Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study

AIM The effect of long-term high-intensity statin therapy on coronary atherosclerosis among patients with acute ST-segment elevation myocardial infarction (STEMI) is unknown. The aim of this study was to quantify the impact of high-intensity statin therapy on plaque burden, composition, and phenotype in non-infarct-related arteries of STEMI patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS Between September 2009 and January 2011, 103 STEMI patients underwent intravascular ultrasonography (IVUS) and radiofrequency ultrasonography (RF-IVUS) of the two non-infarct-related epicardial coronary arteries (non-IRA) after successful primary PCI. Patients were treated with high-intensity rosuvastatin (40 mg/day) throughout 13 months and serial intracoronary imaging with the analysis of matched segments was available for 82 patients with 146 non-IRA. The primary IVUS end-point was the change in per cent atheroma volume (PAV). After 13 months, low-density lipoprotein cholesterol (LDL-C) had decreased from a median of 3.29 to 1.89 mmol/L (P < 0.001), and high-density lipoprotein cholesterol (HDL-C) levels had increased from 1.10 to 1.20 mmol/L (P < 0.001). PAV of the non-IRA decreased by -0.9% (95% CI: -1.56 to -0.25, P = 0.007). Patients with regression in at least one non-IRA were more common (74%) than those without (26%). Per cent necrotic core remained unchanged (-0.05%, 95% CI: -1.05 to 0.96%, P = 0.93) as did the number of RF-IVUS defined thin cap fibroatheromas (124 vs. 116, P = 0.15). CONCLUSION High-intensity rosuvastatin therapy over 13 months is associated with regression of coronary atherosclerosis in non-infarct-related arteries without changes in RF-IVUS defined necrotic core or plaque phenotype among STEMI patients.

Peak Last Glacial weathering intensity on the North American continent recorded by the authigenic Hf isotope composition of North Atlantic deep-sea sediments

We have retrieved radiogenic hafnium (Hf) isotope compositions (ɛHf) from authigenic Fe–Mn oxyhydroxides of deep northwest Atlantic sediments deposited over the past 26 ka to investigate the oceanic evidence of changes in dissolved weathering inputs from NE America during the last deglaciation. The extraction of seawater-derived Hf isotopic compositions from Fe–Mn oxyhydroxides is not a standard procedure. Comparisons between the Al/Hf ratios and Hf isotopic compositions of the chemically extracted authigenic phase on the one hand, and those of the corresponding detrital fractions on the other, provide evidence that the composition of past seawater has been reliably obtained for most sampled depths with our leaching procedures. This is endorsed most strongly by data for a sediment core from 4250 m water depth at the deeper Blake Ridge, for which consistent replicates were produced throughout. The Hf isotopic composition of the most recent sample in this core also closely matches that of nearby present day central North Atlantic seawater. Comparison with previously published seawater Nd and Pb isotope compositions obtained on the same cores shows that both Hf and Pb were released incongruently during incipient chemical weathering, but responded differently to the deglacial retreat of the Laurentide Ice Sheet. Hafnium was released more congruently during peak glacial conditions of the Last Glacial Maximum (LGM) and changed to typical incongruent interglacial ɛHf signatures either during or shortly after the LGM. This indicates that some zircon-derived Hf was released to seawater during the LGM. Conversely, there is no clear evidence for an increase in the influence of weathering of Lu-rich mineral phases during deglaciation, possibly since relatively unradiogenic Hf contributions from feldspar weathering were superimposed. While the authigenic Pb isotope signal in the same marine sediment samples traced peak chemical weathering rates on continental North America during the transition to the Holocene a similar incongruent excursion is notably absent in the Hf isotope record. The early change towards more radiogenic ɛHf in relation to the LGM may provide direct evidence for the transition from a cold-based to a warm-based Laurentide Ice Sheet on the Atlantic sector of North America.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Multimodal treatment for high-risk prostate cancer with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel and long-term androgen deprivation therapy: results of a prospective phase II trial.

BACKGROUND The optimal management of high-risk prostate cancer remains uncertain. In this study we assessed the safety and efficacy of a novel multimodal treatment paradigm for high-risk prostate cancer. METHODS This was a prospective phase II trial including 35 patients with newly diagnosed high-risk localized or locally advanced prostate cancer treated with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel-based chemotherapy and long-term androgen deprivation therapy. Primary endpoint was acute and late toxicity evaluated with the Common Terminology Criteria for Adverse Events version 3.0. Secondary endpoint was biochemical and clinical recurrence-free survival explored with the Kaplan-Meier method. RESULTS Acute gastro-intestinal and genito-urinary toxicity was grade 2 in 23% and 20% of patients, and grade 3 in 9% and 3% of patients, respectively. Acute blood/bone marrow toxicity was grade 2 in 20% of patients. No acute grade ≥ 4 toxicity was observed. Late gastro-intestinal and genito-urinary toxicity was grade 2 in 9% of patients each. No late grade ≥ 3 toxicity was observed. Median follow-up was 63 months (interquartile range 31-79). Actuarial 5-year biochemical and clinical recurrence-free survival rate was 55% (95% confidence interval, 35-75%) and 70% (95% confidence interval, 52-88%), respectively. CONCLUSIONS In our phase II trial testing a novel multimodal treatment paradigm for high-risk prostate cancer, toxicity was acceptably low and mid-term oncological outcome was good. This treatment paradigm, thus, may warrant further evaluation in phase III randomized trials.

Temporal evolution of strut light intensity after implantation of bioresorbable polymeric intracoronary scaffolds in the ABSORB cohort B trial-an application of a new quantitative method based on optical coherence tomography.

BACKGROUND Quantitative light intensity analysis of the strut core by optical coherence tomography (OCT) may enable assessment of changes in the light reflectivity of the bioresorbable polymeric scaffold from polymer to provisional matrix and connective tissues, with full disappearance and integration of the scaffold into the vessel wall. The aim of this report was to describe the methodology and to apply it to serial human OCT images post procedure and at 6, 12, 24 and 36 months in the ABSORB cohort B trial. METHODS AND RESULTS In serial frequency-domain OCT pullbacks, corresponding struts at different time points were identified by 3-dimensional foldout view. The peak and median values of light intensity were measured in the strut core by dedicated software. A total of 303 corresponding struts were serially analyzed at 3 time points. In the sequential analysis, peak light intensity increased gradually in the first 24 months after implantation and reached a plateau (relative difference with respect to baseline [%Dif]: 61.4% at 12 months, 115.0% at 24 months, 110.7% at 36 months), while the median intensity kept increasing at 36 months (%Dif: 14.3% at 12 months, 75.0% at 24 months, 93.1% at 36 months). CONCLUSIONS Quantitative light intensity analysis by OCT was capable of detecting subtle changes in the bioresorbable strut appearance over time, and could be used to monitor the bioresorption and integration process of polylactide struts.

Beta-alanine supplementation improves jumping power and affects severe-intensity performance in professional alpine skiers.

INTRODUCTION Supplementation with beta-alanine may have positive effects on severe-intensity, intermittent, and isometric strength-endurance performance. These could be advantageous for competitive alpine skiers, whose races last 45 to 150 s, require metabolic power above the aerobic maximum, and involve isometric muscle work. Further, beta-alanine supplementation affects the muscle force-frequency relationship, which could influence explosiveness. We explored the effects of beta-alanine on explosive jump performance, severe exercise energy metabolism, and severe-intensity ski-like performance. METHODS Nine male elite alpine skiers consumed 4.8 g/d beta-alanine or placebo for 5 weeks in a double-blind fashion. Before and after, they performed countermovement jumps (CMJ), a 90-s cycling bout at 110% VO2max (CLT), and a maximal 90-s box jump test (BJ90). RESULTS Beta-alanine improved maximal (+7 ± 3%, d = 0.9) and mean CMJ power (+7 ± 2%, d = 0.7), tended to reduce oxygen deficit (-3 ± 8%, p = .06) and lactate accumulation (-12 ± 31%) and enhance aerobic energy contribution (+1.3 ± 2.9%, p = .07) in the CLT, and improved performance in the last third of BJ90 (+7 ± 4%, p = .02). These effects were not observed with placebo. CONCLUSIONS Beta-alanine supplementation improved explosive and repeated jump performance in elite alpine skiers. Enhanced muscle contractility could possibly explain improved explosive and repeated jump performance. Increased aerobic energy production could possibly help explain repeated jump performance as well.

Definitive intensity modulated radiotherapy in locally advanced hypopharygeal and laryngeal squamous cell carcinoma: mature treatment results and patterns of locoregional failure.

PurposeTo assess clinical outcomes and patterns of loco-regional failure (LRF) in relation to clinical target volumes (CTV) in patients with locally advanced hypopharyngeal and laryngeal squamous cell carcinoma (HL-SCC) treated with definitive intensity modulated radiotherapy (IMRT) and concurrent systemic therapy.MethodsData from HL-SCC patients treated from 2007 to 2010 were retrospectively evaluated. Primary endpoint was loco-regional control (LRC). Secondary endpoints included local (LC) and regional (RC) controls, distant metastasis free survival (DMFS), laryngectomy free survival (LFS), overall survival (OS), and acute and late toxicities. Time-to-event endpoints were estimated using Kaplan-Meier method, and univariate and multivariate analyses were performed using Cox proportional hazards models. Recurrent gross tumor volume (RTV) on post-treatment diagnostic imaging was analyzed in relation to corresponding CTV (in-volume, > 95% of RTV inside CTV; marginal, 20¿95% inside CTV; out-volume, < 20% inside CTV).ResultsFifty patients (stage III: 14, IVa: 33, IVb: 3) completed treatment and were included in the analysis (median follow-up of 4.2 years). Three-year LRC, DMFS and overall survival (OS) were 77%, 96% and 63%, respectively. Grade 2 and 3 acute toxicity were 38% and 62%, respectively; grade 2 and 3 late toxicity were 23% and 15%, respectively. We identified 10 patients with LRF (8 local, 1 regional, 1 local¿+¿regional). Six out of 10 RTVs were fully included in both elective and high-dose CTVs, and 4 RTVs were marginal to the high-dose CTVs.ConclusionThe treatment of locally advanced HL-SCC with definitive IMRT and concurrent systemic therapy provides good LRC rates with acceptable toxicity profile. Nevertheless, the analysis of LRFs in relation to CTVs showed in-volume relapses to be the major mode of recurrence indicating that novel strategies to overcome radioresistance are required.

Measuring Intensity of End of Life Care: A Systematic Review.

BACKGROUND Many studies have measured the intensity of end of life care. However, no summary of the measures used in the field is currently available. OBJECTIVES To summarise features, characteristics of use and reported validity of measures used for evaluating intensity of end of life care. METHODS This was a systematic review according to PRISMA guidelines. We performed a comprehensive literature search in Ovid Medline, Embase, The Cochrane Library of Systematic Reviews and reference lists published between 1990-2014. Two reviewers independently screened titles, abstracts, full texts and extracted data. Studies were eligible if they used a measure of end of life care intensity, defined as all quantifiable measures describing the type and intensity of medical care administered during the last year of life. RESULTS A total of 58 of 1590 potentially eligible studies met our inclusion criteria and were included. The most commonly reported measures were hospitalizations (n = 44), intensive care unit admissions (n = 39) and chemotherapy use (n = 27). Studies measured intensity of care in different timeframes ranging from 48 hours to 12 months. The majority of studies were conducted in cancer patients (n = 31). Only 4 studies included information on validation of the measures used. None evaluated construct validity, while 3 studies considered criterion and 1 study reported both content and criterion validity. CONCLUSIONS This review provides a synthesis to aid in choosing intensity of end of life care measures based on their previous use but simultaneously highlights the crucial need for more validation studies and consensus in the field.

Tree Species Composition and Harvest Intensity Affect Herbivore Density and Leaf Damage on Beech, Fagus sylvatica, in Different Landscape Contexts

Most forests are exposed to anthropogenic management activities that affect tree species composition and natural ecosystem processes. Changes in ecosystem processes such as herbivory depend on management intensity, and on regional environmental conditions and species pools. Whereas influences of specific forest management measures have already been addressed for different herbivore taxa on a local scale, studies considering effects of different aspects of forest management across different regions are rare. We assessed the influence of tree species composition and intensity of harvesting activities on arthropod herbivores and herbivore-related damage to beech trees, Fagus sylvatica, in 48 forest plots in three regions of Germany. We found that herbivore abundance and damage to beech trees differed between regions and that – despite the regional differences - density of tree-associated arthropod taxa and herbivore damage were consistently affected by tree species composition and harvest intensity. Specifically, overall herbivore damage to beech trees increased with increasing dominance of beech trees – suggesting the action of associational resistance processes – and decreased with harvest intensity. The density of leaf chewers and mines was positively related to leaf damage, and several arthropod groups responded to beech dominance and harvest intensity. The distribution of damage patterns was consistent with a vertical shift of herbivores to higher crown layers during the season and with higher beech dominance. By linking quantitative data on arthropod herbivore abundance and herbivory with tree species composition and harvesting activity in a wide variety of beech forests, our study helps to better understand the influence of forest management on interactions between a naturally dominant deciduous forest tree and arthropod herbivores.