Abstract The Proceedings of a Canadian Working Group Consensus Conference, first published in 2011, provided a summary of statin-associated adverse effects and intolerance and management suggestions. ...In this update, new clinical studies identified since then that provide further insight into effects on muscle, cognition, cataracts, diabetes, kidney disease, and cancer are discussed. Of these, the arenas of greatest controversy pertain to purported effects on cognition and the emergence of diabetes during long-term therapy. Regarding cognition, the available evidence is not strongly supportive of a major adverse effect of statins. In contrast, the linkage between statin therapy and incident diabetes is more firm. However, this risk is more strongly associated with traditional risk factors for new-onset diabetes than with statin itself and any possible negative effect of new-onset diabetes during statin treatment is far outweighed by the cardiovascular risk reduction benefits. Additional studies are also discussed, which support the principle that systematic statin rechallenge, and lower or intermittent statin dosing strategies are the main methods for dealing with suspected statin intolerance at this time.
Thermal radiative emission from a hot surface to a cold surface plays an important role in many applications, including energy conversion, thermal management, lithography, data storage and thermal ...microscopy. Recent studies on bulk materials have confirmed long-standing theoretical predictions indicating that when the gap between the surfaces is reduced to tens of nanometres, well below the peak wavelength of the blackbody emission spectrum, the radiative heat flux increases by orders of magnitude. However, despite recent attempts, whether such enhancements can be obtained in nanoscale dielectric films thinner than the penetration depth of thermal radiation, as suggested by theory, remains experimentally unknown. Here, using an experimental platform that comprises a heat-flow calorimeter with a resolution of about 100 pW (ref. 7), we experimentally demonstrate a dramatic increase in near-field radiative heat transfer, comparable to that obtained between bulk materials, even for very thin dielectric films (50-100 nm) when the spatial separation between the hot and cold surfaces is comparable to the film thickness. We explain these results by analysing the spectral characteristics and mode shapes of surface phonon polaritons, which dominate near-field radiative heat transport in polar dielectric thin films.
Planck 2018 results Akrami, Y.; Ashdown, M.; Aumont, J. ...
Astronomy and astrophysics (Berlin),
09/2020, Letnik:
641
Journal Article
Recenzirano
Odprti dostop
Analysis of the
Planck
2018 data set indicates that the statistical properties of the cosmic microwave background (CMB) temperature anisotropies are in excellent agreement with previous studies using ...the 2013 and 2015 data releases. In particular, they are consistent with the Gaussian predictions of the ΛCDM cosmological model, yet also confirm the presence of several so-called “anomalies” on large angular scales. The novelty of the current study, however, lies in being a first attempt at a comprehensive analysis of the statistics of the polarization signal over all angular scales, using either maps of the Stokes parameters,
Q
and
U
, or the
E
-mode signal derived from these using a new methodology (which we describe in an appendix). Although remarkable progress has been made in reducing the systematic effects that contaminated the 2015 polarization maps on large angular scales, it is still the case that residual systematics (and our ability to simulate them) can limit some tests of non-Gaussianity and isotropy. However, a detailed set of null tests applied to the maps indicates that these issues do not dominate the analysis on intermediate and large angular scales (i.e.,
ℓ
≲ 400). In this regime, no unambiguous detections of cosmological non-Gaussianity, or of anomalies corresponding to those seen in temperature, are claimed. Notably, the stacking of CMB polarization signals centred on the positions of temperature hot and cold spots exhibits excellent agreement with the ΛCDM cosmological model, and also gives a clear indication of how
Planck
provides state-of-the-art measurements of CMB temperature and polarization on degree scales.
Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer ...profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer.
Adjuvant radiation therapy, which has proven benefit against breast cancer, has historically been associated with an increased incidence of ischemic heart disease. Modern techniques have reduced this ...risk, but a detailed evaluation has not recently been conducted. The present study evaluated the effect of current radiation practices on ischemia-related cardiac events and procedures in a population-based study of older women with nonmetastatic breast cancer.
A total of 29,102 patients diagnosed from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Medicare claims were used to identify the radiation therapy and cardiac outcomes. Competing risk models were used to assess the effect of radiation on these outcomes.
Patients with left-sided breast cancer had a small increase in their risk of percutaneous coronary intervention (PCI) after radiation therapy-the 10-year cumulative incidence for these patients was 5.5% (95% confidence interval CI 4.9%-6.2%) and 4.5% (95% CI 4.0%-5.0%) for right-sided patients. This risk was limited to women with previous cardiac disease. For patients who underwent PCI, those with left-sided breast cancer had a significantly increased risk of cardiac mortality with a subdistribution hazard ratio of 2.02 (95% CI 1.23-3.34). No other outcome, including cardiac mortality for the entire cohort, showed a significant relationship with tumor laterality.
For women with a history of cardiac disease, those with left-sided breast cancer who underwent radiation therapy had increased rates of PCI and a survival decrement if treated with PCI. The results of the present study could help cardiologists and radiation oncologists better stratify patients who need more aggressive cardioprotective techniques.
A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer.
Seventy-six women with International Federation of ...Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV.
The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval CI: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed.
This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.
Planck 2018 results Akrami, Y.; Ashdown, M.; Aumont, J. ...
Astronomy and astrophysics (Berlin),
09/2020, Letnik:
641
Journal Article
Recenzirano
Odprti dostop
We present full-sky maps of the cosmic microwave background (CMB) and polarized synchrotron and thermal dust emission, derived from the third set of
Planck
frequency maps. These products have ...significantly lower contamination from instrumental systematic effects than previous versions. The methodologies used to derive these maps follow closely those described in earlier papers, adopting four methods (
Commander
,
NILC
,
SEVEM
, and
SMICA
) to extract the CMB component, as well as three methods (
Commander
,
GNILC
, and
SMICA
) to extract astrophysical components. Our revised CMB temperature maps agree with corresponding products in the
Planck
2015 delivery, whereas the polarization maps exhibit significantly lower large-scale power, reflecting the improved data processing described in companion papers; however, the noise properties of the resulting data products are complicated, and the best available end-to-end simulations exhibit relative biases with respect to the data at the few percent level. Using these maps, we are for the first time able to fit the spectral index of thermal dust independently over 3° regions. We derive a conservative estimate of the mean spectral index of polarized thermal dust emission of
β
d
= 1.55 ± 0.05, where the uncertainty marginalizes both over all known systematic uncertainties and different estimation techniques. For polarized synchrotron emission, we find a mean spectral index of
β
s
= −3.1 ± 0.1, consistent with previously reported measurements. We note that the current data processing does not allow for construction of unbiased single-bolometer maps, and this limits our ability to extract CO emission and correlated components. The foreground results for intensity derived in this paper therefore do not supersede corresponding
Planck
2015 products. For polarization the new results supersede the corresponding 2015 products in all respects.
Abstract
BACKGROUND:
Blister aneurysms of the internal carotid artery (ICA) are uncommon. There is a paucity of data on the long-term outcomes of patients.
OBJECTIVE:
To review our experience with ...the treatment of these lesions.
METHODS:
We retrospectively reviewed all aneurysms treated at our institution between 1994 and 2005. Relevant operative notes, radiology reports, and inpatient/outpatient records were reviewed.
RESULTS:
Seventeen patients (3 male, 14 female) with 18 blister aneurysms of the ICA were identified. The mean age was 44.6 years (range, 17–72; median, 42 years). Twelve patients (70.6%) presented with aneurysmal subarachnoid hemorrhage. The mean admission Glasgow Outcome Scale score was 4.3 (range, 2–5; median, 5). All patients were initially treated using microsurgical technique with direct clipping (n = 15; 83.3%) or clip-wrapping with Gore-Tex (n = 3, 16.7%). There were 4 cases of intraoperative rupture, all associated with attempted direct clipping; all 4 cases were successfully clipped. Two cases rebled post-treatment. Both rebleeding episodes were managed with endovascular stenting. Follow-up angiography was available for 14 patients and revealed a new aneurysm adjacent to the site of clipping in 1 patient and in-stent stenosis in 2. At the mean follow-up of 74.5 months (median, 73; range, 7–165), the mean Glasgow Outcome Scale score was 4.6 (range, 2–5; median, 5).
CONCLUSION:
Microsurgical treatment of blister aneurysms of the ICA results in excellent outcome. In the evolution of treating these friable aneurysms, we have modified our clip-wrapping technique and use this technique when direct clipping is not feasible.
Neutrophil extracellular traps (NETs) are critical for anti-bacterial activity of the innate immune system. We have previously shown that mitochondrial damage-associated molecular patterns (mtDAMPs), ...including mitochondrial DNA (mtDNA), are released into the circulation after injury. We therefore questioned whether mtDNA is involved in trauma-induced NET formation. Treatment of human polymorphoneutrophils (PMN) with mtDNA induced robust NET formation, though in contrast to phorbol myristate acetate (PMA) stimulation, no NADPH-oxidase involvement was required. Moreover, formation of mtDNA-induced NETs was completely blocked by TLR9 antagonist, ODN-TTAGGG. Knowing that infective outcomes of trauma in elderly people are more severe than in young people, we measured plasma mtDNA and NET formation in elderly and young trauma patients and control subjects. MtDNA levels were significantly higher in the plasma of elderly trauma patients than young patients, despite lower injury severity scores in the elderly group. NETs were not visible in circulating PMN isolated from either young or old control subjects. NETs were however, detected in PMN isolated from young trauma patients and to a lesser extent from elderly patients. Stimulation by PMA induced widespread NET formation in PMN from both young volunteers and young trauma patients. NET response to PMA was much less pronounced in both elderly volunteers' PMN and in trauma patients' PMN. We conclude that mtDNA is a potent inducer of NETs that activates PMN via TLR9 without NADPH-oxidase involvement. We suggest that decreased NET formation in the elderly regardless of higher mtDNA levels in their plasma may result from decreased levels of TLR9 and/or other molecules, such as neutrophil elastase and myeloperoxidase that are involved in NET generation. Further study of the links between circulating mtDNA and NET formation may elucidate the mechanisms of trauma-related organ failure as well as the greater susceptibility to secondary infection in elderly trauma patients.
Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in ...radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
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