CERAMENT treatment of fracture defects (CERTiFy): protocol for a prospective, multicenter, randomized study investigating the use of CERAMENT™ BONE VOID FILLER in tibial plateau fractures.
Bone graft substitutes are widely used for reconstruction of posttraumatic bone defects. However, their clinical significance in comparison to autologous bone grafting, the gold-standard in reconstruction of larger bone defects, still remains under debate. This prospective, randomized, controlled clinical study investigates the differences in pain, quality of life, and cost of care in the treatment of tibia plateau fractures-associated bone defects using either autologous bone grafting or bioresorbable hydroxyapatite/calcium sulphate cement (CERAMENT™|BONE VOID FILLER (CBVF)). CERTiFy (CERament™ Treatment of Fracture defects) is a prospective, multicenter, controlled, randomized trial. We plan to enroll 136 patients with fresh traumatic depression fractures of the proximal tibia (types AO 41-B2 and AO 41-B3) in 13 participating centers in Germany. Patients will be randomized to receive either autologous iliac crest bone graft or CBVF after reduction and osteosynthesis of the fracture to reconstruct the subchondral bone defect and prevent the subsidence of the articular surface. The primary outcome is the SF-12 Physical Component Summary at week 26. The co-primary endpoint is the pain level 26 weeks after surgery measured by a visual analog scale. The SF-12 Mental Component Summary after 26 weeks and costs of care will serve as key secondary endpoints. The study is designed to show non-inferiority of the CBVF treatment to the autologous iliac crest bone graft with respect to the physical component of quality of life. The pain level at 26 weeks after surgery is expected to be lower in the CERAMENT bone void filler treatment group. CERTiFy is the first randomized multicenter clinical trial designed to compare quality of life, pain, and cost of care in the use of the CBVF and the autologous iliac crest bone graft in the treatment of tibia plateau fractures. The results are expected to influence future treatment recommendations. ClinicalTrials.gov: NCT01828905.


Maternal depressive symptoms, mother-child interactions, and children's executive function.
This study examined the independent and mediated associations between maternal depression symptoms (MDS), mother-child interaction, and child executive function (EF) in a prospective longitudinal sample of 1,037 children (50% boys) from predominantly low-income and rural communities. When children were 6, 15 and 24 months of age, mothers reported their level of depressive symptomatology. At 24 and 36 months of age, mother-child interactions during play were rated for warmth-sensitivity and harsh-intrusiveness, and dyadic joint attention and maternal language complexity were assessed from a book sharing activity. Children's EF (i.e., inhibitory control, working memory, and set shifting) were assessed at ages 36 and 48 months using a battery of six tasks. Results indicated that MDS at ages 15 and 24 months were negatively associated with children's EF at age 48 months. Additionally, harsh-intrusive mother-child interactions partially mediated this link. Although warmth-sensitivity, dyadic joint attention and maternal language complexity were all longitudinally related to EF, they did not serve as mediating mechanisms between MDS and EF. These results were obtained while controlling for multiple demographic factors, children's earlier cognitive abilities, maternal general distress and childcare experiences. Findings from this study identify 1 mechanism through which early exposure to MDS could be related to children's EF. (PsycINFO Database Record


[Removal of nickel from aqueous solutions using complexation-ultrafiltration process].
Polyacrylate (PAANa) and polyethylenimine (PEI) were used as complexing agents to combine with nickel ions. This complexation solution was transferred to the ultrafiltration cell and the separation by polyethersulfone (PES) ultrafiltration membranes was carried out under the pressure of 0.1 MPa. Effects of solution pH and polymer/Ni2+ mass ratio on nickel removal were investigated. The complex reaction equilibrium constants were calculated according to Langmuir isotherm model. Effects of concentration time on nickel removal and membrane flux were also studied. With PAANa as a polymer, the removal rate of nickel went the highest to 99.5% at pH 8 with PAANa/Ni2+ ratio of 5. When PEI was used, the removal rate of nickel ions went highest to 93.0% at pH 7 with PEI/Ni2+ ratio of 5. Best-fit complexation equilibrium constants at different pH values showed that pH 7 was most beneficial to the complex reaction. In addition, the number of nickel ions bound to a single monomer complexing agent increased with increase of pH value. During 12 h ultrafiltration process, the decline of membrane flux was less than 10% with PAANa as the complexing agent, while the membrane flux remains the same when PEI was used. The removal rates of Ni2+ kept constant with both complexing agents. Results showed that complexation-ultrafiltration can effectively remove nickel from aqueous solution at appropriate conditions.


Oxiplex reduces leg pain, back pain, and associated symptoms after lumbar discectomy.
Prospective, randomized, blinded clinical trial. To evaluate effectiveness of Oxiplex gel for reduction of pain and associated symptoms after lumbar discectomy. Oxiplex gel (carboxymethylcellulose, polyethylene oxide, and calcium) is used during discectomy to coat the surgical site for reduction of pain and symptoms after lumbar discectomy. Patients undergoing single-level lumbar discectomy performed by laminectomy or laminotomy and randomized to receive either surgery plus Oxiplex gel (treatment group) or surgery alone (control group) were assessed 6 months after surgery using (1) a quality of life questionnaire (Lumbar Spine Outcomes Questionnaire [LSOQ]) and (2) clinical evaluations. There were no statistically significant differences in baseline demographics, surgical procedures, LSOQ scores, and clinical evaluations between treatment (N = 177) and control (N = 175) groups. More gel-treated patients were satisfied with outcome of their surgical treatment than control patients (P = 0.05). The gel-treated group showed greater reductions in pain and symptoms from baseline compared with surgery-only controls. Additional benefits of gel were consistently shown in reduction of leg and back pain at 6 months in the patient population having substantial back pain at baseline (greater than or equal to the median LSOQ pain score of 63). In that population, there was a statistically significant reduction of leg pain and back pain (P < 0.01) in the treatment group compared with controls. Fewer patients in the treatment group had abnormal musculoskeletal physical examinations at 6 months compared with controls. There were no cases of cerebrospinal fluid leaks and no differences in laboratory values or vital signs. Patients in the treatment group had less hypoesthesia, paraesthesia, sensory loss, and fewer reoperations during the 6-month follow-up than controls (1 vs. 6). These data demonstrate improvements in clinical outcomes resulting from the use of Oxiplex gel in discectomy procedures for treatment of lumbar disc herniation.


Overcoming therapy resistance in EGFR-mutant lung cancer.
Tyrosine kinase inhibitors (TKIs) have dramatically changed the clinical prospects of patients with non-small cell lung cancer harboring epidermal growth factor receptor (EGFR)-activating mutations. Despite prolonged disease control and high tumor response rates, all patients eventually progress on EGFR TKI treatment. Here, we review the mechanisms of acquired EGFR TKI resistance, the methods for monitoring its appearance, as well as current and future efforts to define treatment strategies to overcome resistance.


Health complaints among nurses working near MRI scanners--a descriptive pilot study.
A questionnaire-based descriptive pilot study was conducted among all nurses routinely working with MRI in the Northern part of Sweden to provide an indication of the self-reported prevalence of health complaints related to working with MRI systems. Fifty-nine nurses (88% response rate), with on average 8 (±6) years experience with MRI scanning procedures, returned the questionnaire. In total, 9 nurses (15%) reported regularly experiencing at least one of the health complaints (1-5% for specific health complaints) attributed to arise or be aggravated by their presence in the MRI scanning room. Stratification of the results indicated that reporting of adverse symptoms was not related to the level of occupational workload/stress. However, reporting of health complaints was related to the strength of the magnet(s) the nurses worked with, with 57% of symptoms reported by those nurses working with the strongest systems (both 1.5 and 3T scanners in this population). Although this descriptive study did not include a control population and was based on self-reporting of health complaints, these data indicate that the prevalence of reported health complaints is not related to perceived work load or occupational stress, but does confirm data from other occupational sectors and indicates that the prevalence of adverse health complaints increases with the strength of the MRI system for nurses as well.


Synthesis of phytoalexins in sorghum as a site-specific response to fungal ingress.
Sorghum produces phytoalexins that are 3-deoxyanthocyanidin flavonoids. The compounds inhibit the growth of phytopathogenic fungi in vitro. The phytoalexins appear to be synthesized in subcellular inclusions within a host epidermal cell that is about to be penetrated by a fungus. This site-restricted synthesis suggests that the phytoalexin response occurs initially in the first cells that come under fungal attack and is not simply a response of cells that surround the original infection site.


Do Serum Urate-associated Genetic Variants Influence Gout Risk in People Taking Diuretics? Analysis of the UK Biobank.
The aim of this study was to determine whether serum urate (SU)-associated genetic variants differ in their influence on gout risk in people taking a diuretic compared to those not taking a diuretic. This research was conducted using the UK Biobank Resource (n = 359,876). Ten SU-associated single-nucleotide polymorphisms (SNP) were tested for their association with gout according to diuretic use. Gene-diuretic interactions for gout association were tested using a genetic risk score (GRS) and individual SNP by logistic regression adjusting for relevant confounders. After adjustment, use of a loop diuretic was positively associated with prevalent gout (OR 2.34, 95% CI 2.08-2.63), but thiazide diuretics were inversely associated with prevalent gout (OR 0.60, 95% CI 0.55-0.66). Compared with a lower GRS (< mean), a higher GRS (≥ mean) was positively associated with gout in those not taking diuretics (OR 2.63, 2.49-2.79), in those taking loop diuretics (OR 2.04, 95% CI 1.65-2.53), in those taking thiazide diuretics (OR 2.70, 2.26-3.23), and in those taking thiazide-like diuretics (OR 2.11, 95% CI 1.37-3.25). No nonadditive gene-diuretic interactions were observed. In people taking diuretics, SU-associated genetic variants contribute strongly to gout risk, with a similar effect to that observed in those not taking a diuretic. These findings suggest that the contribution of genetic variants is not restricted to people with "primary" gout, and that genetic variants can play an important role in gout susceptibility in the presence of other risk factors.


Complexity in pediatric primary care.
The management of patients in primary care is often complicated by the presence of multiple chronic conditions and psychosocial issues that increase the complexity of the encounter and have important impacts on care. There is a paucity of literature on this subject in the pediatric population. The aim of this study was to quantify the burden of chronic conditions in pediatric primary care. The problem lists of 3995 randomly selected patients from a community pediatric clinic and an academic hospital-based pediatric clinic in the same metropolitan area were analyzed for the presence and number of any chronic condition. In total, 53% of patients suffered from at least one chronic problem, 25% had two or more chronic conditions and 5.1% had four or more conditions. Compared with the community clinic, the academic clinic had significantly more children with catastrophic complex conditions (P<0.001). A regression analysis showed a significant positive correlation between the number of chronic medical conditions and mental health diagnoses. The burden of chronic disease in the pediatric primary care setting may be significantly higher than has been previously suggested. To ensure optimal quality of care, health planners should take into account the high burden of chronic illness, psychosocial issues and multimorbidity among patients in the pediatric primary care setting, as well as the higher complexity profile of patients attending academic clinics.


World Health Organization International Standard To Harmonize Assays for Detection of Mycoplasma DNA.
Nucleic acid amplification technique (NAT)-based assays (referred to here as NAT assays) are increasingly used as an alternative to culture-based approaches for the detection of mycoplasma contamination of cell cultures. Assay features, like the limit of detection or quantification, vary widely between different mycoplasma NAT assays. Biological reference materials may be useful for harmonization of mycoplasma NAT assays. An international feasibility study included lyophilized preparations of four distantly related mycoplasma species (Acholeplasma laidlawii, Mycoplasma fermentans, M. orale, M. pneumoniae) at different concentrations which were analyzed by 21 laboratories using 26 NAT assays with a qualitative, semiquantitative, or quantitative design. An M. fermentans preparation was shown to decrease the interassay variation when used as a common reference material. The preparation was remanufactured and characterized in a comparability study, and its potency (in NAT-detectable units) across different NATs was determined. The World Health Organization (WHO) Expert Committee on Biological Standardization (ECBS) established this preparation to be the "1st World Health Organization international standard for mycoplasma DNA for nucleic acid amplification technique-based assays designed for generic mycoplasma detection" (WHO Tech Rep Ser 987:42, 2014) with a potency of 200,000 IU/ml. This WHO international standard is now available as a reference preparation for characterization of NAT assays, e.g., for determination of analytic sensitivity, for calibration of quantitative assays in a common unitage, and for defining regulatory requirements in the field of mycoplasma testing.


Atherogenesis in youth--early consequence of adolescent smoking.
Cigarette smoking is a prevalent risk behavior among adolescents and tracks into adulthood. Little is known on the early impact of smoking on the vasculature in adolescence, although smoking is considered highly atherogenic in adults. We investigated the association between active smoking and Carotid artery Intima Media Thickness (CIMT), an early indicator of atherosclerosis. The SAPALDIA Youth Study is a nested study involving 356 offspring (8-20 yrs) of the Swiss SAPALDIA cohort who reported on early life, health and lifestyle, smoking habits and disease history. 288 youth underwent clinical examination. Mean average and maximum CIMT were calculated across all images of right and left common carotid. Multi-level linear regression was performed with weekly smoking, daily number of cigarettes and serum cotinine, adjusting for participant's and parental confounders. Valid CIMT data was available in 275 offspring (mean age 15 yrs, 53% girls). Weekly smoking was reported by 10% and current parental smoking by 24%. Individual mean and maximal CIMT averaged to 0.52 mm (sd 0.05) and 0.60 mm (sd. 0.05), respectively. Regression analyses yielded significant increase in average CIMT (mm) in weekly smokers (0.025, 95% CI 0.006; 0.045), per cigarette/day (0.003, 95% CI 0.001; 0.005) and serum cotinine level (0.008/100 μg/l, 95% CI 0.002; 0.015), which remained consistent after adjusting for parental confounders. Our study yields evidence of an early adverse impact of active tobacco exposure on atherogenesis in adolescents, independent of parental smoking, underlining the public health importance of prevention of adolescent smoking.


Detection of breast cancer cells using targeted magnetic nanoparticles and ultra-sensitive magnetic field sensors.
Breast cancer detection using mammography has improved clinical outcomes for many women, because mammography can detect very small (5 mm) tumors early in the course of the disease. However, mammography fails to detect 10 - 25% of tumors, and the results do not distinguish benign and malignant tumors. Reducing the false positive rate, even by a modest 10%, while improving the sensitivity, will lead to improved screening, and is a desirable and attainable goal. The emerging application of magnetic relaxometry, in particular using superconducting quantum interference device (SQUID) sensors, is fast and potentially more specific than mammography because it is designed to detect tumor-targeted iron oxide magnetic nanoparticles. Furthermore, magnetic relaxometry is theoretically more specific than MRI detection, because only target-bound nanoparticles are detected. Our group is developing antibody-conjugated magnetic nanoparticles targeted to breast cancer cells that can be detected using magnetic relaxometry. To accomplish this, we identified a series of breast cancer cell lines expressing varying levels of the plasma membrane-expressed human epidermal growth factor-like receptor 2 (Her2) by flow cytometry. Anti-Her2 antibody was then conjugated to superparamagnetic iron oxide nanoparticles using the carbodiimide method. Labeled nanoparticles were incubated with breast cancer cell lines and visualized by confocal microscopy, Prussian blue histochemistry, and magnetic relaxometry. We demonstrated a time- and antigen concentration-dependent increase in the number of antibody-conjugated nanoparticles bound to cells. Next, anti Her2-conjugated nanoparticles injected into highly Her2-expressing tumor xenograft explants yielded a significantly higher SQUID relaxometry signal relative to unconjugated nanoparticles. Finally, labeled cells introduced into breast phantoms were measured by magnetic relaxometry, and as few as 1 million labeled cells were detected at a distance of 4.5 cm using our early prototype system. These results suggest that the antibody-conjugated magnetic nanoparticles are promising reagents to apply to in vivo breast tumor cell detection, and that SQUID-detected magnetic relaxometry is a viable, rapid, and highly sensitive method for in vitro nanoparticle development and eventual in vivo tumor detection.


Abnormal expression of p27kip1 protein in levator ani muscle of aging women with pelvic floor disorders - a relationship to the cellular differentiation and degeneration.
BACKGROUND: Pelvic floor disorders affect almost 50% of aging women. An important role in the pelvic floor support belongs to the levator ani muscle. The p27/kip1 (p27) protein, multifunctional cyclin-dependent kinase inhibitor, shows changing expression in differentiating skeletal muscle cells during development, and relatively high levels of p27 RNA were detected in the normal human skeletal muscles. METHODS: Biopsy samples of levator ani muscle were obtained from 22 symptomatic patients with stress urinary incontinence, pelvic organ prolapse, and overlaps (age range 38-74), and nine asymptomatic women (age 31-49). Cryostat sections were investigated for p27 protein expression and type I (slow twitch) and type II (fast twitch) fibers. RESULTS: All fibers exhibited strong plasma membrane (and nuclear) p27 protein expression. cytoplasmic p27 expression was virtually absent in asymptomatic women. In perimenopausal symptomatic patients (ages 38-55), muscle fibers showed hypertrophy and moderate cytoplasmic p27 staining accompanied by diminution of type II fibers. Older symptomatic patients (ages 57-74) showed cytoplasmic p27 overexpression accompanied by shrinking, cytoplasmic vacuolization and fragmentation of muscle cells. The plasma membrane and cytoplasmic p27 expression was not unique to the muscle cells. Under certain circumstances, it was also detected in other cell types (epithelium of ectocervix and luteal cells). CONCLUSIONS: This is the first report on the unusual (plasma membrane and cytoplasmic) expression of p27 protein in normal and abnormal human striated muscle cells in vivo. Our data indicate that pelvic floor disorders are in perimenopausal patients associated with an appearance of moderate cytoplasmic p27 expression, accompanying hypertrophy and transition of type II into type I fibers. The patients in advanced postmenopause show shrinking and fragmentation of muscle fibers associated with strong cytoplasmic p27 expression.


Hereditary angioneurotic edema: review of the literature.
Congenital C1-inhibitor deficiency, or hereditary angioneurotic edema (HAE), is a rare autosomal dominant disease due to alterations in the C1 inhibitor gene that results in a deficiency of antigenic and/or functional C1-INH. Affected patients are heterozygous, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor. The disease is characterised by recurrent, circumscribed, non-pitting, and non-pruritic subepithelial swellings of sudden onset, which fade during the course of 48-72 hours, but can persist up to 1 week. Lesions can be solitary or multiple and primarily involve the extremities, larynx, face, and bowel wall. Bradykinin is believed to be the main, but certainly not the sole, mediator responsible for the bouts of edema in HAE. The diagnosis is suggested by family history, the lack of accompanying pruritus or urticaria, the presence of recurrent gastrointestinal attacks of colics, and episodes of laryngeal edema. Diminished C4 concentrations during symptomatic periods are highly suggestive for the diagnosis. Further laboratory diagnosis depends on demonstrating a deficiency of C1-INH antigen (type I) in most kindreds, but some kindreds have an antigenically intact but dysfunctional protein (type II) and require a functional assay to establish the diagnosis. Prophylactic administration of either attenuated androgens or protease inhibitors has proved useful in reducing frequency or severity of attacks. Infusions of a vapour-heated C1-INH concentrate are safe and effective means of both preventing and treating attacks. Nevertheless, this treatment is expensive and this extract is not readily available. It is emphasised that administration of angiotensin converting enzyme inhibitors is contraindicated in patients suffering from protease inhibitor deficiency states.


Embodied cognition and the cerebellum: Perspectives from the Dysmetria of Thought and the Universal Cerebellar Transform theories.
In this report, we analyze the relationship between embodied cognition and current theories of the cerebellum, particularly the Dysmetria of Thought theory and the concept of the Universal Cerebellar Transform (UCT). First, we describe the UCT and the Dysmetria of Thought theories, highlight evidence supporting these hypotheses and discuss their mechanisms, functions and relevance. We then propose the following relationships. (i) The UCT strengthens embodied cognition because it provides an example of embodiment where the nature and intensity of the dependence between cognitive, affective and sensorimotor processes are defined. (ii) Conversely, embodied cognition bolsters the UCT theory because it contextualizes a cerebellum-focused theory within a general neurological theory. (iii) Embodied cognition supports the extension to other brain regions of the principles of organization of cerebral cortical connections that underlie the UCT: The notion that cytoarchitectonically determined transforms manifest via connectivity as sensorimotor, cognitive and affective functions resonates with the embodiment thesis that cognitive, affective and sensorimotor systems are interdependent. (iv) Embodied cognition might shape future definitions of the UCT because embodiment redefines the relationship between the neurological systems modulated by the UCT. We conclude by analyzing the relationship between our hypotheses and the concept of syntax and action semantics deficits in motor diseases.


Analyses of cancer data from three ezetimibe trials.
Five years of statin therapy lowers low-density lipoprotein (LDL) cholesterol substantially and, over a 5-year period, results in reductions in the incidence of cardiovascular events. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677) has raised the hypothesis that adding ezetimibe to statin therapy for larger LDL cholesterol reductions might increase the incidence of cancer. We compared the results of a hypothesis-generating analysis of the incidence of cancer in the SEAS trial of ezetimibe plus simvastatin in 1873 patients (mean follow-up after ezetimibe or matching placebo was begun, 4.1 years) with a hypothesis-testing analysis of cancer data from the two large ongoing trials of this regimen: the Study of Heart and Renal Protection (SHARP) (NCT00125593) with 9264 patients (mean follow-up, 2.7 years) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), currently with 11,353 patients (mean follow-up, 1.0 year). In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P=0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up. The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.


Cannabinoid receptor CB2 protects against balloon-induced neointima formation.
Cannabinoid receptor CB(2) activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE(-/-)) mice receiving daily intraperitoneal injection of the CB(2) agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB(2)(-/-) and wild-type (WT) mice to balloon injury. We determined CB(2) mRNA and protein expression in dilated arteries of ApoE(-/-) mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB(2)(-/-) and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB(2) expression in ApoE(-/-) mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB(2) deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB(2)(-/-) mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB(2) knockouts. In vitro, bone marrow-derived CB(2)(-/-) macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB(2)(-/-) smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB(2) receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells.


High global diversity of cycloviruses amongst dragonflies.
Members of the family Circoviridae, specifically the genus Circovirus, were thought to infect only vertebrates; however, members of a sister group under the same family, the proposed genus Cyclovirus, have been detected recently in insects. In an effort to explore the diversity of cycloviruses and better understand the evolution of these novel ssDNA viruses, here we present five cycloviruses isolated from three dragonfly species (Orthetrum sabina, Xanthocnemis zealandica and Rhionaeschna multicolor) collected in Australia, New Zealand and the USA, respectively. The genomes of these five viruses share similar genome structure to other cycloviruses, with a circular ~1.7 kb genome and two major bidirectionally transcribed ORFs. The genomic sequence data gathered during this study were combined with all cyclovirus genomes available in public databases to identify conserved motifs and regulatory elements in the intergenic regions, as well as determine diversity and recombinant regions within their genomes. The genomes reported here represent four different cyclovirus species, three of which are novel. Our results confirm that cycloviruses circulate widely in winged-insect populations; in eight different cyclovirus species identified in dragonflies to date, some of these exhibit a broad geographical distribution. Recombination analysis revealed both intra- and inter-species recombination events amongst cycloviruses, including genomes recovered from disparate sources (e.g. goat meat and human faeces). Similar to other well-characterized circular ssDNA viruses, recombination may play an important role in cyclovirus evolution.


Detection of multi-resistant clinical strains of E. coli with Raman spectroscopy.
In recent years, we have seen a steady rise in the prevalence of antibiotic-resistant bacteria. This creates many challenges in treating patients who carry these infections, as well as stopping and preventing outbreaks. Identifying these resistant bacteria is critical for treatment decisions and epidemiological studies. However, current methods for identification of resistance either require long cultivation steps or expensive reagents. Raman spectroscopy has been shown in the past to enable the rapid identification of bacterial strains from single cells and cultures. In this study, Raman spectroscopy was applied for the differentiation of resistant and sensitive strains of Escherichia coli. Our focus was on clinical multi-resistant (extended-spectrum β-lactam and carbapenem-resistant) bacteria from hospital patients. The spectra were collected using both UV resonance Raman spectroscopy in bulk and single-cell Raman microspectroscopy, without exposure to antibiotics. We found resistant strains have a higher nucleic acid/protein ratio, and used the spectra to train a machine learning model that differentiates resistant and sensitive strains. In addition, we applied a majority of voting system to both improve the accuracy of our models and make them more applicable for a clinical setting. This method could allow rapid and accurate identification of antibiotic resistant bacteria, and thus improve public health.


Experiences of noninvasive ventilation in adults with hypercapnic respiratory failure: a review of evidence.
Noninvasive ventilation (NIV) has been shown to be beneficial for patients with respiratory failure; however, many patients fail to tolerate it and require other interventions. The objective of this thematic synthesis was to describe the nature of NIV experiences in adults with hypercapnic respiratory failure. A systematic, computerised literature search of English-language databases was undertaken with no restriction on date of publication. A total of 99 papers was identified and screened for eligibility from databases including CINAHL, Medline and PsycINFO, and some were hand searched. 45 papers were critically appraised and 32 met our inclusion criteria. Thematic analysis identified six key themes: benefits of NIV; fear (of various categories, namely, fear of technology/mask, fear of death and dying, and fear of pain and suffering); adaptation to NIV machine; decision making; need for information; and relationship with healthcare professionals. For people using NIV treatment, the experience of being on the NIV machine is unexpected and can be stressful. Findings from this review offer healthcare professionals insights and understanding into the patient experience of NIV. Healthcare professionals may use these findings to implement new strategies in NIV provision and the exploration of the applicability of age-specific supportive care NIV guidelines.


The importance of first pass success when performing orotracheal intubation in the emergency department.
The goal of this study was to determine the association of first pass success with the incidence of adverse events (AEs) during emergency department (ED) intubations. This was a retrospective analysis of prospectively collected continuous quality improvement data based on orotracheal intubations performed in an academic ED over a 4-year period. Following each intubation, the operator completed a data form regarding multiple aspects of the intubation, including patient and operator characteristics, method of intubation, device used, the number of attempts required, and AEs. Numerous AEs were tracked and included events such as witnessed aspiration, oxygen desaturation, esophageal intubation, hypotension, dysrhythmia, and cardiac arrest. Multivariable logistic regression was used to assess the relationship between the primary predictor variable of interest, first pass success, and the outcome variable, the presence of one or more AEs, after controlling for various other potential risk factors and confounders. Over the 4-year study period, there were 1,828 orotracheal intubations. If the intubation was successful on the first attempt, the incidence of one or more AEs was 14.2% (95% confidence interval [CI] = 12.4% to 16.2%). In cases requiring two attempts, the incidence of one or more AEs was 47.2% (95% CI = 41.8% to 52.7%); in cases requiring three attempts, the incidence of one or more AEs was 63.6% (95% CI = 53.7% to 72.6%); and in cases requiring four or more attempts, the incidence of one or more AEs was 70.6% (95% CI = 56.2.3% to 82.5%). Multivariable logistic regression showed that more than one attempt at tracheal intubation was a significant predictor of one or more AEs (adjusted odds ratio [aOR] = 7.52, 95% CI = 5.86 to 9.63). When performing orotracheal intubation in the ED, first pass success is associated with a relatively small incidence of AEs. As the number of attempts increases, the incidence of AEs increases substantially.


Low population Japanese encephalitis virus (JEV) seroprevalence in Udayapur district, Nepal, three years after a JE vaccination programme: A case for further catch up campaigns?
The live attenuated Japanese encephalitis (JE) vaccine SA14-14-2 has been used in Nepal for catch-up campaigns and is now included in the routine immunisation schedule. Previous studies have shown good vaccine efficacy after one dose in districts with a high incidence of JE. The first well-documented dengue outbreak occurred in Nepal in 2006 with ongoing cases now thought to be secondary to migration from India. Previous infection with dengue virus (DENV) partially protects against JE and might also influence serum neutralising antibody titres against JEV. This study aimed to determine whether serum anti-JEV neutralisation titres are: 1. maintained over time since vaccination, 2. vary with historic local JE incidence, and 3. are associated with DENV neutralising antibody levels. We conducted a cross-sectional study in three districts of Nepal: Banke, Rupandehi and Udayapur. Udayapur district had been vaccinated against JE most recently (2009), but had been the focus of only one campaign, compared with two in Banke and three in Rupandehi. Participants answered a short questionnaire and serum was assayed for anti-JEV and anti-DENV IgM and IgG (by ELISA) and 50% plaque reduction neutralisation titres (PRNT50) against JEV and DENV serotypes 1-4. A titre of ≥1:10 was considered seropositive to the respective virus. JEV neutralising antibody seroprevalence (PRNT50 ≥ 1:10) was 81% in Banke and Rupandehi, but only 41% in Udayapur, despite this district being vaccinated more recently. Sensitivity of ELISA for both anti-JEV and anti-DENV antibodies was low compared with PRNT50. DENV neutralising antibody correlated with the JEV PRNT50 ≥1:10, though the effect was modest. IgM (indicating recent infection) against both viruses was detected in a small number of participants. We also show that DENV IgM is present in Nepali subjects who have not travelled to India, suggesting that DENV may have become established in Nepal. We therefore propose that further JE vaccine campaigns should be considered in Udayapur district, and similar areas that have had fewer vaccination campaigns.


Systematic planning of genome-scale experiments in poorly studied species.
Genome-scale datasets have been used extensively in model organisms to screen for specific candidates or to predict functions for uncharacterized genes. However, despite the availability of extensive knowledge in model organisms, the planning of genome-scale experiments in poorly studied species is still based on the intuition of experts or heuristic trials. We propose that computational and systematic approaches can be applied to drive the experiment planning process in poorly studied species based on available data and knowledge in closely related model organisms. In this paper, we suggest a computational strategy for recommending genome-scale experiments based on their capability to interrogate diverse biological processes to enable protein function assignment. To this end, we use the data-rich functional genomics compendium of the model organism to quantify the accuracy of each dataset in predicting each specific biological process and the overlap in such coverage between different datasets. Our approach uses an optimized combination of these quantifications to recommend an ordered list of experiments for accurately annotating most proteins in the poorly studied related organisms to most biological processes, as well as a set of experiments that target each specific biological process. The effectiveness of this experiment- planning system is demonstrated for two related yeast species: the model organism Saccharomyces cerevisiae and the comparatively poorly studied Saccharomyces bayanus. Our system recommended a set of S. bayanus experiments based on an S. cerevisiae microarray data compendium. In silico evaluations estimate that less than 10% of the experiments could achieve similar functional coverage to the whole microarray compendium. This estimation was confirmed by performing the recommended experiments in S. bayanus, therefore significantly reducing the labor devoted to characterize the poorly studied genome. This experiment-planning framework could readily be adapted to the design of other types of large-scale experiments as well as other groups of organisms.


Production systems and breeding practices of Arab and Oromo goat keepers in northwestern Ethiopia: implications for community-based breeding programs.
We conducted a household survey in the semi-arid and sub-humid parts of Benishangul Gumuz region in northwestern Ethiopia to better understand and describe production systems and breeding practices of Arab and Oromo goat keepers. Multistage random sampling was employed to select peasant associations, while probability proportional to size sampling was used to select households. Data were collected from 249 households, out of which 86 were Arab and 163 were Oromo goat keepers that live in semi-arid and sub-humid agroecologies, respectively. Personal observations, focus group discussions, and structured questionnaires were used to collect data. Data were analyzed using SPSS and results were presented using descriptive statistics and indices. Ninety-two percent of Arab and 86% of Oromo goat keepers indicated crop and livestock production as their main occupation. Goats were kept for a variety of purposes. Income generation, meat, and savings were the highest priorities. The average flock size owned by Arab goat keepers (12.5 ± 4.0) was significantly (p < 0.01) higher than that of Oromo goat keepers (9.9 ± 3.8). Breeding does constituted the largest average flock size followed by kids, young does, and young bucks. Body size, twining ability, coat color, and kid growth were considered important in selecting breeding does, while body size, growth rate, coat color, and libido were the most preferred traits for buck selection. Mating was predominantly uncontrolled mainly due to communal grazing lands. Castration of bucks was significantly (p < 0.01) more frequent in Arab goat keepers than in Oromo goat keepers. Arab goats have better reproductive performance than Oromo goats. On average, female goats in the study areas gave first births at the age of 1.2 years, kidded every 7.5 months, stayed on reproduction for about 7.6 years, and produced 10.7 kids per lifetime. Compared with Arab goats, Oromo goats had significantly (p < 0.01) higher average age at first mating, age at first kidding, kidding interval, and reproductive lifetime but produced lower average number of kids per lifetime. Nucleus breeding schemes are recommended to optimize the limited available resources in the study areas. A single nucleus could serve both Arab and Oromo goat keepers. In conclusion, breeding programs implemented in the study areas should consider the production systems and breeding practices of Arab and Oromo goat keepers appropriately.


Parallel changes in gut microbiome composition and function during colonization, local adaptation and ecological speciation.
The processes of local adaptation and ecological speciation are often strongly shaped by biotic interactions such as competition and predation. One of the strongest lines of evidence that biotic interactions drive evolution comes from the repeated divergence of lineages in association with repeated changes in the community of interacting species. Yet relatively little is known about the repeatability of changes in gut microbial communities and their role in adaptation and divergence of host populations in nature. Here we use three cases of rapid, parallel adaptation and speciation in freshwater threespine stickleback to test for parallel changes in associated gut microbiomes. We find that features of the gut microbial communities have shifted repeatedly in the same direction in association with parallel divergence and speciation of stickleback hosts. These results suggest that changes to gut microbiomes can occur rapidly and predictably in conjunction with host evolution, and that host-microbe interactions might play an important role in host adaptation and diversification.


When has an induction failed?
To evaluate the length of the latent phase that, during labor inductions in nulliparous women, is associated with significantly decreased chance of vaginal delivery and increased risk of maternal and neonatal morbidity. All inductions of labor during a 6-month period were identified. Only those women who were nulliparous with a pregnancy of 36 weeks or more of gestation underwent further data analysis. Demographic data, intrapartum course, and maternal and neonatal outcomes were abstracted from the medical record. The latent phase was defined as beginning after oxytocin had been initiated and amniotomy performed and continuing until either 4 cm cervical dilation and 80% effacement or 5 cm cervical dilation regardless of effacement. A total of 397 nulliparous women, 32% of whom underwent cervical ripening, presented during the study period. Only 8 women (2%) never achieved active phase labor before cesarean, and the overall cesarean rate was 26.0%. A longer latent phase was associated with a greater rate of cesarean delivery, although only after 18 hours did a majority of induced labors result in cesarean. Chorioamnionitis and postpartum hemorrhage were more frequent with latent phases of labor greater than 18 hours (16% and 26%, respectively), although these diagnoses did not translate into greater risk of transfusion, hysterectomy, or prolonged hospitalization. Neonatal outcomes, including meconium passage, fetal acidemia, neonatal intensive care unit admission, or other morbidity did not increase in conjunction with longer latent phases. A latent phase of as long as 18 hours during induction of labor in nulliparous women allows the majority of these women to achieve a vaginal delivery without being subject to a significantly increased risk of significant maternal or neonatal morbidity. II-2.


Particle flow assays for fluorescent protein microarray applications.
Microarray technology has brought a paradigmatic change in bioanalytics. However, highly sensitive and accurate assays are still needed for a real breakthrough. We present a simple and generic approach for fluorescent signal amplification with fluorescent microparticle labels. The assay principle was demonstrated using a reverse array model consisting of spots of bovine serum albumin with a small fraction of the proteins biotinylated. Specific binding of streptavidin coated fluorescent microparticles to the spots was promoted by applying a controlled continuous microparticle flow. The surface bound beads were visualized and quantified with confocal microscopy images. Comparison with standard fluorescent and flow discrimination assays has revealed several advantages of our approach. First, non-specific particle binding could be reduced to less than 1 particle/spot making therefore the visualization of single biomolecular bonds possible. Second, the amplification scheme presented here is generic and can be applied to any fluorescent microarray. Furthermore, this assay makes use of a biotin-streptavidin linkage and can therefore be applied to all kind of assays. Finally, single fluorescent microbeads can be easily visualized with standard optical equipments, so that no high performance equipment is required.


Sterol composition of Cryptococcus neoformans in the presence and absence of fluconazole.
Analysis of the sterol compositions of 13 clinical isolates of the pathogenic yeast Cryptococcus neoformans obtained from five patients with recurring cryptococcal meningitis showed that, unlike Candida albicans, the major sterols synthesized by this yeast were obtusifoliol (range, 21.1 to 68.2%) and ergosterol (range, 0.0 to 46.5%). There was considerable variation in the sterol contents among the 13 isolates, with total sterol contents ranging from 0.31 to 5.9% of dry weight. The isolates from the five patients who had relapses had different total sterol contents and compositions in comparison with those of the pretreatment isolates, indicating either that the sterols had been changed by therapy or that the patients were infected with new isolates with different sterol compositions. Growth of the cryptococcal isolates in the presence of subinhibitory concentrations of fluconazole (0.25x the MIC) significantly altered the sterol content and pattern. The total sterol content decreased in nine isolates and increased in four isolates in response to pretreatment with fluconazole. Fluconazole had no consistent effect on ergosterol levels. In contrast, fluconazole caused a decrease in obtusifoliol levels and an increase in 4,14-dimethylzymosterol levels in all isolates. These results indicate extensive diversity in sterol content, sterol composition, and sterol synthesis in response to subinhibitory concentrations of fluconazole in C. neoformans strains. We propose that fluconazole inhibits the sterol synthesis of C. neoformans by interfering with both 14 alpha-demethylase-dependent and -independent pathways. No correlation between the sterol compositions of C. neoformans isolates and their susceptibilities to fluconazole was found.


The additive effects of the active component of grapefruit juice (naringenin) and antiarrhythmic drugs on HERG inhibition.
Grapefruit juice causes significant QT prolongation in healthy volunteers and naringenin has been identified as the most potent human ether-a-go-go-related gene (HERG) channel blocker among several dietary flavonoids. The interaction between naringenin and I(Kr)-blocking antiarrhythmic drugs has not been studied. We evaluated the effect of combining naringenin with I(Kr)-inhibiting antiarrhythmic drugs on cardiac I(Kr). I(Kr) current was studied by using HERG expressed in Xenopus oocytes, and the two-electrode voltage clamp technique was employed. Antiarrhythmic drugs (azimilide, amiodarone, dofetilide and quinidine) were tested. Experiments were performed at room temperature. Naringenin blocked HERG current dose dependently with an IC(50) of 173.3 +/- 3.1 microM. Naringenin 100 microM alone inhibited HERG current by 31 +/- 6%, and this inhibitory effect was increased with coadministration of 1 or 10 microM antiarrhythmic drugs. When 100 microM naringenin was added to antiarrhythmic drugs, greater HERG inhibition was demonstrated, compared to the current inhibition caused by antiarrhythmic drugs alone. Addition of naringenin significantly increased current inhibition (p < 0.05). There is an additive inhibitory effect on HERG current when naringenin is combined with I(Kr)-blocking antiarrhythmic drugs. This additive HERG inhibition could pose an increased risk of arrhythmias by increasing repolarization delay and possible repolarization heterogeneity.


Enhanced cognitive performance with estrogen use in nondemented community-dwelling older women.
To examine the association between history of postmenopausal estrogen use and cognitive function in a large sample of nondemented community-dwelling older women. A community of older residents in Cache County, Utah. A total of 2338 nondemented women aged 65 and older. All subjects were administered the Modified Mini-Mental State Examination (3MSE). Self-reported information on current and past use of estrogen after menopause was also obtained using a structured interview. Estrogen use was trichotomized as: no use, past use, and current use. Apolipoprotein E (APOE) genotype was determined and was dichotomized by the presence of an epsilon4 allele. A series of variance/covariance models was conducted with the 3MSE score as the dependent variable, first considering estrogen use alone, then adding, sequentially as covariates, education, age, health status, APOE genotype, current depression status, and history of head injury. In the simplest bivariate model, the 3MSE means (and confidence intervals) were 92.1 (91.7-92.4), 93.5 (93.1-93.9), and 94.4 (94.0-94.7) for never-, past-, and current users, respectively. In the final model (R2 = 0.28), no use of estrogen replacement therapy (P = .006), lower education (P < .001), poorer perceived health status (P = .035), current depression (P = .014), and presence of at least one APOE epsilon4 allele (P < .001) each independently predicted lower 3MSE score. Both current and past estrogen users had significantly higher 3MSE scores than never-users (P = .0063 and P = .0096, respectively). In this large community study, women who had used estrogen after menopause scored higher on the 3MSE. This finding remained, even after controlling for the effects of age, education, APOE genotype, and other variables that may affect cognition. These data support studies reporting a beneficial role of estrogen on cognition in postmenopausal women, particularly among current estrogen users.


A predicted protein, KIAA0247, is a cell cycle modulator in colorectal cancer cells under 5-FU treatment.
Colorectal cancer (CRC) is the predominant gastrointestinal malignancy and the leading cause of cancer death. The identification of genes related to CRC is important for the development of successful therapies and earlier diagnosis. Molecular analysis of feces was evaluated as a potential method for CRC detection. Expression of a predicted protein with unknown function, KIAA0247, was found in feces evaluated using specific quantitative real-time polymerase chain reaction. Its cellular function was then analyzed using immunofluorescent staining and the changes in the cell cycle in response to 5-fluorouracil (5-FU) were assessed. Gastrointestinal tissues and peripheral blood lymphocytes ubiquitously expressed KIAA0247. 56 CRC patients fell into two group categories according to fecal KIAA0247 mRNA expression levels. The group with higher fecal KIAA0247 (n=22; ≥0.4897) had a significantly greater five-year overall survival rate than the group with lower fecal KIAA0247 (n = 30; <0.4897) (66.0 ± 11.6%; p=0.035, log-rank test). Fecal expression of KIAA0247 inversely related to CRC tumor size (Kendall's tau-b=-0.202; p=0.047). Immunofluorescent staining revealed that the cytoplasm of CRC cells evenly expresses KIAA0247 without 5-FU treatment, and KIAA0247 accumulates in the nucleus after 40 μM 5-FU treatment. In HCT116 p53(-/-) cells, which lack p53 cell cycle control, the proportion of cells in the G2/M phase was larger (13%) in KIAA0247-silent cells than in the respective shLuc control (10%) and KIAA0247-overexpressing cells (7%) after the addition of low dose (40 μM) 5-FU. Expression of three cyclin genes (cyclin A2, cyclin B1, and cyclin B2) also downregulated in the cells overexpressing KIAA0247. This is the first description of a linkage between KIAA0247 and CRC. The study's data demonstrate overexpression of KIAA0247 associates with 5-FU therapeutic benefits, and also identify the clinical significance of fecal KIAA0247 in CRC.


Stress response and child health.
Stress is defined as a state of real or perceived threat to homeostasis. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for various endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of stressful event(s). Prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors. This review summarizes the topics presented at the fifth New Inroads to Child Health (NICHe) Conference "Stress Response and Child Health" held at Heraklion, Crete, Greece, in May 2012.


Stiffness control of balance in quiet standing.
Our goal was to provide some insights into how the CNS controls and maintains an upright standing posture, which is an integral part of activities of daily living. Although researchers have used simple performance measures of maintenance of this posture quite effectively in clinical decision making, the mechanisms and control principles involved have not been clear. We propose a relatively simple control scheme for regulation of upright posture that provides almost instantaneous corrective response and reduces the operating demands on the CNS. The analytic model is derived and experimentally validated. A stiffness model was developed for quiet standing. The model assumes that muscles act as springs to cause the center-of-pressure (COP) to move in phase with the center-of-mass (COM) as the body sways about some desired position. In the sagittal plane this stiffness control exists at the ankle plantarflexors, in the frontal plane by the hip abductors/adductors. On the basis of observations that the COP-COM error signal continuously oscillates, it is evident that the inverted pendulum model is severely underdamped, approaching the undamped condition. The spectrum of this error signal is seen to match that of a tuned mass, spring, damper system, and a curve fit of this "tuned circuit" yields omega n the undamped natural frequency of the system. The effective stiffness of the system, Ke, is then estimated from Ke = I omega n2, and the damping B is estimated from B = BW X I, where BW is the bandwidth of the tuned response (in rad/s), and I is the moment of inertia of the body about the ankle joint. Ten adult subjects were assessed while standing quietly at three stance widths: 50% hip-to-hip distance, 100 and 150%. Subjects stood for 2 min in each position with eyes open; the 100% stance width was repeated with eyes closed. In all trials and in both planes, the COP oscillated virtually in phase (within 6 ms) with COM, which was predicted by a simple 0th order spring model. Sway amplitude decreased as stance width increased, and Ke increased with stance width. A stiffness model would predict sway to vary as Ke-0.5. The experimental results were close to this prediction: sway was proportional to Ke(-0.55). Reactive control of balance was not evident for several reasons. The visual system does not appear to contribute because no significant difference between eyes open and eyes closed results was found at 100% stance width. Vestibular (otolith) and joint proprioceptive reactive control were discounted because the necessary head accelerations, joint displacements, and velocities were well below reported thresholds. Besides, any reactive control would predict that COP would considerably lag (150-250 ms) behind the COM. Because the average COP was only 4 ms delayed behind the COM, reactive control was not evident; this small delay was accounted for by the damping in the tuned mechanical system.


Neighborhood socioeconomic disadvantage modifies the relationship between weight status and weight-related satisfaction.
Are adults living in disadvantaged communities less likely to recognize or be dissatisfied with being overweight than their counterparts in more affluent areas? Multilevel logistic regression was used to analyze a cross-sectional sample of 10 880 people aged 15 years or older selected from the 2009 wave of the 'Household, Income and Labour Dynamics in Australia'. Outcome variables included whether participants perceived themselves as 'overweight' or not, and their self-reported (dis)satisfaction with their weight. Key covariates included: (i) actual weight status, derived from the World Health Organization (WHO) criteria for 'normal', 'overweight' and 'obese' intervals of body mass index, on the basis of self-reported height and weight; and (ii) the Socio-Economic Index For Areas, an indicator of neighborhood socioeconomic disadvantage defined for Census Collection Districts. Data were analyzed in 2015. In more disadvantaged neighborhoods, self-classification as overweight or obese tended to be higher, but dissatisfaction with current weight appeared to be lower. For people who by WHO criteria are of 'normal' weight, 16.8% (95% CI 15.6, 17.9) felt dissatisfied with their weight and 11.5% (95% CI 10.5, 12.5) classified themselves as overweight or obese. For people classified as overweight or obese by these criteria, the level of dissatisfaction and perceived overweight or obese status were much higher. Overweight and obese participants in affluent areas were more likely to be dissatisfied and consider themselves overweight or obese in comparison with their peers living in disadvantaged areas. Interventions aiming to prevent weight gain and to narrow socioeconomic inequity in overweight must reconcile with the findings that people in disadvantaged communities are less likely to recognize their overweight or be dissatisfied with their weight status.


Bridging Reinforcement Learning and Iterative Learning Control: Autonomous Motion Learning for Unknown, Nonlinear Dynamics.
This work addresses the problem of reference tracking in autonomously learning robots with unknown, nonlinear dynamics. Existing solutions require model information or extensive parameter tuning, and have rarely been validated in real-world experiments. We propose a learning control scheme that learns to approximate the unknown dynamics by a Gaussian Process (GP), which is used to optimize and apply a feedforward control input on each trial. Unlike existing approaches, the proposed method neither requires knowledge of the system states and their dynamics nor knowledge of an effective feedback control structure. All algorithm parameters are chosen automatically, i.e. the learning method works plug and play. The proposed method is validated in extensive simulations and real-world experiments. In contrast to most existing work, we study learning dynamics for more than one motion task as well as the robustness of performance across a large range of learning parameters. The method's plug and play applicability is demonstrated by experiments with a balancing robot, in which the proposed method rapidly learns to track the desired output. Due to its model-agnostic and plug and play properties, the proposed method is expected to have high potential for application to a large class of reference tracking problems in systems with unknown, nonlinear dynamics.


Forceful dilatation under endoscopic control in the treatment of achalasia: a randomised trial of pneumatic versus metallic dilator.
Forceful dilatation under endoscopic control is a well established treatment of achalasia; several different types of dilators can be used. This study prospectively compared the clinical and manometric efficacy of a single dilatation using two different dilators. Forty one patients were randomly assigned to forceful dilatation under endoscopic control with either a pneumatic dilator (n = 17) or a metallic dilator (n = 24). Thereafter, the patients received periodic clinical and manometric evaluation for one year (before and one, six, and 12 months after dilatation). One month after dilatation all but one of the subjects in each group had experienced good to excellent results and their clinical improvement persisted for the one year follow up. Two patients (one in each group) were perforated during the procedure and required surgical treatment. Recovery was uneventful in both cases. Resting lower oesophageal sphincter pressure (mean (SEM)) significantly and similarly decreased after both methods of dilatation (pneumatic dilator: before dilatation 37 (3) mm Hg, one year after dilatation 18 (3) mm Hg; metallic dilator: before dilatation 34 (2) mm Hg, one year after dilatation 17 (3) mm Hg; p < 0.05 for both). It is concluded that in the treatment of achalasia a single dilatation under endoscopic control with either pneumatic or metallic dilator yield comparable clinical and manometric results and similar complication rates. The use of one or other dilator should depend more on the preference and experience of the endoscopist than on the type of device.


Preventing blood-borne virus infection in people who inject drugs in the UK: systematic review, stakeholder interviews, psychosocial intervention development and feasibility randomised controlled trial.
Opioid substitution therapy and needle exchanges have reduced blood-borne viruses (BBVs) among people who inject drugs (PWID). Some PWID continue to share injecting equipment. To develop an evidence-based psychosocial intervention to reduce BBV risk behaviours and increase transmission knowledge among PWID, and conduct a feasibility trial among PWID comparing the intervention with a control. A pragmatic, two-armed randomised controlled, open feasibility trial. Service users were Steering Group members and co-developed the intervention. Peer educators co-delivered the intervention in London. NHS or third-sector drug treatment or needle exchanges in Glasgow, London, Wrexham and York, recruiting January and February 2016. Current PWID, aged ≥ 18 years. A remote, web-based computer randomisation system allocated participants to a three-session, manualised, psychosocial, gender-specific group intervention delivered by trained facilitators and BBV transmission information booklet plus treatment as usual (TAU) (intervention), or information booklet plus TAU (control). Recruitment, retention and follow-up rates measured feasibility. Feedback questionnaires, focus groups with participants who attended at least one intervention session and facilitators assessed the intervention's acceptability. A systematic review of what works to reduce BBV risk behaviours among PWID; in-depth interviews with PWID; and stakeholder and expert consultation informed the intervention. Sessions covered improving injecting technique and good vein care; planning for risky situations; and understanding BBV transmission. Fifty-six per cent (99/176) of eligible PWID were randomised: 52 to the intervention group and 47 to the control group. Only 24% (8/34) of male and 11% (2/18) of female participants attended all three intervention sessions. Overall, 50% (17/34) of men and 33% (6/18) of women randomised to the intervention group and 47% (14/30) of men and 53% (9/17) of women randomised to the control group were followed up 1 month post intervention. Variations were reported by location. The intervention was acceptable to both participants and facilitators. At 1 month post intervention, no increase in injecting in 'risky' sites (e.g. groin, neck) was reported by participants who attended at least one session. PWID who attended at least one session showed a trend towards greater reduction in injecting risk behaviours, a greater increase in withdrawal planning and were more confident about finding a vein. A mean cost of £58.17 per participant was calculated for those attending one session, £148.54 for those attending two sessions and £270.67 for those attending all three sessions, compared with £0.86 in the control group. Treatment costs across the centres vary as a result of the different levels of attendance, as total session costs are divided by attendees to obtain a cost per attendee. The economic analysis suggests that a cost-effectiveness study would be feasible given the response rates and completeness of data. However, we have identified aspects where the service use questionnaire could be abbreviated given the low numbers reported in several care domains. No adverse events were reported. As only 19% of participants attended all three intervention sessions and 47% were followed up 1 month post intervention, a future definitive randomised controlled trial of the intervention is not feasible. Exposure to information on improving injecting techniques did not encourage riskier injecting practices or injecting frequency, and benefits were reported among attendees. The intervention has the potential to positively influence BBV prevention. Harm reduction services should ensure that the intervention content is routinely delivered to PWID to improve vein care and prevent BBVs. The intervention did not meet the complex needs of some PWID, more tailoring may be needed to reach PWID who are more frequent injectors, who are homeless and female. Intervention delivery proved more feasible in London than other locations. Non-attendance at the York trial site substantially influenced the results. Current Controlled Trials ISRCTN66453696 and PROSPERO 014:CRD42014012969. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 72. See the NIHR Journals Library website for further project information.


Physical Fitness and Anthropometric Measures of Young Brazilian Judo and Wrestling Athletes and Its Relations to Cardiorespiratory Fitness.
This study aimed to compare the anthropometric profile and physical fitness of young judo and wrestling athletes. Twenty-four young athletes (judo (n = 13) and wrestling (n = 11)) participated in this study. The first visit involved anthropometric and flexibility evaluation, abdominal endurance test, upper limbs resistance and cardiorespiratory test. After 48 h, horizontal jump test (HJT), vertical jump test (VJT), medicine ball throw test (MBT), chin-up test (CUT), chin-up isometric test (CUIT) and the anaerobic resistance test were performed. Judo athletes presented greater values for body mass (p = 0.020), height (p = 0.010), and body mass index (p = 0.026) than wrestlers. Judo athletes also performed better for abdominal endurance (p = 0.044), upper limb resistance tests (p < 0.001), VJT (p = 0.022) and MBT (p = 0.023) than wrestling athletes. These results suggest that young judo athletes presented a higher performance in abdominal endurance, upper limbs resistance, HJT, VJT and MBT than wrestling athletes, suggesting that strength and conditioning are related to modality specificity.


Does continuity of care impact decision making in the next birth after a caesarean section (VBAC)? a randomised controlled trial.
Caesarean section (CS) has short and long-term health effects for both the woman and her baby. One of the greatest contributors to the CS rate is elective repeat CS. Vaginal birth after caesarean (VBAC) is an option for many women; despite this the proportion of women attempting VBAC remains low. Potentially the relationship that women have with their healthcare professional may have a major influence on the uptake of VBAC. Models of service delivery, which enable an individual approach to care, may make a difference to the uptake of VBAC. Midwifery continuity of care could be an effective model to encourage and support women to choose VBAC. A randomised, controlled trial will be undertaken. Eligible pregnant women, whose most recent previous birth was by lower-segment CS, will be randomly allocated 1:1 to an intervention group or control group. The intervention provides midwifery continuity of care to women through pregnancy, labour, birth and early postnatal care. The control group will receive standard hospital care from different midwives through pregnancy, labour, birth and early postnatal care. Both groups will receive an obstetric consultation during pregnancy and at any other time if required. Clinical care will follow the same guidelines in both groups. This study will determine whether midwifery continuity of care influences the decision to attempt a VBAC and impacts on mode of birth, maternal experiences with care and the health of the neonate. Outcomes from this study might influence the way maternity care is provided to this group of women and thus impact on the CS rate. This information will provide high level evidence to policy makers, health service managers and practitioners who are working towards addressing the increased rate of CS. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12611001214921.


Characterization of spores of Bacillus subtilis which lack dipicolinic acid.
Spores of Bacillus subtilis with a mutation in spoVF cannot synthesize dipicolinic acid (DPA) and are too unstable to be purified and studied in detail. However, the spores of a strain lacking the three major germinant receptors (termed Deltager3), as well as spoVF, can be isolated, although they spontaneously germinate much more readily than Deltager3 spores. The Deltager3 spoVF spores lack DPA and have higher levels of core water than Deltager3 spores, although sporulation with DPA restores close to normal levels of DPA and core water to Deltager3 spoVF spores. The DPA-less spores have normal cortical and coat layers, as observed with an electron microscope, but their core region appears to be more hydrated than that of spores with DPA. The Deltager3 spoVF spores also contain minimal levels of the processed active form (termed P(41)) of the germination protease, GPR, a finding consistent with the known requirement for DPA and dehydration for GPR autoprocessing. However, any P(41) formed in Deltager3 spoVF spores may be at least transiently active on one of this protease's small acid-soluble spore protein (SASP) substrates, SASP-gamma. Analysis of the resistance of wild-type, Deltager3, and Deltager3 spoVF spores to various agents led to the following conclusions: (i) DPA and core water content play no role in spore resistance to dry heat, dessication, or glutaraldehyde; (ii) an elevated core water content is associated with decreased spore resistance to wet heat, hydrogen peroxide, formaldehyde, and the iodine-based disinfectant Betadine; (iii) the absence of DPA increases spore resistance to UV radiation; and (iv) wild-type spores are more resistant than Deltager3 spores to Betadine and glutaraldehyde. These results are discussed in view of current models of spore resistance and spore germination.


Communication and choice in dying from heart disease.
In heart disease palliative care has received less attention than in cancer. In the Regional Study of Care for the Dying, carers of a random sample of deaths in 20 English health districts were interviewed about 10 months after the death. There were 675 respondents for patients dying with heart disease, and we report data on 600 deaths that were not sudden. 54% of patients died in hospital, 30% in their own home, 11% in a nursing or residential home, and 4% in other places. Half the patients were said to have known, or probably known, that they were likely to die; of these, 82% were said to have worked this out for themselves rather than been told by a doctor or nurse. More than one-third of patients (39%) died without an informal carer present. Respondents said that a quarter of the patients had wanted to die earlier: this desire was associated with older age and the number and severity of symptoms. The study suggests the need for health services to give greater attention to palliative care for patients dying with heart disease.


Common variants in mismatch repair genes and risk of colorectal cancer.
The mismatch repair (MMR) genes are in charge of maintaining genomic integrity. Mutations in the MMR genes are at the origin of a familial form of colorectal cancer (CRC). This syndrome accounts for only a small proportion of the excess familial risk of CRC. The characteristics of the alleles that account for the remainder of cases are unknown. To assess the putative associations between common variants in MMR genes and CRC, we performed a genetic case-control study using a single-nucleotide polymorphism (SNP) tagging approach. A total of 2299 cases and 2284 unrelated controls were genotyped for 68 tagging SNPs in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were measured in cases and controls and analysed using univariate analysis. Haplotypes were constructed and analysed using logistic regression. We also carried out a two-locus interaction analysis and a global test analysis. Genotype frequencies were found to be marginally different in cases and controls for MSH3 rs26279 with a rare homozygote OR = 1.31 [95% confidence interval (CI) 1.05 to 1.62], p(trend) = 0.04. We found a rare MLH1 (frequency <5%) haplotype, increasing the risk of colorectal cancer: (OR = 9.76; 95% CI, 1.25 to 76.29; p = 0.03). The two-locus interaction analysis has exhibited signs of interaction between SNPs located in genes MSH6 and MSH2. Global testing has showed no evidence of interaction. It is unlikely that common variants in MMR genes contribute significantly to colorectal cancer.


Focus issue: organ development from beginning to end.
Science Signaling complements the Science special issue on organ development (http://www.sciencemag.org/organdevelopment) with a Perspective and Review highlighting organogenesis in plants and a Research Article on mammalian kidney formation. A Review from Crespi and Frugier focuses on the bacterial and host-generated signals that induce and regulate nodule organogenesis. A Perspective from Gray et al. addresses peptide signals that activate leucine-rich repeat (LRR) receptor pathways to regulate vein versus stoma cell fate in the leaf. In a Research Article, Tsigelny et al. report metagene analysis that revealed insight into the molecular mechanisms that drive various stages of kidney formation during mammalian embryogenesis.


Uptake of bovine serum albumin by rainbow trout from hypersmotic solutions: a model for vaccinating fish.
Immersion of juvenile rainbow trout (Salmo gairdneri) in a solution containing either urea or sodium chloride at 1650 milliosmoles and 2 percent of bovine serum albumin (BSA) resulted in an uptake of BSA into the blood of the fish after a 3-minute exposure. Similar blood levels of BSA were also obtained by placing the fish in 1650 millosmoles of sodium chloride for about 2 minutes, and then immersing them in 2 percent BSA solution for 3 minutes. Uptake of BSA into the fish appeared to be primarily through the lateral line system and secondarily through the gills.


New Developments in Publishing Related to Authorship.
To present the inappropriate types of authorship and practice, and the most recent developments related to basic principles and criteria to a fair system for allocating authorship in scientific publications. An analysis of relevant materials and documents, sources from the internet and published literature and personal experience and observations of the author. Working in multidisciplinary teams is a common feature of modern research processes. The most sensitive question is how to decide on who to acknowledge as author of a multi-authored publication. The pertinence of this question is growing with the increasing importance of individual scientists' publication records for professional status and career. However, discussions about authorship allocation might lead to serious conflicts and disputes among coworkers which could even endanger cooperation and successful completion of a research project. It seems that discussion and education about ethical standards and practical guidelines for fairly allocating authorship are insufficient and the question of ethical practices related to authorship in multi-authored publications remains generally unresolved. It is necessary to work for raising awareness about the importance and need for education about principles of scientific communication and fair allocation of authorship, ethics of research and publication of results. The use of various forms of education in the scientific community, especially young researchers and students, in order to create an ethical environment, is one of the most effective ways to prevent the emergence of scientific and publication dishonesty and fraud, including pathology of authorship.


Managing COVID-19 within and across health systems: why we need performance intelligence to coordinate a global response.
The COVID-19 pandemic is a complex global public health crisis presenting clinical, organisational and system-wide challenges. Different research perspectives on health are needed in order to manage and monitor this crisis. Performance intelligence is an approach that emphasises the need for different research perspectives in supporting health systems' decision-makers to determine policies based on well-informed choices. In this paper, we present the viewpoint of the Innovative Training Network for Healthcare Performance Intelligence Professionals (HealthPros) on how performance intelligence can be used during and after the COVID-19 pandemic. A lack of standardised information, paired with limited discussion and alignment between countries contribute to uncertainty in decision-making in all countries. Consequently, a plethora of different non-data-driven and uncoordinated approaches to address the outbreak are noted worldwide. Comparative health system research is needed to help countries shape their response models in social care, public health, primary care, hospital care and long-term care through the different phases of the pandemic. There is a need in each phase to compare context-specific bundles of measures where the impact on health outcomes can be modelled using targeted data and advanced statistical methods. Performance intelligence can be pursued to compare data, construct indicators and identify optimal strategies. Embracing a system perspective will allow countries to take coordinated strategic decisions while mitigating the risk of system collapse.A framework for the development and implementation of performance intelligence has been outlined by the HealthPros Network and is of pertinence. Health systems need better and more timely data to govern through a pandemic-induced transition period where tensions between care needs, demand and capacity are exceptionally high worldwide. Health systems are challenged to ensure essential levels of healthcare towards all patients, including those who need routine assistance. Performance intelligence plays an essential role as part of a broader public health strategy in guiding the decisions of health system actors on the implementation of contextualised measures to tackle COVID-19 or any future epidemic as well as their effect on the health system at large. This should be based on commonly agreed-upon standardised data and fit-for-purpose indicators, making optimal use of existing health information infrastructures. The HealthPros Network can make a meaningful contribution.


Environmental sensing and response genes in cnidaria: the chemical defensome in the sea anemone Nematostella vectensis.
The starlet sea anemone Nematostella vectensis has been recently established as a new model system for the study of the evolution of developmental processes, as cnidaria occupy a key evolutionary position at the base of the bilateria. Cnidaria play important roles in estuarine and reef communities, but are exposed to many environmental stressors. Here, I describe the genetic components of a "chemical defensome" in the genome of N. vectensis and review cnidarian molecular toxicology. Gene families that defend against chemical stressors and the transcription factors that regulate these genes have been termed a chemical defensome and include the cytochromes P450 and other oxidases, various conjugating enyzymes, the ATP-dependent efflux transporters, oxidative detoxification proteins, as well as various transcription factors. These genes account for about 1% (266/27,200) of the predicted genes in the sea anemone genome, similar to the proportion observed in tunicates and humans, but lower than that observed in sea urchins. While there are comparable numbers of stress-response genes, the stress sensor genes appear to be reduced in N. vectensis relative to many model protostomes and deuterostomes. Cnidarian toxicology is understudied, especially given the important ecological roles of many cnidarian species. New genomic resources should stimulate the study of chemical stress sensing and response mechanisms in cnidaria and allow us to further illuminate the evolution of chemical defense gene networks.


Unmasking of intestinal epithelial lateral membrane beta1 integrin consequent to transepithelial neutrophil migration in vitro facilitates inv-mediated invasion by Yersinia pseudotuberculosis.
Idiopathic intestinal disease states characterized by active inflammation associated with transepithelial migration of neutrophils may, paradoxically, be associated with an increased risk of infection by enteric pathogens. Although the specific ligands with which various intestinal pathogens associate remain largely unknown, it is thought that many reside on the basolateral membrane. For example, beta1 integrin, a basolateral membrane protein, mediates the specific interaction between epithelial cells and the inv gene product (invasin) on the surface of Yersinia pseudotuberculosis. Our observations indicate that neutrophil migration across model T84 cell intestinal epithelia produced transient separation of epithelial cells at sites of neutrophil migration, resulting in microdiscontinuities that remained unsealed for several hours. We hypothesized that such sites of microdiscontinuities would yield a potential route for luminal pathogens to gain access to basolateral ligands and, thus, provide a window of risk for enteric infection. The surface biotinylation and fluorescence localization studies reported here revealed that, as in natural intestinal epithelia, beta1 integrin was strictly polarized to the basolateral membrane in confluent T84 monolayers. However, the transient microdiscontinuities resulting from neutrophil migration permitted access to beta1 integrin from the apical reservoir. Coincident with such basolateral exposure of beta1 integrin, monolayers became susceptible to invasion by Y. pseudotuberculosis. Fluorescence localization indicated that Y. pseudotuberculosis selectively associated with monolayers at sites where small discontinuities resulting from neutrophil transmigration were found. An increased risk for Y. pseudotuberculosis infection was specifically related to exposure of beta1 integrin (normally concealed by tight junctions) to the apical compartment, as Y. pseudotuberculosis cells lacking the inv gene were unable to invade following neutrophil transepithelial migration. Following closure of the microdiscontinuities associated with neutrophil migration, a small pool of beta1 integrin remained apically localized, presumably due to incomplete repolarization. However, this small apical pool of beta1 integrin was insufficient to support a detectable increased risk of Yersinia infection. Together, these observations indicate that by transiently perturbing monolayer continuity, neutrophil transepithelial migration is associated with a window of risk in which luminal pathogens can access basolateral ligands such as beta1 integrin.


Comparative tests of primate cognition: different scaling methods produce different results.
Although early comparative studies supported hypotheses that ecological demands selected for primate cognition, later work indicated that social demands were more important. One difference between earlier and later studies is that earlier studies scaled brain structures by (A) taking residuals from an interspecific regression of the brain structure in question on body mass, whereas later studies scaled them by (B) taking residuals from an interspecific regression of the brain structure in question on another brain structure or by (C) taking ratios of the brain structure in question to another brain structure. We conducted a series of comparative tests to explore the possibility that the different methods are responsible for the discrepancy between earlier and later studies. Specifically, we tested the ability of a social variable - group size - and an ecological variable - home range size - to explain variation in the non-V1 isocortex (isocortex minus primary visual cortex) when this structure was scaled with the three different methods. In multiple regression analysis, group size was a better predictor of the non-V1 isocortex with method (B). With methods (A) and (C), however, results were ambiguous: either home range size or group size explained more of the variation, depending on the inclusion of outliers, the use of independent contrasts, and whether home range size was scaled relative to body mass. We examine the three scaling methods and find no reasonable basis for preferring any of them. Hence, our results do not allow a distinction between social and ecological hypotheses. The general implications of our study are that (1) previous comparative studies are inconclusive and (2) further research is needed to develop a scaling method where relative measures of brain structure size are demonstrated to correspond with behavioral performance.


Iron treatment normalizes cognitive functioning in young women.
Evidence suggests that brain iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning. Women of reproductive age are among those most vulnerable to iron deficiency and may be at high risk for cognitive alterations due to iron deficiency. We aimed to examine the relation between iron status and cognitive abilities in young women. A blinded, placebo-controlled, stratified intervention study was conducted in women aged 18-35 y of varied iron status who were randomly assigned to receive iron supplements or a placebo. Cognition was assessed by using 8 cognitive performance tasks (from Detterman's Cognitive Abilities Test) at baseline (n = 149) and after 16 wk of treatment (n = 113). At baseline, the iron-sufficient women (n = 42) performed better on cognitive tasks (P = 0.011) and completed them faster (P = 0.038) than did the women with iron deficiency anemia (n = 34). Factors representing performance accuracy and the time needed to complete the tasks by the iron-deficient but nonanemic women (n = 73) were intermediate between the 2 extremes of iron status. After treatment, a significant improvement in serum ferritin was associated with a 5-7-fold improvement in cognitive performance, whereas a significant improvement in hemoglobin was related to improved speed in completing the cognitive tasks. Iron status is a significant factor in cognitive performance in women of reproductive age. Severity of anemia primarily affects processing speed, and severity of iron deficiency affects accuracy of cognitive function over a broad range of tasks. Thus, the effects of iron deficiency on cognition are not limited to the developing brain.


Unplanned extubation in pediatric critically ill patients: a systematic review and best practice recommendations.
The aim of this study was to update the state of knowledge of unplanned extubations in the pediatric population. The main topics addressed in the current literature on unplanned extubations were: 1) incidence; 2) risk factors; 3) risk factors for reintubation after unplanned extubations; and 4) strategies to prevent unplanned extubations. Based on this review we summarize and propose best practices in preventing unplanned extubations. MEDLINE, CINAHL, Scielo, Lilacs, and Cochrane databases were searched for bibliography for the period spanning from January 1966 to March 2009. We used the following key words: unplanned extubation, accidental extubation, self extubation, unintentional extubation, unexpected extubation, inadvertent extubation, spontaneous extubation, and treatment interference. Eleven pediatric articles were eligible for data abstraction. Study quality was assessed using four levels of aggregate evidence adapted from the American Academy of Pediatrics. Unplanned extubations occurs at a rate of 0.11 to 2.27 events per 100 intubation days. Risk factors associated with unplanned extubations were age (younger patients), inadequate tube fixation, agitation, copious secretions, performance of patient procedures, and nursing workload. Reintubation rates ranged from 14% to 65% of unplanned extubations. Three cohort studies evaluated the effectiveness of strategies in reducing unplanned extubations. One study reported the institution of a standardized algorithm of goal-directed sedation, whereas two studies evaluated the implementation of a continuous quality-improvement program. These studies reported significant reductions in unplanned extubations rate after program implementation. Methods of securing the endotracheal tube varied across studies and the use of physical restraints yielded conflicting findings. There are few studies assessing unplanned extubations in pediatric intensive care units. The available quality studies have shown that improvement of quality components is effective in reducing unplanned extubations. Although further rigorous studies are needed to establish strong recommendations on unplanned extubations prevention, we present a summary of recommendations based on review of the current literature.


High dimensional endophenotype ranking in the search for major depression risk genes.
Despite overwhelming evidence that major depression is highly heritable, recent studies have localized only a single depression-related locus reaching genome-wide significance and have yet to identify a causal gene. Focusing on family-based studies of quantitative intermediate phenotypes or endophenotypes, in tandem with studies of unrelated individuals using categorical diagnoses, should improve the likelihood of identifying major depression genes. However, there is currently no empirically derived statistically rigorous method for selecting optimal endophentypes for mental illnesses. Here, we describe the endophenotype ranking value, a new objective index of the genetic utility of endophenotypes for any heritable illness. Applying endophenotype ranking value analysis to a high-dimensional set of over 11,000 traits drawn from behavioral/neurocognitive, neuroanatomic, and transcriptomic phenotypic domains, we identified a set of objective endophenotypes for recurrent major depression in a sample of Mexican American individuals (n = 1122) from large randomly selected extended pedigrees. Top-ranked endophenotypes included the Beck Depression Inventory, bilateral ventral diencephalon volume, and expression levels of the RNF123 transcript. To illustrate the utility of endophentypes in this context, each of these traits were utlized along with disease status in bivariate linkage analysis. A genome-wide significant quantitative trait locus was localized on chromsome 4p15 (logarithm of odds = 3.5) exhibiting pleiotropic effects on both the endophenotype (lymphocyte-derived expression levels of the RNF123 gene) and disease risk. The wider use of quantitative endophenotypes, combined with unbiased methods for selecting among these measures, should spur new insights into the biological mechanisms that influence mental illnesses like major depression.


Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation.
T cells of patients with rheumatoid arthritis (RA) do not control the rate of B lymphoblast transformation induced by Epstein-Barr virus (EBV) as efficiently as T cells from healthy individuals; thus, lymphoblast cell lines are established more readily in RA lymphocytes in vitro after EBV infection. In the present experiments, we have asked whether this T cell regulation can be reproduced by lymphocytes. We found that normal T cells, activated in allogeneic or autologous mixed leukocyte reactions (MLR), produce lymphokines that inhibit in vitro EBV-induced B cell proliferation. Allogeneic MLR supernatants inhibited EBV-induced DNA synthesis 62 +/- 4% (mean +/- SE) at 10 d post-infection, whereas autologous MLR supernatants suppressed it 50 +/- 3%. RA T cell supernatants produced in an allogeneic MLR suppressed as well as normal T cell supernatants (64 +/- 5% inhibition). In contrast, supernatants from RA autologous MLR had little inhibitory activity. EBV-induced DNA synthesis at 10 d was reduced only 8 +/- 3%, compared with the 50 +/- 3% suppressive activity of normal autologous MLR supernatants. The magnitude of the proliferative responses in the autologous MLR regenerating the lymphokines was similar in the normal and RA populations. After depletion of adherent cells from the RA auto-MLR stimulators, supernatant inhibitory activities increased to normal levels (from 11 +/- 6 [SE] to 52 +/- 6% [SE]). The inhibitory factor involved in the regulation of in vitro EBV infection is a protein with a molecular weight of approximately 50,000. Its activity is eliminated by hearing at 56 degrees C and by exposure to acid at pH 2. The inhibitory activity is blocked by mixing the MLR supernatants with a polyvalent antisera or monoclonal antibodies specific for human gamma interferon. Gamma interferon produced by activating T cells in allo- or auto-MLR can reproduce T cell-mediated regulation of EBV-induced B cell proliferation, and the failure of RA auto-MLR to generate that lymphokine parallels the defective T cell regulation of EBV-induced B cell proliferation characteristic of RA lymphoid cells.


Antimicrobial peptides from chili pepper seeds causes yeast plasma membrane permeabilization and inhibits the acidification of the medium by yeast cells.
During the last few years, a growing number of cysteine-rich antimicrobial peptides has been isolated from plants and particularly from seeds. It has become increasingly clear that these peptides play an important role in the protection of plants against microbial infection. In this work, proteins from chili pepper (Capsicum annuum L.) seeds were extracted in phosphate buffer, pH 5.4 and peptides purification were performed by employing ion-exchange chromatographies on DEAE, CM-Sepharose, Sephacryl S-100 and reverse phase in HPLC. Three peptide enriched fractions, namely F1, F2 and F3, were obtained after the CM-Sepharose chromatography. The F1 fraction, mainly composed of three peptides ranging from 6 to 10 kDa, was submitted to N-terminal amino acid sequencing. The closer to 10 kDa peptide showed high sequence homology to lipid transfer proteins (LTPs) previously isolated from others seeds. F1 fraction exhibited strong fungicidal activity against Candida albicans, Saccharomyces cerevisiae and Schizosaccharomyces pombe and also promoted several morphological changes to C. albicans, including the formation of pseudohyphae, as revealed by scanning electron micrography. F1 fraction also reduced the glucose stimulated acidification of the medium mediated by H(+)-ATPase of S. cerevisiae cells in a dose-dependent manner and caused the permeabilization of yeast plasma membrane to the dye SYTOX Green, as verified by confocal laser microscopy.