Fine tuning of reactive oxygen species homeostasis regulates primed immune responses in Arabidopsis.
Selected stimuli can prime the plant immune system for a faster and stronger defense reaction to pathogen attack. Pretreatment of Arabidopsis with the chemical agent β-aminobutyric acid (BABA) augmented H2O2 and callose production after induction with the pathogen-associated molecular pattern (PAMP) chitosan, or inoculation with the necrotrophic fungus Plectosphaerella cucumerina. However, BABA failed to prime H2O2 and callose production after challenge with the bacterial PAMP Flg22. Analysis of Arabidopsis mutants in reactive oxygen species (ROS) production (rbohD) or ROS scavenging (pad2, vtc1, and cat2) suggested a regulatory role for ROS homeostasis in priming of chitosan- and P. cucumerina-inducible callose and ROS. Moreover, rbohD and pad2 were both impaired in BABA-induced resistance against P. cucumerina. Gene expression analysis revealed direct induction of NADPH/respiratory burst oxidase protein D (RBOHD), γ-glutamylcysteine synthetase 1 (GSH1), and vitamin C defective 1 (VTC1) genes after BABA treatment. Conversely, ascorbate peroxidase 1 (APX1) transcription was repressed by BABA after challenge with chitosan or P. cucumerina, probably to provide a more oxidized environment in the cell and facilitate augmented ROS accumulation. Measuring ratios between reduced and oxidized glutathione confirmed that augmented defense expression in primed plants is associated with a more oxidized cellular status. Together, our data indicate that an altered ROS equilibrium is required for augmented defense expression in primed plants.


Evidence of uncultivated bacteria in the adult female bladder.
Clinical urine specimens are usually considered to be sterile when they do not yield uropathogens using standard clinical cultivation procedures. Our aim was to test if the adult female bladder might contain bacteria that are not identified by these routine procedures. An additional aim was to identify and recommend the appropriate urine collection method for the study of bacterial communities in the female bladder. Consenting participants who were free of known urinary tract infection provided urine samples by voided, transurethral, and/or suprapubic collection methods. The presence of bacteria in these samples was assessed by bacterial culture, light microscopy, and 16S rRNA gene sequencing. Bacteria that are not or cannot be routinely cultivated (hereinafter called uncultivated bacteria) were common in voided urine, urine collected by transurethral catheter (TUC), and urine collected by suprapubic aspirate (SPA), regardless of whether the subjects had urinary symptoms. Voided urine samples contained mixtures of urinary and genital tract bacteria. Communities identified in parallel urine samples collected by TUC and SPA were similar. Uncultivated bacteria are clearly present in the bladders of some women. It remains unclear if these bacteria are viable and/or if their presence is relevant to idiopathic urinary tract conditions.


Mobilization of hydrophobic contaminants from soils by enzymatic depolymerization of soil organic matter.
The effect of hydrolytic exoenzymes on the release of hydrophobic organic contaminants (HOC) from two different surface soils was studied in laboratory batch experiments. Incubation of the soils with cellulase with an activity fivefold above the inherent soil activity enhanced the release of hydrophobic contaminants (polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and hydroxylated PCB) by 40-200%. Xylanase and invertase did not show measurable effects at comparable relative activity levels. This suggests that cellulose substructures are important for the retention of HOC in soil organic matter (SOM). Hydrolytic exoenzymes, and the microorganisms that release them, contribute to the mobilization of HOC from soil, by shifting the sorption equilibrium in the course of SOM transformation into dissolved organic matter or by facilitating HOC diffusion as a consequence of reduced rigidity of SOM. We conclude that not only biodegradation but also sorption and desorption of HOC in soil can be influenced by (micro-) biology and the factors that determine its activity.


Nanoparticle-based capillary electroseparation of proteins in polymer capillaries under physiological conditions.
Totally porous lipid-based liquid crystalline nanoparticles were used as pseudostationary phase for capillary electroseparation with LIF detection of proteins at physiological conditions using unmodified cyclic olefin copolymer capillaries (Topas, 6.7 cm effective length). In the absence of nanoparticles, i.e. in CE mode, the protein samples adsorbed completely to the capillary walls and could not be recovered. In contrast, nanoparticle-based capillary electroseparation resolved green fluorescent protein from several of its impurities within 1 min. Furthermore, a mixture of native green fluorescent protein and two of its single-amino-acid-substituted variants was separated within 2.5 min with efficiencies of 400 000 plates/m. The nanoparticles prevent adsorption by introducing a large interacting surface and by obstructing the attachment of the protein to the capillary wall. A one-step procedure based on self-assembly of lipids was used to prepare the nanoparticles, which benefit from their biocompatibility and suspension stability at high concentrations. An aqueous tricine buffer at pH 7.5 containing lipid-based nanoparticles (2% w/w) was used as electrolyte, enabling separation at protein friendly conditions. The developed capillary-based method facilitates future electrochromatography of proteins on polymer-based microchips under physiological conditions and enables the initial optimization of separation conditions in parallel to the chip development.


Resting-State Functional Connectivity of the Thalamus in Complete Spinal Cord Injury.
Background. Neuroimaging studies of spinal cord injury (SCI) have mostly examined the functional organization of the cortex, with only limited focus on the subcortical substrates of the injury. However, thalamus is an important modulator and sensory relay that requires investigation at a subnuclei level to gain insight into the neuroplasticity following SCI. Objective. To use resting-state functional magnetic resonance imaging to examine the functional connectivity (FC) of thalamic subnuclei in complete SCI patients. Methods. A seed-based connectivity analysis was applied for 3 thalamic subnuclei: pulvinar, mediodorsal, and ventrolateral nucleus in each hemisphere. A nonparametric 2-sample t test with permutations was applied for each of the 6 thalamic seeds to compute FC differences between 22 healthy controls and 19 complete SCI patients with paraplegia. Results. Connectivity analysis showed a decrease in the FC of the bilateral mediodorsal nucleus with right superior temporal gyrus and anterior cingulate cortex in the SCI group. Similarly, the left ventrolateral nucleus exhibited decreased FC with left superior temporal gyrus in SCI group. In contrast, left pulvinar nucleus demonstrated an increase in FC with left inferior frontal gyrus and left inferior parietal lobule in SCI group. Our findings also indicate a negative relationship between postinjury durations and thalamic FC to regions of sensorimotor and visual cortices, where longer postinjury durations (~12 months) is associated with higher negative connectivity between these regions. Conclusion. This study provides evidence for reorganization in the thalamocortical connections known to be involved in multisensory integration and affective processing, with possible implications in the generation of sensory abnormalities after SCI.


Associations between Meteorological Parameters and Influenza Activity in Berlin (Germany), Ljubljana (Slovenia), Castile and León (Spain) and Israeli Districts.
Studies in the literature have indicated that the timing of seasonal influenza epidemic varies across latitude, suggesting the involvement of meteorological and environmental conditions in the transmission of influenza. In this study, we investigated the link between meteorological parameters and influenza activity in 9 sub-national areas with temperate and subtropical climates: Berlin (Germany), Ljubljana (Slovenia), Castile and León (Spain) and all 6 districts in Israel. We estimated weekly influenza-associated influenza-like-illness (ILI) or Acute Respiratory Infection (ARI) incidence to represent influenza activity using data from each country's sentinel surveillance during 2000-2011 (Spain) and 2006-2011 (all others). Meteorological data was obtained from ground stations, satellite and assimilated data. Two generalized additive models (GAM) were developed, with one using specific humidity as a covariate and another using minimum temperature. Precipitation and solar radiation were included as additional covariates in both models. The models were adjusted for previous weeks' influenza activity, and were trained separately for each study location. Influenza activity was inversely associated (p<0.05) with specific humidity in all locations. Minimum temperature was inversely associated with influenza in all 3 temperate locations, but not in all subtropical locations. Inverse associations between influenza and solar radiation were found in most locations. Associations with precipitation were location-dependent and inconclusive. We used the models to estimate influenza activity a week ahead for the 2010/2011 period which was not used in training the models. With exception of Ljubljana and Israel's Haifa District, the models could closely follow the observed data especially during the start and the end of epidemic period. In these locations, correlation coefficients between the observed and estimated ranged between 0.55 to 0.91and the model-estimated influenza peaks were within 3 weeks from the observations. Our study demonstrated the significant link between specific humidity and influenza activity across temperate and subtropical climates, and that inclusion of meteorological parameters in the surveillance system may further our understanding of influenza transmission patterns.


Transcription map of Xq27: candidates for several X-linked diseases.
Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found.


A novel nonanuclear hafnium oxide-hydroxide-sulphate cluster crystallised from aqueous solution.
Single crystals of (NH4)14[Hf9O8(OH)6(SO4)14]·nH2O (1) were obtained by heating a sealed aqueous solution of HfOCl2·8H2O, (NH4)2SO4 and H2SO4 at 80 °C for 10 days. The discrete [Hf9O8(OH)6(SO4)14](14-) anionic clusters have no inter-cluster connectivity. This rare nonameric architecture has only been observed previously in two Bi(3+) oxo clusters.


Alcohol induced epigenetic perturbations during the inflammatory stage of fracture healing.
It is well recognized by orthopedic surgeons that fractures of alcoholics are more difficult to heal successfully and have a higher incidence of non-union, but the mechanism of alcohol's effect on fracture healing is unknown. In order to give direction for the study of the effects of alcohol on fracture healing, we propose to identify gene expression and microRNA changes during the early stages of fracture healing that might be attributable to alcohol consumption. As the inflammatory stage appears to be the most critical for successful fracture healing, this paper focuses on the events at day three following fracture or the stage of inflammation. Sprague-Dawley rats were placed on an ethanol-containing or pair-fed Lieber and DeCarli diet for four weeks prior to surgical fracture. Following insertion of a medullary pin, a closed mid-diaphyseal fracture was induced using a Bonnarens and Einhorn fracture device. At three days' post-fracture, the region of the fracture calluses was harvested from the right hind-limb. RNA was extracted and microarray analysis was conducted against the entire rat genome. There were 35 genes that demonstrated significant increased expression due to alcohol consumption and 20 that decreased due to alcohol. In addition, the expression of 20 microRNAs was increased and six decreased. In summary, while it is recognized that mRNA levels may or may not represent protein levels successfully produced by the cell, these studies reveal changes in gene expression that support the hypothesis that alcohol consumption affects events involved with inflammation. MicroRNAs are known to modulate mRNA and these findings were consistent with much of what was seen with mRNA microarray analysis, especially the involvement of smad4 which was demonstrated by mRNA microarray, microRNA and polymerase chain reaction.


Factors influencing outcomes of clinical information systems implementation: a systematic review.
Healthcare agencies spend significant resources to acquire or develop clinical information systems. However, implementation of clinical information systems often report significant failures. A systematic review of the research literature identified processes and outcomes of clinical information system implementation and factors that influenced success or failure. Of 124 original papers, 18 met the primary inclusion criteria-clinical systems implementation, healthcare facility, and outcome measures. Data extraction elements included study characteristics, outcomes, and implementation risk factors classified according to the Expanded Systems Life Cycle. The quality of each study was also assessed. Forty-nine outcomes of clinical information system implementation were identified. No single implementation strategy proved completely effective. The findings of this synthesis direct the attention of managers and decision makers to the importance of clinical context to successful implementation of clinical information systems. The highest number of factors influencing success or failure was reported during implementation and system "go-live." End-user support or lack thereof was the important factor in both successful and failed implementations, respectively. Following the Expanded Systems Life Cycle management model instead of a traditional project management approach may contribute to greater success over time, by paying particular attention to the underrecognized maintenance phase of implementation.


Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.
Defects of complex I of the mitochondrial respiratory chain are important causes of neurological disease. We report studies that demonstrate a severe deficiency of complex I activity with less severe abnormalities of complexes III and IV (less than 5, 63, and 30% of control values, respectively) in a skeletal muscle mitochondrial fraction from a 22-yr-old female with weakness, lactic acidemia, and the deposition of intramuscular neutral lipid. The observation that lipid accumulates in this and other patients with complex I deficiency suggests impaired mitochondrial fatty acid oxidation. To investigate this mechanism we have shown impaired flux through beta-oxidation [( U-14C]hexadecanoate oxidation was 66% of control rate) and accumulation of specific acyl-CoA ester intermediates. The changes in fatty acid metabolism in complex I deficiency are secondary to the reduced state within the mitochondrial matrix with low NAD+/NADH ratios.


Combining multiple biomarkers linearly to maximize the partial area under the ROC curve.
It is now common in clinical practice to make clinical decisions based on combinations of multiple biomarkers. In this paper, we propose new approaches for combining multiple biomarkers linearly to maximize the partial area under the receiver operating characteristic curve (pAUC). The parametric and nonparametric methods that have been developed for this purpose have limitations. When the biomarker values for populations with and without a given disease follow a multivariate normal distribution, it is easy to implement our proposed parametric approach, which adopts an alternative analytic expression of the pAUC. When normality assumptions are violated, a kernel-based approach is presented, which handles multiple biomarkers simultaneously. We evaluated the proposed as well as existing methods through simulations and discovered that when the covariance matrices for the disease and nondisease samples are disproportional, traditional methods (such as the logistic regression) are more likely to fail to maximize the pAUC while the proposed methods are more robust. The proposed approaches are illustrated through application to a prostate cancer data set, and a rank-based leave-one-out cross-validation procedure is proposed to obtain a realistic estimate of the pAUC when there is no independent validation set available.


Investigating the link between gun possession and gun assault.
We investigated the possible relationship between being shot in an assault and possession of a gun at the time. We enrolled 677 case participants that had been shot in an assault and 684 population-based control participants within Philadelphia, PA, from 2003 to 2006. We adjusted odds ratios for confounding variables. After adjustment, individuals in possession of a gun were 4.46 (P < .05) times more likely to be shot in an assault than those not in possession. Among gun assaults where the victim had at least some chance to resist, this adjusted odds ratio increased to 5.45 (P < .05). On average, guns did not protect those who possessed them from being shot in an assault. Although successful defensive gun uses occur each year, the probability of success may be low for civilian gun users in urban areas. Such users should reconsider their possession of guns or, at least, understand that regular possession necessitates careful safety countermeasures.


Community pharmacy personnel interventions for smoking cessation.
Community pharmacists could provide effective smoking cessation treatment because they offer easy access to members of the community. They are well placed to provide both advice on the correct use of smoking cessation products and behavioural support to aid smoking cessation. To assess the effectiveness of interventions delivered by community pharmacy personnel to assist people to stop smoking, with or without concurrent use of pharmacotherapy. We searched the Cochrane Tobacco Addiction Group Specialised Register, along with clinicaltrials.gov and the ICTRP, for smoking cessation studies conducted in a community pharmacy setting, using the search terms pharmacist* or pharmacy or pharmacies. Date of the most recent search: January 2019. Randomised controlled trials of interventions delivered by community pharmacy personnel to promote smoking cessation amongst their clients who were smokers, compared with usual pharmacy support or any less intensive programme. The main outcome measure was smoking cessation rates at six months or more after the start of the intervention. We used standard methodological procedures expected by Cochrane for study screening, data extraction and management. We conducted a meta-analysis using a Mantel-Haenszel random-effects model to generate risk ratios (RRs) and 95% confidence intervals (CIs). We identified seven studies including 1774 participants. We judged three studies to be at high risk of bias and four to be at unclear risk. Each study provided face-to-face behavioural support delivered by pharmacy staff, and required pharmacy personnel training. Typically such programmes comprised support starting before quit day and continuing with weekly appointments for several weeks afterwards. Comparators were either minimal or less intensive behavioural support for smoking cessation, typically comprising a few minutes of one-off advice on how to quit. Participants in both intervention and control arms received equivalent smoking cessation pharmacotherapy in all but one study. All studies took place in high-income countries, and recruited participants visiting pharmacies. We pooled six studies of 1614 participants and detected a benefit of more intensive behavioural smoking cessation interventions delivered by community pharmacy personnel compared with less intensive cessation interventions at longest follow-up (RR 2.30, 95% CI 1.33 to 3.97; I2 = 54%; low-certainty evidence). Community pharmacists can provide effective behavioural support to people trying to stop smoking. However, this conclusion is based on low-certainty evidence, limited by risk of bias and imprecision. Further research could change this conclusion.


Genomic amplification patterns of human telomerase RNA gene and C-MYC in liquid-based cytological specimens used for the detection of high-grade cervical intraepithelial neoplasia.
The amplification of oncogenes initiated by high-risk human papillomavirus (HPV) infection is an early event in cervical carcinogenesis and can be used for cervical lesion diagnosis. We measured the genomic amplification rates and the patterns of human telomerase RNA gene (TERC) and C-MYC in the liquid-based cytological specimens to evaluate the diagnostic characteristics for the detection of high-grade cervical lesions. Two hundred and forty-three residual cytological specimens were obtained from outpatients aged 25 to 64 years at Qilu Hospital, Shandong University. The specimens were evaluated by fluorescence in situ hybridization (FISH) using chromosome probes to TERC (3q26) and C-MYC (8q24). All of the patients underwent colposcopic examination and histological evaluation. A Chi-square test was used for categorical data analysis. In the normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3) and squamous cervical cancer (SCC) cases, the TERC positive rates were 9.2%, 17.2%, 76.2%, 100.0% and 100.0%, respectively; the C-MYC positive rates were 20.7%, 31.0%, 71.4%, 81.8% and 100.0%, respectively. The TERC and C-MYC positive rates were higher in the CIN2+ (CIN2, CIN3 and SCC) cases than in the normal and CIN1 cases (p < 0.01). Compared with cytological analysis, the TERC test showed higher sensitivity (90.0% vs. 84.0%) and higher specificity (89.6% vs. 64.3%). The C-MYC test showed lower sensitivity (80.0% vs. 84.0%) and higher specificity (77.7% vs. 64.3%). Using a cut-off value of 5% or more aberrant cells, the TERC test showed the highest combination of sensitivity and specificity. The CIN2+ group showed more high-level TERC gene copy number (GCN) cells than did the normal/CIN1 group (p < 0.05). For C-MYC, no significant difference between the two histological categories was detected (p > 0.05). The TERC test is highly sensitive and is therefore suitable for cervical cancer screening. The C-MYC test is not suitable for cancer screening because of its lower sensitivity. The amplification patterns of TERC become more diverse and complex as the severity of cervical diseases increases, whereas for C-MYC, the amplification patterns are similar between the normal/CIN1 and CIN2+ groups. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1308004512669913.


Inhibition of intestinal Cl- secretion by clotrimazole: direct effect on basolateral membrane K+ channels.
We evaluated the effects of clotrimazole and clofibrate on Ca(2+)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- secretion in the colonic cell line, T84. We used 1-ethyl-2-benzimidazolinone (1-EBIO) to activate the Ca(2+)-dependent K+ channel (KCa) in these cells to induce a sustained Cl- secretory current (Isc). Clotrimazole potently inhibited the KCa-dependent Isc, with an inhibition constant (Ki) of 0.27 +/- 0.02 microM. Clofibrate also inhibited the 1-EBIO-induced Isc albeit with lower affinity (Ki = 6.5 +/- 1.2 microM). Clotrimazole (10 microM) inhibited the Isc response to the Ca(2+)-mediated agonist, carbachol, by 82%. Similarly, both clotrimazole and clofibrate inhibited cAMP-mediated Cl- secretion, with Ki values of 5.2 +/- 1.0 and 6.7 +/- 1.1 microM, respectively. We used nystatin to permeabilize the apical or basolateral membrane to determine the effects of clotrimazole and clofibrate on the basolateral K+ (IK) and apical Cl- (ICl) currents following stimulation by either 1-EBIO or forskolin. Both clotrimazole and clofibrate inhibited the 1-EBIO- and forskolin-induced IK without affecting ICl. We determined the effects of clotrimazole and clofibrate on KCa using 86Rb+ uptake studies into membrane vesicles. Both clotrimazole and clofibrate inhibited the 1-EBIO-induced 86Rb+ uptake, with Ki values of 0.31 +/- 0.08 and 10.8 +/- 5.5 microM, respectively. Similarly, clotrimazole inhibited the Ca(2+)-induced 86Rb+ uptake with a Ki of 0.51 +/- 0.15 microM. Charybdotoxin inhibited both the 1-EBIO- and Ca(2+)-induced 86Rb+ uptakes with similar affinities (Ki values of 0.57 +/- 0.07 and 0.47 +/- 0.08 nM, respectively), suggesting 1-EBIO and Ca2+ activate the same channel (KCa) in this assay. In excised, single-channel recordings both clotrimazole and clofibrate inhibited KCa, demonstrating a direct inhibition of the channel by these compounds. We demonstrate that clotrimazole blocks the intestinal KCa, thereby inhibiting Cl- secretion. These results suggest that clotrimazole may be useful as an antidiarrheal.


Inhibition of fibrocyte differentiation by serum amyloid P.
Wound healing and the dysregulated events leading to fibrosis both involve the proliferation and differentiation of fibroblasts and the deposition of extracellular matrix. Whether these fibroblasts are locally derived or from a circulating precursor population is unclear. Fibrocytes are a distinct population of fibroblast-like cells derived from peripheral blood monocytes that enter sites of tissue injury to promote angiogenesis and wound healing. We have found that CD14(+) peripheral blood monocytes cultured in the absence of serum or plasma differentiate into fibrocytes within 72 h. We purified the factor in serum and plasma that prevents the rapid appearance of fibrocytes, and identified it as serum amyloid P (SAP). Purified SAP inhibits fibrocyte differentiation at levels similar to those found in plasma, while depleting SAP reduces the ability of plasma to inhibit fibrocyte differentiation. Compared with sera from healthy individuals and patients with rheumatoid arthritis, sera from patients with scleroderma and mixed connective tissue disease, two systemic fibrotic diseases, were less able to inhibit fibrocyte differentiation in vitro and had correspondingly lower serum levels of SAP. These results suggest that low levels of SAP may thus augment pathological processes leading to fibrosis. These data also suggest mechanisms to inhibit fibrosis in chronic inflammatory conditions, or conversely to promote wound healing.


Giant optical forces in planar dielectric photonic metamaterials.
We demonstrate that resonant optical forces generated within all-dielectric planar photonic metamaterials at near-infrared illumination wavelengths can be an order of magnitude larger than in corresponding plasmonic metamaterials, reaching levels many tens of times greater than the force resulting from radiation pressure. This is made possible by the dielectric structures' freedom from Joule losses and the consequent ability to sustain Fano-resonances with high quality factors that are unachievable in plasmonic nanostructures. Dielectric nano-optomechanical metamaterials can thus provide a functional platform for a range of novel dynamically controlled and self-adaptive nonlinear, tunable/switchable photonic metamaterials.


Ganglion-specific impairment of the norepinephrine transporter in the hypertensive rat.
Hypertension is associated with enhanced cardiac sympathetic transmission, although the exact mechanisms underlying this are still unknown. We hypothesized that defective function of the norepinephrine uptake transporter (NET) may contribute to the sympathetic phenotype of the spontaneously hypertensive rat, and that this may occur before the development of hypertension itself. The dynamic kinetics of NET were monitored temporally using a novel fluorescent assay of the transporter in cultured postganglionic sympathetic neurons from the cardiac stellate ganglion, the superior cervical ganglion, the celiac ganglia/superior mesenteric ganglia, and the renal sympathetic chain. All NET activity was blocked by desipramine. NET rate was significantly impaired in cardiac stellate sympathetic neurons from the prehypertensive spontaneously hypertensive rat compared with age-matched normotensive Wistar-Kyoto rats. A similar response was seen in hypertensive spontaneously hypertensive rats stellate sympathetic neurons. However, no reduction in transporter rate was observed at either age in the other major noncardiac sympathetic ganglia. Depolarization of cardiac stellate neurons by electrical field stimulation further potentiated the difference in transporter rate observed between the hypertensive and normotensive rats at both developmental ages. In conclusion, dysregulation of the norepinephrine transporter in the hypertensive rat is ganglion-specific, where NET impairment in the stellate neurons may contribute to the increased cardiac norepinephrine spillover seen in hypertension.


The effect of coenzyme Q₁₀ supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open-label prospective study.
It has been shown that coenzyme Q(10) (CoQ(10)) supplementation in men with idiopathic oligoasthenoteratozoospermia (OAT) results in improved semen parameters. In present study, we evaluated the effects of coenzyme CoQ(10) supplementation on semen parameters and pregnancy rates in infertile men with idiopathic OAT. Two hundred and eighty-seven infertile men with idiopathic OAT were recruited in this study. These patients were treated with CoQ(10) 300 mg orally twice daily for 12 months. Two semen analyses and determination of resting levels of sex hormones were done in all participants. Patients were followed up for another 12 months after CoQ(10) discontinuation. Mean sperm concentration, sperm progressive motility, and sperm with normal morphology improved significantly after 12-month CoQ(10) therapy by 113.7, 104.8, and 78.9%, respectively (all Ps < 0.05). The overall pregnancy rate was 34.1% within a mean of 8.4 ± 4.7 months. CoQ(10) supplementation improves semen quality with beneficial effect on pregnancy rate.


Antibody uptake assay and in vivo imaging to study intracellular trafficking of Notch and Delta in Drosophila.
Notch signaling depends on regulated intracellular trafficking of the receptor and its ligands (Kopan and Ilagan, Cell 137:216-233, 2009; Le Borgne et al., Development 132:1751-1762, 2005). Here we describe two methods to study the intracellular trafficking of Notch and Delta in Drosophila. First, an ex vivo antibody uptake assay is used to monitor endocytosis of Notch and Delta by living cells in dissected explants (Le Borgne and Schweisguth, Dev Cell 5:139-148, 2003). Second, real-time imaging of fluorescent proteins that are expressed at physiological levels is used to study trafficking of Notch in living flies (Venken et al., Science 314:1747-1751, 2006; Couturier et al., Nat Cell Biol 14, 131-139, 2012).


Do case studies mislead about the nature of reality?
This paper attempts a partial, critical look at the construction and use of case studies in ethics education. It argues that the authors and users of case studies are often insufficiently aware of the literary nature of these artefacts: this may lead to some confusion between fiction and reality. Issues of the nature of the genre, the fictional, story-constructing aspect of case studies, the nature of authorship, and the purposes and uses of case studies as "texts" are outlined and discussed. The paper concludes with some critical questions that can be applied to the construction and use of case studies in the light of the foregoing analysis.


Mobility has a non-linear association with falls risk among people in residential aged care: an observational study.
What is the association between mobility and falls risk for people living in residential aged care? Can the Physical Mobility Scale discriminate between residents at risk of falling and those not at risk? Prospective longitudinal observational study. Six residential aged care facilities in Australia. Eighty-seven high- and low-level care permanent residents. The primary outcome measure was the number of falls in the six months after the initial mobility assessment. Mobility of all participants was assessed using the Physical Mobility Scale, which includes nine mobility items assessed on a 0-5 scale yielding a total score out of 45. During the six-month study period, 131 falls were reported. Residents with mild mobility impairment (Physical Mobility Scale total score 28-36) had the highest fall risk (hazard ratio = 1.98, 95% CI 1.30 to 3.03). Residents with fully dependent mobility (Physical Mobility Scale total score 0-9) had the lowest risk for falls (HR=0.05, 95% CI 0.01 to 0.32). Aged care residents with mild mobility impairment are at increased risk of falls and are an appropriate target for falls prevention strategies. Although improving the mobility of residents with moderate to severe mobility impairment may enhance their independence and reduce their burden on staff, paradoxically this may also increase their risk of falls. When these residents improve enough to progress into a higher category of mobility, physiotherapists should be aware that this may increase the risk of falls and should consider instituting appropriate falls prevention strategies.


Can the impact of an acute hospital end-of-life care tool on care and symptom burden be measured contemporaneously?
To determine the utility of a screening question to identify patients who might die during hospital admission and feasibility of scoring symptoms in dying patients within a study assessing the impact of a brief end-of-life (EOL) tool. Between March 2008 and July 2010 patients admitted to five wards of an acute hospital were screened using the question 'Is this patient so unwell you feel they could die during this admission?' Once 40 patients were recruited, the brief EOL tool was introduced to the wards and a further 30 patients were recruited. Symptom scoring using the Edmonton Symptom Assessment System (ESAS) began when the patient was recognised as dying. Relatives were asked to complete the Views of Informal Carers-Evaluation of Services questionnaire to validate the results of the contemporaneous symptom assessments and assess the impact of the tool. The sensitivity of the screening question was 57%, specificity 98% and positive predictive value 67%, so the question was useful in enrolling study patients. There were limitations with the ESAS but core EOL symptoms were scored more frequently after the tool was introduced. Questionnaire responses suggested relatives perceived aspects of care improved with the EOL tool in place. It is possible to identify dying patients and study care given to them in hospital in real time. Outcome measures need to be refined, but contemporaneous symptom monitoring was possible. We argue interventions to improve EOL care should be unequivocally evidence-based, and research to provide evidence of impact on the patient experience is possible.


Light propagation in twisted anisotropic media: application to photoreceptors.
The propagation of light through a slowly twisting anisotropic medium is described by a coupled-mode theory; expressions are derived for the electric field for the case of a birefringent dichroic medium with a constant rate of twist. The method provides a simple and intuitive means for determing the effect of twisting on the linear birefringence and dichroic absorption of the medium, particularly when the light is initially linearly polarized. The theory is well suited to the analysis of light absorption in twisting insect photoreceptors, such as found in bees and ants. We provide full expressions and useful approximations for polarization sensitivity and the initial direction of polarization to give maximum absorption for several types of photoreceptors.


Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates.
Meconium aspiration syndrome (MAS) is a life-threatening neonatal lung injury, whose pathophysiology has been mainly studied in animal models. In such models, pancreatic secretory phospholipase A2 (sPLA2-IB) and proinflammatory cytokines present in meconium challenge the lungs, catabolising surfactant and harming the alveoli. Locally produced phospholipases might perpetuate the injury and influence clinical pictures and therapeutic approaches. Our aim is to verify whether pulmonary phospholipase A2 (sPLA2-IIA) is involved in the damage and to determine if phospholipases and their modulators are associated with MAS clinical pictures. We studied distinct phospholipases A2 and their modulators in broncho-alveolar lavage (BAL) fluids and in meconium of five MAS neonates and in five control neonates ventilated for extrapulmonary reasons. MAS patients have higher amounts of pulmonary phospholipase (sPLA2-IIA; P = 0.016) and Clara cell secretory protein (CCSP; P = 0.032). The local production of such proteins by the lung is confirmed by their very low levels in meconium. sPLA2-IIA contributes to the higher total enzyme activity in MAS patients, as compared to controls (P = 0.008). Cytosolic phospholipase was not detected in meconium or alveolar fluid. sPLA2 activity and sPLA2-IIA concentrations are correlated with the TNFα and with the release of CCSP. sPLA2 total activity, sPLA2-IIA and TNFα concentrations in BAL fluids correlate with the oxygenation impairment and haemorrhagic lung oedema. Pulmonary sPLA2 is locally produced and contributes to the total sPLA2 activity during MAS. CCSP is also produced in trying to lower the inflammation. Both sPLA2 activity and sPLA2-IIA are significantly correlated with oxygenation impairment and haemorrhagic lung oedema.


Vitamin D metabolism in adult rats at low and normal calcium intake and the effect of cadmium exposure.
1. Chromatography measurements indicated that adult rats converted 25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol at a lower rate than that reported earlier for young animals. In serum, less-polar metabolites were found which probably represented vitamin D esters and vitamin D3. 2. A low dietary intake of calcium resulted in an evident increase in the fraction corresponding to 1,25-dihydroxycholecalciferol in the kidneys and also in the intestinal mucosa and serum. 3. Inclusion of 0.67 mmol of cadmium/l of drinking water at a low dietary intake of calcium resulted in an increased accumulation of both cadmium and zinc in the kidneys and liver compared with values at a normal dietary calcium intake. 4. At a normal dietary calcium intake, cadmium exposure caused inhibited production of 1,25-dihydroxycholecalciferol by the kidneys and an increased accumulation of 24,25-dihydroxycholecalciferol, vitamin D3 and vitamin D esters in the serum. 5. The inhibitory effect of cadmium on the renal conversion of 25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol was almost completely counteracted by a simultaneous low dietary calcium intake. Cadmium-exposed, calcium-deficient animals also showed a maintained accumulation of 1,25-dihydroxycholecalciferol in the intestinal mucosa.


The Pharmacokinetics of Atomized Lidocaine Administered via the Trachea: A Randomized Trial.
Under emergent conditions, endotracheal drug administration may be an effective method of delivering emergency drugs. A common technique is to administer these drugs using a nonatomized spray. Atomized drug delivery may be an attractive alternative to nonatomized delivery because atomized particles are small, cover a large surface area, and may better adhere to endotracheal membrane resulting in more effective drug absorption. In this study, we compared the pharmacokinetic profile of lidocaine administered into the trachea using an atomized or a nonatomized technique. Twenty patients were anesthetized using propofol and remifentanil. Ten minutes after rocuronium was administered, patients received 4% lidocaine (2 mg/kg) intratracheally over 2 seconds before tracheal intubation. Ten patients received atomized lidocaine using a mucosal atomization device, and the other 10 patients received nonatomized lidocaine using a traditional spray tube. Arterial lidocaine plasma concentrations were measured before; at 1, 3, 5, 7, 10, 15, 20, 30, 45, and 60 minutes; and then every 60 minutes after the administration of lidocaine until the end of the operation. We developed a pharmacokinetic model to examine whether bioavailability or absorption rate was different between atomized versus nonatomized lidocaine administration. The total body clearance was fixed at a published value to determine the bioavailability. Peak plasma concentrations were larger using the mucosal atomization device (median [range]: 1.9 [1.4-3.2] μg/mL) than the spray tube (1.1 [0.6-2.0] μg/mL; P = 0.0021). Our pharmacokinetic model estimated a difference of bioavailability between the atomized and the nonatomized lidocaine (0.801 and 0.559 respectively, P = 0.0005), whereas our model estimated no difference in the absorption rate constant (0.00688/min). Our results suggest that when using atomized delivery of lidocaine, less drug is required to achieve a near equivalent plasma lidocaine concentration. Atomized drug administration may be a more efficient method for endotracheal drug administration.


Nanoscale resolution in infrared imaging of protein-containing lipid membranes.
The precise imaging of biomolecular entities contributes to an understanding of the relationship between their structure and function. However, the resolution of conventional infrared microscopic imaging is diffraction limited and does not exceed a few micrometres. Atomic force microscopy, on the other hand, can detect infrared absorption down to the sub-micrometer level. In the present report, we demonstrate that for multi-bilayer lipid samples containing the plant photosynthetic pigment-protein complex LHCII, the resolution of this latter technique can be better than 20 nm. Such a high resolution is attributable to two factors: (i) the relatively high infrared absorption by the complex that is integrated perpendicular to the plane of the multilayer film, and (ii) the distinctly different mechanical properties and thermal conductivity of the lipid and protein components of the sample.


A facile hybrid 'flow and batch' access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones.
We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a-l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a-l) in 38-87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a-l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8-0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.


A combination of MLST and CRISPR typing reveals dominant Campylobacter jejuni types in organically farmed laying hens.
To elucidate the Campylobacter jejuni population in organically farmed laying hens in Finland, multilocus sequence typing (MLST) was combined with characterization of clustered regularly interspaced short palindromic repeat (CRISPR) sequences. A total of 147 Camp. jejuni isolates, collected from organically farmed laying hens from 18 farms in 2003-2004, were previously analysed by pulsed-field gel electrophoresis. In the present study, subsets of the isolates were further analysed by MLST and CRISPR sequences. Fourteen STs were found by MLST. ST-50 (27%, 7/18 farms), ST-3272 (20%, 8/18 farms), ST-45 (12%, 7/18 farms) and ST-356 (12%, 5/18 farms) were the most common STs. CRISPR types were identical among all isolates of ST-50 (ST-21 clonal complex (CC)) and the most variable among ST-45 (ST-45 CC). ST-3272 (UA), a common ST in this study, has been infrequently detected in other hosts. Other major STs (ST-50 and ST-45) have been common in several hosts such as conventional poultry and bovines. CRISPR typing provided additional discrimination between isolates of certain dominant STs and could be useful in further epidemiological studies. This study gives new information about MLST and CRISPR types of Camp. jejuni among organically farmed laying hens.


Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells.
Chronic myeloid leukemia is characterized by the Philadelphia (Ph1) translocation t(9;22) that generates a hybrid gene, bcr/abl, translated to a Mr210,000 tyrosine kinase (p210bcr/abl) with transforming activity for hematopoietic cells. Hematopoietic cell transformation by p2l0bcr/abl seems to involve activation of the Ras signaling pathway by at least two different signaling intermediates, growth factor receptor-bound protein 2 and Src homology and collagen protein, but additional signaling proteins are likely to be required as well. In an effort to identify additional phosphoproteins activated by p210bcr/abl, we studied the murine, interleukin 3-dependent, myeloid cell line, 32D, and a bcr/abl-transfected, factor-independent subline, 32Dp210. The analysis of whole-cell lysates of 32D and 32Dp210 cells showed that several proteins with a molecular weight of Mr50,000-60,000 were phosphorylated on tyrosine residues in 32Dp210 cells. Because Src family kinases have an apparent molecular weight of Mr50,000-60,000, we asked whether they could become activated by p2l0bcr/abl. Two Src family kinases, p53/56lyn and p59hck, showed a severalfold higher phosphokinase activity in 32Dp210 cells than in 32D cells. Coimmunoprecipitation experiments with anti-Lyn, anti-Hck, and anti-Abl antibodies demonstrated an intracellular association of p210bcr/abl with p53/56lyn and p59hck. Moreover, the phosphokinase activity of p53/56lyn was higher in bcr/abl-positive myeloid cell lines (K562, BV173, and LAMA84) than in the bcr/abl-negative myeloid cell line JOSK-M. In conclusion, the results show that p210bcr/abl induces the activation of at least two Src family kinases, P53/56lyn and p59hck, in myeloid cells. These findings extend the range of potential targets of p210bcr/abl that might mediate its transforming effects.


Laparoendoscopic single-site surgery for benign ovarian cystectomies.
Single-port laparoscopy (LESS) utilizes a single, multichannel port in an attempt to decrease postoperative pain, while enhancing cosmesis and minimizing the potential risks and morbidities associated with the multiple ports used in conventional laparoscopy. We performed a retrospective study examining three tertiary care referral centers. From September 2009 until March 2013, 31 patients with ovarian cystic lesions were treated using the LESS technique. A control group of 57 patients who underwent conventional laparoscopic ovarian cystectomy was included for comparison. All patients underwent a technically successful cystectomy. There were no statistically significant differences in the mean operative time or estimated blood loss between the two groups. Narcotic use during the recovery period was reported in less patients in the LESS group than in the laparoscopic group (p = 0.05). The LESS technique can be used to safely perform cystectomies on women with benign ovarian cysts. Additional investigation is needed to evaluate the safety, cost-effectiveness and long-term outcomes of this new approach.


Metastasis: new functional implications of platelets and megakaryocytes.
Platelets are essential components of hemostasis. Due to a plethora of factors released on activation, platelet functions are also connected to tumor growth, notably by acting on angiogenesis. It is now well recognized that major roles of platelets in the poor outcome of cancer patients occurs during hematogenous dissemination of cancer cells. In this review, we describe recent insights into the molecular mechanisms supporting the prometastatic activity of platelets. Platelets have been shown to promote survival of circulating tumor cells (CTCs) in the bloodstream by conferring resistance to the shear stress and attack from natural killer cells. Recently, platelets were found to promote and/or maintain the state of epithelial to mesenchymal transition on CTCs through platelet secretion of transforming growth factor β in response to CTC activation. At a later stage in the metastatic process, platelets promote extravasation and establishment of metastatic cells in distant organs as observed in bone. This particular environment is also the site of hematopoiesis, megakaryocytopoiesis, and platelet production. Increasing the number of megakaryocytes (MKs) in the bone marrow results in a high bone mass phenotype and inhibits skeletal metastasis formation of prostate cancer cells. As a result of their specific location in vascular niches in the bone marrow, MK activity might contribute to the "seed and soil" suitability between CTCs and bone. In conclusion, recent findings have made a great advance in our knowledge on how platelets contribute to the metastatic dissemination of cancer cells and that may support the development of new antimetastasis therapies.


Estimating the value of improved wastewater treatment: the case of River Ganga, India.
In this paper we employ a stated preference environmental valuation technique, namely the choice experiment method, to estimate local public's willingness to pay (WTP) for improvements in the capacity and technology of a sewage treatment plant (STP) in Chandernagore municipality, located on the banks of the River Ganga in India. A pilot choice experiment study is administered to 150 randomly selected Chandernagore residents and the data are analysed using the conditional logit model with interactions. The results reveal that residents of this municipality are willing to pay significant amounts in terms of higher monthly municipality taxes to ensure the full capacity of the STP is used for primary treatment and the technology is upgraded to enable secondary treatment. Overall, the results reported in this paper support increased investments to improve the capacity and technology of STPs to reduce water pollution, and hence environmental and health risks that are currently threatening the sustainability of the economic, cultural and religious values this sacred river generates.


Collapse of optical pulses.
Under the combined effect of diffraction, anomalous dispersion, and nonlinear refraction, an optical pulse can collapse simultaneously in time and space. Such a collapse could yield short pulses with extremely large optical fields. Light bullets-pulses that propagate without change in space or time-are also possible. The condition for such a collapse and possible experiments are discussed.


ART class II restoration loss in primary molars: re-restoration or not?
The purpose of this study was to find an answer as to what to do with Atraumatic Restorations (ART) failures: re-restore or leave the preparation further unfilled? Cross sectional study. In 2006, 804 children in Kenya each had one proximal cavity treated using the ART approach. Out of the original group of 192 children, who had lost their restorations but still had the treated molars in situ, were selected for further study in 2008. The length of time that the restorations had been in situ was known while the colour, hardness and the extent of infected dentine was then evaluated and documented. Analysis of the data obtained was conducted using SPSS 16.0. Chi Square tests were performed with the variables of hardness, colour and infected dentine, and a 5% confidence interval was used. The Spearman's Rank Correlation Coefficient was also calculated. The results showed that 66% of the molars that had lost restorations had hard dentine, 78% of the preparations showed dark dentine and 50.7% appeared to have no infected dentine. These percentages increased with the increase in the survival time of the restorations. It is not always necessary to re-restore primary molars after ART restoration loss. Further research is necessary to confirm these findings.


Fine-Scale Inference of Ancestry Segments Without Prior Knowledge of Admixing Groups.
We present an algorithm for inferring ancestry segments and characterizing admixture events, which involve an arbitrary number of genetically differentiated groups coming together. This allows inference of the demographic history of the species, properties of admixing groups, identification of signatures of natural selection, and may aid disease gene mapping. The algorithm employs nested hidden Markov models to obtain local ancestry estimation along the genome for each admixed individual. In a range of simulations, the accuracy of these estimates equals or exceeds leading existing methods. Moreover, and unlike these approaches, we do not require any prior knowledge of the relationship between subgroups of donor reference haplotypes and the unseen mixing ancestral populations. Our approach infers these in terms of conditional "copying probabilities." In application to the Human Genome Diversity Project, we corroborate many previously inferred admixture events (e.g., an ancient admixture event in the Kalash). We further identify novel events such as complex four-way admixture in San-Khomani individuals, and show that Eastern European populations possess [Formula: see text] ancestry from a group resembling modern-day central Asians. We also identify evidence of recent natural selection favoring sub-Saharan ancestry at the human leukocyte antigen (HLA) region, across North African individuals. We make available an R and C++ software library, which we term MOSAIC (which stands for MOSAIC Organizes Segments of Ancestry In Chromosomes).


Evaluation of trait adjectives and ego pathology in schizophrenia: an N400 study.
The N400, an event-related brain potential (ERP), can be triggered by semantic or arithmetic violations in visual or auditory stimulus material. Schizophrenia patients exhibit an altered N400 presumably resulting from impaired semantic memory associative networks. The present study investigates, whether an altered N400 can also be found in semantic violations of the own self-concept. We use simple descriptive sentences to combine semantics with the self-concept in order to explore differences and possible deficits in schizophrenia patients. Schizophrenia patients and controls were shown trait adjectives in reference to themselves. Participants had to decide if the presented trait adjective was congruent or incongruent with their own self-concept. Only in controls, the N400 was significantly more negative in the incongruent compared to the congruent condition. Controls seemed to profit from a stable self-concept as they were faster in judging if a given trait was descriptive for the self than for someone else, which might result from processes related to the self-reference effect. Interestingly, in schizophrenia patients, the higher the scores for ego pathology were, the smaller the N400 effect turned out to be. The diminished N400 effect is probably associated with a disturbed self-concept in schizophrenia.


Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer.
Numerous prospective and retrospective studies have concluded that elderly patients (> or = 70 years old) achieve a similar survival benefit, with acceptable toxicity, from first-line cytotoxic chemotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) compared with their younger counterparts. However, few published data exist on the efficacy and tolerability of second-line cytotoxic therapy in this population. Retrospective analysis of a large second-line trial was performed. Data from 571 patients randomly assigned to docetaxel 75 mg/m2 or pemetrexed 500 mg/m2 every 3 weeks were analyzed for efficacy and toxicity comparisons between age groups and treatment arms. Eighty-six of 571 patients (15%) were > or = 70 years old, similar to rates of elderly observed in the first-line setting. Elderly patients receiving pemetrexed (n = 47) or docetaxel (n = 39) had a median survival of 9.5 and 7.7 months compared with 7.8 and 8.0 months for younger patients receiving pemetrexed (n = 236) or docetaxel (n = 249), respectively. Elderly patients treated with pemetrexed had a longer time to progression and a longer survival than their counterpart patients treated with docetaxel (not statistically significant). Febrile neutropenia was less frequent in elderly patients treated with pemetrexed (2.5%) compared with docetaxel (19%; P = .025), with only one death as a result of toxicity (docetaxel arm). Elderly patient participation was similar to rates observed in the first-line setting. There was no significant difference in outcome or toxicity between elderly and younger patients. For elderly patients with advanced NSCLC and good performance status, second-line cytotoxic therapy is appropriate. In this subset, pemetrexed produced a more favorable toxicity profile.


A latent transition model of the effects of a teen dating violence prevention initiative.
Patterns of physical and psychological teen dating violence (TDV) perpetration, victimization, and related behaviors were examined with data from the evaluation of the Start Strong: Building Healthy Teen Relationships initiative, a dating violence primary prevention program targeting middle school students. Latent class and latent transition models were used to estimate distinct patterns of TDV and related behaviors of bullying and sexual harassment in seventh grade students at baseline and to estimate transition probabilities from one pattern of behavior to another at the 1-year follow-up. Intervention effects were estimated by conditioning transitions on exposure to Start Strong. Latent class analyses suggested four classes best captured patterns of these interrelated behaviors. Classes were characterized by elevated perpetration and victimization on most behaviors (the multiproblem class), bullying perpetration/victimization and sexual harassment victimization (the bully-harassment victimization class), bullying perpetration/victimization and psychological TDV victimization (bully-psychological victimization), and experience of bully victimization (bully victimization). Latent transition models indicated greater stability of class membership in the comparison group. Intervention students were less likely to transition to the most problematic pattern and more likely to transition to the least problem class. Although Start Strong has not been found to significantly change TDV, alternative evaluation models may find important differences. Latent transition analysis models suggest positive intervention impact, especially for the transitions at the most and the least positive end of the spectrum.


Immunoglobulin sub-class distribution in bipolar disorder and schizophrenia: potential relationship with latent Toxoplasma Gondii infection.
Immune dysfunction could play a significant role in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ), conditions with an underlying pro-inflammatory state. Studies on humoral immune responses (which reflects antibody mediated fight against pathogens) in schizophrenia and bipolar disorder are sparse and often providing contradictory results. The aim of this study was to assess humoral immunity in a group of stable bipolar disorder and schizophrenia patients compared to controls by determining total Immunoglobulins and IgG subclasses and to assess their association with latent Toxoplasma gondii and/or CMV infection. 334 subjects (124 BD, 75 SZ and 135 Healthy Controls [HC]) were included and tested for humoral immunity by determining the total immunoglobulins (IgG,A and M) and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and their relationship with latent Toxoplasma gondii infection, an established risk factor for BD and SZ. Although lower levels of IgG, IgG1, IgG2, IgG4 and IgA were found among BD as compared to HC and/or SZ, after adjustment for confounding variables, only low levels of IgG and IgG1 in BD remai- ned significant. Strikingly highest levels of antibodies to T. gondii (but not CMV) infection in BD and SZ were associated with lowest levels of IgG3 and IgG4 levels as compared to controls. Schizophrenia and bipolar disorder patients with latent T. gondii specific infection may be more vulnerable to changes in immuno-inflammatory processes than controls with similar latent infectious state. Simultaneous sequential immunological monitoring both in steady state and active disease phases in the same BD and SZ patients are warranted to understand the role of Toxoplasma gondii latency in these disorders.


Heterogeneity of mitochondrial DNA from Saccharomyces carlsbergensis. Denaturation mapping by electron microscopy.
Electronmicroscopic observation of the denaturation pattern of 130 partially denaturated linear mitochondrial DNA molecules from Saccharomyces carlsbergensis was used to investigate the distribution of AT-rich sequences within the mitochondrial genome. The molecules were observed after heating to 43 degrees C in the presence of 12% formaldehyde. These conditions resulted in an average denaturation per molecule of 21%. The average length of the molecules was 10 mum, and a few molecules had a length corresponding to the size of the complete genome. The undenaturated regions varied in length from 0.1 to 5.0 mum with denaturated regions of length 0.02 to 0.1 mum in between. A denaturation map was constructed by use of one of the long molecules (28.7 mum) as a master molecule for positioning of all other molecules. This map shows distinct regions corresponding to the position of easily denaturated sequences in the mitochondrial DNA. These sequences which presumably correspond to the very AT-rich regions, known to exist in the yeast mitochondrial DNA, were found at intervals of about 0.5 - 3 mum on the map.


The thoracolumbar spine in Marfan syndrome.
We analyzed the prevalence, inheritance, progression, and functional implications of spinal deformity in Marfan syndrome using four different groups of patients. We studied 113 patients who had Marfan syndrome, eighty-two of whom were skeletally immature, in order to characterize the alignment and function of the spine. The patients were selected from a clinic that provides total care with no bias toward the presence of orthopaedic conditions. Scoliosis was identified in fifty-two of the eighty-two patients, and the prevalences for the sexes were equal. The thoracic portion of the curve was convex to the right in all but two patients. The mean kyphosis was greater than that in the general population. Five distinct sagittal profiles were identified on the basis of whether the thoracic kyphosis was within, greater than, or less than normal limits and whether the transition between the kyphosis and lordosis occurred at or caudad to the normal level or whether the curves were reversed. Spondylolisthesis was present in five patients (6 per cent), with a mean slip of 30 per cent. Fourteen pedigrees were studied in depth. There was no familial pattern of the scoliosis. A separate group of fifty-six patients with scoliosis, for whom serial follow-up radiographs were available, was studied for progression. Patients who had a curve of more than 30 degrees had mild progression, and those who had a curve of more than 50 degrees had marked progression (mean, 3 +/- 4 degrees per year). Pain and function of the back were studied in thirty patients who were thirty-five to forty-five years old; these patients were found to be more impaired than matched controls. The presence of scoliosis was associated with pain in the region of the curve in these patients.


Comparison of Perioperative Complications by Route of Hysterectomy Performed for Benign Conditions.
The aim of this study was to compare perioperative complications by route of hysterectomy before and after the introduction of robotic surgery. This is an ancillary analysis of a multicenter, retrospective cohort study with historical controls through the Fellows' Pelvic Research Network. Hysterectomies performed for benign conditions were collected prior to introduction of the robot (prerobot) and the year after introduction of the robot (postrobot) at each institution. To obtain a representative annual case distribution for each institution, a maximum of 20 cases per month were selected using stratified random sampling. Patient demographics and intraoperative and postoperative complication data were collected. One thousand four hundred forty cases were included in this study, 732 in the prerobot and 708 in the postrobot period. Intraoperative complications in the prerobot group were highest in the abdominal group (7.4%) followed by vaginal (3.9%) and laparoscopic (3.7%) groups. Postoperative complications were higher in the vaginal (8.3%) and abdominal (7.4%) groups compared with laparoscopic (1.8%) groups (P = 0.03), because of a higher proportion of infections. In the postrobot period, intraoperative complications were lower in the vaginal (2.8%), robotic (3%), and laparoscopic (4.6%) groups compared with abdominal (10.8%) (P = 0.04). Postoperative complications were lowest in the vaginal (5.1%), laparoscopic (3.6%), and robotic (3%) approaches compared with the abdominal (13.9%) approach (P = 0.003). Vaginal hysterectomy has comparable rates of perioperative complications when compared with robotic and laparoscopic approaches and should be considered as a primary surgical approach in the growing armamentarium of minimally invasive approaches for hysterectomy for benign conditions.


Are the correlates of sport participation similar to those of screen time?
To explore longitudinal and cross-sectional correlates of sport participation and screen time in a nationally representative sample of Australian children. The sample included 3956 child participants taken from the Longitudinal Study of Australian Children. Data were collected in 2004 (age range = 4-5 years) and 2012 (age range = 12-13 years) and included parental estimates of sport participation and total screen time (electronic gaming and television viewing) in addition to demographic, socioeconomic and environmental factors. Sport participation and total screen time were inversely correlated (r = - .10). Child demographics (sex, pubertal status, general health, and body mass index [BMI]), socioeconomic (neighborhood socioeconomic position, household income, parental education, and parental BMI) and environmental (neighborhood belonging, neighborhood safety, and neighborhood facilities) factors were related to both outcomes - in most cases a positive [negative] correlation with sport participation yielded a corresponding negative [positive] correlation with total screen time. Our findings show that demographic, socioeconomic and environmental factors measured at age 4 predict sport participation and screen time at age 12, and that the correlates of childhood sport participation and childhood sedentary behavior may be more similar than previously estimated.


"Quantized" Doping of Individual Colloidal Nanocrystals Using Size-Focused Metal Quantum Clusters.
The insertion of intentional impurities, commonly referred to as doping, into colloidal semiconductor quantum dots (QDs) is a powerful paradigm for tailoring their electronic, optical, and magnetic behaviors beyond what is obtained with size-control and heterostructuring motifs. Advancements in colloidal chemistry have led to nearly atomic precision of the doping level in both lightly and heavily doped QDs. The doping strategies currently available, however, operate at the ensemble level, resulting in a Poisson distribution of impurities across the QD population. To date, the synthesis of monodisperse ensembles of QDs individually doped with an identical number of impurity atoms is still an open challenge, and its achievement would enable the realization of advanced QD devices, such as optically/electrically controlled magnetic memories and intragap state transistors and solar cells, that rely on the precise tuning of the impurity states (i.e., number of unpaired spins, energy and width of impurity levels) within the QD host. The only approach reported to date relies on QD seeding with organometallic precursors that are intrinsically unstable and strongly affected by chemical or environmental degradation, which prevents the concept from reaching its full potential and makes the method unsuitable for aqueous synthesis routes. Here, we overcome these issues by demonstrating a doping strategy that bridges two traditionally orthogonal nanostructured material systems, namely, QDs and metal quantum clusters composed of a "magic number" of atoms held together by stable metal-to-metal bonds. Specifically, we use clusters composed of four copper atoms (Cu4) capped with d-penicillamine to seed the growth of CdS QDs in water at room temperature. The elemental analysis, performed by electrospray ionization mass spectrometry, X-ray fluorescence, and inductively coupled plasma mass spectrometry, side by side with optical spectroscopy and transmission electron microscopy measurements, indicates that each Cu:CdS QD in the ensemble incorporates four Cu atoms originating from one Cu4 cluster, which acts as a "quantized" source of dopant impurities.


Cdx gene deficiency compromises embryonic hematopoiesis in the mouse.
Cdx genes (Cdx1, Cdx2, and Cdx4) encode a family of caudal-related transcription factors that mediate anterior-posterior patterning during embryogenesis through Hox gene regulation. Homologues in the zebrafish have been shown to play key roles in blood formation. To define the role of Cdx genes during embryonic hematopoiesis in a mammalian system, we examined the hematopoietic potential of Cdx-deficient mouse embryonic stem cells (ESCs) in vitro and in vivo. Individual Cdx-deficient ESCs exhibited impaired embryonic hematopoietic progenitor formation and altered Hox gene expression, most notably for Cdx2 deficiency. A more severe hematopoietic defect was observed with compound Cdx deficiency than loss of function of any single Cdx gene. Reduced hematopoietic progenitor formation of ESCs deficient in multiple Cdx genes could be rescued by ectopic expression of Cdx4, concomitant with partially restored Hox gene expression. These results reveal an essential and partially redundant role for multiple Cdx genes during embryonic hematopoiesis in the mouse.


Spontaneous glial calcium waves in the retina develop over early adulthood.
Intercellular glial Ca(2+) waves constitute a signaling pathway between glial cells. Artificial stimuli have previously been used to evoke these waves, and their physiological significance has been questioned. We report here that Ca(2+) waves occur spontaneously in rat retinal glial cells, both in the isolated retina and in vivo. These spontaneous waves are propagated by ATP release. In the isolated retina, suramin (P2 receptor antagonist) reduces the frequency of spontaneous wave generation by 53%, and apyrase (ATP-hydrolyzing enzyme) reduces frequency by 95-100%. Luciferin-luciferase chemiluminescence reveals waves of ATP matching the spontaneous Ca(2+) waves, indicating that ATP release occurs as spontaneous Ca(2+) waves are generated. Wave generation also depends on age. Spontaneous wave frequency rises from 0.27 to 1.0 per minute per mm(2), as rats age from 20 to 120 d. The sensitivity of glia to ATP does not increase with age, but the ATP released by evoked waves is 31% greater in 120-d-old than in 20-d-old rats, suggesting that increased ATP release in older animals could account for the higher frequency of wave generation. Simultaneous imaging of glial Ca(2+) and arterioles in the isolated retina demonstrates that spontaneous waves alter vessel diameter, implying that spontaneous waves may have a significant impact on retinal physiology. Spontaneous intercellular glial Ca(2+) waves also occur in the retina in vivo, with frequency, speed, and diameter similar to the isolated retina. Increased spontaneous wave occurrence with age suggests that wave generation may be related to retinal pathology.


Stabilization method for signal drifts in terahertz chemical microscopy.
A stabilization method for signal drifts in terahertz chemical microscopy (TCM) due to unexpected chemical potential changes in sample solutions was proposed and developed. The sensing plate was separated into two areas: a detection area and a control area. The detection area radiated a THz pulse whose amplitude was related to both the chemical reactions in the sample solutions and unexpected potential changes. The THz pulse from the control area was related only to unexpected potential changes. In the proposed system, the THz pulse from each area was interfered and detected. By adjusting the timing of the positive peak of the THz pulse from the detection area and the negative peak of the THz pulse from the control area, we detected the difference in both peaks as the interference signal. Thus, the signal deviation of 390 when the environmental condition changes in the temperature range of 38 °C and the pH range of 8.33 was stabilized to be the signal deviation of 31. As the result, the TCM with stabilization method could detect the signal shift of 121 when the 275-nmol/L immunoglobulin G was immobilized on the sensing plate.


Effects of the standardized Ginkgo biloba extract EGb 761® on neuroplasticity.
Neuroplasticity, the ability of synapses to undergo structural adaptations in response to functional demand or dysfunctions is increasingly impaired in aging and Alzheimer's disease. EGb761® has been shown in several preclinical reports to increase nearly all aspects of impaired neuroplasticity (long-term potentiation, spine density, neuritogenesis, neurogenesis). While all three fractions of constituents (ginkgolides, flavonoids, bilobalide) seem to be active, the flavonoids and specifically the aglycone isorhamnetin seem to be most relevant.


Design of a process evaluation of the implementation of a physical activity and sports stimulation programme in Dutch rehabilitation setting: ReSpAct.
There is a growing interest to study the transfer of evidence-based information into daily practice. The evidence-based programme Rehabilitation, Sports and Exercise (RSE) that aims to stimulate an active lifestyle during and after a rehabilitation period in people with a disability and/or chronic disease is prepared for nationwide dissemination. So far, however, little is known about the implementation of a new programme to stimulate physical activity in people with a disability in a rehabilitation setting. Therefore, a process evaluation of the implementation of the RSE programme within 18 Dutch rehabilitation centres and hospitals is performed in order to gain more insight into the implementation process itself and factors that facilitate or hamper the implementation process. This paper describes the study design of this process evaluation. During a three-year period, the adoption, implementation and continuation of the RSE programme is monitored and evaluated in 12 rehabilitation centres and 6 hospitals with a rehabilitation department in The Netherlands. The main process outcomes are: recruitment, reach, dose delivered, dose received, fidelity, satisfaction, maintenance and context. The process outcomes are evaluated at different levels (organisational and patient) and different time points. Data collection includes both quantitative (online registration system and questionnaires) and qualitative (focus groups and semi-structured interviews) methods. The nationwide dissemination of an evidence-based programme to stimulate physical activity and sports during and after a rehabilitation period is extensively monitored and evaluated on different levels (organization and patients) using mixed methods. The study will contribute to the science of translating evidence-based programmes into daily practice of the rehabilitation care. The results of the study can be used to further optimize the content of the RSE programme and to facilitate the implementation in other health facilities. Furthermore, the results of the study can help future implementation processes in the rehabilitation setting. The study is registered by The Netherlands National Trial Register: NTR3961.


Chronic obstructive pulmonary disease and engagement in occupation.
The goal of this study was to gain an understanding of participants' experiences with chronic obstructive pulmonary disease (COPD) and their perceptions of an occupational therapy intervention as it related to occupational behaviors. The researcher conducted semistructured interviews with three participants recruited from a pulmonary rehabilitation program in Hong Kong. Using thematic analysis, five themes related to the disease experience were identified: (1) uncertainty during the course of the disease, (2) external attribution, (3) activity restriction and isolation, (4) anxiety and depression, and (5) passive fortitude. Regarding the participants' perceptions of the effects of the occupational therapy intervention on occupation engagement, four themes were identified: (1) increased knowledge of COPD, (2) taking control of the disease and reengagement in activities, (3) alleviation of mental burden, and (4) social support from peers and therapists. The study suggests a temporal framework for better understanding participants' experiences of COPD as well as for developing more appropriate occupational therapy interventions.


Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2): An open-label randomised trial and updated meta-analysis.
Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix. We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses. These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out. ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181.


Laser bandwidth effects in quantitative cavity ring-down spectroscopy.
We have investigated the effects of laser bandwidth on quantitative cavity ring-down spectroscopy using the (r)R transitions of the b(ν = 0)?X(ν = 0) band of molecular oxygen. It is found that failure to account properly for the laser bandwidth leads to systematic errors in the number densities determined from measured ring-down signals. When the frequency-integrated expression for the ring-down signal is fitted and measured laser line shapes are used, excellent agreement between measured and predicted number densities is found.


D-psicose is a rare sugar that provides no energy to growing rats.
D-Psicose (D-ribo-2-hexulose), a C-3 epimer of D-fructose, is present in small quantities in commercial carbohydrate complexes and agricultural products. We have previously reported that D-psicose supplements in diets suppressed hepatic lipogenic enzyme activity The lower fat accumulation in rats fed D-psicose may be due to lower lipogenesis in the liver. The present study examined the energy available in D-psicose for rat growth. Male Wistar rats received 7 g daily of a basal diet to which fixed amounts of sucrose, D-fructose, or D-psicose (0.5-2.0 g) were added for 20 d. Body weight gain and body energy gain increased with increases in sucrose and D-fructose, but not with D-psicose. One gram of sucrose, D-fructose, and D-psicose produced a net energy gain of 2.29, 1.76, and 0.007 kcal, respectively. The efficiency of energy deposition from D-psicose was 0.3% that of sucrose. The energy value of D-psicose was effectively zero. These results suggest that D-psicose is a rare sugar providing zero energy that may be useful in sweeteners for obese people as an aid for weight reduction.


Risk-treatment paradox in the selection of transradial access for percutaneous coronary intervention.
Access site complications contribute to morbidity and mortality during percutaneous coronary intervention (PCI). Transradial arterial access significantly lowers the risk of access site complications compared to transfemoral arteriotomy. We sought to develop a prediction model for access site complications in patients undergoing PCI with femoral arteriotomy, and assess whether transradial access was selectively used in patients at high risk for complications. We analyzed 17 509 patients who underwent PCI without circulatory support from 2008 to 2011 at 5 institutions. Transradial arterial access was used in 17.8% of patients. In those who underwent transfemoral access, 177 (1.2%) patients had access site complications. Using preprocedural clinical and demographic data, a prediction model for femoral arteriotomy complications was generated. The variables retained in the model included: elevated age (P<0.001), female gender (P<0.001), elevated troponin (P<0.001), decreased renal function or dialysis (P=0.002), emergent PCI (P=0.01), prior PCI (P=0.005), diabetes (P=0.008), and peripheral artery disease (P=0.003). The model showed moderate discrimination (optimism-adjusted c-statistic=0.72) and was internally validated via bootstrap resampling. Patients with higher predicted risk of complications via transfemoral access were less likely to receive transradial access (P<0.001). Similar results were seen in patients presenting with and without ST-segment myocardial infarction and when adjusting for individual physician operator. We generated and validated a model for transfemoral access site complications during PCI. Paradoxically, patients most likely to develop access site complications from transfemoral access, and therefore benefit from transradial access, were the least likely to receive transradial access.


Influence of reward delays on responses of dopamine neurons.
Psychological and microeconomic studies have shown that outcome values are discounted by imposed delays. The effect, called temporal discounting, is demonstrated typically by choice preferences for sooner smaller rewards over later larger rewards. However, it is unclear whether temporal discounting occurs during the decision process when differently delayed reward outcomes are compared or during predictions of reward delays by pavlovian conditioned stimuli without choice. To address this issue, we investigated the temporal discounting behavior in a choice situation and studied the effects of reward delay on the value signals of dopamine neurons. The choice behavior confirmed hyperbolic discounting of reward value by delays on the order of seconds. Reward delay reduced the responses of dopamine neurons to pavlovian conditioned stimuli according to a hyperbolic decay function similar to that observed in choice behavior. Moreover, the stimulus responses increased with larger reward magnitudes, suggesting that both delay and magnitude constituted viable components of dopamine value signals. In contrast, dopamine responses to the reward itself increased with longer delays, possibly reflecting temporal uncertainty and partial learning. These dopamine reward value signals might serve as useful inputs for brain mechanisms involved in economic choices between delayed rewards.


Calibration of an outdoor distributed camera network with a 3D point cloud.
Outdoor camera networks are becoming ubiquitous in critical urban areas of the largest cities around the world. Although current applications of camera networks are mostly tailored to video surveillance, recent research projects are exploiting their use to aid robotic systems in people-assisting tasks. Such systems require precise calibration of the internal and external parameters of the distributed camera network. Despite the fact that camera calibration has been an extensively studied topic, the development of practical methods for user-assisted calibration that minimize user intervention time and maximize precision still pose significant challenges. These camera systems have non-overlapping fields of view, are subject to environmental stress, and are likely to suffer frequent recalibration. In this paper, we propose the use of a 3D map covering the area to support the calibration process and develop an automated method that allows quick and precise calibration of a large camera network. We present two cases of study of the proposed calibration method: one is the calibration of the Barcelona Robot Lab camera network, which also includes direct mappings (homographies) between image coordinates and world points in the ground plane (walking areas) to support person and robot detection and localization algorithms. The second case consist of improving the GPS positioning of geo-tagged images taken with a mobile device in the Facultat de Matemàtiques i Estadística (FME) patio at the Universitat Politècnica de Catalunya (UPC).


Temporality of body mass index, blood tests, comorbidities and medication use as early markers for pancreatic ductal adenocarcinoma (PDAC): a nested case-control study.
Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk . We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression. Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC. Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.


Cut Points for Identifying Clinically Significant Diabetes Distress in Adolescents With Type 1 Diabetes Using the PAID-T: Results From Diabetes MILES Youth-Australia.
To establish cut point(s) for the Problem Areas in Diabetes-teen version (PAID-T) scale to identify adolescents with clinically meaningful, elevated diabetes distress. Data were available from the Diabetes Management and Impact for Long-term Empowerment and Success (MILES) Youth-Australia Study, a national survey assessing various psychosocial indicators among self-selected National Diabetes Services Scheme registrants. Participants in the current study (n = 537) were (mean ± SD) 16 ± 2 years old, had type 1 diabetes for 6 ± 4 years, and 62% (n = 334) were girls. They completed measures of diabetes distress (PAID-T) and depressive symptoms (Patient Health Questionnaire for Adolescents) and self-reported their most recent HbA1c and frequency of self-monitoring of blood glucose (SMBG). Relationships between the PAID-T and the psychological and clinical variables were examined to identify a clinically meaningful threshold for elevated diabetes distress. ANOVA was used to test whether these variables differed by levels of distress. Two cut points distinguished none-to-mild (<70), moderate (70-90), and high (>90) diabetes distress. Moderate distress was experienced by 18% of adolescents and high distress by 36%. Mean depressive symptoms, self-reported HbA1c, and SMBG differed significantly across the three levels of diabetes distress (all P < 0.001), with moderate-to-large effect sizes. Using the PAID-T, this study defined two clinically meaningful cut points to distinguish none-to-mild, moderate, and high diabetes distress in adolescents (aged 13-19). Based on these cut points, most respondents experienced at least moderate diabetes distress, which was clinically significant. Establishing thresholds for elevated diabetes distress will aid clinicians and researchers to interpret PAID-T scores, prompt discussion and intervention for those with unmet needs, and enable the effectiveness of interventions to be evaluated.


Supporting patients with female genital mutilation in primary care: a qualitative study exploring the perspectives of GPs' working in England.
Female genital mutilation (FGM) includes all procedures that intentionally harm or alter female genitalia for non-medical reasons. In 2015, reporting duties were introduced, applicable to GPs working in England including a mandatory reporting duty and FGM Enhanced Dataset. Our patient and public involvement work identified the exploration of potential impacts of these duties as a research priority. To explore the perspectives of GPs working in England on potential challenges and resource needs when supporting women and families affected by FGM. Qualitative study with GPs working in English primary care. Semi-structured interviews focused around a fictional scenario of managing FGM in primary care. The authors spoke to 17 GPs from five English cities, including those who saw women who have experienced FGM often, rarely, or never. Interviews were audio recorded and transcribed verbatim for thematic analysis. Lipsky's theory of street-level bureaucracy was drawn on to support analysis. Managing women with FGM was experienced as complex. Challenges included knowing how and when to speak about FGM, balancing care of women and their family's potential care and safeguarding needs, and managing the mandated reporting and recording requirements. GPs described strategies to manage these tensions that helped them balance maintaining patient-doctor relationships with reporting requirements. This was facilitated by access to FGM holistic services. FGM reporting requirements complicate consultations. The potential consequences on trust between women affected by FGM and their GP are clear. The tensions that GPs experience in supporting women affected by FGM can be understood through the theoretical lens of street-level bureaucracy. This is likely to be relevant to other areas of proposed mandated reporting.


Pathophysiology and Management of Moderate and Severe Traumatic Brain Injury in Children.
Traumatic brain injury remains a leading cause of morbidity and mortality in children. Key pathophysiologic processes of traumatic brain injury are initiated by mechanical forces at the time of trauma, followed by complex excitotoxic cascades associated with compromised cerebral autoregulation and progressive edema. Acute care focuses on avoiding secondary insults, including hypoxia, hypotension, and hyperthermia. Children with moderate or severe traumatic brain injury often require intensive monitoring and treatment of multiple parameters, including intracranial pressure, blood pressure, metabolism, and seizures, to minimize secondary brain injury. Child neurologists can play an important role in acute and long-term care. Acutely, as members of a multidisciplinary team in the intensive care unit, child neurologists monitor for early signs of neurological change, guide neuroprotective therapies, and transition patients to long-term recovery. In the longer term, neurologists are uniquely positioned to treat complications of moderate and severe traumatic brain injury, including epilepsy and cognitive and behavioral issues.


A French multicenter clinical trial of SPARC for stress urinary incontinence.
To evaluate the safety and efficacy of the SPARC procedure in women with genuine stress urinary incontinence. We conducted a prospective multicenter trial of a suprapubic approach to suburethral polypropylene (SPARC) taping for the treatment of genuine stress urinary incontinence. Between June 2001 and June 2002, 104 consecutive women (mean age 58.7 years) underwent SPARC in three centers. All the women had urethral hypermobility preoperatively. Detrusor instability was ruled out by cystometry. The women were evaluated 1, 3, 6 and 12 months postoperatively. The objective cure rate was evaluated by clinical and urodynamic examination, and the subjective cure rate was assessed using the Kings and Bristol questionnaire. The mean follow-up time was 11.9+/-1.9 months (range 8 to 20 months). The mean operating time was 30 min (25-50 min). Most of the patients received general anesthesia (48%). The overall complication rate was 44.2% (46/104). The perioperative complication rate was 10.5%, including 11 bladder injuries. A significant difference in the bladder injury rate was observed between women with and without previous incontinence surgery (respectively 4/11, 36.3% versus 7/93, 7.5%; p<0.001). No hemorrhaging occurred. The early postoperative complication rate was 22.1%. The main complication was voiding disorders (11 patients), which necessitated intermittent self-catheterization for less than 15 days (1.3+/-1.1 days, range 1 to 10 days). The late postoperative complication rate was 11.5%, including de novo urge symptoms in 12 women. The objective cure rate was 90.4%. No difference was found between patients with genuine stress incontinence and those with mixed incontinence. The subjective cure rate was 72%. The objective and subjective cure rates differed significantly (p<0.05). The subjective cure rate among patients with de novo urge symptoms was 58%. The SPARC procedure is a safe and effective treatment for women with stress urinary incontinence, despite a high incidence of de novo urge symptoms.