the SXR-emitting plasma exceeds, by about half an order of magnitude, the peak energy content of the thermal plasma that produces this radiation; (2) the energy content in flare-accelerated electrons and ions is sufficient to supply the bolometric energy radiated across all wavelengths throughout the event; (3) the energy contents of flare-accelerated electrons and ions are comparable; (4) the energy in SEPs is typically a few percent of the CME kinetic energy (measured in the rest frame of the solar wind); and (5) the available magnetic energy is sufficient to power the CME, the flare-accelerated particles, and the hot thermal plasma.
Gastrointestinal (GI) disease is a major health concern in preweaned dairy calves. The objective of this fixed cohort study was to use RNA isolated from preweaned Holstein and Jersey heifer calf ...feces to study the molecular adaptations to variable clinical GI disease. The study was conducted on a commercial calf ranch in the western U.S. Enrolled calves were assessed twice daily for variations in demeanor, milk intake, and hydration. Fecal consistency scores were recorded at enrollment (day 1), and on the day (day 10) that a fecal sample was collected for differential gene expression (DGE). Calves with diarrhea on either day were classified as having either uncomplicated, localized GI disease (scours), or systemic GI disease (systemic enteritis). Eighty-four calves' fecal RNA was evaluated for DGE, of which 33 calves (n = 20 Holstein; n = 13 Jersey) were consistently healthy. The remaining 51 calves (n = 23 Holstein; n = 28 Jersey) experienced varying severity of GI disease during the sampling window. Genes of interest were related to the inflammatory response (i.e., IFNG, NFKB1, NOD2, TLR2, and TLR4) and cell membrane or cytoplasmic transport (i.e., AQP3, FABP2, KRT8 and SLC5A1). Breed-specific findings indicated that AQP3, IFNG, and TLR4 were upregulated in Holsteins with systemic enteritis, whereas KRT8 was downregulated in systemically affected Jerseys. Holsteins did not appear affected by scours aside from a tendency for DGE of toll-like receptors (TLRs) on the day of diarrhea. However, Jersey calves consistently demonstrated a tendency to upregulate IFNG, NFKB1, and TLR4 when affected with either scours or systemic enteritis. These findings were more pronounced in systemically affected Jersey calves and were observed as a delayed response to both scours and systemic enteritis. These findings support previous observations suggesting that Holstein calves may be better equipped than Jersey calves to rapidly fight pathogen invasion.
The combination of nontrivial band topology and symmetry-breaking phases gives rise to novel quantum states and phenomena such as topological superconductivity, quantum anomalous Hall effect, and ...axion electrodynamics. Evidence of intertwined charge density wave (CDW) and superconducting order parameters has recently been observed in a novel kagome material AV_{3}Sb_{5} (A=K, Rb, Cs) that features a Z_{2} topological invariant in the electronic structure. However, the origin of the CDW and its intricate interplay with the topological state has yet to be determined. Here, using hard-x-ray scattering, we demonstrate a three-dimensional CDW with 2×2×2 superstructure in (Rb,Cs)V_{3}Sb_{5}. Unexpectedly, we find that the CDW fails to induce acoustic phonon anomalies at the CDW wave vector but yields a novel Raman mode that quickly damps into a broad continuum below the CDW transition temperature. Our observations exclude strong electron-phonon-coupling-driven CDW in AV_{3}Sb_{5} and support an unconventional CDW that was proposed in the kagome lattice at van Hove filling.
Summary Background New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of ...neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Methods Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies ( r2 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2–8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5–9·4) for pregabalin; 7·2 (5·9–9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4–19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Interpretation Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. Funding NeuPSIG of the International Association for the Study of Pain.
In addition to a bulk energy gap, topological insulators accommodate a conducting, linearly dispersed Dirac surface state. This state is predicted to become massive if time reversal symmetry is ...broken, and to become insulating if the Fermi energy is positioned inside both the surface and bulk gaps. We introduced magnetic dopants into the three-dimensional topological insulator dibismuth triselenide (Bi₂Se₃) to break the time reversal symmetry and further position the Fermi energy inside the gaps by simultaneous magnetic and charge doping. The resulting insulating massive Dirac fermion state, which we observed by angle-resolved photoemission, paves the way for studying a range of topological phenomena relevant to both condensed matter and particle physics.
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription ...factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.
We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL.
Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.
Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).
To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task MET hours/week) are associated with lower cancer risk, describe the shape of the ...dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.
Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (
< .05) and 95% CIs (< 1.0).
A total of 755,459 participants (median age, 62 years range, 32-91 years; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.
Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
Abstract Background Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We ...examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab. Methods Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care BSC), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS). Results Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 0.79–1.44, p = 0.67) or OS (HR 0.96 0.70–1.31, p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 0.18–0.45, p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 0.42–1.27, p = 0.26), interaction p = 0.002. Conclusion In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.
This review is an update of a review published in 2011, itself a major update of previous reviews published in 2005 and 2000, investigating the effects of gabapentin in chronic neuropathic pain (pain ...due to nerve damage). Antiepileptic drugs are used to manage chronic neuropathic pain and fibromyalgia.
To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia.
We identified randomised trials of gabapentin for chronic neuropathic pain or fibromyalgia by searching the databases MEDLINE (1966 to March 2014), EMBASE (1980 to 2014 week 10), and CENTRAL in The Cochrane Library (Issue 3 of 12, 2014). We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched Clinicaltrials.gov. Searches were run originally in 2011 and the date of the most recent search was 17 March 2014.
Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain or fibromyalgia with assessment of pain intensity, pain relief, or both, using validated scales. Participants were adults.
Three review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.For efficacy, we calculated the number needed to treat to benefit (NNT), concentrating on at least 50% pain intensity reduction, and Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) definitions of at least moderate and substantial benefit. For harm we calculated number needed to treat for harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. We emphasised differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, complex regional painsyndrome type 1 (CRPS-1), and fibromyalgia.
Seven new studies with 1919 participants were added. Another report (147 participants) provided results for a study already included, but which previously had no usable data. A further report (170 participants) used an experimental formulation of intrathecal gabapentin. Thirty-seven studies (5633 participants) studied oral gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 84% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. There was no first tier evidence.Second tier evidence for the outcome of at least 50% pain intensity reduction, considered valuable by patients with chronic pain, showed that gabapentin was significantly better than placebo in postherpetic neuralgia (34% gabapentin versus 21% placebo; NNT 8.0, 95% CI 6.0 to 12) and painful diabetic neuropathy (38% versus 21%, NNT 5.9, 95% CI 4.6 to 8.3). There was insufficient information in other pain conditions to reach any reliable conclusion. There was no obvious difference between standard gabapentin formulations and recently-introduced extended-release or gastro-retentive formulations, or between different doses of gabapentin.Adverse events occurred significantly more often with gabapentin. Persons taking gabapentin could expect to have at least one adverse event (62%), withdraw because of an adverse event (11%), suffer dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (9%). Serious adverse events (3%) were no more common than with placebo.There were insufficient data for direct comparisons with other active treatments, and only third tier evidence for other painful conditions.
There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.The levels of efficacy found for gabapentin are consistent with those found for other drug therapies in postherpetic neuralgia and painful diabetic neuropathy.
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