The categorization of intraductal proliferative lesions of the breast based on routine light microscopic examination of histopathologic sections is in many cases challenging, even for experienced ...pathologists. The development of computational tools to aid pathologists in the characterization of these lesions would have great diagnostic and clinical value. As a first step to address this issue, we evaluated the ability of computational image analysis to accurately classify DCIS and UDH and to stratify nuclear grade within DCIS. Using 116 breast biopsies diagnosed as DCIS or UDH from the Massachusetts General Hospital (MGH), we developed a computational method to extract 392 features corresponding to the mean and standard deviation in nuclear size and shape, intensity, and texture across 8 color channels. We used L1-regularized logistic regression to build classification models to discriminate DCIS from UDH. The top-performing model contained 22 active features and achieved an AUC of 0.95 in cross-validation on the MGH data-set. We applied this model to an external validation set of 51 breast biopsies diagnosed as DCIS or UDH from the Beth Israel Deaconess Medical Center, and the model achieved an AUC of 0.86. The top-performing model contained active features from all color-spaces and from the three classes of features (morphology, intensity, and texture), suggesting the value of each for prediction. We built models to stratify grade within DCIS and obtained strong performance for stratifying low nuclear grade vs. high nuclear grade DCIS (AUC = 0.98 in cross-validation) with only moderate performance for discriminating low nuclear grade vs. intermediate nuclear grade and intermediate nuclear grade vs. high nuclear grade DCIS (AUC = 0.83 and 0.69, respectively). These data show that computational pathology models can robustly discriminate benign from malignant intraductal proliferative lesions of the breast and may aid pathologists in the diagnosis and classification of these lesions.
This phase III randomized study compared concurrent cisplatin–radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 ...patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m2 weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval CI = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio HR = 0.71 95% CI = 0.5 to 1.0). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 95% CI = 0.59 to 1.4), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 95% CI = 0.3 to 0.88), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.
Virtually all liquids can be maintained for some time in a supercooled state, that is, at temperatures below their equilibrium melting temperatures, before eventually crystallizing. If cooled ...sufficiently quickly, some of these liquids will solidify into an amorphous solid, upon passing their glass transition temperature. Studies of these supercooled liquids reveal a considerable diversity in behaviour in their dynamical properties, particularly the viscosity. Angell characterized this in terms of their kinetic fragility. Previous synchrotron X-ray scattering studies have shown an increasing degree of short- and medium-range order that develops with increased supercooling. Here we demonstrate from a study of several metallic glass-forming liquids that the rate of this structural ordering as a function of temperature correlates with the kinetic fragility of the liquid, demonstrating a structural basis for fragility.
This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of ...nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (
= 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (
< 0.0001). The mean NTZ MIC for
isolates was 12.3 μg/ml; the mean NTZ maximum concentration (
) in plasma was 10.2 μg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against
Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).
Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from ...severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone. We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentration-dependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method. SD282 (10(-7) M), with dexamethasone (10( -6) M), caused a greater inhibition of release of IL-1beta, IL-6, macrophage inflammatory protein-1alpha and IL-10, than with dexamethasone alone in AMs from severe and non-severe asthma. At 10(-9) and 10(-10) M, GW-A, that had no direct effects, increased the inhibitory activity of dexamethasone (10(-8) and 10( -6) M) on LPS-induced IL-8 release in PBMCs from severe asthma. Corticosteroid insensitivity in severe asthma patients may be improved by inhibitors of p38 MAPK.
Background: Cancer patients who are hepatitis B virus (HBV) carriers and undergoing chemotherapy (CT) may be complicated by HBV reactivation. Over 80% of hepatocellular carcinoma (HCC) patients are ...HBV carriers; however, the incidence of HBV reactivation during CT has not been well-reported. A prospective study was conducted to determine the incidence of HBV reactivation, the associated morbidity and mortality, and possible risk factors. Patients and methods: 102 HBsAg-positive patients with inoperable HCC underwent systemic CT. Patients received either combination cisplatin, interferon, doxorubicin and fluorouracil (PIAF) or single-agent doxorubicin. They were followed up during and for 8 weeks after CT. Results: In 102 patients, 59 (58%) developed hepatitis amongst whom 37 (36%) were attributable to HBV reactivation. Twelve (30%) died of HBV reactivation. CT was interrupted in 32 patients (86%) with reactivation and 54 (83%) without reactivation (P>0.05). The median survivals were 6.00 and 5.62 months, respectively (P=0.694). Elevated baseline alanine aminotransferase (ALT) was found to be a risk factor. Conclusion: HBV reactivation is a common cause of liver damage during CT in HBsAg-positive HCC patients. The only identifiable associated risk factor was elevated pre-treatment ALT. Further studies into the role of antiviral and novel anticancer therapies are required to improve the prognosis of these patients.
The rearing period has a key influence on the later performance of cattle, affecting future fertility and longevity. Producers usually aim to breed replacement heifers by 15 months to calve at 24 ...months. An age at first calving (AFC) close to 2 years (23 to 25 months) is optimum for economic performance as it minimises the non-productive period and maintains a seasonal calving pattern. This is rarely achieved in either dairy or beef herds, with average AFC for dairy herds usually between 26 and 30 months. Maintaining a low AFC requires good heifer management with adequate growth to ensure an appropriate BW and frame size at calving. Puberty should occur at least 6 weeks before the target breeding age to enable animals to undergo oestrous cycles before mating. Cattle reach puberty at a fairly consistent, but breed-dependent, proportion of mature BW. Heifer fertility is a critical component of AFC. In US Holsteins the conception rate peaked at 57% at 15 to 16 months, declining in older heifers. Wide variations in growth rates on the same farm often lead to some animals having delayed first breeding and/or conception. Oestrous synchronisation regimes and sexed semen can both be used but unless heifers have been previously well-managed the success rates may be unacceptably low. Altering the nutritional input above or below those needed for maintenance at any stage from birth to first calving clearly alters the average daily gain (ADG) in weight. In general an ADG of around 0.75 kg/day seems optimal for dairy heifers, with lower rates delaying puberty and AFC. There is some scope to vary ADG at different ages providing animals reach an adequate size by calving. Major periods of nutritional deficiency and/or severe calfhood disease will, however, compromise development with long-term adverse consequences. Infectious disease can also cause pregnancy loss/abortion. First lactation milk yield may be slightly lower in younger calving cows but lifetime production is higher as such animals usually have good fertility and survive longer. There is now extensive evidence that as long as the AFC is >23 months then future performance is not adversely influenced. On the other hand, delayed first calving >30 months is associated with poor survival. Underfeeding of young heifers reduces their milk production potential and is a greater problem than overfeeding. Farmers are more likely to meet the optimum AFC target of 23 to 25 months if they monitor growth rates and adjust feed accordingly.
Heavy-ion data suggest that a common mechanism is responsible for single-event burnout (SEB) in 1200-V power MOSFETs and junction barrier Schottky (JBS) diodes. Similarly, heavy-ion data suggest a ...common mechanism is also responsible for leakage current degradation in both devices. This mechanism, based on ion-induced, highly localized energy pulses, is demonstrated in simulations and shown to be capable of causing degradation and SEB for both the MOSFETs and JBS diodes.
Mercury (Hg) levels in the environment have substantially increased over the past century leading to increased concentrations in many high trophic level predators, including Arctic seabirds. From the ...Canadian high Arctic, research on seabird eggs has documented some of the greatest concentrations of egg Hg anywhere in the Arctic. Farther east, in high Arctic Greenland, no similar data on Hg concentrations in eggs exist, making spatial comparisons unfeasible. To address this paucity of data, we collected whole eggs from Thick-billed Murre
Uria lomvia
(
n
= 11), Black-legged Kittiwake
Rissa tridactyla
(
n
= 9), and Common Eider
Somateria mollissima
(
n
= 12) in the high Arctic of northwest Greenland in the summer of 2014 and assessed their concentration of total Hg. Thick-billed Murre eggs had the highest mean total Hg concentrations (1.32 ± 0.42 mg g
−1
dw) followed by kittiwakes (0.64 ± 0.19) and eiders (0.23 ± 0.10). When compared with murre and kittiwake egg samples collected in high Arctic Canada during the same time period, total Hg concentrations from northwest Greenland were higher, but not significantly. Based on what is known about lethal Hg concentrations in murre eggs, these results indicate that some murre eggs may be at risk for increased embryonic mortality and further monitoring is suggested to determine long-term trends in egg Hg concentrations.
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