A pilot study of surgical training using a virtual robotic surgery simulator.
Our objectives were to compare the utility of learning a suturing task on the virtual reality da Vinci Skills Simulator versus the da Vinci Surgical System dry laboratory platform and to assess user satisfaction among novice robotic surgeons. Medical trainees were enrolled prospectively; one group trained on the virtual reality simulator, and the other group trained on the da Vinci dry laboratory platform. Trainees received pretesting and post-testing on the dry laboratory platform. Participants then completed an anonymous online user experience and satisfaction survey. We enrolled 20 participants. Mean pretest completion times did not significantly differ between the 2 groups. Training with either platform was associated with a similar decrease in mean time to completion (simulator platform group, 64.9 seconds [P = .04]; dry laboratory platform group, 63.9 seconds [P < .01]). Most participants (58%) preferred the virtual reality platform. The majority found the training "definitely useful" in improving robotic surgical skills (mean, 4.6) and would attend future training sessions (mean, 4.5). Training on the virtual reality robotic simulator or the dry laboratory robotic surgery platform resulted in significant improvements in time to completion and economy of motion for novice robotic surgeons. Although there was a perception that both simulators improved performance, there was a preference for the virtual reality simulator. Benefits unique to the simulator platform include autonomy of use, computerized performance feedback, and ease of setup. These features may facilitate more efficient and sophisticated simulation training above that of the conventional dry laboratory platform, without loss of efficacy.


Oral antidiabetic agents: current role in type 2 diabetes mellitus.
Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.


Hypernetwork-Based Physics-Driven Personalized Federated Learning for CT Imaging.
In clinical practice, computed tomography (CT) is an important noninvasive inspection technology to provide patients' anatomical information. However, its potential radiation risk is an unavoidable problem that raises people's concerns. Recently, deep learning (DL)-based methods have achieved promising results in CT reconstruction, but these methods usually require the centralized collection of large amounts of data for training from specific scanning protocols, which leads to serious domain shift and privacy concerns. To relieve these problems, in this article, we propose a hypernetwork-based physics-driven personalized federated learning method (HyperFed) for CT imaging. The basic assumption of the proposed HyperFed is that the optimization problem for each domain can be divided into two subproblems: local data adaption and global CT imaging problems, which are implemented by an institution-specific physics-driven hypernetwork and a global-sharing imaging network, respectively. Learning stable and effective invariant features from different data distributions is the main purpose of global-sharing imaging network. Inspired by the physical process of CT imaging, we carefully design physics-driven hypernetwork for each domain to obtain hyperparameters from specific physical scanning protocol to condition the global-sharing imaging network, so that we can achieve personalized local CT reconstruction. Experiments show that HyperFed achieves competitive performance in comparison with several other state-of-the-art methods. It is believed as a promising direction to improve CT imaging quality and personalize the needs of different institutions or scanners without data sharing. Related codes have been released at https://github.com/Zi-YuanYang/HyperFed.


Definition of global and transcript-specific mRNA export pathways in metazoans.
Eukaryotic gene expression requires export of messenger RNAs (mRNAs) from their site of transcription in the nucleus to the cytoplasm where they are translated. While mRNA export has been studied in yeast, the complexity of gene structure and cellular function in metazoan cells has likely led to increased diversification of these organisms' export pathways. Here we report the results of a genome-wide RNAi screen in which we identify 72 factors required for polyadenylated [poly-(A(+))] mRNA export from the nucleus in Drosophila cells. Using structural and functional conservation analysis of yeast and Drosophila mRNA export factors, we expose the evolutionary divergence of eukaryotic mRNA export pathways. Additionally, we demonstrate the differential export requirements of two endogenous heat-inducible transcripts--intronless heat-shock protein 70 (HSP70) and intron-containing HSP83--and identify novel export factors that participate in HSP83 mRNA splicing. We characterize several novel factors and demonstrate their participation in interactions with known components of the Drosophila export machinery. One of these factors, Drosophila melanogaster PCI domain-containing protein 2 (dmPCID2), associates with polysomes and may bridge the transition between exported messenger ribonucleoprotein particles (mRNPs) and polysomes. Our results define the global network of factors involved in Drosophila mRNA export, reveal specificity in the export requirements of different transcripts, and expose new avenues for future work in mRNA export.


Drug induced intracranial hypertension associated with sulphasalazine treatment.
A 25-year-old female patient developed headache and papilledema under sulphasalazine treatment for ulcerative colitis. The patient met the International Headache Society's criteria for idiopathic intracranial hypertension. Sulphasalazine was discontinued and the patient was given azathioprine for ulcerative colitis and acetazolamide for intracranial hypertension. Three weeks later, her examination was normal and lumbar puncture revealed an opening pressure of 180-mm H(2)O. Sulphasalazine is a product of 5 aminosalicylate (5 ASA) and there seems to be a relationship between the administration of sulphasalazine and the onset of intracranial hypertension symptoms. Early diagnosis of intracranial hypertension is important in patients with ulcerative colitis receiving 5 ASA treatment to prevent visual complications.


Robust Microplate-Based Methods for Culturing and in Vivo Phenotypic Screening of Chlamydomonas reinhardtii.
Chlamydomonas reinhardtii (Cr), a unicellular alga, is routinely utilized to study photosynthetic biochemistry, ciliary motility, and cellular reproduction. Its minimal culture requirements, unicellular morphology, and ease of transformation have made it a popular model system. Despite its relatively slow doubling time, compared with many bacteria, it is an ideal eukaryotic system for microplate-based studies utilizing either, or both, absorbance as well as fluorescence assays. Such microplate assays are powerful tools for researchers in the areas of toxicology, pharmacology, chemical genetics, biotechnology, and more. However, while microplate-based assays are valuable tools for screening biological systems, these methodologies can significantly alter the conditions in which the organisms are cultured and their subsequent physiology or morphology. Herein we describe a novel method for the microplate culture and in vivo phenotypic analysis of growth, viability, and photosynthetic pigments of C. reinhardtii. We evaluated the utility of our assay by screening silver nanoparticles for their effects on growth and viability. These methods are amenable to a wide assortment of studies and present a significant advancement in the methodologies available for research involving this model organism.


YopM inhibits platelet aggregation and is necessary for virulence of Yersinia pestis in mice.
In Yersinia pestis KIM there are 11 Yops (yersinial outer membrane proteins) encoded by the low-Ca2+ response virulence plasmid pCD1. Only YopM and YopN are found in easily detectable amounts in the culture medium. In our previous work, we characterized the yopM gene. In the present study, we constructed a YopM- mutant to elucidate the role of YopM in the virulence of Y. pestis. A lacZYA sequence was inserted 126 base pairs downstream from the start codon of the yopM gene in pCD1. The YopM- mutant had the same growth properties as the parent, Y. pestis KIM5-3001. The inserted lacZ gene was regulated by the promoter of the yopM gene. Accordingly, it was expressed strongly at 37 degrees C in the absence of Ca2+ and was decreased in expression when Ca2+ was present. Northern blot (RNA blot) analysis revealed that the yopM gene was in a monocistronic operon, suggesting that the yopM insertion mutation was unlikely to have polar effects on other genes. The YopM- mutant had strongly decreased virulence in mice, with a 50% lethal dose of 3.4 x 10(5) CFU. Virulence was restored by the cloned yopM-containing 5.5-kilobase HindIII F fragment of pCD1. However, supplying a cloned 1.57-kilobase fragment containing little more than the yopM structural gene caused the yopM mutant to significantly overexpress YopM and failed to restore virulence. The infection kinetics of the YopM- mutant revealed growth in both spleens and livers from days 2 to 4 after infection, followed by a precipitous clearance of the bacteria. YopM-containing supernatant proteins of Y. pestis inhibited thrombin- or ristocetin-induced platelet aggregation, whereas there was no inhibition by supernatant proteins from the YopM- Y. pestis mutant. Accordingly, YopM may prevent platelet-mediated events and serve as an important strategy for the yersiniae in the initial stages of a plague infection.


IMRT/VMAT for malignancies in the head-and-neck region : Outcome in patients aged 80.
Elderly patients with malignant head-and-neck tumors (HNT) often pose a therapeutic challenge. They frequently have significant comorbidities which may influence their ability to tolerate tumor-specific therapies. Our aim was to investigate the outcome of patients aged 80+ years undergoing curative intent intensity- or volume-modulated radiation therapy (IMRT/VMAT). We retrospectively reviewed our HNT patients aged 80+ treated with curative IMRT/VMAT from December 2003 to November 2015. Overall survival (OS), disease-free survival (DFS), local control (LC), and treatment tolerance were assessed. Outcome results were compared with that of a younger HNT patient cohort from our hospital. A total of 140 consecutive patients were included (65 postoperative, 75 definitive). Mean/median age at treatment start was 84.8/84.1 years (range 80-96 years). Mean/median follow-up time was 25/16 months (range 2-92 months). Of the 140 patients, 80 were alive with no evidence of disease when last seen, 28 had died due to the cancer, 12 remained alive with disease, the remaining 20 died intercurrently. Systemic concomitant therapy was administered in 7 %. Late grade 3-4 toxicity was observed in 2 %. All patients completed treatment. Hospitalization and feeding tube rates were 26 % and 11 %, respectively. The 2‑/3-year LC, DFS, and OS rates for the entire cohort were 81/80 %, 69/63 %, and 68/66 %, respectively. Squamous cell carcinoma (SCC) patients showed an inferior 3-year OS rate as compared to non-SCC patients (62 % vs 77 %, p = 0.0002), while LC and DFS did not differ. Patients undergoing postoperative radiation attained a higher OS compared to the definitively irradiated subgroup with 74 vs. 60 % at 3 years (p = 0.01); however, DFS rates were similar for both groups (68 vs. 61 %, p = 0.15). Corresponding rates for >1400 HNT patients <80 years treated during the same time interval were 81/80 %, 69/67 %, and 77/72 %, respectively. Treatment tolerance in our patients aged 80+ was high. These results suggest that elderly HNT patients should not be denied potentially curative treatment strategies.


Exploring parents' use of strategies to promote social participation of school-age children with acquired brain injuries.
To understand parents' perspectives about the strategies they use to promote social participation of their school-age children with acquired brain injuries (ABI) in home, school, and community life. A descriptive research design employing a semistructured interview format was used. Interviews were conducted in the homes of 16 families of school-age children with ABI discharged up to 7 years earlier from one inpatient rehabilitation program. Data were examined using content and constant-comparison analyses. Parents needed time to allow the recovery process to unfold for themselves and their children and developed strategies that fit into or assisted with managing family routines. Over time parents developed insight into the activity demands and their child's potential success to participate in desired activities. Based on these insights, parents used "anticipatory planning," which involved previewing upcoming events and activities and using strategies to promote positive and prevent negative experiences for their children. Specific strategies that parents used to promote social participation were classified into three categories: Creating opportunities, teaching skills, and regulating cognitive and behavioral function. Understanding how families use and integrate strategies within the context of their daily lives and what factors influence strategy use may provide practitioners with insights needed to support families in promoting their children's social participation.


Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes.
The role of reactive oxygen species (ROS) and their dissipation in type 1 diabetes pathogenesis have garnered considerable controversy. Our recent work has demonstrated the importance of NADPH oxidase (NOX) activity for type 1 diabetes development and modulating T-cell autoreactivity. We previously linked decreased monocyte ROS with diabetes resistance in the alloxan-resistant mouse, and NOD-Ncf1(m1J) mice with a genetic ablation of NOX activity had reduced and delayed type 1 diabetes compared with NOD mice. To determine the required cellular sources of ROS that are necessary for type 1 diabetes initiation, we used antibody depletion and adoptive transfer experiments into NOD and NOD-Scid females, respectively. After receiving treatment, female mice were monitored for hyperglycemia and overt diabetes. Depletion of macrophages and neutrophils fully protected NOD mice from type 1 diabetes. However, elimination of neutrophils alone showed no significant reduction or delay. Type 1 diabetes induction in NOD-Scid mice by adoptive transfer with NOD-Ncf1(m1J) splenocytes was significantly delayed compared with NOD splenocytes, suggesting macrophage ROS and modulation of effector responses are critical for diabetes. The adaptive immune response was also altered by the absence of NOX activity, as purified T cells from NOD-Ncf1(m1J) mice exhibited delayed transfer kinetics. Cotransfer experiments demonstrated the defect was intrinsic to NOX-deficient CD8(+) T cells. After stimulation, cytotoxic T cells exhibited decreased effector function in the absence of superoxide production. These data demonstrate that the impaired autoreactive response of NOX-deficient NOD-Ncf1(m1J) immune system results from an alteration in the antigen-presenting cell-T-cell axis rather than failure of neutrophils to act as effector cells and that ROS signaling is important for the initiation of β-cell-directed autoimmunity by T cells.


Ontogenetic shape trajectory of Trichomycterus areolatus varies in response to water velocity environment.
Body and head shape among fishes both vary between environments influenced by water velocity and across ontogeny. Although the shape changes associated with variation in average water velocity and ontogeny are well documented, few studies have tested for the interaction between these two variables (i.e., does ontogenetic shape variation differ between velocity environments). We use geometric morphometrics to characterize shape differences in Trichomycterus areolatus, a freshwater catfish found in high and low-velocity environments in Chile. We identify a significant interaction between velocity environment and body size (i.e., ontogeny). Ontogenetic patterns of shape change are consistent with other studies, but velocity environment differentially affects the ontogenetic trajectory of shape development in T. areolatus. Shape change over ontogeny appears more constrained in high-velocity environments compared to low-velocity environments.


Administration Safety of Blood Products - Lessons Learned from a National Registry for Transfusion and Hemotherapy Practice.
Compared to blood component safety, the administration of blood may not be as safe as intended. The German Interdisciplinary Task Force for Clinical Hemotherapy (IAKH) specialized registry for administration errors of blood products was chosen for a detailed analysis of reports. Voluntarily submitted critical incident reports (n = 138) from 2009 to 2013 were analyzed. Incidents occurred in the operation room (34.1%), in the ICU (25.2%), and in the peripheral ward (18.5%). Procedural steps with errors were administration to the patient (27.2%), indication and blood order (17.1%), patient identification (17.1%), and blood sample withdrawal and tube labeling (18.0%). Bedside testing (BST) of blood groups avoided errors in only 2.6%. Associated factors were routine work conditions (66%), communication error (36%), emergency case (26%), night or weekend team (39%), untrained personnel (19%). Recommendations addressed process and quality (n = 479) as well as structure quality (n = 314). In 189 instances, an IT solution would have helped to avoid the error. The administration process is prone to errors at the patient assessment for the need to transfuse and the application of blood products to patients. BST is only detecting a minority of handling errors. According to the expert recommendations for practice improvement, the potential to improve transfusion safety by a technical solution is considerable.


Laminarly orthogonal excitation of fast-spiking and low-threshold-spiking interneurons in mouse motor cortex.
In motor cortex, long-range output to subcortical motor circuits depends on excitatory and inhibitory inputs converging on projection neurons in layers 5A/B. How interneurons interconnect with these projection neurons, and whether these microcircuits are interneuron and/or projection specific, is unclear. We found that fast-spiking interneurons received strong intralaminar (horizontal) excitation from pyramidal neurons in layers 5A/B including corticostriatal and corticospinal neurons, implicating them in mediating disynaptic recurrent, feedforward, and feedback inhibition within and across the two projection classes. Low-threshold-spiking (LTS) interneurons were instead strongly excited by descending interlaminar (vertical) input from layer 2/3 pyramidal neurons, implicating them in mediating disynaptic feedforward inhibition to both projection classes. Furthermore, in a novel pattern, lower layer 2/3 preferentially excited interneurons in one layer (5A/LTS) and excitatory neurons in another (5B/corticospinal). Thus, these inhibitory microcircuits in mouse motor cortex follow an orderly arrangement that is laminarly orthogonalized by interneuron-specific, projection-nonspecific connectivity.


Co-residence patterns in hunter-gatherer societies show unique human social structure.
Contemporary humans exhibit spectacular biological success derived from cumulative culture and cooperation. The origins of these traits may be related to our ancestral group structure. Because humans lived as foragers for 95% of our species' history, we analyzed co-residence patterns among 32 present-day foraging societies (total n = 5067 individuals, mean experienced band size = 28.2 adults). We found that hunter-gatherers display a unique social structure where (i) either sex may disperse or remain in their natal group, (ii) adult brothers and sisters often co-reside, and (iii) most individuals in residential groups are genetically unrelated. These patterns produce large interaction networks of unrelated adults and suggest that inclusive fitness cannot explain extensive cooperation in hunter-gatherer bands. However, large social networks may help to explain why humans evolved capacities for social learning that resulted in cumulative culture.


Tobacco use and smoking cessation among third-year dental students in southern Brazil.
The aim of the present cross-sectional study was to assess tobacco use and smoking cessation among third-year dental students in southern Brazil. The Global Health Professions Student Survey questionnaire was used in eight dental schools in Rio Grande do Sul state, Brazil. Of the 663 eligible students, 576 (87%) participated. The prevalence of current smoking was 19.1% [95% confidence interval (CI): 12.9-25.3%], and 61.6% (95% CI: 54.9-68.3%) of students reported having smoked at least once in their lifetime. The prevalence of dental students who had smoked ≥ 100 cigarettes in their lifetime was 17.1% (95% CI: 12.5-21.7%). Being frequently exposed to other smokers at home or in other places (second-hand smoke) increased the likelihood of current smoking by two- to threefold. Approximately 6.1% (95% CI: 3.5-8.7%) of the students reported that they currently wanted to stop smoking and 7.5% (95% CI: 5.3-9.6%) had tried to stop smoking in the last year. Friends and family were the most frequent sources of help or counselling, and only a limited proportion of students received help from health professionals. Tobacco use and exposure to second-hand smoking is widespread among dental students in southern Brazil. Smoking-cessation initiatives targeting health care students are urgently needed.


Calcium score, coronary artery disease extent and severity, and clinical outcomes among low Framingham risk patients with low vs high lifetime risk: results from the CONFIRM registry.
Short-term risk scores, such as the Framingham risk score (FRS), frequently classify younger patients as low risk despite the presence of uncontrolled cardiovascular risk factors. Among patients with low FRS, estimation of lifetime risk is associated with significant differences in coronary arterial calcium scores (CACS); however, the relationship of lifetime risk to coronary atherosclerosis on coronary CT angiography (CCTA) and prognosis has not been studied. We evaluated asymptomatic 20-60-year-old patients without diabetes or known coronary artery disease (CAD) within an international CT registry who underwent ≥64-slice CCTA. Patients with low FRS (<10%) were stratified as low (<39%) or high (≥39%) lifetime CAD risk, and compared for the presence and severity of CAD and prognosis for death, myocardial infarction, and late coronary revascularization (>90 days post CCTA). 1,863 patients of mean age of 47 years were included, with 48% of the low FRS patients at high lifetime risk. Median follow-up was 2.0 years. Comparing low-to-high lifetime risk, respectively, the prevalence of any CAD was 32% vs 41% (P < .001) and ≥50% stenosis was 7.4% vs 9.6% (P = .09). For those with CAD, subjects at low vs high lifetime risk had lower CACS (median 12 [IQR 0-94] vs 38 [IQR 0.05-144], P = .02) and less purely calcified plaque, 35% vs 45% (P < .001). Prognosis did not differ due to low number of events. Assessment of lifetime risk among patients at low FRS identified those with the increase in CAD prevalence and severity and a higher proportion of calcified plaque.


Outcomes of Care for 1,892 Doula-Supported Adolescent Births in the United States: The DONA International Data Project, 2000 to 2013.
This is the largest study to-date to report on outcomes of care for a national sample of doula-supported adolescent births (n = 1,892, birth years 2000 to 2013). Descriptive statistics were calculated for maternal demographics, risk profiles, labor/birth interventions and occurrences, and birth outcomes. In this national sample, childbearing adolescents and their neonates experienced improved health outcomes and lower rates of intervention relative to national statistics for adolescent deliveries in the United States. Key findings are consistent with previous studies on the effects of doula care for marginalized and medically underserved communities. Results strengthen the case for doulas as a perinatal care strategy for improving maternal and infant health outcomes and decreasing inequities among childbearing adolescents.


Dual-energy computed tomography for the differentiation of uric acid stones: ex vivo performance evaluation.
We assessed the potential of dual-energy computed tomography (CT) for the differentiation between uric acid (UA)-containing and non-UA-containing urinary stones. Forty urinary stones of 16 different compositions in two sizes (<and>or=5 mm) were examined in an ex vivo model. Thirty stones consisted of pure calcium oxalate (whewellite or wheddellite), calcium phosphate (apatite, brushite, or vaterite), ammonium magnesium phosphate (struvite), UA, ammonium acid urate, ammonium phosphate, sodium hydrogen urate, or cystine, and ten stones were of mixed composition (UA-sodium hydrogen urate, whewellite-urate, wheddellite-urate, whewellite-brushite, or whewellite-brushite-struvite). Scans were performed using dual-source CT in a dual-energy mode with the tubes simultaneously operating at 80 and 140 kV. Two readers analysed the data with respect to stone attenuation at each energy level. The stones were classified as UA- or non-UA-containing using manual attenuation measurements and software analysis results. Sensitivity, specificity, PPV, and NPV were calculated using crystallographic stone analysis as the gold standard. Twenty-six out of 40 stones (65%) contained no UA; 14 stones (35%) contained UA. When compared with UA-containing stones, the differences in attenuation values at 80 and 140 kV were significantly (P<0.001) higher in stones containing no UA. The software automatically mapped 39/40 stones (98%). Only one (2%) 2 mm UA-stone was missed. The software correctly classified all detected stones as UA- or non-UA-containing. The attenuation values of the missed stone were manually plotted into the analysis sheet which allowed for the correct classification of the stone (containing UA). Therefore, the sensitivity, specificity, PPV, and NPV for the detection of UA-containing stones was 100%. Ex vivo experience indicates that differentiation between UA- and non-UA-containing stones can be accurately performed using dual-source dual-energy CT.


Biology, methodology or chance? The degree distributions of bipartite ecological networks.
The distribution of the number of links per species, or degree distribution, is widely used as a summary of the topology of complex networks. Degree distributions have been studied in a range of ecological networks, including both mutualistic bipartite networks of plants and pollinators or seed dispersers and antagonistic bipartite networks of plants and their consumers. The shape of a degree distribution, for example whether it follows an exponential or power-law form, is typically taken to be indicative of the processes structuring the network. The skewed degree distributions of bipartite mutualistic and antagonistic networks are usually assumed to show that ecological or co-evolutionary processes constrain the relative numbers of specialists and generalists in the network. I show that a simple null model based on the principle of maximum entropy cannot be rejected as a model for the degree distributions in most of the 115 bipartite ecological networks tested here. The model requires knowledge of the number of nodes and links in the network, but needs no other ecological information. The model cannot be rejected for 159 (69%) of the 230 degree distributions of the 115 networks tested. It performed equally well on the plant and animal degree distributions, and cannot be rejected for 81 (70%) of the 115 plant distributions and 78 (68%) of the animal distributions. There are consistent differences between the degree distributions of mutualistic and antagonistic networks, suggesting that different processes are constraining these two classes of networks. Fit to the MaxEnt null model is consistently poor among the largest mutualistic networks. Potential ecological and methodological explanations for deviations from the model suggest that spatial and temporal heterogeneity are important drivers of the structure of these large networks.


Transport of Residual Nitrogen and Carbon through Intact Soil Cores Amended with Stockpiled Feedlot Manure with Wood-Chip or Straw Bedding.
The environmental impact of using wood chips instead of straw bedding with feedlot manure on transport and leaching potential from feedlot manure is unknown. Our main objective was to determine if transport of total N, total organic N, NO-N, and nonpurgeable organic C (NPOC) to subsurface soil was lower for soils amended with feedlot manure if combined with wood chips compared with straw. A secondary objective was to compare transport of N and NPOC with organic amendments versus inorganic fertilizer. Stockpiled feedlot manure (SM) with wood chip (SM-WD) or barley straw (SM-ST) bedding at 39 Mg (dry wt.) ha, and inorganic fertilizer (IN) at 100 kg N ha, was applied annually for 13 yr to a clay loam soil in a replicated field experiment in southern Alberta, Canada. Intact soil cores were taken in fall 2011 (0-30 cm depth) from the three treatments, and the residual N and NPOC were eluted from the soil cores. Total N, total organic N, and NPOC were determined on filtered (1.0 μm) effluent samples that are primarily dissolved fraction but may contain some small particulate N and C. Peak concentrations, flow-weighted mean concentrations, and mass loss of total N, total organic N, NO-N, and NPOC were significantly ( ≤ 0.05) lower by 35 to 86% for SM-WD compared with SM-ST. Mean recoveries were also significantly lower for SM-WD than SM-ST by 0.07 to 8% (absolute difference). The transport behavior was similar for SM-WD and IN treatment, but solute transport was greater for SM-ST than for IN. Application of stockpiled feedlot manure with wood chips instead of straw bedding may be a beneficial management practice to reduce transport and leaching potential of N fractions and NPOC.


Homophobia among doctors.
Homophobia creates stress for gay men and women. An interview study of 28 doctors, 20 gay and eight non-gay, was performed to assess whether homophobia is strong among the medical profession, the stress it causes, and whether the advent of AIDS and HIV infection has increased the stress. The doctors, recruited by word of mouth and by a letter in the medical and gay press, were asked about their own attitudes to homosexuality and AIDS. Only one (non-gay) doctor thought that there was no prejudice against gay doctors in the medical profession. The gay doctors certainly perceived prejudice, which they claimed caused them extra stress; the advent of AIDS had increased this stress to an extent. Doctors who had not openly declared themselves to be gay feared doing so because of the effect on their job prospects, but those who had declared themselves openly reported less stress than previously. Homophobia clearly exists within the medical profession. Non-gay doctors should use the power of the profession to challenge homophobia in the profession and in society. HIV infection could then be treated as a purely medical condition; sufferers would receive wider understanding and the pressures of extra workload could be more equally shared.


Automatic spinal cord localization, robust to MRI contrasts using global curve optimization.
During the last two decades, MRI has been increasingly used for providing valuable quantitative information about spinal cord morphometry, such as quantification of the spinal cord atrophy in various diseases. However, despite the significant improvement of MR sequences adapted to the spinal cord, automatic image processing tools for spinal cord MRI data are not yet as developed as for the brain. There is nonetheless great interest in fully automatic and fast processing methods to be able to propose quantitative analysis pipelines on large datasets without user bias. The first step of most of these analysis pipelines is to detect the spinal cord, which is challenging to achieve automatically across the broad range of MRI contrasts, field of view, resolutions and pathologies. In this paper, a fully automated, robust and fast method for detecting the spinal cord centerline on MRI volumes is introduced. The algorithm uses a global optimization scheme that attempts to strike a balance between a probabilistic localization map of the spinal cord center point and the overall spatial consistency of the spinal cord centerline (i.e. the rostro-caudal continuity of the spinal cord). Additionally, a new post-processing feature, which aims to automatically split brain and spine regions is introduced, to be able to detect a consistent spinal cord centerline, independently from the field of view. We present data on the validation of the proposed algorithm, known as "OptiC", from a large dataset involving 20 centers, 4 contrasts (T2-weighted n = 287, T1-weighted n = 120, T2∗-weighted n = 307, diffusion-weighted n = 90), 501 subjects including 173 patients with a variety of neurologic diseases. Validation involved the gold-standard centerline coverage, the mean square error between the true and predicted centerlines and the ability to accurately separate brain and spine regions. Overall, OptiC was able to cover 98.77% of the gold-standard centerline, with a mean square error of 1.02 mm. OptiC achieved superior results compared to a state-of-the-art spinal cord localization technique based on the Hough transform, especially on pathological cases with an averaged mean square error of 1.08 mm vs. 13.16 mm (Wilcoxon signed-rank test p-value < .01). Images containing brain regions were identified with a 99% precision, on which brain and spine regions were separated with a distance error of 9.37 mm compared to ground-truth. Validation results on a challenging dataset suggest that OptiC could reliably be used for subsequent quantitative analyses tasks, opening the door to more robust analysis on pathological cases.


Bowel problem management among nursing home residents: a mixed methods study.
Bowel problems such as constipation, diarrhoea and faecal incontinence (FI) are prevalent conditions among nursing home residents and little is known about nursing management. This study aimed to elucidate how Norwegian registered nurses (RNs) manage bowel problems among nursing home residents. A mixed methods approach was used combining quantitative data from a population-based cross-sectional survey and qualitative data from a focus group interview. In the cross sectional part of the study 27 of 28 nursing homes in one Norwegian municipality participated. Residents were included if they, at the time of data collection, had been a resident in a nursing home for more than three weeks or had prior stays of more than four weeks during the last six months. Residents were excluded from the study if they were younger than 65 years or had a stoma (N = 980 after exclusions). RNs filled in a questionnaire for residents regarding FI, constipation, diarrhoea, and treatments/interventions. In the focus group interview, 8 RNs participated. The focus group interview used an interview guide that included six open-ended questions. Pad use (88.9%) and fixed toilet schedules (38.6%) were the most commonly used interventions for residents with FI. In addition, the qualitative data showed that controlled emptying of the bowels with laxatives and/or enemas was common. Common interventions for residents with constipation were laxatives (66.2%) and enemas (47%), dietary interventions (7.3%) and manual emptying of feces (6.3%). In addition, the qualitative data showed that the RNs also used fixed toilet schedules for residents with constipation. Interventions for residents with diarrhoea were Loperamide (18.3%) and dietary interventions (20.1%). RNs described bowel care management as challenging due to limited time and resources. Consequently, compromises were a part of their working strategies. Constipation was considered to be the main focus of bowel management. Emptying the residents' bowels was the aim of nursing intervention. FI was mainly treated passively with pads and interventions for residents with diarrhoea were limited. The RNs prioritized routine tasks in the nursing homes due to limited resources, and thereby compromising with the resident's need for individualized bowel care.


Secretion without membrane fusion: porocytosis.
We have recently proposed a mechanism to describe secretion, a fundamental process in all cells. That hypothesis, called porocytosis, embodies all available data and encompasses both forms of secretion, i.e., vesicular and constitutive. The current accepted view of exocytotic secretion involves the physical fusion of vesicle and plasma membranes; however, that hypothesized mechanism does not fit all available physiological data. Energetics of apposed lipid bilayers do not favor unfacilitated fusion. We consider that calcium ions (e.g., 10(-4) to 10(-3) M calcium in microdomains when elevated for 1 ms or less), whose mobility is restricted in space and time, establish salt bridges among adjacent lipid molecules. This establishes transient pores that span both the vesicle and plasma membrane lipid bilayers; the diameter of this transient pore would be approximately 1 nm (the diameter of a single lipid molecule). The lifetime of the transient pore is completely dependent on the duration of sufficient calcium ion levels. This places the porocytosis hypothesis for secretion squarely in the realm of the physical and physical chemical interactions of calcium and phospholipids and places mass action as the driving force for release of secretory material. The porocytosis hypothesis that we propose satisfies all of the observations and provides a framework to integrate our combined knowledge of vesicular and constitutive secretion.


Brain-specific expression of MAP2 detected using a cloned cDNA probe.
We describe the isolation of a set of overlapping cDNAs encoding mouse microtubule associated protein 2 (MAP2), using an anti-MAP antiserum to screen a mouse brain cDNA expression library cloned in bacteriophage lambda gt11. The authenticity of these clones was established by the following criteria: (a) three non-identical clones each expressing a MAP2 immunoreactive fusion protein were independently isolated from the expression library; each of these clones cross-hybridized at the nucleic acid level; (b) anti-MAP antiserum was affinity purified using nitrocellulose-bound fusion protein; these antibodies detected only MAP2 in an immunoblot experiment of whole brain microtubule protein; (c) a series of cDNA "walking" experiments was done so as to obtain a non-overlapping cloned fragment corresponding to a different part of the same mRNA molecule. Upon subcloning this non-overlapping fragment into plasmid expression vectors, a fusion protein was synthesized that was immunoreactive with an anti-MAP2 specific antiserum. Thus, a single contiguous cloned mRNA molecule encodes at least two MAP2-specific epitopes; (d) the cloned cDNA probes detect an mRNA species in mouse brain that is of a size (approximately 9 kb) consistent with the coding capacity required by a 250,000-D protein. The MAP2-specific cloned cDNA probes were used in RNA blot transfer experiments to assay for the presence of MAP2 mRNA in a variety of mouse tissues. Though brain contained abundant quantities of MAP2 mRNA, no corresponding sequences were detectable in RNA prepared from liver, kidney, spleen, stomach, or thymus. We conclude that the expression of MAP2 is brain-specific. Use of the MAP2 specific cDNA probes in genomic Southern blot transfer experiments showed the presence of a single gene encoding MAP2 in mouse. The microheterogeneity of MAP2 is therefore ascribable either to alternative splicing within a single gene, or to posttranslational modification(s), or both. Under conditions of low stringency, the mouse MAP2 cDNA probe cross-hybridizes with genomic sequences from rat, human, and (weakly) chicken, but not with sequences in frog, Drosophila, or sea urchin DNA. Thus, there is significant interspecies divergence of MAP2 sequences. The implications of the above observations are discussed in relationship to the potential biological function of MAP2.


Diurnal and seasonal mood vary with work, sleep, and daylength across diverse cultures.
We identified individual-level diurnal and seasonal mood rhythms in cultures across the globe, using data from millions of public Twitter messages. We found that individuals awaken in a good mood that deteriorates as the day progresses--which is consistent with the effects of sleep and circadian rhythm--and that seasonal change in baseline positive affect varies with change in daylength. People are happier on weekends, but the morning peak in positive affect is delayed by 2 hours, which suggests that people awaken later on weekends.


Development and validation of the Skills Assessment in Microsurgery for Brain Aneurysms (SAMBA) instrument for predicting proficiency in aneurysm surgery.
Surgical performance evaluation was first described with the OSATS (Objective Structured Assessment of Technical Skills) and modified for aneurysm microsurgery simulation with the OSAACS (Objective Structured Assessment of Aneurysm Clipping Skills). These methods rely on the subjective opinions of evaluators, however, and there is a lack of objective evaluation for proficiency in the microsurgical treatment of brain aneurysms. The authors present a new instrument, the Skill Assessment in Microsurgery for Brain Aneurysms (SAMBA) scale, which can be used similarly in a simulation model and in the treatment of unruptured middle cerebral artery (MCA) aneurysms to predict surgical performance; the authors also report on its validation. The SAMBA scale was created by consensus among 5 vascular neurosurgeons from 2 different neurosurgical departments. SAMBA results were analyzed using descriptive statistics, Cronbach's alpha indexes, and multivariate ANOVA analyses (p < 0.05). Expert, intermediate-level, and novice surgeons scored, respectively, an average of 33.9, 27.1, and 16.4 points in the real surgery and 33.3, 27.3, and 19.4 points in the simulation. The SAMBA interrater reliability index was 0.995 for the real surgery and 0.996 for the simulated surgery; the intrarater reliability was 0.983 (Cronbach's alpha). In both the simulation and the real surgery settings, the average scores achieved by members of each group (expert, intermediate level, and novice) were significantly different (p < 0.001). Scores among novice surgeons were more diverse (coefficient of variation = 12.4). Predictive validation of the placenta brain aneurysm model has been previously reported, but the SAMBA scale adds an objective scoring system to verify microsurgical ability in this complex operation, stratifying proficiency by points. The SAMBA scale can be used as an interface between learning and practicing, as it can be applied in a safe and controlled environment, such as is provided by a placenta model, with similar results obtained in real surgery, predicting real surgical performance.


Quantum chemistry reveals thermodynamic principles of redox biochemistry.
Thermodynamics dictates the structure and function of metabolism. Redox reactions drive cellular energy and material flow. Hence, accurately quantifying the thermodynamics of redox reactions should reveal design principles that shape cellular metabolism. However, only few redox potentials have been measured, and mostly with inconsistent experimental setups. Here, we develop a quantum chemistry approach to calculate redox potentials of biochemical reactions and demonstrate our method predicts experimentally measured potentials with unparalleled accuracy. We then calculate the potentials of all redox pairs that can be generated from biochemically relevant compounds and highlight fundamental trends in redox biochemistry. We further address the question of why NAD/NADP are used as primary electron carriers, demonstrating how their physiological potential range fits the reactions of central metabolism and minimizes the concentration of reactive carbonyls. The use of quantum chemistry can revolutionize our understanding of biochemical phenomena by enabling fast and accurate calculation of thermodynamic values.


Hippocampal damage associated with prolonged and fatal stress in primates.
Sustained exposure to glucocorticoids (GCs), adrenal hormones secreted during stress, can cause neural degeneration in the rat. This is particularly so in the hippocampus, a principal neural target site for GCs, in which GCs can exacerbate the rate of neuron death during normal aging, as well as the severity of neuronal damage after various neurological insults. Thus, stress can be a potent modulator of hippocampal degeneration in the rat. The present report suggests a similar association in the primate. Eight vervet monkeys, housed in a primate center in Kenya, that had died spontaneously from 1984 to 1986, were found at necropsy to have multiple gastric ulcers; a retrospective, neuropathological study was then done of this opportunistic population. Compared with controls euthanized for other research purposes, ulcerated monkeys had marked hippocampal degeneration that was apparent both quantitatively and qualitatively, and both ultrastructurally and on the light-microscopic level. Minimal damage occurred outside the hippocampus. Damage was unlikely to have been due to an agonal or post-mortem artifact. Instead, ulcerated monkeys appear to have been subject to sustained social stress, perhaps in the form of social subordinance in captive breeding groups: most came from social groups, had significantly high incidences of bite wounds at necropsy, and had hyperplastic adrenal cortices, indicative of sustained GC release. Moreover, the specific hippocampal cell fields damaged in ulcerated animals matched those damaged by GCs in the rodent hippocampus. Thus, this represents the first evidence suggesting that sustained stress, via GC hypersecretion, might be neurodegenerative in the primate.


Compliance to prescribing guidelines among public health care facilities in Namibia; findings and implications.
Background The World Health Organization estimates that over 50% medicines are prescribed inappropriately and the main driver of antimicrobial resistance globally. There have only been a limited number of studies evaluating prescribing patterns against national standard treatment guidelines (STGs) in sub-Saharan African countries including Namibia. This is important given the high prevalence of both infectious and non-infectious diseases in sub-Saharan Africa alongside limited resources. Objective Our aim was to assess prescribing practices and drivers of compliance to National guidelines among public health care facilities in Namibia to provide future guidance. Setting Three levels of public healthcare in Namibia. Method A mixed method approach including patient exit and prescriber interviews at three levels of health care in Namibia, i.e. hospital, health centre and clinic. Main outcome measures Medicine prescribing indicators, compliance to and attitudes towards National guidelines. Results Of the 1243 prescriptions analysed, 73% complied with the STGs and 69% had an antibiotic. Of the 3759 medicines (i.e. mean of 3.0 ± 1.1) prescribed, 64% were prescribed generically. The vast majority of prescribers were aware of, and had access to, the Namibian STGs (94.6%), with the majority reporting that the guidelines are easy to use and they regularly refer to them. The main drivers of compliance to guidelines were programmatic, that is access to up-to date objective guidelines, support systems for continued education on their use, and ease of referencing. Lack of systems to regulate noncompliance impacted on their use. Conclusion Whilst the findings were encouraging, ongoing concerns included limited prescribing of generic medicines and high use of antibiotics. A prescribing performance management system should be introduced to improve and monitor compliance to prescribing guidelines in public healthcare.


Comparative immunogenicity of HIV-1 gp160, gp140 and gp120 expressed by live attenuated newcastle disease virus vector.
The development of a vaccine against human immunodeficiency virus-1 (HIV-1) capable of inducing broad humoral and cellular responses at both the systemic and mucosal levels will be critical for combating the global AIDS epidemic. We previously demonstrated the ability of Newcastle disease virus (NDV) as a vaccine vector to express oligomeric Env protein gp160 and induce potent humoral and mucosal immune responses. In the present study, we used NDV vaccine strain LaSota as a vector to compare the biochemical and immunogenic properties of vector-expressed gp160, gp120, and two versions of gp140 (a derivative of gp160 made by deleting the transmembrane and cytoplasmic domains), namely: gp140L, which contained the complete membrane-proximal external region (MPER), and gp140S, which lacks the distal half of MPER. We show that, similar to gp160, NDV-expressed gp140S and gp120, but not gp140L, formed higher-order oligomers that retained recognition by conformationally sensitive monoclonal antibodies. Immunization of guinea pigs by the intranasal route with rLaSota/gp140S resulted in significantly greater systemic and mucosal antibody responses compared to the other recombinants. Immunization with rLaSota/140S, rLaSota/140L rLaSota/120 resulted in mixed Th1/Th2 immune responses as compared to Th1-biased immune responses induced by rLaSota/160. Importantly, rLaSota/gp140S induced neutralizing antibody responses to homologous HIV-1 strain BaL.26 and laboratory adapted HIV-1 strain MN.3 that were stronger than those elicited by the other NDV recombinants. Additionally, rLaSota/gp140S induced greater CD4+ and CD8+ T-cell responses in mice. These studies illustrate that rLaSota/gp140S is a promising vaccine candidate to elicit potent mucosal, humoral and cellular immune responses to the HIV-1 Env protein.


Mental Health Symptoms Among Student Service Members/Veterans and Civilian College Students.
The aim of this study was to investigate if and to what extent student service members/veterans differ from civilian college students in the prevalence of self-reported symptoms of poor mental health. The Fall 2011 implementation of the American College Health Association-National College Health Assessment included 27,774 respondents from 44 colleges and universities. Participants were matched using propensity scores, and the prevalence of symptoms was compared using logistic regression and zero-inflated negative binomial regression models. The odds of feeling overwhelmed in the last 12 months were significantly lower among student service members/veterans with a history of hazardous duty (odd ratio [OR] = 0.46, adjusted p value <.05) compared with civilian students. Military service, with and without hazardous duty deployment, was not a significant predictor of the total number of symptoms of poor mental health. Current student service members/veterans may not be disproportionately affected by poor psychological functioning.


Epigenetic silencing of the osteoblast-lineage gene program during hippocampal maturation.
Accumulating evidence indicates that epigenetic control of gene expression plays a significant role during cell lineage commitment and subsequent cell fate maintenance. Here, we assess epigenetic mechanisms operating in the rat brain that mediate silencing of genes that are expressed during early and late stages of osteogenesis. We report that repression of the osteoblast master regulator Sp7 in embryonic (E18) hippocampus is mainly mediated through the Polycomb complex PRC2 and its enzymatic product H3K27me3. During early postnatal (P10), juvenile (P30), and adult (P90) hippocampal stages, the repressive H3K27me3 mark is progressively replaced by nucleosome enrichment and increased CpG DNA methylation at the Sp7 gene promoter. In contrast, silencing of the late bone phenotypic Bglap gene in the hippocampus is PRC2-independent and accompanied by strong CpG methylation from E18 through postnatal and adult stages. Forced ectopic expression of the primary master regulator of osteogenesis Runx2 in embryonic hippocampal neurons activates the expression of its downstream target Sp7 gene. Moreover, transcriptomic analyses show that several genes associated with the mesenchymal-osteogenic lineages are transcriptionally activated in these hippocampal cells that express Runx2 and Sp7. This effect is accompanied by a loss in neuronal properties, including a significant reduction in secondary processes at the dendritic arbor and reduced expression of critical postsynaptic genes like PSD95. Together, our results reveal a developmental progression in epigenetic control mechanisms that repress the expression of the osteogenic program in hippocampal neurons at embryonic, postnatal, and adult stages.


Acceptability of second-step treatments to depressed outpatients: a STAR*D report.
Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment.


Interactions among Hageman factor, plasma prekallikrein, high molecular weight kininogen, and plasma thromboplastin antecedent.
To investigate the earliest steps of the intrinsic clotting pathway, Hageman factor (Factor XII) was exposed to Sephadex gels to which ellagic acid had been adsorbed; Hageman factor was then separated from the gels and studied in the fluid phase. Sephadex-ellagic acid-exposed Hageman factor, whether purified or in plasma, activated plasma thromboplastin antecedent, but only when high molecular weight kininogen was presnet. In the absence of plasma prekallikrein, maximal activation of plasma thromboplastin antecedent was slightly delayed in plasma, a delay not observed with similarly treated purified Hageman factor. Thus, high molecular weight kininogen was needed for expression of Hageman factor's clot-promoting properties and plasma prekallikrein played a minor role in the interaction of ellagic acid-treated Hageman factor and plasma thromboplastin antecedent.


Validation and Refinement of Prediction Models to Estimate Exercise Capacity in Cancer Survivors Using the Steep Ramp Test.
To further test the validity and clinical usefulness of the steep ramp test (SRT) in estimating exercise tolerance in cancer survivors by external validation and extension of previously published prediction models for peak oxygen consumption (Vo2peak) and peak power output (Wpeak). Cross-sectional study. Multicenter. Cancer survivors (N=283) in 2 randomized controlled exercise trials. Not applicable. Prediction model accuracy was assessed by intraclass correlation coefficients (ICCs) and limits of agreement (LOA). Multiple linear regression was used for model extension. Clinical performance was judged by the percentage of accurate endurance exercise prescriptions. ICCs of SRT-predicted Vo2peak and Wpeak with these values as obtained by the cardiopulmonary exercise test were .61 and .73, respectively, using the previously published prediction models. 95% LOA were ±705mL/min with a bias of 190mL/min for Vo2peak and ±59W with a bias of 5W for Wpeak. Modest improvements were obtained by adding body weight and sex to the regression equation for the prediction of Vo2peak (ICC, .73; 95% LOA, ±608mL/min) and by adding age, height, and sex for the prediction of Wpeak (ICC, .81; 95% LOA, ±48W). Accuracy of endurance exercise prescription improved from 57% accurate prescriptions to 68% accurate prescriptions with the new prediction model for Wpeak. Predictions of Vo2peak and Wpeak based on the SRT are adequate at the group level, but insufficiently accurate in individual patients. The multivariable prediction model for Wpeak can be used cautiously (eg, supplemented with a Borg score) to aid endurance exercise prescription.


Do Children Carry the Weight of Divorce?
Relatively few studies have examined the physical health of children who experience parental separation. The few studies on this topic have largely focused on the United States and have used cross-sectional designs. Our study investigates the relationship between parental separation and children's body mass index (BMI) and overweight/obesity risk using the UK Millennium Cohort Study. Treating parental separation as a process, we analyze variations in children's physical health before and after the date of their parents' separation in order to capture potential anticipation, adaptation, delayed, or cumulative effects. We estimate fixed-effects models to account for the potential correlation between children's physical health and unobserved factors associated with parental separation, such as socioeconomic background and other time-invariant parental characteristics. We find no evidence of statistically significant anticipation effects in the build-up to parental separation or of statistically significant changes in children's physical health immediately after separation. However, our results show that in the longer term, the BMI of children whose parents separate significantly deviates from the BMI of children from intact families. Furthermore, this association is especially strong for separations that occur when children are under age 6.


Critical congenital heart disease screening.
Critical congenital heart disease (CCHD) is a heart lesion for which neonates require early surgical intervention to survive. Without intervention, the rates of mortality and survival with significant disability are extremely high. Early diagnosis can potentially improve health outcomes in newborns with CCHD. Until recent years, no routine screening protocol existed. In the last few years, pulse oximetry screening for CCHD in newborns has been added to the list of recommended uniform screening panels and advocated by several health-care authorities. A positive screening test result warrants an echocardiogram to evaluate for CCHD. Newborn screens do not usually require parental consent. However, most of the states mandates in the United States include a statement allowing exemption from the screen on the basis of parental religious or personal beliefs.


A Journey Toward Cultural Competence: The Role of Researcher Reflexivity in Indigenous Research.
This article highlights the personal journey of reflective development that a non-Aboriginal White researcher and health professional underwent to be "fully positioned" in the everyday lives of a rural Australian Aboriginal community in Western Australia. The article explains the researcher's personal development in areas important to building respect, building relationships, and ensuring reciprocity while undertaking Aboriginal research. The researcher reports on the reflective evaluation of her worldview. Understanding that judgment is a natural tendency, the researcher used reflexivity as a tool to examine and contextualize her judgments, presumptions, and preconceptions, which positioned her to be open to differing viewpoints and actively explore alternate perspectives. The researcher explores her evolutionary understanding that cultural competence is not a destination but a continual journey, and she details her knowledge development regarding the Aboriginal research paradigm, which requires that all the learning, sharing, and growth taking place is reciprocal and engages all parties actively.


MicroRNA signatures in chemotherapy resistant esophageal cancer cell lines.
To investigate expression of microRNA (miRNA) and potential targets in chemotherapy resistant esophageal cancer cell lines. An in-vitro model of acquired chemotherapy resistance in esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) cells was used, and microRNA expression profiles for cisplatin or 5-fluorouracil (5-FU) resistant variants vs chemotherapy sensitive controls were compared using microarray and quantitative real-time polymerase chain reaction (PCR). The expression of chemotherapy-relevant genes potentially targeted by the dysregulated microRNAs in the chemotherapy resistant variants was also evaluated. Chemotherapy resistant sublines were found to have specific miRNA signatures, and these miRNA signatures were different for the cisplatin vs 5-FU resistant cells from the same tumor cell line, and also for EAC vs ESCC cells with resistance to the same specific chemotherapy agent. Amongst others, miR-27b-3p, miR-193b-3p, miR-192-5p, miR-378 a-3p, miR-125a-5p and miR-18a-3p were dysregulated, consistent with negative posttranscriptional control of KRAS, TYMS, ABCC3, CBL-B and ERBB2 expression via these miRNAs. The current study supports the hypothesis that microRNA expression has an impact on chemotherapy resistance in esophageal cancer.


5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling.
The circulating form of folic acid, 5-methyltetrahydrofolate (5-MTHF), may have beneficial effects on endothelial function; however, its mechanisms of action remain uncertain. Decreased nitric oxide (NO) bioavailability and increased vascular superoxide production in vascular disease states are due in part to endothelial NO synthase (eNOS) uncoupling related to deficiency of the eNOS cofactor tetrahydrobiopterin (BH4), but whether this mechanism is important in human atherosclerosis and represents a rational therapeutic target remains unclear. We hypothesized that 5-MTHF would improve endothelial function by decreasing superoxide and peroxynitrite production and by improving eNOS coupling, mediated by BH4 availability. Vascular superoxide/peroxynitrite production and vasomotor responses to acetylcholine and bradykinin were determined in saphenous veins and internal mammary arteries from 117 patients undergoing CABG. The effects of 5-MTHF were examined ex vivo (n = 61) by incubating vessels with 5-MTHF (1 to 100 micromol/L) and in vivo by intravenous infusion of 5-MTHF or placebo before vessel harvest (n = 56). 5-MTHF improved NO-mediated endothelium-dependent vasomotor responses and reduced vascular superoxide, both ex vivo and in vivo. These changes were not explained by direct superoxide scavenging by 5-MTHF in vitro or by changes in plasma total homocysteine in vivo. Rather, 5-MTHF was a strong peroxynitrite scavenger and increased vascular BH4 and the BH4/total biopterin ratio. Furthermore, 5-MTHF reversed eNOS uncoupling, as assessed by NG-nitro-l-arginine methyl ester-inhibitable superoxide production, increased the eNOS dimer:monomer ratio, and enhanced eNOS activity. 5-MTHF has beneficial effects on endothelial function and vascular superoxide production in human atherosclerosis, by preventing peroxynitrite-mediated BH4 oxidation and improving eNOS coupling.


Effect of oral immunotherapy to peanut on food-specific quality of life.
Peanut allergy is an increasingly common problem for which the only available treatment is avoidance. Oral immunotherapy has shown promise for increasing tolerance of peanut in allergic children. Food allergy has an effect on the quality of life of children and adolescents. To measure the effect of oral immunotherapy to peanut on food-specific quality of life in children and adolescents. One hundred patients (5-18 years of age) were enrolled in an open trial of peanut oral immunotherapy. Parents of children 5 to 12 years old, children 8 to 12 years old, and teenagers completed validated, age-specific, food-related quality-of-life surveys before and after peanut oral immunotherapy. Ninety patients (76 children 5-12 years old and 14 adolescents 13-18 years old) achieved the maintenance daily dose of 450 mg of peanut protein. A significant improvement in quality of life was found in all survey domains (allergen avoidance, dietary restriction, risk of accidental exposure, emotional impact, food-related anxiety, and social and dietary limitations) with the exception of the emotional impact domain on the adolescents' survey. Quality of life significantly improved (P < .02) on all 30 questions when parents assessed their children 5 to 12 years old. When children (8-12 years old) and teens assessed themselves, quality of life improved (P < .05) on 22 of 24 questions and 12 of 18 questions, respectively. Peanut oral immunotherapy significantly improves food-specific quality of life.


Occupational stress among Swedish audiologists in clinical practice: Reasons for being stressed.
The present study reports on the application of a Swedish translation of the audiologist occupational stress questionnaire (AOSQ) on audiologists working in Sweden. The relations between AOSQ scores and perceived effort, perceived rewards, coping strategies at work, demographic variables such as salary, education length, practise length, and practice type were tested. A cross-sectional e-mail survey using the AOSQ, effort-reward imbalance questionnaire, and demographic questions. Four-hundred and four Swedish licensed audiologists working with clients. The Swedish AOSQ translation demonstrated high inter-item correlations and high internal consistency. Several stress factors were identified: time spent at work, accountability, leadership at the workplace, paperwork and practice demands, equipment and clinical protocols, own health concerns, and job control. The outcome on the complete AOSQ questionnaire was related to perceived effort, perceived rewards, coping strategies at work, and age. The Swedish AOSQ translation seems to provide a valid measure of occupational stress among audiologists.


The contrasting nature of woody plant species in different neotropical forest biomes reflects differences in ecological stability.
A fundamental premise of this review is that distinctive phylogenetic and biogeographic patterns in clades endemic to different major biomes illuminate the evolutionary process. In seasonally dry tropical forests (SDTFs), phylogenies are geographically structured and multiple individuals representing single species coalesce. This pattern of monophyletic species, coupled with their old species stem ages, is indicative of maintenance of small effective population sizes over evolutionary timescales, which suggests that SDTF is difficult to immigrate into because of persistent resident lineages adapted to a stable, seasonally dry ecology. By contrast, lack of coalescence in conspecific accessions of abundant and often widespread species is more frequent in rain forests and is likely to reflect large effective population sizes maintained over huge areas by effective seed and pollen flow. Species nonmonophyly, young species stem ages and lack of geographical structure in rain forest phylogenies may reflect more widespread disturbance by drought and landscape evolution causing resident mortality that opens up greater opportunities for immigration and speciation. We recommend full species sampling and inclusion of multiple accessions representing individual species in phylogenies to highlight nonmonophyletic species, which we predict will be frequent in rain forest and savanna, and which represent excellent case studies of incipient speciation.


Homoplasy in genome-wide analysis of rare amino acid replacements: the molecular-evolutionary basis for Vavilov's law of homologous series.
Rare genomic changes (RGCs) that are thought to comprise derived shared characters of individual clades are becoming an increasingly important class of markers in genome-wide phylogenetic studies. Recently, we proposed a new type of RGCs designated RGC_CAMs (after Conserved Amino acids-Multiple substitutions) that were inferred using genome-wide identification of amino acid replacements that were: i) located in unambiguously aligned regions of orthologous genes, ii) shared by two or more taxa in positions that contain a different, conserved amino acid in a much broader range of taxa, and iii) require two or three nucleotide substitutions. When applied to animal phylogeny, the RGC_CAM approach supported the coelomate clade that unites deuterostomes with arthropods as opposed to the ecdysozoan (molting animals) clade. However, a non-negligible level of homoplasy was detected. We provide a direct estimate of the level of homoplasy caused by parallel changes and reversals among the RGC_CAMs using 462 alignments of orthologous genes from 19 eukaryotic species. It is shown that the impact of parallel changes and reversals on the results of phylogenetic inference using RGC_CAMs cannot explain the observed support for the Coelomata clade. In contrast, the evidence in support of the Ecdysozoa clade, in large part, can be attributed to parallel changes. It is demonstrated that parallel changes are significantly more common in internal branches of different subtrees that are separated from the respective common ancestor by relatively short times than in terminal branches separated by longer time intervals. A similar but much weaker trend was detected for reversals. The observed evolutionary trend of parallel changes is explained in terms of the covarion model of molecular evolution. As the overlap between the covarion sets in orthologous genes from different lineages decreases with time after divergence, the likelihood of parallel changes decreases as well. The level of homoplasy observed here appears to be low enough to justify the utility of RGC_CAMs and other types of RGCs for resolution of hard problems in phylogeny. Parallel changes, one of the major classes of events leading to homoplasy, occur much more often in relatively recently diverged lineages than in those separated from their last common ancestor by longer time intervals of time. This pattern seems to provide the molecular-evolutionary underpinning of Vavilov's law of homologous series and is readily interpreted within the framework of the covarion model of molecular evolution.


Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2.
In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.


Regulation of large calcium-activated potassium channels by protein phosphatase 2A.
Vasodilating agents induce relaxation of mesangial cells, in part through cGMP-mediated activation of large calcium-activated potassium channels (BKCa). Normally quiescent in cell-attached patches, the response of BKCa to nitric oxide, atrial natriuretic peptide, and dibutyryl cGMP (Bt2cGMP) is characterized by a biphasic increase and then decrease ("rundown") in open probability. Using the patch-clamp method in conjunction with phosphatase inhibitors, we investigated whether the run-down phase was the result of dephosphorylation by an endogenous protein phosphatase. In cell-attached patches, cantharidic acid (500 nM), okadaic acid (100 nM), and calyculin A (100 nM), nondiscriminant inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A) at these concentrations, caused a significantly greater and sustained response of BKCa to Bt2cGMP. Within 2 min, the response of BKCa to the combination of cantharidic acid and Bt2cGMP was greater than the response to these agents added separately. Incubation of mesangial cells with okadaic acid for 20 min at a concentration (5 nM) specific for PP2A increased the basal open probability of BKCa and completely inhibited rundown after activation by Bt2cGMP. Incubation with calyculin A (10 nM), a more potent inhibitor of PP1, did not affect BKCa activity. In inside-out patches, Bt2cGMP plus MgATP caused a sustained activation of BKCa that was inhibited by exogenous PP2A but not PP1. It is concluded that either BKCa or a tightly associated regulator of BKCa is a common substrate for endogenous cGMP-activated protein kinase, which activates BKCa, and PP2A, which inactivates BKCa, in human mesangial cells.


Effectiveness and cost-effectiveness of early screening and treatment of malnourished patients.
About 25-40% of hospital patients are malnourished. With current clinical practices, only 50% of malnourished patients are identified by the medical and nursing staff. The objective of this study was to report the cost and effectiveness of early recognition and treatment of malnourished hospital patients with the use of the Short Nutritional Assessment Questionnaire (SNAQ). The intervention group consisted of 297 patients who were admitted to 2 mixed medical and surgical wards and who received both malnutrition screening at admission and standardized nutritional care. The control group consisted of a comparable group of 291 patients who received the usual hospital clinical care. Outcome measures were weight change, use of supplemental drinks, use of tube feeding, use of parenteral nutrition and in-between meals, number of consultations by the hospital dietitian, and length of hospital stay. The recognition of malnutrition improved from 50% to 80% with the use of the SNAQ malnutrition screening tool during admission to the hospital. The standardized nutritional care protocol added approximately 600 kcal and 12 g protein to the daily intake of malnourished patients. Early screening and treatment of malnourished patients reduced the length of hospital stay in malnourished patients with low handgrip strength (ie, frail patients). To shorten the mean length of hospital stay by 1 d for all malnourished patients, a mean investment of 76 euros (91 US dollars) in nutritional screening and treatment was needed. The incremental costs were comparably low in the whole group and in the subgroup of malnourished patients with low handgrip strength. Screening with the SNAQ and early standardized nutritional care improves the recognition of malnourished patients and provides the opportunity to start treatment at an early stage of hospitalization. The additional costs of early nutritional care are low, especially in frail malnourished patients.


Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial.
Transjugular intrahepatic portosystemic shunt (TIPS) has recently been reported to be effective in the treatment of cirrhotic patients with refractory ascites. However, the clinical utility of TIPS in the subset of refractory ascitic patients with good hepatic and renal function is uncertain. The aim of this study was to compare the efficacy of TIPS to that of large-volume paracentesis in cirrhotic patients with refractory ascites who have good hepatic and renal function. Sixty cirrhotic patients with refractory ascites who presented with a Child-Pugh score of <11, serum bilirubin of <3 mg/dl and creatinine of <1.9 mg/dl were assigned randomly to TIPS (n = 30) or large-volume paracentesis plus albumin (n = 30). The primary endpoint was survival. The secondary endpoints were response to treatment and development of hepatic encephalopathy. The baseline characteristics were similar in the two groups. Seventeen patients treated with TIPS and 21 treated with paracentesis died during the study period. The cumulative probabilities of survival at 1 and 2 years were 80 and 64% in the TIPS group and 49 and 35% in the paracentesis group (p < 0.005). TIPS was significantly superior to paracentesis in the control of ascites (p < 0.005). Treatment failure was more frequent in the paracentesis group, whereas the frequency of hepatic encephalopathy was greater in the TIPS group. In cirrhotic patients with refractory ascites who have good hepatic and renal function, TIPS improves survival and provides better control of ascites than large-volume paracentesis.


Classification and clinical diagnosis of fibromyalgia syndrome: recommendations of recent evidence-based interdisciplinary guidelines.
Objectives. Fibromyalgia syndrome (FMS), characterized by subjective complaints without physical or biomarker abnormality, courts controversy. Recommendations in recent guidelines addressing classification and diagnosis were examined for consistencies or differences. Methods. Systematic searches from January 2008 to February 2013 of the US-American National Guideline Clearing House, the Scottish Intercollegiate Guidelines Network, Guidelines International Network, and Medline for evidence-based guidelines for the management of FMS were conducted. Results. Three evidence-based interdisciplinary guidelines, independently developed in Canada, Germany, and Israel, recommended that FMS can be clinically diagnosed by a typical cluster of symptoms following a defined evaluation including history, physical examination, and selected laboratory tests, to exclude another somatic disease. Specialist referral is only recommended when some other physical or mental illness is reasonably suspected. The diagnosis can be based on the (modified) preliminary American College of Rheumatology (ACR) 2010 diagnostic criteria. Discussion. Guidelines from three continents showed remarkable consistency regarding the clinical concept of FMS, acknowledging that FMS is neither a distinct rheumatic nor mental disorder, but rather a cluster of symptoms, not explained by another somatic disease. While FMS remains an integral part of rheumatology, it is not an exclusive rheumatic condition and spans a broad range of medical disciplines.


p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration.
Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.


Physiological conditioning by electric field stimulation promotes cardiomyogenic gene expression in human cardiomyocyte progenitor cells.
The optimal cell lineage for cardiac-regeneration approaches remains mysterious. Additionally, electrical stimulation promotes cardiomyogenic differentiation of stimulated cells. Therefore, we hypothesized that electrical conditioning of cardiomyocyte progenitor cells (CMPCs) might enrich their cardiovascular potential. CMPCs were isolated from human adult atrial appendages, characterized, and electrically stimulated for 7 and 14 days. Electrical stimulation modulated CMPCs gene and protein expression, increasing all cardiac markers. GATA-binding protein 4 (GATA4) early transcription factor was significantly overexpressed (P = 0.008), but also its coactivator myocyte enhancer factor 2A (MEF2A) was upregulated (P = 0.073) under electrical stimulation. Moreover, important structural proteins and calcium handling-related genes were enhanced. The cardioregeneration capability of CMPCs is improved by electrical field stimulation. Consequently, short-term electrical stimulation should be a valid biophysical approach to modify cardiac progenitor cells toward a cardiogenic phenotype, and can be incorporated into transdifferentiation protocols. Electrostimulated CMPCs may be best-equipped cells for myocardial integration after implantation.


Gene-expression profiling of adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex, associated with a generally dismal prognosis owing to its aggressive behavior. The clinical management of ACC is complicated by the inadequacy of current diagnostic modalities to accurately distinguish benign from malignant adrenocortical tumors. In addition, efforts to better predict clinical tumor behavior are limited by the lack of a better understanding of the molecular mechanisms of adrenocortical carcinogenesis. There have been no significant improvements in the treatment of ACC. Thus, there is a pressing need for the development of new therapeutic approaches for patients with ACC, as most patients present with advanced locoregional and metastatic disease. The prospects of identifying diagnostic and prognostic markers or gene profiles for ACC have significantly improved with the development of genome-wide gene-expression analysis. Since 2003, several studies have reported distinct gene-expression profiles between benign and malignant adrenocortical tumors that may have diagnostic and prognostic clinical utility. In this article, we discuss the limitations of the clinical management of ACC, and the gene-expression profile studies that have attempted to address these limitations.


Checklist for standardized reporting of drug-drug interaction management guidelines.
Inconsistencies and omissions in drug-drug interaction (DDI) management guidelines may lead to harm and suboptimal therapy. The purpose of this study was to define a checklist for DDI management guidelines to help developers produce high-quality guidelines that will support healthcare providers in clinical practice. We carried out a two-round Delphi process with an international panel of healthcare providers, most of whom are pharmacists involved in providing DDI information, in order to select those items that should be addressed in DDI management guidelines (including grading systems that could be used). Twenty-three panellists reached consensus on 19 items in two main domains. These were consolidated into a checklist of 15 elements for standardized reporting in management guidelines. For each element a description is provided to specify what information should be documented in that specific element. It was possible to reach a broad consensus on which relevant items should be included in a checklist for the development of DDI management guidelines.


Replication of associations between genetic polymorphisms and chronic graft-versus-host disease.
Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs.


Effects of clonality on the genetic variability of rare, insular species: the case of Ruta microcarpa from the Canary Islands.
Many plant species combine sexual and clonal reproduction. Clonal propagation has ecological costs mainly related to inbreeding depression and pollen discounting; at the same time, species able to reproduce clonally have ecological and evolutionary advantages being able to persist when conditions are not favorable for sexual reproduction. The presence of clonality has profound consequences on the genetic structure of populations, especially when it represents the predominant reproductive strategy in a population. Theoretical studies suggest that high rate of clonal propagation should increase the effective number of alleles and heterozygosity in a population, while an opposite effect is expected on genetic differentiation among populations and on genotypic diversity. In this study, we ask how clonal propagation affects the genetic diversity of rare insular species, which are often characterized by low levels of genetic diversity, hence at risk of extinction. We used eight polymorphic microsatellite markers to study the genetic structure of the critically endangered insular endemic Ruta microcarpa. We found that clonality appears to positively affect the genetic diversity of R. microcarpa by increasing allelic diversity, polymorphism, and heterozygosity. Moreover, clonal propagation seems to be a more successful reproductive strategy in small, isolated population subjected to environmental stress. Our results suggest that clonal propagation may benefit rare species. However, the advantage of clonal growth may be only short-lived for prolonged clonal growth could ultimately lead to monoclonal populations. Some degree of sexual reproduction may be needed in a predominantly clonal species to ensure long-term viability.


School level correlates with adiposity in 9-10 year old children.
We examined the associations between the physical, social, and policy environments of schools and adiposity in 9-10 year old children in Norfolk, UK. The relationships between 56 school-level variables and Fat Mass Index (FMI; fat mass (kg)/height (m(2))) were investigated among 1724 well characterised children from 92 schools in this cross-sectional study. After stepwise removal of variables from multilevel linear regression models stratified by gender, only three variables were significantly associated with FMI. Among girls, attending a school with more pupils in the year group was associated with lower FMI, and attending a school with better cycle provision was associated with higher FMI. In boys being allowed to eat any food at break-time was associated with higher FMI. There was some evidence of moderation of the relationship between cycle provision and FMI by urban-rural location. These data suggest that few school factors are associated with FMI, and provide limited pointers to inform potential future school-based interventions to reduce obesity.