To explore the prognostic value of the plasma load of Epstein-Barr viral (EBV) DNA and the tumor response to neoadjuvant chemotherapy (NACT) in advanced-stage nasopharyngeal carcinoma (NPC).
In all, ...185 consecutive patients with stage III to IVb NPC treated with NACT followed by concurrent chemoradiation therapy (CCRT) were prospectively enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS).
EBV DNA was detected in 165 (89%) patients before treatment but was undetectable in 127 (69%) patients after NACT. Detectable EBV DNA levels after NACT were correlated with poor prognosis (3-year PFS 71.8% vs 85.2%, P=.008 and 3-year DMFS 82.5% vs 92.3%, P=.013). An unsatisfactory tumor response (stable disease or disease progression) after NACT was also correlated with poor clinical outcome (3-year PFS 71.1% vs 85.9%, P=.005 and 3-year LRFS 82.7% vs 93.5%, P=.012). Multivariate analysis showed that the EBV DNA level after NACT (hazard ratio HR 2.31, 95% CI 1.18-4.54, P=.015) and the tumor response to NACT (HR 2.84, 95% CI 1.42-5.67, P=.003) were both significant prognostic factors for PFS. Multivariate analysis also showed that EBV DNA after NACT was the only significant predictor of DMFS (HR 2.99, 95% CI 1.25-7.15, P=.014) and that tumor response to NACT was the only significant predictor of LRFS (HR 3.31, 95% CI 1.21-9.07, P=.020).
Detectable EBV DNA levels and an unsatisfactory tumor response (stable disease or disease progression) after NACT serve as predictors of poor prognosis for patients with advanced-stage NPC. These findings will facilitate further risk stratification, early treatment modification, or both before CCRT.
Summary Background Lower extremity peripheral artery disease is the third leading cause of atherosclerotic cardiovascular morbidity, following coronary artery disease and stroke. This study provides ...the first comparison of the prevalence of peripheral artery disease between high-income countries (HIC) and low-income or middle-income countries (LMIC), establishes the primary risk factors for peripheral artery disease in these settings, and estimates the number of people living with peripheral artery disease regionally and globally. Methods We did a systematic review of the literature on the prevalence of peripheral artery disease in which we searched for community-based studies since 1997 that defined peripheral artery disease as an ankle brachial index (ABI) lower than or equal to 0·90. We used epidemiological modelling to define age-specific and sex-specific prevalence rates in HIC and in LMIC and combined them with UN population numbers for 2000 and 2010 to estimate the global prevalence of peripheral artery disease. Within a subset of studies, we did meta-analyses of odds ratios (ORs) associated with 15 putative risk factors for peripheral artery disease to estimate their effect size in HIC and LMIC. We then used the risk factors to predict peripheral artery disease numbers in eight WHO regions (three HIC and five LMIC). Findings 34 studies satisfied the inclusion criteria, 22 from HIC and 12 from LMIC, including 112 027 participants, of which 9347 had peripheral artery disease. Sex-specific prevalence rates increased with age and were broadly similar in HIC and LMIC and in men and women. The prevalence in HIC at age 45–49 years was 5·28% (95% CI 3·38–8·17%) in women and 5·41% (3·41–8·49%) in men, and at age 85–89 years, it was 18·38% (11·16–28·76%) in women and 18·83% (12·03–28·25%) in men. Prevalence in men was lower in LMIC than in HIC (2·89% 2·04–4·07% at 45–49 years and 14·94% 9·58–22·56% at 85–89 years). In LMIC, rates were higher in women than in men, especially at younger ages (6·31% 4·86–8·15% of women aged 45–49 years). Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2·72 (95% CI 2·39–3·09) in HIC and 1·42 (1·25–1·62) in LMIC, followed by diabetes (1·88 1·66–2·14 vs 1·47 1·29–1·68), hypertension (1·55 1·42–1·71 vs 1·36 1·24–1·50), and hypercholesterolaemia (1·19 1·07–1·33 vs 1·14 1·03–1·25). Globally, 202 million people were living with peripheral artery disease in 2010, 69·7% of them in LMIC, including 54·8 million in southeast Asia and 45·9 million in the western Pacific Region. During the preceding decade the number of individuals with peripheral artery disease increased by 28·7% in LMIC and 13·1% in HIC. Interpretation In the 21st century, peripheral artery disease has become a global problem. Governments, non-governmental organisations, and the private sector in LMIC need to address the social and economic consequences, and assess the best strategies for optimum treatment and prevention of this disease. Funding Peripheral Arterial Disease Research Coalition (Europe).
Present paper reports about the strong correlation of the heat treatment conditions (annealing), crystal structure parameters, microstructure and magnetic properties evolution in nanosized BaFe12O19 ...M-type hexaferrites or BaM nanohexaferrites. Samples of the BaM nanohexaferrites were obtained using sol-gel method with further annealing in the range 600–1100 °C. All investigated samples were single phase and described by the P63/mmc space group. Unusual and non-linear behavior of the lattice parameters with annealing temperature increasing from 600 to 1100 °C was explained by the competition of the increase in the average crystallite size (decrease in the surface tension effect) and increase in the level of their chemical homogeneity (anionic stoichiometry). Increase of the heat treatment temperature leads to increase of the microstructure parameters (average crystal size and specific surface area) and non-linear changes in magnetic properties. Correlation of the annealing temperature and magnetic properties was discussed in terms of the structural features.
•BaM nanohexaferrites were synthesized using sol-gel method with further annealing.•Strong correlation between average crystal size and annealing temperature was established.•Non-linear behavior of the structure and magnetic properties after annealing was observed.•All changes in BaM were discussed in terms of the morphology evolution.
Disturbances that result in the mass mortality of reef-building corals are changing the appearance of reefs worldwide. Many reefs are transitioning away from scleractinian-coral-dominated assemblages ...to benthic communities composed primarily of non-scleractinian taxa. This study evaluated recovery patterns of reef communities in the Florida Keys following the mortality associated with the 1997/1998 El Niño. We examined temporal trends among the 5 most spatially abundant reef taxa and stony coral species from 1999 to 2009 at 3 spatial scales, and applied a Principal Coordinate Analysis (PCoA) to determine whether changes in their cover resulted in a shift in community structure. Trends of decreasing stony coral cover were not identified Keys-wide between 1999 and 2009, but 2 of the 3 habitats examined—shallow and deep forereefs—did show a significant decline in cover. Concomitantly, octocoral cover significantly increased Keys-wide and in all 3 habitats. The transition to octocorals was most evident on shallow forereefs, where octocoral cover significantly increased at 9 of 12 reefs and overwhelmingly influenced the PCoA. On deep forereefs, octocoral and sponge cover did significantly increase, but did not impart a clearly defined shift in community structure like that observed on shallow forereefs. Community composition at patch reefs was relatively consistent during the study, but the increase in octocoral cover may accelerate further following a cold-water mortality event in 2010. These results demonstrate that octocorals are emerging as the predominant benthic taxa in the Florida Keys. Although the transition to octocorals may have started long ago, their apparent resilience to present-day stressors will likely allow this shift to continue into the foreseeable future.
This randomized, controlled trial shows that acetaminophen reduces kidney dysfunction and risk of developing acute kidney injury, particularly in severe malaria patients who present with high plasma ...hemoglobin, supporting the hypothesis that acetaminophen inhibits cell-free hemoglobin-mediated renal tubular oxidative damage.
Abstract
Background
Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria.
Methods
This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin.
Results
Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to −71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity.
Conclusions
In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis.
Clinical Trials Registration
NCT01641289.
Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain.
We conducted ...an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia.
A total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval CI, 0.77 to 0.96; P = 0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P<0.001) and death (39.28 events vs. 44.61 events per 1000 person-years; rate ratio, 0.88; 95% CI, 0.82 to 0.95; P<0.001). The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37; P = 0.76).
Among persons who had a history of stroke or were 60 years of age or older and had high blood pressure, the rates of stroke, major cardiovascular events, and death from any cause were lower with the salt substitute than with regular salt. (Funded by the National Health and Medical Research Council of Australia; SSaSS ClinicalTrials.gov number, NCT02092090.).
Abstract Objective To evaluate the performance characteristics of florbetapir F18 positron emission tomography (PET) in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and ...healthy control subjects (HCs). Methods Florbetapir PET was acquired in 184 subjects (45 AD patients, 60 MCI patients, and 79 HCs) within a multicenter phase 2 study. Amyloid burden was assessed visually and quantitatively, and was classified as positive or negative. Results Florbetapir PET was rated visually amyloid positive in 76% of AD patients, 38% of MCI patients, and 14% of HCs. Eighty-four percent of AD patients, 45% of MCI patients, and 23% of HCs were classified as amyloid positive using a quantitative threshold. Amyloid positivity and mean cortical amyloid burden were associated with age and apolipoprotein E ε4 carrier status. Conclusions: The data are consistent with expected rates of amyloid positivity among individuals with clinical diagnoses of AD and MCI, and indicate the potential value of florbetapir F18 PET as an adjunct to clinical diagnosis.
The Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) is one of the three core subunits of the Polycomb Repressive Complex 2 (PRC2). It harbors histone methyltransferase activity ...(MTase) that specifically catalyze histone 3 lysine 27 (H3K27) methylation on target gene promoters. As such, PRC2 are epigenetic silencers that play important roles in cellular identity and embryonic stem cell maintenance. In the past two decades, mounting evidence supports EZH2 mutations and/or over-expression in a wide array of hematological cancers and solid tumors, including prostate cancer. Further, EZH2 is among the most upregulated genes in neuroendocrine prostate cancers, which become abundant due to the clinical use of high-affinity androgen receptor pathway inhibitors. While numerous studies have reported epigenetic functions of EZH2 that inhibit tumor suppressor genes and promote tumorigenesis, discordance between EZH2 and H3K27 methylation has been reported. Further, enzymatic EZH2 inhibitors have shown limited efficacy in prostate cancer, warranting a more comprehensive understanding of EZH2 functions. Here we first review how canonical functions of EZH2 as a histone MTase are regulated and describe the various mechanisms of PRC2 recruitment to the chromatin. We further outline non-histone substrates of EZH2 and discuss post-translational modifications to EZH2 itself that may affect substrate preference. Lastly, we summarize non-canonical functions of EZH2, beyond its MTase activity and/or PRC2, as a transcriptional cofactor and discuss prospects of its therapeutic targeting in prostate cancer.
Purpose To evaluate the utility of amide proton transfer (APT) imaging in the characterization of head and neck tumors. Materials and Methods This retrospective study of APT imaging included 117 ...patients with 70 nasopharyngeal undifferentiated carcinomas (NUCs), 26 squamous cell carcinomas (SCCs), eight non-Hodgkin lymphomas (NHLs), and 13 benign salivary gland tumors (BSGTs). Normal tissues were examined in 25 patients. The APT means of malignant tumors, normal tissues, and benign tumors were calculated and compared with the Student t test and analysis of variance. The added value of the mean APT to the mean apparent diffusion coefficient (ADC) for differentiating malignant and benign tumors was evaluated by using receiver operating characteristic analysis and integrated discrimination index. Results The mean APT of malignant tumors (2.40% ± 0.97 standard deviation) was significantly higher than that of brain tissue (1.13% ± 0.43), muscle tissue (0.23% ± 0.73), and benign tumors (1.32% ± 1.20) (P < .001). There were no differences between malignant groups (NUC, 2.37% ± 0.90; SCC, 2.41% ± 1.16; NHL, 2.65% ± 0.89; P = .45 to P = .86). The mean ADC of malignant tumors (0.85 ± 0.17 × 10
mm
/sec) was significantly lower than that of benign tumors (1.46 ± 0.47 × 10
mm
/sec) (P = .001). Adding APT to ADC increased the area under the curve from 0.87 to 0.96, with an integrated discrimination index of 7.6% (P = .13). Conclusion These preliminary data demonstrate differences in amide proton transfer (APT) mean of malignant tumors, normal tissues, and benign tumors, although APT mean could not be used to differentiate between malignant tumor groups. APT imaging has the potential to be of added value to apparent diffusion coefficient in differentiating malignant from benign tumors.
The rate of survival after out-of-hospital cardiac arrest is low. It is not known whether this rate will increase if laypersons are trained to attempt defibrillation with the use of automated ...external defibrillators (AEDs).
We conducted a prospective, community-based, multicenter clinical trial in which we randomly assigned community units (e.g., shopping malls and apartment complexes) to a structured and monitored emergency-response system involving lay volunteers trained in cardiopulmonary resuscitation (CPR) alone or in CPR and the use of AEDs. The primary outcome was survival to hospital discharge.
More than 19,000 volunteer responders from 993 community units in 24 North American regions participated. The two study groups had similar unit and volunteer characteristics. Patients with treated out-of-hospital cardiac arrest in the two groups were similar in age (mean, 69.8 years), proportion of men (67 percent), rate of cardiac arrest in a public location (70 percent), and rate of witnessed cardiac arrest (72 percent). No inappropriate shocks were delivered. There were more survivors to hospital discharge in the units assigned to have volunteers trained in CPR plus the use of AEDs (30 survivors among 128 arrests) than there were in the units assigned to have volunteers trained only in CPR (15 among 107; P=0.03; relative risk, 2.0; 95 percent confidence interval, 1.07 to 3.77); there were only 2 survivors in residential complexes. Functional status at hospital discharge did not differ between the two groups.
Training and equipping volunteers to attempt early defibrillation within a structured response system can increase the number of survivors to hospital discharge after out-of-hospital cardiac arrest in public locations. Trained laypersons can use AEDs safely and effectively.
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