Recruitment and retention: A randomized controlled trial of video-enhanced versus standard consent processes within the E-OPTIMAL study.
In this study, we compared two research consent techniques: a standardized video plus usual consent and usual consent alone. Individuals who completed 24-month outcomes (completers) in the Operations and Pelvic Muscle Training in the Management of Apical Support Loss study were invited to participate in an extended, longitudinal follow-up study (extended Operations and Pelvic Muscle Training in the Management of Apical Support Loss). Potential participants who were (1) able to provide consent and (2) not in long-term care facilities were randomized 1:1 to a standardized video detailing the importance of long-term follow-up studies of pelvic floor disorders followed by the usual institutional consent process versus the usual consent process alone. Randomization, stratified by site, used randomly permuted blocks. The primary outcome was the proportion of participants who enrolled in the extended study and completed data collection events 5 years after surgery. Secondary outcomes included the proportion enrolled in the extended study, completion of follow-up at each study year, completion of data collection points, completion of in-person visits, and completion of quality of life calls. Motivation and barriers to enrollment (study-level and personal-level) and satisfaction with the study consent process were measured by questionnaire prior to recruitment into extended Operations and Pelvic Muscle Training in the Management of Apical Support Loss. Groups were compared using an intention-to-treat principle, using unadjusted Student's t-test (continuous) and chi-square or Fisher's exact (categorical) test. A sample size of 340 (170/group) was estimated to detect a 15% difference in enrollment and study completion between groups with p < 0.05. Of the 327 Operations and Pelvic Muscle Training in the Management of Apical Support Loss completers, 305 were randomized to the consent process study (153 video vs 152 no video). Groups were similar in demographics, surgical treatment, and outcomes. The overall rate of extended study enrollment was high, without significant differences between groups (video 92.8% vs no video 94.1%, p = 0.65). There were no significant differences in the primary outcome (video 79.1% vs no video 75.7%, p = 0.47) or in any secondary outcomes. Being "very satisfied" overall with study information (97.7% vs 88.5%, p = 0.01); "strong agreement" for feeling informed about the study (81.3% vs 70.8%, p = 0.06), understanding the study purpose (83.6% vs 71.0%, p = 0.02), nature and extent (82.8% vs 70.2%, p = 0.02), and potential societal benefits (82.8% vs 67.9%, p = 0.01); and research coordinator/study nurse relationship being "very important" (72.7% vs 63.4%, p = 0.03) were better in the video compared to the no video consent group. The extended study had high enrollment; most participants completed most study tasks during the 3-year observational extension, regardless of the use of video to augment research consent. The video was associated with a higher proportion of participants reporting improved study understanding and relationship with study personnel.


Modifying spike jump landing biomechanics in female adolescent volleyball athletes using video and verbal feedback.
Landing awkwardly from a jump is a common mechanism of injury for the anterior cruciate ligament (ACL) of the knee. Augmented feedback, such as verbal or visual instruction, has been shown to cause an immediate, positive change in landing biomechanics in a laboratory setting. No data exist on the longer term effects of feedback on jump landing biomechanics in a sports-specific setting. The purpose of this study was to explore whether providing video and verbal feedback to adolescent (12-14 years old) female volleyball athletes would improve their landing technique. Trunk and lower extremity kinematic variables were measured in 19 participants before a feedback session was provided to the intervention group (IG). Follow-up kinematic measurements of the IG were taken immediately postintervention, and again after 2 and 4 weeks. Two-way repeated measures analysis of variance (ANOVA) was used to compare the IG with a control group (CG), who received no feedback. The IG (n = 10) demonstrated increased maximal hip and trunk flexion compared with the CG (n = 9) at week 4 (p ≤ 0.05). One-way repeated measures ANOVA was used to determine if changes were evident within the IG over time. Ankle dorsiflexion, right knee and hip flexion, and trunk flexion changed significantly (p ≤ 0.05) over the 4-week period. Augmented feedback appeared to produce a positive change in landing biomechanics in adolescent female volleyball athletes performing a sports-specific skill. Courtside video and verbal feedback may present a relatively simple, cost-effective method of introducing one component of a comprehensive ACL injury prevention program at a young age.


Variants within HNF1α and ANGPTL4 genes and acute coronary syndrome in Czech population. The GENDEMIP study.
Atherosclerosis is a complex arterial disease involving interactions between multiple genetic and environmental factors. A large number of genetic polymorphisms associated with atherosclerotic diseases have been identified in recent years. We investigated the possible association between hepatic nuclear factor (HNF1-α) and angiopoietin-like 4 (ANGPTL4) single nucleotide polymorphisms and the risk of acute coronary syndrome (ACS) in the Czech population. A total of 1,182 patients with ACS (835 males and 347 females) and 1,200 healthy controls (827 males and 373 females) were included in the study. All patients were younger than 65 years of age. rs7310409 (A>G within the HNF1-α gene) and rs116843064 (G>A within the ANGPTL4 gene) were genotyped using TaqMan genotyping assays. The frequencies of the genotypes in patients with ACS did not significantly differ from the control group for the rs7310409 polymorphism (AA=17.1%, AG=46.6%, GG=36.2% vs. AA=14.4%, AG=50.3%, GG=35.3%, respectively; p=0.12) or the rs116843064 polymorphism (AA=0.1%, AG=3.5%, GG=96.4% vs. AA=0.1%, AG=4.2%, GG=95.7%, respectively; p=0.69). There was no interaction with gender. In addition, gene variants were not associated with common cardiovascular risk factors (dyslipidaemia, hypertension, smoking, obesity and diabetes). No association was observed between polymorphisms within the HNF1-α and ANGPTL4 genes and the risk of ACS in the Czech population.


Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.
QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years. Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs. 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate. Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins. Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome.


[Peri-pregnancy folic acid supplementation must be improved].
The correct usage of folic acid (FA) supplements to prevent neural tube defects (NTDs) increased from 28% in 1996 to 50% in 2005 and remained stable until 2009. Recent data from national birth defect registries show a decrease of NTD prevalence from 13.2 (per 10,000) in 1997 to 8.3 in 2005 and stabilization up to 2009. It is estimated that between 2005 and 2009 FA supplementation prevented 583 NTD cases. The medical costs thus averted are € 75 M. If the correct usage of FA were to be increased to 70%, another 34 cases per year could be prevented. Part of the gain from continued prevention and other averted costs should be invested beforehand in the promotion of FA supplement usage.


The effect of postnatal depression on mother-infant interaction, infant response to the Still-face perturbation, and performance on an Instrumental Learning task.
A representative community sample of primiparous depressed women and a nondepressed control group were assessed while in interaction with their infants at 2 months postpartum. At 3 months, infants were assessed on the Still-face perturbation of face to face interaction, and a subsample completed an Instrumental Learning paradigm. Compared to nondepressed women, depressed mothers' interactions were both less contingent and less affectively attuned to infant behavior. Postnatal depression did not adversely affect the infant's performance in either the Still-face perturbation or the Instrumental Learning assessment. Maternal responsiveness in interactions at 2 months predicted the infant's performance in the Instrumental Learning assessment but not in the Still-face perturbation. The implications of these findings for theories of infant cognitive and emotional development are discussed.


Differential effects of high-fat and high-carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in lean and obese women.
Food ingestion can influence autonomic nervous system activity. This study compares the effects of 2 different isoenergetic meals on sympathetic nervous system (SNS) activity, assessed by heart rate variability (HRV) and plasma norepinephrine (NE) levels, in lean and obese women. Fifteen lean and 15 obese healthy women were examined on 2 occasions: after a carbohydrate (CHO)-rich and after a fat-rich test meal. Measurements of blood pressure, heart rate, resting energy expenditure, plasma glucose, lipids, insulin, leptin, and NE, as well as spectral analysis of the HRV, were performed at baseline and every 1 hour for 3 hours after meals. At baseline, obese women had higher SNS activity than lean controls (higher values of low-to-high frequency ratio [LF/HF], 1.52 +/- 0.31 v 0.78 +/- 0.13, P=.04; and plasma NE levels, 405.6 +/- 197.9 v 240.5 +/- 95.8 pg/mL, P<.0001). After the CHO-rich meal a greater increase in LF/HF and in plasma NE levels was observed in lean, compared to obese women (1.21 +/- 0.6 v 0.32 +/- 0.06, P=.04; and 102.9 +/- 35.4 v 38.7 +/- 12.3 pg/mL, P=.01, respectively), while no differences were observed after the fat-rich meal. Meal-induced thermogenesis was higher after the CHO-rich as compared to the fat-rich meal and was comparable between lean and obese women. Changes in HRV were not associated with the thermogenic response to the test meals. In conclusion, consumption of a CHO-rich meal causes greater cardiac SNS activation in lean than in obese women, while fat ingestion does not result in any appreciable change in either group. SNS activation does not appear to influence the thermic effect of the food in either lean or obese women.


A Global Overview of Male Escort Websites.
This article details a preliminary dataset of global male escort sites to give insight into the scale of the online market. We conducted a content analysis of 499 Web sites and also measured traffic to these sites. Our analysis examined the structural characteristics of escort services, geographical and regulatory contexts, and resilience of such services. Results suggest that most sites are independent and not affiliated to escort agencies, and the majority cater to male escorts soliciting male clients, with a number of sites for female clientele and couples. These Web sites are dispersed globally, with Asian, European, and South American countries the major hubs in the market and a small number of large multinational sites based in the United States and Europe figuring as a major presence in markets. Although still subject to high levels of regulation in many parts of the world, the data suggest that male escorting is becoming more visible in diverse cultural contexts as measured by the number of Web sites appearing in public spaces.


Mechanistic dissection of the enzyme complexes involved in biosynthesis of lacticin 3147 and nisin.
The thioether rings in the lantibiotics lacticin 3147 and nisin are posttranslationally introduced by dehydration of serines and threonines, followed by coupling of these dehydrated residues to cysteines. The prepeptides of the two-component lantibiotic lacticin 3147, LtnA1 and LtnA2, are dehydrated and cyclized by two corresponding bifunctional enzymes, LtnM1 and LtnM2, and are subsequently processed and exported via one bifunctional enzyme, LtnT. In the nisin synthetase complex, the enzymes NisB, NisC, NisT, and NisP dehydrate, cyclize, export, and process prenisin, respectively. Here, we demonstrate that the combination of LtnM2 and LtnT can modify, process, and transport peptides entirely different from LtnA2 and that LtnT can process and transport unmodified LtnA2 and unrelated peptides. Furthermore, we demonstrate a higher extent of NisB-mediated dehydration in the absence of thioether rings. Thioether rings apparently inhibited dehydration, which implies alternating actions of NisB and NisC. Furthermore, certain (but not all) NisC-cyclized peptides were exported with higher efficiency as a result of their conformation. Taken together, these data provide further insight into the applicability of Lactococcus lactis strains containing lantibiotic enzymes for the design and production of modified peptides.


Effect of calcium on superoxide production by phagocytic vesicles from rabbit alveolar macrophages.
Phagocytic vesicles from rabbit lung macrophages produced superoxide in the presence of NADH or NADPH. At 37 degrees C, these vesicles generated 51+/-7.8 nmol O(2) (-)/min per mg protein in the presence of 0.5 mM NADPH. The apparent K(m) for NADPH and NADH (66 and 266 muM, respectively), the pH optimum for the reaction (6.9), and the cyanide insensitivity were similar to properties of plasma membrane-rich fractions of stimulated polymorphonuclear leukocytes studied by others. The activity of the phagocytic vesicles was trypsin sensitive. The specific superoxide-generating activity of macrophage phagocytic vesicles isolated from cells incubated up to 90 min with phagocytic particles remained constant. Calcium in micromolar concentrations inhibited the NADPH-dependent O(2) (-)-generating activity of phagocytic vesicles. In a physiological ionic medium (100 mM KCl, 2.5 mM MgCl(2), 30 mM imidazole-HCl, pH 6.9), a maximal inhibition of O(2) (-) generation by phagocytic vesicles of 80% was observed at 40 muM free Ca(2+). The half maximum inhibitory effect was at 0.7 muM Ca(2+). Variations of the calcium concentration resulted in rapid and reversible alterations in O(2) (-)-forming activity. Preincubation of phagocytic vesicles in the presence of EGTA rendered their O(2) (-) generation rate in the presence of NADPH insensitive to alterations in the free calcium concentration. This desensitization by low EGTA concentrations (</=100 muM) was reversible by the addition of excess calcium, but desensitization by high EGTA concentrations (>1 mM) was not reversible by the addition of calcium either in the presence or absence of purified rabbit lung macrophage or bovine brain calmodulins. Furthermore, trifluoperazine, a drug that inhibits calmodulin-stimulated reactions, did not alter the activity or the calcium sensitivity of the superoxide-generating system of sensitive phagocytic vesicles. Peripheral plasma membrane vesicles (podosomes) prepared by gentle sonication of macrophages possessed on O(2) (-)-generating system with similar properties to those of phagocytic vesicles. We conclude that the activated O(2) (-)-generating system of rabbit lung macrophages has its initial localization in the plasmalemma and undergoes subsequent internalization into phagocytic vesicles, where it can function for prolonged periods of time. Calcium at concentrations likely to exist in macrophage cytoplasm exerts a regulatory effect on the activated system.


The dynamics of the interrelation of perception and action across the life span.
Successful social interaction relies on the interaction partners' perception, anticipation and understanding of their respective actions. The perception of a particular action and the capability to produce this action share a common representational ground. So far, no study has explored the interrelation between action perception and production across the life span using the same tasks and the same measurement techniques. This study was designed to fill this gap. Participants between 3 and 80 years (N = 214) observed two multistep actions of different familiarities and then reproduced the according actions. Using eye tracking, we measured participants' action perception via their prediction of action goals during observation. To capture subtler perceptual processes, we additionally analysed the dynamics and recurrent patterns within participants' gaze behaviour. Action production was assessed via the accuracy of the participants' reproduction of the observed actions. No age-related differences were found for the perception of the familiar action, where participants of all ages could rely on previous experience. In the unfamiliar action, where participants had less experience, action goals were predicted more frequently with increasing age. The recurrence in participants' gaze behaviour was related to both, age and action production: gaze behaviour was more recurrent (i.e. less flexible) in very young and very old participants, and lower levels of recurrence (i.e. greater flexibility) were related to higher scores in action production across participants. Incorporating a life-span perspective, this study illustrates the dynamic nature of developmental differences in the associations of action production with action perception.


A review of the toxicology of oil in vertebrates: what we have learned following the Deepwater Horizon oil spill.
In the wake of the Deepwater Horizon (DWH) oil spill, a number of government agencies, academic institutions, consultants, and nonprofit organizations conducted lab- and field-based research to understand the toxic effects of the oil. Lab testing was performed with a variety of fish, birds, turtles, and vertebrate cell lines (as well as invertebrates); field biologists conducted observations on fish, birds, turtles, and marine mammals; and epidemiologists carried out observational studies in humans. Eight years after the spill, scientists and resource managers held a workshop to summarize the similarities and differences in the effects of DWH oil on vertebrate taxa and to identify remaining gaps in our understanding of oil toxicity in wildlife and humans, building upon the cross-taxonomic synthesis initiated during the Natural Resource Damage Assessment. Across the studies, consistency was found in the types of toxic response observed in the different organisms. Impairment of stress responses and adrenal gland function, cardiotoxicity, immune system dysfunction, disruption of blood cells and their function, effects on locomotion, and oxidative damage were observed across taxa. This consistency suggests conservation in the mechanisms of action and disease pathogenesis. From a toxicological perspective, a logical progression of impacts was noted: from molecular and cellular effects that manifest as organ dysfunction, to systemic effects that compromise fitness, growth, reproductive potential, and survival. From a clinical perspective, adverse health effects from DWH oil spill exposure formed a suite of signs/symptomatic responses that at the highest doses/concentrations resulted in multi-organ system failure.


Accuracy improvement in peak positioning of spectrally distorted fiber Bragg grating sensors by Gaussian curve fitting.
To improve measurement accuracy of spectrally distorted fiber Bragg grating temperature sensors, reflection profiles were curve fitted to Gaussian shapes, of which center positions were transformed into temperature information. By applying the Gaussian curve-fitting algorithm in a tunable bandpass filter demodulation scheme, approximately 0.3 degrees C temperature resolution was obtained with a severely distorted grating sensor, which was much better than that obtained using the highest peak search algorithm. A binary search was also used to retrieve the optimal fitting curves with the least amount of processing time.


A simple behavioral-developmental checklist versus formal screening for children in an epilepsy center.
We compare a 7-item checklist for developmental and behavioral concerns to formal screening with the Ages & Stages Questionnaires, Third Edition (ASQ-3) in children aged 1-5.5years old seen in a tertiary epilepsy care setting. The checklist was derived from a 35-item parent questionnaire used as a routine component of pediatric neuropsychology evaluations at our center. In our sample of 104 children, having even one checklist item endorsed was associated with a 97% (66/68) positive predictive value for screening positive on the ASQ-3. Fifty percent of children for whom no items were endorsed on the checklist scored negative for developmental concerns on the ASQ-3. The overall sensitivity of the checklist to a positive ASQ-3 screen was 83%, and the specificity was 88%. Use of this simple checklist may facilitate screening in the outpatient epilepsy care setting where time and resources are often limited.


Increased risk for persistent intestinal metaplasia in patients with Barrett's esophagus and uncontrolled reflux exposure before radiofrequency ablation.
Radiofrequency ablation (RFA) is a safe alternative to esophagectomy for patients with dysplastic Barrett's esophagus (BE). Although some studies have indicated that RFA is effective at eradicating dysplasia, most have found that RFA is not as effective in eradicating intestinal metaplasia. We investigated whether uncontrolled reflux is associated with persistent intestinal metaplasia after RFA. Thirty-seven patients with BE underwent RFA, high-resolution manometry, and 24-hour impedance-pH testing; they received proton pump inhibitors twice daily. Patients returned every 2 months for repeat treatment or standard surveillance. Patients were classified as complete responders (CRs) if all intestinal metaplasia was eradicated in fewer than 3 ablation sessions. We analyzed clinical parameters to identify factors associated with a CR or incomplete responder (ICR). Among the 37 patients, 22 had a CR and 15 had an ICR. Mann-Whitney U tests revealed that length of BE, size of hiatal hernia, and frequency of reflux, but not acid reflux, differed between CRs and ICRs. CRs had fewer weakly acidic events than ICRs (29.5 vs 52; P < .05) and total reflux events (33.5 vs 60; P < .05), and a trend toward fewer weakly alkaline events (1.0 vs 5.0; P = .06). No other clinical or manometric features differed between groups. Uncontrolled, predominantly weakly acidic reflux despite twice-daily proton pump inhibitor therapy before RFA increases the incidence of persistent intestinal metaplasia after ablation in patients with BE. Length of BE and size of hiatal hernia also were associated with persistent intestinal metaplasia after RFA.


Bipedality and hair loss in human evolution revisited: The impact of altitude and activity scheduling.
Bipedality evolved early in hominin evolution, and at some point was associated with hair loss over most of the body. One classic explanation (Wheeler 1984: J. Hum. Evol. 13, 91-98) was that these traits evolved to reduce heat overload when australopiths were foraging in more open tropical habitats where they were exposed to the direct effects of sunlight at midday. A recent critique of this model (Ruxton & Wilkinson 2011a: Proc. Natl. Acad. Sci. USA 108, 20965-20969) argued that it ignored the endogenous costs of heat generated by locomotion, and concluded that only hair loss provided a significant reduction in heat load. We add two crucial corrections to this model (the altitude at which australopiths actually lived and activity scheduling) and show that when these are included there are substantial reductions in heat load for bipedal locomotion even for furred animals. In addition, we add one further consideration to the model: we extend the analysis across the full 24 h day, and show that fur loss could not have evolved until much later because of the thermoregulatory costs this would have incurred at the altitudes where australopiths actually lived. Fur loss is most likely associated with the exploitation of open habitats at much lower altitudes at a much later date by the genus Homo.


Novel roles for ERK5 and cofilin as critical mediators linking ERα-driven transcription, actin reorganization, and invasiveness in breast cancer.
Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype and are regulated through diverse signaling networks involving kinases and transcription factors. This study establishes an estrogen receptor (ERα)/MAPK (ERK5)/cofilin (CFL1) network that specifies the degree of breast cancer cell aggressiveness through coupling of actin reorganization and hormone receptor-mediated transcription. Using dominant negative and constitutively active forms, as well as small-molecule inhibitors of extracellular signal-regulated kinase (ERK)5 and MAP-ERK kinase (MEK)5, it was revealed that hormone activation of ERα determined the subcellular localization of ERK5, which functions as a coregulator of ERα-dependent gene transcription. Notably, ERK5 acted in concert with the actin remodeling protein, CFL1, and upon hormone exposure, both localized to active nuclear transcriptional hubs as verified by immunofluorescence and proximity ligation assays. Both ERK5 and CFL1 facilitated PAF1 recruitment to the RNA Pol II complex and both were required for regulation of gene transcription. In contrast, in cells lacking ERα, ERK5 and CFL1 localized to cytoplasmic membrane regions of high actin remodeling, promoting cell motility and invasion, thereby revealing a mechanism likely contributing to the generally poorer prognosis of patients with ERα-negative breast cancer. Thus, this study uncovers the dynamic interplay of nuclear receptor-mediated transcription and actin reorganization in phenotypes of breast cancer aggressiveness. Identification of the ER/ERK5/CFL1 axis suggests new prognostic biomarkers and novel therapeutic avenues to moderate cancer aggressiveness.


The 6-minute walk test as a predictor of objectively measured aerobic fitness in healthy working-aged adults.
There is a paucity of research examining the 6-minute walk test (6MWT) in young to middle-aged healthy individuals, and little is known about the utility of the 6MWT for predicting aerobic fitness. 1) To characterize the aerobic demand of the 6MWT in a group of healthy working-aged adults; 2) to examine the ability of the 6MWT to objectively differentiate the fitness level between participants; and 3) to create prediction equations for 6MWT distance and maximal oxygen consumption (VO2 max) using the 6MWT results in combination with easily measured anthropometric and demographic variables. Participants (N = 44; men, 23; women, 21) completed the 6MWT, VO2 max, and a battery of simple fitness measures. The aerobic demand of the 6MWT was 28.7 ± 5.7 mL·kg(-1)·min(-1) (72.7% ± 11.6% of VO2 max). Rank order correlation revealed a moderate strength association between 6MWT distance and VO2 max (r = 0.49; P = 0.001). Using stepwise multiple linear regression, we were able to account for 72.4% of the variance in VO2 max using the 6MWT when combined with participant body weight, sex, resting heart rate (HR), and age according to the following equation: VO2 max (mL·kg(-1)·min(-1)) = 70.161 + (0.023 × 6MWT [m]) - (0.276 × weight [kg]) - (6.79 × sex, where m = 0, f = 1) - (0.193 × resting HR [beats per minute]) - (0.191 × age [y]). The 6MWT is of moderate-to-vigorous intensity, and may be useful in the classification of aerobic fitness, which is associated with health outcomes. Inclusion of further patient characteristics greatly increases the predictive value of the 6MWT for estimating VO2 max, which has important implications for those seeking a noninvasive and simple-to-use determinant of maximal aerobic power.


Patients' participation as it appears in the nursing documentation, when care is ruled by standardized care plans.
This study aimed to describe inpatients with myocardial infarction and their participation in care as documented in the nursing records when standardized care plans are used in care. The use of standardized care plans not only has increased the quality of medical treatment but has also overlooked patients' opportunities to participate in their own care. There is a lack of knowledge about how standardized care plans influence patients' participation in nursing care. Data were collected from thirteen patients' records with diagnoses of myocardial infarction. Participation in the decision-making process and participation associated with "sharing with others" were searched for in the analysis. The analytical process was guided by content analysis. The findings were grouped into two categories: patients' intermediary participation and patients' active participation. The main results indicated that patients' intermediary participation depended on healthcare professionals' power to rule the nursing care situation.


Porcine oocyte maturation in vitro: role of cAMP and oocyte-secreted factors - A practical approach.
Polyspermy or the penetration of more than one sperm cell remains a problem during porcine in vitro fertilization (IVF). After in vitro culture of porcine zygotes, only a low percentage of blastocysts develop and their quality is inferior to that of in vivo derived blastocysts. It is unknown whether the cytoplasmic maturation of the oocyte is sufficiently sustained in current in vitro maturation (IVM) procedures. The complex interplay between oocyte and cumulus cells during IVM is a key factor in this process. By focusing on this bidirectional communication, it is possible to control the coordination of cumulus expansion, and nuclear and cytoplasmic maturation during IVM to some extent. Therefore, this review focuses on the regulatory mechanisms between oocytes and cumulus cells to further the development of new in vitro embryo production (IVP) procedures, resulting in less polyspermy and improved oocyte developmental potential. Specifically, we focused on the involvement of cAMP in maturation regulation and function of oocyte-secreted factors (OSFs) in the bidirectional regulatory loop between oocyte and cumulus cells. Our studies suggest that maintaining high cAMP levels in the oocyte during the first half of IVM sustained improved oocyte maturation, resulting in an enhanced response after IVF and cumulus matrix disassembly. Recent research indicated that the addition of OSFs during IVM enhanced the developmental competence of small follicle-derived oocytes, which was stimulated by epidermal growth factor (EGF) via developing EGF-receptor signaling.


Predicting Suicide Attempts for Racial and Ethnic Groups of Patients During Routine Clinical Care.
The aim of this study was to examine variation in suicide ideation and its relationship to risk of suicide attempt in the subsequent 90 days by race and ethnicity. Participants were adults who completed the Patient Health Questionnaire depression module (PHQ9) during an outpatient encounter between January 10, 2010, and December 12, 2012 (N = 509,945 patients; N = 1,228,308 completed PHQ9). Data came from the Virtual Data Warehouse from four health care systems in the Mental Health Research Network. The sample was majority female (73.7%), primarily 30-64 years old (60.1%), healthy (64.5% comorbidity index = 0), and over half were non-Hispanic White (52.9%). Only Asian patients (OR: 1.31; 95% CI: 1.24, 1.39) had higher odds of reporting suicide ideation when compared to non-Hispanic White people. All racial and ethnic groups had increased risk for suicide attempt with increased frequency of suicide ideation. The PHQ9 item 9 can be used as an indicator of suicide ideation and risk for suicide attempt up to 90 days after the reported ideation in racial and ethnic minority patients during routine clinical care.


Basal and metoclopramide induced prolactin secretion in lean PCOS women.
Polycystic ovary syndrome (PCOS) as well as hyperprolactinemia can cause infertility. In retrospective study the prolactin levels during the oral metoclopramide test among lean PCOS woman according to four phenotypes and free androgen index (FAI) were compared. The study population consisted of 314 lean PCOS women. The population was divided into four groups according to the FAI and menstrual cycle regularity. The group A consisted 126 women with FAI≥5 and irregular menstruation, the group B- 53 patients with FAI≥5 and regular menstruation. Group C- 70 patients with FAI<5 and irregular menstruation, group D - 65 patients with FAI<5 and regular menstruation. The ratio of prolactin value in 120th minute in the metoclopramide test to the basal prolactin value was higher in group D than in groups A and B. The prolactin basal concentration was higher in patients with FAI≥5 than in patients with FAI<5, (262.9 vs 228.9 µIU/ml; p<0.001). The ratio of prolactin in 60th minute (12.3 vs 16.7; p=0.006) and in the 120th minute (10.9 versus 13.3; p<0.001) of the metoclopramide test to the basal prolactin were lower in patients with FAI≥5. The prolactin secretion in lean PCOS women may be associated with their FAI.


Improved gray matter surface based spatial statistics in neuroimaging studies.
Neuroimaging often involves acquiring high-resolution anatomical images along with other low-resolution image modalities, like diffusion and functional magnetic resonance imaging. Performing gray matter statistics with low-resolution image modalities is a challenge due to registration artifacts and partial volume effects. Gray matter surface based spatial statistics (GS-BSS) has been shown to provide higher sensitivity using gray matter surfaces compared to that of skeletonization approach of gray matter based spatial statistics which is adapted from tract based spatial statistics in diffusion studies. In this study, we improve upon GS-BSS incorporating neurite orientation dispersion and density imaging (NODDI) based search (denoted N-GSBSS) by 1) enhancing metrics mapping from native space, 2) incorporating maximum orientation dispersion index (ODI) search along surface normal, and 3) proposing applicability to other modalities, such as functional MRI (fMRI). We evaluated the performance of N-GSBSS against three baseline pipelines: volume-based registration, FreeSurfer's surface registration and ciftify pipeline for fMRI and simulation studies. First, qualitative mean ODI results are shown for N-GSBSS with and without NODDI based search in comparison with ciftify pipeline. Second, we conducted one-sample t-tests on working memory activations in fMRI to show that the proposed method can aid in the analysis of low resolution fMRI data. Finally we performed a sensitivity test in a simulation study by varying percentage change of intensity values within a region of interest in gray matter probability maps. N-GSBSS showed higher sensitivity in the simulation test compared to the other methods capturing difference between the groups starting at 10% change in the intensity values. The computational time of N-GSBSS is 68 times faster than that of traditional surface-based or 86 times faster than that of ciftify pipeline analysis.


Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T.
Proton magnetic resonance spectroscopy ((1)H-MRS) has been used to demonstrate metabolic changes in the visual cortex on visual stimulation. Small (2% to 11%) but significant stimulation induced increases in lactate, glutamate, and glutathione were observed along with decreases in aspartate, glutamine, and glycine, using (1)H-MRS at 7 T during single and repeated visual stimulation. In addition, decreases in glucose and increases in γ-aminobutyric acid (GABA) were seen but did not reach significance. Changes in glutamate and aspartate are indicative of increased activity of the malate-aspartate shuttle, which taken together with the opposite changes in glucose and lactate, reflect the expected increase in brain energy metabolism. These results are in agreement with those of Mangia et al. In addition, increases in glutamate and GABA coupled with the decrease in glutamine can be interpreted in terms of increased activity of the neurotransmitter cycles. An entirely new observation is the increase of glutathione during prolonged visual stimuli. The similarity of its time course to that of glutamate suggests that it may be a response to the increased release of glutamate or to the increased production of reactive oxygen species. Together, these observations constitute the most detailed analysis to date of functional changes in human brain metabolites.


The acute effects of yoga on executive function.
Despite an increase in the prevalence of yoga exercise, research focusing on the relationship between yoga exercise and cognition is limited. The purpose of this study was to examine the effects of an acute yoga exercise session, relative to aerobic exercise, on cognitive performance. A repeated measures design was employed where 30 female college-aged participants (Mean age = 20.07, SD = 1.95) completed 3 counterbalanced testing sessions: a yoga exercise session, an aerobic exercise session, and a baseline assessment. The flanker and n-back tasks were used to measure cognitive performance. Results showed that cognitive performance after the yoga exercise bout was significantly superior (ie, shorter reaction times, increased accuracy) as compared with the aerobic and baseline conditions for both inhibition and working memory tasks. The aerobic and baseline performance was not significantly different, contradicting some of the previous findings in the acute aerobic exercise and cognition literature. These findings are discussed relative to the need to explore the effects of other nontraditional modes of exercise such as yoga on cognition and the importance of time elapsed between the cessation of the exercise bout and the initiation of cognitive assessments in improving task performance.


Evaluation of the 2012 18th Maternal and Child Health (MCH) Epidemiology and 22nd CityMatCH MCH Urban Leadership Conference: six month impact on science, program, and policy.
The 18th Maternal and Child Health (MCH) Epidemiology and 22nd CityMatCH MCH Urban Leadership Conference took place in December 2012, covering MCH science, program, and policy issues. Assessing the impact of the Conference on attendees' work 6 months post-Conference provides information critical to understanding the impact and the use of new partnerships, knowledge, and skills gained during the Conference. Evaluation assessments, which included collection of quantitative and qualitative data, were administered at two time points: at Conference registration and 6 months post-Conference. The evaluation files were merged using computer IP address, linking responses from each assessment. Percentages of attendees reporting Conference impacts were calculated from quantitative data, and common themes and supporting examples were identified from qualitative data. Online registration was completed by 650 individuals. Of registrants, 30 % responded to the 6 month post-Conference assessment. Between registration and 6 month post-Conference evaluation, the distribution of respondents did not significantly differ by organizational affiliation. In the 6 months following the Conference, 65 % of respondents reported pursuing a networking interaction; 96 % shared knowledge from the Conference with co-workers and others in their agency; and 74 % utilized knowledge from the Conference to translate data into public health action. The Conference produced far-reaching impacts among Conference attendees. The Conference served as a platform for networking, knowledge sharing, and attaining skills that advance the work of attendees, with the potential of impacting organizational and workforce capacity. Increasing capacity could improve MCH programs, policies, and services, ultimately impacting the health of women, infants, and children.


Targeted interventions for improved equity in maternal and child health in low- and middle-income settings: a systematic review and meta-analysis.
Targeted interventions to improve maternal and child health is suggested as a feasible and sometimes even necessary strategy to reduce inequity. The objective of this systematic review was to gather the evidence of the effectiveness of targeted interventions to improve equity in MDG 4 and 5 outcomes. We identified primary studies in all languages by searching nine health and social databases, including grey literature and dissertations. Studies evaluating the effect of an intervention tailored to address a structural determinant of inequity in maternal and child health were included. Thus general interventions targeting disadvantaged populations were excluded. Outcome measures were limited to indicators proposed for Millennium Development Goals 4 and 5. We identified 18 articles, whereof 15 evaluated various incentive programs, two evaluated a targeted policy intervention, and only one study evaluated an intervention addressing a cultural custom. Meta-analyses of the effectiveness of incentives programs showed a pooled effect size of RR 1.66 (95% CI 1.43-1.93) for antenatal care attendance (four studies with 2,476 participants) and RR 2.37 (95% CI 1.38-4.07) for health facility delivery (five studies with 25,625 participants). Meta-analyses were not performed for any of the other outcomes due to scarcity of studies. The targeted interventions aiming to improve maternal and child health are mainly limited to addressing economic disparities through various incentive schemes like conditional cash transfers and voucher schemes. This is a feasible strategy to reduce inequity based on income. More innovative action-oriented research is needed to speed up progress in maternal and child survival among the most disadvantaged populations through interventions targeting the underlying structural determinants of inequity.


Species delimitation analyses of NE Atlantic Chaetozone (Annelida, Cirratulidae) reveals hidden diversity among a common and abundant marine annelid.
The polychaetes of the family Cirratulidae (Annelida) are common inhabitants in continental shelf benthic environments and considered an important group of organisms in environmental monitoring surveys. The family represents a taxonomic and systematic challenge, as monophyly of genera and evolutionary relationships within the family remain to be explored in a proper phylogenetic framework. Bitentaculate cirratulids, especially the genus Chaetozone, form one of the most species-diverse group of polychaetes worldwide. In this study, we aimed at evaluating the species diversity of the genus Chaetozonein benthic environments in the North East Atlantic by molecular means. We tested whether traditional morphological diagnostic characters are able to discriminate between the species hypothesis after species delimitation analyses, and assessed monophyly of the genera involved. Two DNA markers were sequenced from about 200 specimens belonging to Chaetozone, Aphelochaeta, Dodecaceria, Cirriformia and Cirratulus - the universal mitochondrial barcoding region COI, and the D1-D2 regions of the nuclear 28S rRNA - and analyzed with Bayesian inference, Maximum Likelihood and the species delimitation methods mPTP and GMYC. The first phylogeny of the family Cirratulidae is inferred and the genera Chaetozone, Dodecaceria and Cirratulus are recovered monophyletic. A total of 14 clusters of sequences - corresponding to species of Chaetozone - were found in the study area, and only one of them is here referred to a nominal species, Chaetozone setosa. Our results reveal several species complexes in the genus Chaetozone, that some of these independent lineages are unnamed and undescribed, and that morphological diagnostic features are in most cases unable to discriminate between the most similar species.


Augmentation of rat alveolar macrophage migration by surfactant protein.
Since the alveolar macrophage (AM) resides in an environment made unique by the presence of pulmonary surfactant, we studied the effect of constituents of pulmonary surfactant on the migration of these cells in vitro. Whole pulmonary surfactant, surfactant phospholipids, and a delipidated preparation of surfactant consisting mainly of protein were tested for their effect on AM migration. Migration was measured in multiwell chemotaxis chambers with endotoxin-activated rat serum (EARS) as the stimulus. The delipidated surfactant material (DSM) markedly augmented the migration of rat AM. Enhancement was seen only when migration was stimulated with EARS. Augmentation of stimulated migration occurred over a wide range of protein concentrations in DSM (3.5 to 56 micrograms/ml) in a dose-dependent fashion. Rat AM that were preincubated with DSM and then tested in the chemotaxis assay without DSM showed increased migration towards EARS when compared with AM preincubated in buffer alone. The enhancing effect of DSM on AM migration was significantly diminished by heating the DSM and by enzymatic digestion with trypsin, suggesting that the active constituent in DSM was protein. Thus, it appears that proteins isolated from pulmonary surfactant augment the stimulated migration of AM via an interaction between the protein and the macrophage. Although the identity of these proteins remains to be elucidated, it is unlikely they include albumin since purified rat serum albumin in concentrations comparable to that of protein in DSM did not enhance the stimulated migration of AM. These results represent further confirmation that constituents of surfactant modulate the clearance function of AM in vitro. Thus, it is likely that surfactant plays a role in lung defense mediated by AM.


Epidemiology of eating disorders: a two year follow up in an early adolescent school population.
The aims of this study were to determine the prevalence of eating disorders (ED) in a representative school population of early adolescents of both sexes and to evaluate persistence and incidence after two years. An initial sample of 1336 (mean age = 11.37) was assessed in a two-phase design. The Children Eating Attitudes Test was used to select 258 participants (T1) from the initial sample who were followed-up two years later (T2; n = 200). Diagnoses of ED were obtained using the Diagnostic Interview for Children and Adolescents- Children and Parent Version (DICA-C and DICA-P) at T1, and Adolescent Version (DICA-A) at T2. At T2, participants were also assessed with the Eating Attitudes Test, the Bulimic Investigatory Test, and the Eating Disorders Inventory. The Body mass index (BMI) was obtained for all participants. The estimated prevalence of any ED according to DICA-C (T1) and DICA-A was 3.44% and 3.81%, respectively. The most frequent diagnoses were syndromes that were not full-blown. Biannual incidence of any ED was 2.02%. Amongst those with an ED, 52.17% persisted. Females showed a higher incidence and persistence of any ED than males. Participants who had the highest BMI were those who had a persistent diagnosis of ED. ED that began at early ages in less severe forms and in females often persisted with increasing severity.


Active recovery training does not affect the antioxidant response to soccer games in elite female players.
Changes in plasma endogenous and dietary antioxidants and oxidative stress markers were studied following two 90 min elite female soccer games separated by 72 h of either active or passive recovery. The active recovery group (n 8) trained for 1 h at 22 and 46 h after the first game (low-intensity cycling and resistance training), while the passive group rested (n 8). Blood samples were taken before the games; immediately after the games; 21, 45 and 69 h after the first game; and immediately after the second game. The oxidative stress markers and antioxidants were not affected by active recovery. The oxidative stress marker GSSG increased by the same extent after both the games, while the lipid peroxidation marker diacron-reactive oxygen metabolite remained unchanged. The endogenous antioxidants total glutathione and uric acid and ferric reducing/antioxidant power increased immediately after both the games with the same amplitude, while increases in cysteine, cysteine-glycine and total thiols reached significant levels only after the second game. The changes in dietary antioxidants after the first game were either rapid and persistent (tocopherols and ascorbic acid (AA) increased; polyphenols decreased) or delayed (carotenoids). This resulted in high pre-second game levels of tocopherols, AA and carotenoids. Polyphenols returned to baseline at 69 h, and were not affected by the second game. In conclusion, the soccer-associated dietary antioxidant defence, but not the endogenous antioxidant defence, is persistent. Similar acute oxidative stress and endogenous antioxidant responses and dissimilar dietary antioxidant reactions occur during two repeated female soccer games. Finally, the complex antioxidant response to soccer is not affected by active recovery training.


OPERA-LG: efficient and exact scaffolding of large, repeat-rich eukaryotic genomes with performance guarantees.
The assembly of large, repeat-rich eukaryotic genomes represents a significant challenge in genomics. While long-read technologies have made the high-quality assembly of small, microbial genomes increasingly feasible, data generation can be expensive for larger genomes. OPERA-LG is a scalable, exact algorithm for the scaffold assembly of large, repeat-rich genomes, out-performing state-of-the-art programs for scaffold correctness and contiguity. It provides a rigorous framework for scaffolding of repetitive sequences and a systematic approach for combining data from different second-generation and third-generation sequencing technologies. OPERA-LG provides an avenue for systematic augmentation and improvement of thousands of existing draft eukaryotic genome assemblies.


Current role of radiation therapy for multiple myeloma.
Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors. We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale. Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group. Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.


11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI.
We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1-/- ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'host' myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1-/- mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1-/- mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.


Optimal Lateral Row Anchor Positioning in Posterior-Superior Transosseous Equivalent Rotator Cuff Repair: A Micro-Computed Tomography Study.
The optimal placement of suture anchors in transosseous-equivalent (TOE) double-row rotator cuff repair remains controversial. A 3-dimensional (3D) high-resolution micro-computed tomography (micro-CT) histomorphometric analysis of cadaveric proximal humeral greater tuberosities (GTs) was performed to guide optimal positioning of lateral row anchors in posterior-superior (infraspinatus and supraspinatus) TOE rotator cuff repair. Descriptive laboratory study. Thirteen fresh-frozen human cadaveric proximal humeri underwent micro-CT analysis. The histomorphometric parameters analyzed in the standardized volumes of interest included cortical thickness, bone volume, and trabecular properties. Analysis of the cortical thickness of the lateral rows demonstrated that the entire inferior-most lateral row, 15 to 21 mm from the summit of the GT, had the thickest cortical bone (mean, 0.79 mm; P = .0001), with the anterior-most part of the GT, 15 to 21 mm below its summit, having the greatest cortical thickness of 1.02 mm (P = .008). There was a significantly greater bone volume (BV; posterior, 74.5 ± 27.4 mm3; middle, 55.8 ± 24.9 mm3; anterior, 56.9 ± 20.7 mm3; P = .001) and BV as a percentage of total tissue volume (BV/TV; posterior, 7.3% ± 2.7%, middle, 5.5% ± 2.4%; anterior, 5.6% ± 2.0%; P = .001) in the posterior third of the GT than in intermediate or anterior thirds. In terms of both BV and BV/TV, the juxta-articular medial row had the greatest value (BV, 87.3 ± 25.1 mm3; BV/TV, 8.6% ± 2.5%; P = .0001 for both) followed by the inferior-most lateral row 15 to 21 mm from the summit of the GT (BV, 62.0 ± 22.7 mm3; BV/TV, 6.1% ± 2.2%; P = .0001 for both). The juxta-articular medial row had the greatest value for both trabecular number (0.3 ± 0.06 mm-1; P = .0001) and thickness (0.3 ± 0.08 μm; P = .0001) with the lowest degree of trabecular separation (1.3 ± 0.4 μm; P = .0001). The structure model index (SMI) has been shown to strongly correlate with bone strength, and this was greatest at the inferior-most lateral row 15 to 21 mm from the summit of the GT (2.9 ± 0.9; P = .0001). The inferior-most lateral row, 15 to 21 mm from the tip of the GT, has good bone stock, the greatest cortical thickness, and the best SMI for lateral row anchor placement. The anterior-most part of the GT 15 to 21 mm below its summit had the greatest cortical thickness of all zones. The posterior third of the GT also has good bone stock parameters, second only to the medial row. The best site for lateral row cortical anchor placement is 15 to 21 mm below the summit of the GT. Optimal lateral anchor positioning is 15 to 21 mm below the summit of the greater tuberosity in TOE.


The cost burden of clinically significant esophageal anastomotic leaks-a steep price to pay.
The purpose of this retrospective cohort study was to evaluate resource consumption of clinically significant esophageal anastomotic leaks. Between September 1, 2008, to December 31, 2014, a prospectively maintained database was queried to identify patients with grade III to IV anastomotic leaks after esophagectomy for esophageal cancer. Inflation-adjusted standardized costs were applied to billed services related to leak diagnosis and treatment, from time of leak detection to resumption of oral diet. A matched analysis was used to compare average expenditures in patients without vs. those with an anastomotic leak. Of 448 patients undergoing esophagectomy after neoadjuvant treatment, 399 patients met inclusion criteria. Twenty-four grade III to IV anastomotic leaks were identified (6% leak rate). Five transhiatal esophagectomies accounted for 20.8% of cases, whereas 9 Ivor Lewis and 10 McKeown esophagectomies accounted for 37.5% and 41.7%, respectively. The median time required to treat an anastomotic leak was 73 days (range 14-701). The additional median standardized cost per leak was $68,296 (mean $119,822). Matched analysis demonstrated that mean treatment costs were 2.6 times greater for patients with an anastomotic leak. This was primarily attributed to prolonged hospitalization, with post-leak detection length of stay ranging from 7 to 73 days. The largest contributors to cost for all patients were intensive care stay (30%), hospital room (17%), pharmacy (16%), and surgical intervention (13%). Grade III to IV esophageal anastomotic leaks more than double the cost of an esophagectomy and have a significant cost burden. Focus should be placed on preventative measures to avoid leaks at the time of the index operation.


SU-E-J-98: 3D Tracking of Interfraction Patient Setup Uncertainties Using Multiple Kinect Sensors.
On-board optical 3D imaging enables measuring daily setup patient uncertainties without involving any additional imaging-induced radiation dose to critical structures. We hypothesize that the tumor and normal organ deformation caused by routine patient head and neck misalignments can be determined by coupling a quantitative patient-specific biomechanical model with quantitative skin surface 3D imaging. A set of 3D cameras are used to track the patient anatomy externally. One of the cameras employed a marker less face recognition and tracking for delineating the region of the patient's face. The location of the face was then shared among the camera controllers in real-time and the anatomical contour that closely matches the face region is selected and integrated to form a single 3D anatomical representation. Patient surface aligning was performed between the patient's external surface obtained from a reference 3D anatomy (simulation CT, MRI, patient surface map from previous fraction) and the above-mentioned camera system to quantify the daily patient setup variations. For each of the 3D patient surface, a point feature histogram (PFH) was first generated. Once the PFH descriptors were generated, a non-rigid iterative closest point registration algorithm that minimizes the difference in the PFH descriptor aligns the patient surface to the reference 3D anatomy. The proposed tracking system was able to track both the patient surface setup uncertainty and the internal anatomy when coupledwith a patient specific biomechanical head and neck model. A 3D head and neck tracking system that monitors the interfraction patient setup uncertainties in the head and neck cancer patient is presented. The aligning process was shown to perform for cases with and without the head immobilization system. The external patient surface manifold and the motion vectors will be coupled to align the biomechanical model using model-guided techniques.


Biomarkers of progression of chronic obstructive pulmonary disease (COPD).
Disease progression of chronic obstructive pulmonary disease (COPD) is variable, with some patients having a relatively stable course, while others suffer relentless progression leading to severe breathlessness, frequent acute exacerbations of COPD (AECOPD), respiratory failure and death. Radiological markers such as CT emphysema index, bronchiectasis and coronary artery calcification (CAC) have been linked with increased mortality in COPD patients. Molecular changes in lung tissue reflect alterations in lung pathology that occur with disease progression; however, lung tissue is not routinely accessible. Cell counts (including neutrophils) and mediators in induced sputum have been associated with lung function and risk of exacerbations. Examples of peripheral blood biological markers (biomarkers) include those associated with lung function (reduced CC-16), emphysema severity (increased adiponectin, reduced sRAGE), exacerbations and mortality [increased CRP, fibrinogen, leukocyte count, IL-6, IL-8, and tumor necrosis factor α (TNF-α)] including increased YKL-40 with mortality. Emerging approaches to discovering markers of gene-environment interaction include exhaled breath analysis [volatile organic compounds (VOCs), exhaled breath condensate], cellular and systemic responses to exposure to air pollution, alterations in the lung microbiome, and biomarkers of lung ageing such as telomere length shortening and reduced levels of sirtuins. Overcoming methodological challenges in sampling and quality control will enable more robust yet easily accessible biomarkers to be developed and qualified, in order to optimise personalised medicine in patients with COPD.


Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy.
To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial. Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (∼10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout. In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment. Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.


Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.
Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.


Photosynthesis and respiration decline with light intensity in dominant and suppressed Eucalyptus globulus canopies.
Within canopy gradients in light-saturated photosynthesis (Amax), foliar nitrogen ([N]area) and leaf dark respiration (R15) were studied in the canopies of dominant and suppressed trees within an even-aged (4-year-old) Eucalyptus globulus (Labill) stand in southern Tasmania. Despite being an even-aged stand growing in a relatively uniform environment with respect to nutrient and water availability, the stand exhibited considerable structural complexity. Diameter at 1.3 m ranged between 3 cm and 21 cm, trees average 12 m height and stand leaf area index was ~6 m2 m-2 leading to strong gradients in light availability. We were interested in understanding the processes governing canopy production in trees of contrasting dominance classes. Vertical gradients in photosynthesis and foliar respiration were studied within the canopies of dominant and suppressed trees during 2006 and 2007. Amax varied from ~18 μmol m-2 s-1 in the upper canopy to 3 μmol m-2 s-1 at lower canopy positions. On average, Amax were higher in the dominant trees than in the suppressed trees. However, at any given height, Amax were similar in suppressed and dominant trees and were strongly related to leaf nitrogen content. Dark respiration varied from ~1.4 μmol m-2 s-1 in the upper canopy to 0.2 μmol m-2 s-1 in the lower canopy positions. In contrast to the patterns for Amax, dark respiration rates in the suppressed trees were higher than dominant trees at similar canopy positions. Respiration rates were also strongly related to [N]area and to Amax.


Electron transfer dissociation in conjunction with collision activation to investigate the Drosophila melanogaster phosphoproteome.
Better understanding how cells are regulated and adapt to their environment based on the reversible phosphorylation of proteins is a key question of current molecular and systems biology research. In this study, an advanced mass spectrometry based approach leveraging the electron transfer dissociation (ETD) technique in combination with CID using a linear ion trap mass spectrometer is described. The technique was applied, for the first time, to the identification of phosphorylated peptides isolated from the Drosophila melanogaster Kc167 cell line. We demonstrate that the method is particularly useful for the characterization of large phosphopeptides, including those with multiple phosphorylation sites, as extensive series of c' and z fragment-ions were observed. Finally, we have applied a directed tandem mass spectrometric workflow using inclusion lists to increase the number of identified peptides.


Growth of Escherichia coli MG1655 on LB medium: monitoring utilization of sugars, alcohols, and organic acids with transcriptional microarrays.
Microorganisms respond to environmental changes by reprogramming their metabolism primarily through altered patterns of gene expression. DNA microarrays provide a tool for exploiting microorganisms as living sensors of their environment. The potential of DNA microarrays to reflect availability of nutrient components during fermentations on complex media was examined by monitoring global gene expression throughout batch cultivation of Escherichia coli MG1655 on Luria-Bertani (LB) medium. Gene expression profiles group into pathways that clearly demonstrate the metabolic changes occurring in the course of fermentation. Functional analysis of the gene expression related to metabolism of sugars, alcohols, and organic acids revealed that E. coli growing on LB medium switches from a sequential mode of substrate utilization to the simultaneous one in the course of the growth. Maltose and maltodextrins are the first of these substrates to support growth. Utilization of these nutrients associated with the highest growth rate of the culture was followed by simultaneous induction of enzymes involved in assimilation of a large group of other carbon sources including D-mannose, melibiose, D-galactose, L-fucose, L-rhamnose, D-mannitol, amino sugars, trehalose, L-arabinose, glycerol, and lactate. Availability of these nutrients to the cells was monitored by induction of corresponding transport and/or catabolic systems specific for each of the compounds.


Ethylene polymerization catalyzed by bridging Ni/Zn heterobimetallics.
The effect of proximal Zn halides on Ni-catalyzed ethylene polymerization is reported in this work. A series of (NON)NiLX (NON = 2,6-bis-((2,6-diisopropylphenyl)imino)methyl phenoxide; LX = methallyl or L = py, X = tolyl, 2-4) ethylene polymerization precatalysts have been synthesized, as well as a heterobimetallic Ni/Zn complex, (NON)Ni(C4H7)ZnBr2 (5). Each precatalyst could be activated (or promoted) by ZnX2 (X = Cl, Br, Et) to polymerize ethylene. In situ recruitment of ZnX2 by the free imine binding pocket of the NON complexes results in the generation of heterobimetallic active species that produce lower Mn polyethylene than monometallic controls. Room temperature ZnX2-promoted polymerizations with these catalysts resulted in bimodal Mn distributions that result from different catalyst speciation: "dangling" imine-ligated ZnX2 species yield higher Mn polymer while N,O-chelated ZnX2 species yield lower Mn polymer. Running polymerizations at higher temperature yields in only lower Mn polymer resulting from exclusive formation of the thermodynamically favored N,O chelated Ni/Zn heterobimetallic. DFT calculations indicate that this bridging bimetallic complex undergoes β-H elimination more facilely than monometallic Ni analogues, resulting in lower molecular weight polymers.


Development and validation of stroke risk equation for Hong Kong Chinese patients with type 2 diabetes: the Hong Kong Diabetes Registry.
We sought to develop stroke risk equations for Chinese patients with type 2 diabetes in Hong Kong. A total of 7,209 Hong Kong Chinese type 2 diabetic patients without a history of stroke at baseline were analyzed. The data were randomly and evenly divided into the training subsample and the test subsample. In the training subsample, stepwise Cox models were used to develop the risk equation. Validation of the U.K. Prospective Diabetes Study (UKPDS) stroke risk engine and the current stroke equation was performed in the test dataset. The life-table method was used to check calibration, and the area under the receiver operating characteristic curve (aROC) was used to check discrimination. A total of 372 patients developed incident stroke during a median of 5.37 years (interquartile range 2.88-7.78) of follow-up. Age, A1C, spot urine albumin-to-creatinine ratio (ACR), and history of coronary heart disease (CHD) were independent predictors. The performance of the UKPDS stroke engine was suboptimal in our cohort. The newly developed risk equation defined by these four predictors had adequate performance in the test subsample. The predicted stroke-free probability by the current equation was within the 95% CI of the observed probability. The aROC was 0.77 for predicting stroke within 5 years. The risk score was computed as follows: 0.0634 x age (years) + 0.0897 x A1C + 0.5314 x log(10) (ACR) (mg/mmol) + 0.5636 x history of CHD (1 if yes). The 5-year stroke probability can be calculated by: 1 - 0.9707(EXP (Risk Score - 4.5674)). Although the risk equation performed reasonably well in Chinese type 2 diabetic patients, external validation is required in other populations.


Are rates of pediatric bipolar disorder increasing? Results from a nationwide register study.
Studies from the USA suggest that rates of pediatric bipolar disorder have increased since the mid-90s, but no study outside the USA has been published on the rates of pediatric bipolar disorder. Further, it is unclear whether an increase in rates reflects a true increase in the illness or more diagnostic attention. Using nationwide registers of all inpatients and outpatients contacts to all psychiatric hospitals in Denmark, we investigated (1) gender-specific rates of incident pediatric mania/bipolar disorder during a period from 1995 to 2012, (2) whether age and other characteristics for pediatric mania/bipolar disorder changed during the calendar period (1995 to 2003 versus 2004 to 2012), and (3) whether the diagnosis is more often made at first psychiatric contact in recent time compared to earlier according to gender. Totally, 346 patients got a main diagnosis of a manic episode (F30) or bipolar affective disorder (F31) at least once during the study period from 1995 to 2012. For both sexes, annual rates of mania/bipolar disorder two to four doubled during the study period (0.001% before year 2004 to 0.002%-0.004% in 2010). Median age at the index diagnosis was very similar during the two calendar periods (17.2, quartiles, 16.2-18.3 versus 17.4, quartiles, 16.1-18.2) indicating that the diagnosis of mania/bipolar disorder was not made earlier in the recent calendar period. Similarly, there were no differences between early versus late in the study period in the fractions of first contact diagnosis of mania/bipolar disorder diagnoses, the contact number at which patients got the diagnosis or the duration from first psychiatric contact to the diagnosis of mania/bipolar disorder. The rate of diagnosis of mania/bipolar disorder increased from 1995 to 2014, which did not seem to be explained by more diagnostic attention.


Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants.
Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).


Internalization dissociates β2-adrenergic receptors.
G protein-coupled receptors (GPCRs) self-associate as dimers or higher-order oligomers in living cells. The stability of associated GPCRs has not been extensively studied, but it is generally thought that these receptors move between the plasma membrane and intracellular compartments as intact dimers or oligomers. Here we show that β(2)-adrenergic receptors (β(2)ARs) that self-associate at the plasma membrane can dissociate during agonist-induced internalization. We use bioluminescence-resonance energy transfer (BRET) to monitor movement of β(2)ARs between subcellular compartments. BRET between β(2)ARs and plasma membrane markers decreases in response to agonist activation, while at the same time BRET between β(2)ARs and endosome markers increases. Energy transfer between β(2)ARs is decreased in a similar manner if either the donor- or acceptor-labeled receptor is mutated to impair agonist binding and internalization. These changes take place over the course of 30 minutes, persist after agonist is removed, and are sensitive to several inhibitors of arrestin- and clathrin-mediated endocytosis. The magnitude of the decrease in BRET between donor- and acceptor-labeled β(2)ARs suggests that at least half of the receptors that contribute to the BRET signal are physically segregated by internalization. These results are consistent with the possibility that β(2)ARs associate transiently with each other in the plasma membrane, or that β(2)AR dimers or oligomers are actively disrupted during internalization.


Improved out-of-hospital cardiac arrest survival through the inexpensive optimization of an existing defibrillation program: OPALS study phase II. Ontario Prehospital Advanced Life Support.
Survival rates for out-of-hospital cardiac arrest are low; published survival rates in Ontario are only 2.5%. This study represents phase II of the Ontario Prehospital Advanced Life Support (OPALS) study, which is designed to systematically evaluate the effectiveness and efficiency of various prehospital interventions for patients with cardiac arrest, trauma, and critical illnesses. To assess the impact on out-of-hospital cardiac arrest survival of the implementation of a rapid defibrillation program in a large multicenter emergency medical services (EMS) system with existing basic life support and defibrillation (BLS-D) level of care. Controlled clinical trial comparing survival for 36 months before (phase I) and 12 months after (phase II) system optimization. Nineteen urban and suburban Ontario communities (populations ranging from 16 000 to 750 000 [total, 2.7 million]). All patients who had out-of-hospital cardiac arrest in the study communities for whom resuscitation was attempted by emergency responders. Study communities optimized their EMS systems to achieve the target response interval from when a call was received until a vehicle stopped with a defibrillator of 8 minutes or less for 90% of cardiac arrest cases. Working both locally and provincially, communities implemented multiple measures, including defibrillation by firefighters, base paging, tiered response agreements with fire departments, continuous quality improvement for response intervals, and province-wide revision and implementation of standard dispatch policies. All response times were obtained from a central dispatch system. Survival to hospital discharge. The 4690 cardiac arrest patients studied in phase I and the 1641 in phase II were similar for all clinical and demographic characteristics, including age, sex, witnessed status, rhythm, and receipt of bystander cardiopulmonary resuscitation. The proportion of cases meeting the 8-minute response criterion improved (76.7% vs 92.5%; P<.001) as did most median response intervals. Overall survival to hospital discharge for all rhythm groups combined improved from 3.9% to 5.2 % (P = .03). The 33% relative increase in survival represents an additional 21 lives saved each year in the study communities (approximately 1 life per 120000 residents). The charges were estimated to be US $46900 per life saved for establishing the rapid defibrillation program and US $2400 per life saved annually for maintaining the program. An inexpensive, multifaceted system optimization approach to rapid defibrillation can lead to significant improvements in survival after cardiac arrest in a large BLS-D EMS system.


Who receives their complex cancer surgery at low-volume hospitals?
Previous literature has consistently shown worse operative outcomes at low-volume hospitals (LVH) after complex cancer surgery. Whether patient-related factors impact this association remains unknown. We hypothesize that patient-related factors contribute to receipt of complex cancer surgery at LVH. Using the 2003-2008 National Inpatient Sample, we identified 59,841 patients who underwent cancer operations for lung, esophagus, and pancreas tumors. Logistic regression models were used to examine the impact of sociodemographic factors on receipt of complex cancer surgery at LVH. Overall, 38.4% received their cancer surgery at LVH. A higher proportion of esophagectomies were performed at LVH (70.3%), followed by pancreatectomy (38.2%) and lung resection (33.8%). Patients who were non-white, with non-private insurance, and had more comorbidities were all more likely to receive their cancer surgery at LVH (for all, p < 0.05). Multivariate analyses continued to demonstrate that non-white race, insurance status, increased comorbidities, region, and nonelective admission predicted receipt of cancer surgery at LVH across all 3 procedures. In this large national study, non-white race and increased comorbidities contributed to receipt of cancer surgery at LVH. Patient selection and access to high-volume hospitals are likely reasons worthy of additional investigation. This study provides additional insight into the volume-outcomes relationship. Given the demonstrated outcomes disparity between high-volume hospitals and LVH, future policy and research should encourage mechanisms for referral of patients with cancer to high-volume hospitals for their surgical care.


Predictors for the development of post-thrombotic syndrome in patients with primary lower limb deep venous thrombosis: A case-control study.
Introduction Post-thrombotic syndrome is a common and debilitating sequelae of lower limb deep venous thrombosis. Very little awareness is present about the risk factors and about the diagnosis, prevention, and treatment of this condition. Objective The objective of this study is to identify the predictors of post-thrombotic syndrome after lower limb deep venous thrombosis. Materials and methods A case-control study was conducted on all adult patients who were admitted with lower limb deep venous thrombosis at our institution from January 2005 to June 2012. These patients were scheduled for a research clinic visit, which included informed consent, data collection, and physical examination. Patients found to have post-thrombotic syndrome served as cases and those without post-thrombotic syndrome served as controls. Villalta scoring system was used to diagnose the post-thrombotic syndrome and then to assess the severity of the condition in both the groups. Cox regression risk factor analysis was performed to identify the predictors of post-thrombotic syndrome. Results Out of the 125 patients examined, 49 were found to have post-thrombotic syndrome. Risk factors found to be significant were body mass index of more than 35 kg/m2 ( n = 13, p = 0.003), history of immobilization ( n = 19, p = 0.003), one or more hypercoagable disorders ( n = 32, p = 0.02), iliofemoral deep venous thrombosis ( n = 18, p = 0.001), complete obstruction on ultrasound ( n = 26, p = 0.016), unstable range of international normalized ratio ( n = 23, p = 0.041) and non-compliance for the use of compressions stockings ( n = 14, p = 0.001). On multivariate analysis, one or more hypercoagable disorder, iliofemoral deep venous thrombosis, and non-compliance to the use of compression stockings were found to be independent risk factors for the development of post-thrombotic syndrome. Conclusion One or more hypercoagable disorders, iliofemoral deep venous thrombosis and non-compliance to the use of compression stockings were independent predictors of post-thrombotic syndrome after deep venous thrombosis. These findings will help prognosticate and prevent development of PTS in similar patient populations.


Sensory electrical stimulation for suppression of postural tremor in patients with essential tremor.
Essential tremor is an involuntary trembling of body limbs in people without tremor-related disease. In previous study, suppression of tremor by sensory electrical stimulation was confirmed on the index finger. This study investigates the effect of sensory stimulation on multiple segments and joints of the upper limb. It denotes the observation regarding the effect's continuity after halting the stimulation. 18 patients with essential tremor (8 men and 10 women) participated in this study. The task, "arms stretched forward", was performed and sensory electrical stimulation was applied on four muscles of the upper limb (Flexor Carpi Radialis, Extensor Carpi Radialis, Biceps Brachii, and Triceps Brachii) for 15 seconds. Three 3-D gyro sensors were used to measure the angular velocities of segments (finger, hand, and forearm) and joints (metacarpophalangeal and wrist joints) for three phases of pre-stimulation (Pre), during-stimulation (On), and 5 minute post-stimulation (P5). Three characteristic variables of root-mean-squared angular velocity, peak power, and peak power frequency were derived from the vector sum of the sensor signals. At On phase, RMS velocity was reduced from Pre in all segments and joints while peak power was reduced from Pre in all segments and joints except for forearm segment. Sensory stimulation showed no effect on peak power frequency. All variables at P5 were similar to those at On at all segments and joints. The decrease of peak power of the index finger was noted by 90% during stimulation from that of On phase, which was maintained even after 5 min. The results indicate that sensory stimulation may be an effective clinical method to treat the essential tremor.


Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria.
Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000 pharmacological agents and identified 4 compounds (I-IV) that enhanced the thermal stability of PAH and did not show substantial inhibition of PAH activity. In further studies, compounds III (3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one) and IV (5,6-dimethyl-3-(4-methyl-2-pyridinyl)-2-thioxo-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one) stabilized the functional tetrameric conformation of recombinant WT-PAH and PKU mutants. These compounds also significantly increased activity and steady-state PAH protein levels in cells transiently transfected with either WT-PAH or PKU mutants. Furthermore, PAH activity in mouse liver increased after a 12-day oral administration of low doses of compounds III and IV. Thus, we have identified 2 small molecules that may represent promising alternatives in the treatment of PKU.


[Pharmacoeconomic evaluation of pravastatin in coronary secondary prevention in patients with myocardial infarct or unstable angina pectoris. An analysis based on the LIPID Study].
Secondary coronary prevention with lipid lowering drugs have become a major issue in health policy formulation due to the large upfront investment in drug therapy. The recently completed LIPID trial with pravastatin in secondary prevention immediately raise the question whether pravastatin might be cost-effective in Switzerland. We conducted a cost-effectiveness analysis from the perspective of third party payers. The following costs were included in the analysis: daily treatment costs of pravastatin, non fatal myocardial infarction, coronary bypass operations and stroke. Life years gained was obtained by applying the declining exponential approximation of life expectancy. All calculations were standardized to 1000 treated patients. The net costs of treating 1000 patients (i.e. drug costs minus the costs of sequelae and interventions) are Fr. 3.6 Mio. In addition, a total of 430 life-years may be saved through treatment. The corresponding cost-effectiveness of pravastatin treatment is Fr. 8341 (nominal) Fr. 6985 (discounted). The results suggest that the cost-effectiveness of pravastatin in secondary prevention lie well within the threshold of other commonly accepted medical interventions and may be considered an economically viable approach for secondary coronary prevention.


Anticipating global terrestrial ecosystem state change using FLUXNET.
Ecosystems can be characterized as complex systems that traverse a variety of functional and structural states in response to changing bioclimatic forcings. A central challenge of global change biology is the robust empirical description of these states and state transitions. An ecosystem's functional state can be empirically described using Process Networks (PN) that use timeseries observations to determine the strength of process-level functional couplings between ecosystem components. A globally extensive source of in-situ observations of terrestrial ecosystem dynamics is the FLUXNET eddy-covariance network that provides standardized observations of micrometeorology and carbon, water, and energy flux dynamics. We employ the LaThuile FLUXNET synthesis dataset to delineate each month's functional state for 204 sites, yielding the LaThuile PN version 1.0 database that describes the strength of an ecosystem's functional couplings from air temperature and precipitation to carbon fluxes during each site-month. Then we calculate the elasticity of these couplings to seasonal scale forcings: air temperature, precipitation, solar radiation, and phenophase. Finally, we train artificial neural networks to extrapolate these elasticities from 204 sites to the globe, yielding maps of the estimated functional elasticity of every terrestrial ecosystem's functional states to changing seasonal bioclimatic forcings. These maps provide theoretically novel resource that can be used to anticipate ecological state transitions in response to climate change and to validate process-based models of ecological change. These elasticity maps show that each ecosystem can be expected to respond uniquely to changing forcings. Tropical forests, hot deserts, savannas, and high elevations are most elastic to climate change, and elasticity of ecosystems to seasonal air temperature is on average an order of magnitude higher than elasticity to other bioclimatic forcings. We also observed a reasonable amount of moderate relationships between functional elasticity and structural state change across different ecosystems.


Disability progression in a clinical trial of relapsing-remitting multiple sclerosis: eight-year follow-up.
To investigate the value of Expanded Disability Status Scale (EDSS) worsening sustained for at least 6 months and other parameters as predictors for disability status. Retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data. The intramuscular interferon beta-1a pivotal trial was a double-blind, placebo-controlled phase 3 study. Patients with relapsing-remitting multiple sclerosis who received at least 2 years of treatment and completed an EDSS evaluation 8 years postrandomization. Thirty micrograms of intramuscular interferon beta-1a or placebo once weekly during the 2-year clinical trial. Positive predictive values for 6-month sustained progression during 2 years were calculated to determine the ability to predict disability status at 8 years. A multivariate logistic regression model was used to assess the relationship between predictors and EDSS milestones at follow-up. Forty-five patients had sustained 6-month EDSS progression during the clinical trial and 115 did not. Progression during the trial was the strongest predictor of reaching EDSS milestones at the follow-up visit, 8 years after randomization. Other independent predictors were treatment arm assignment and baseline EDSS score. In this phase 3 clinical trial of intramuscular interferon beta-1a, compared with effects of treatment, baseline EDSS score, and number of relapses during the study, worsening of 1 point or more on EDSS from baseline lasting 6 months was the strongest predictor of clinically significant disability 8 years after randomization into the clinical trial.


Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome.
Recent evidence has shown that the sperm epigenome is vulnerable to dynamic modifications arising from a variety of paternal environment exposures and that this legacy can serve as an important determinant of intergenerational inheritance. It has been postulated that such exchange is communicated to maturing spermatozoa via the transfer of small non-protein-coding RNAs (sRNAs) in a mechanism mediated by epididymosomes; small membrane bound vesicles released by the soma of the male reproductive tract (epididymis). Here we confirm that mouse epididymosomes encapsulate an impressive cargo of >350 microRNAs (miRNAs), a developmentally important sRNA class, the majority (~60%) of which are also represented by the miRNA signature of spermatozoa. This includes >50 miRNAs that were found exclusively in epididymal sperm and epididymosomes, but not in the surrounding soma. We also documented substantial changes in the epididymosome miRNA cargo, including significant fold changes in almost half of the miRNAs along the length of the epididymis. Finally, we provide the first direct evidence for the transfer of several prominent miRNA species between mouse epididymosomes and spermatozoa to afford novel insight into a mechanism of intercellular communication by which the sRNA payload of sperm can be selectively modified during their post-testicular maturation.