Mutations that Separate the Functions of the Proofreading Subunit of the Escherichia coli Replicase.
The dnaQ gene of Escherichia coli encodes the ε subunit of DNA polymerase III, which provides the 3' → 5' exonuclease proofreading activity of the replicative polymerase. Prior studies have shown that loss of ε leads to high mutation frequency, partially constitutive SOS, and poor growth. In addition, a previous study from our laboratory identified dnaQ knockout mutants in a screen for mutants specifically defective in the SOS response after quinolone (nalidixic acid) treatment. To explain these results, we propose a model whereby, in addition to proofreading, ε plays a distinct role in replisome disassembly and/or processing of stalled replication forks. To explore this model, we generated a pentapeptide insertion mutant library of the dnaQ gene, along with site-directed mutants, and screened for separation of function mutants. We report the identification of separation of function mutants from this screen, showing that proofreading function can be uncoupled from SOS phenotypes (partially constitutive SOS and the nalidixic acid SOS defect). Surprisingly, the two SOS phenotypes also appear to be separable from each other. These findings support the hypothesis that ε has additional roles aside from proofreading. Identification of these mutants, especially those with normal proofreading but SOS phenotype(s), also facilitates the study of the role of ε in SOS processes without the confounding results of high mutator activity associated with dnaQ knockout mutants.


Estimating the Horizon of articles to decide when to stop searching in systematic reviews: an example using a systematic review of RCTs evaluating osteoporosis clinical decision support tools.
Researchers conducting systematic reviews need to search multiple bibliographic databases such as MEDLINE and EMBASE. However, researchers have no rational search stopping rule when looking for potentially-relevant articles. We empirically tested a stopping rule based on the concept of capture-mark-recapture (CMR), which was first pioneered in ecology. The principles of CMR can be adapted to systematic reviews and meta-analyses to estimate the Horizon of articles in the literature with its confidence interval. We retrospectively tested this Horizon Estimation using a systematic review of randomized controlled trials (RCTs) that evaluated clinical decision support tools for osteoporosis disease management. The Horizon Estimation was calculated based on 4 bibliographic databases that were included as the main data sources for the review in the following order: MEDLINE, EMBASE, CINAHL, and EBM Reviews. The systematic review captured 68% of known articles from the 4 data sources, which represented 592 articles that were estimated as missing from the Horizon.


Cross-correlation beamforming.
An areal distribution of sensors can be used for estimating the direction of incoming waves through beamforming. Beamforming may be implemented as a phase-shifting and stacking of data recorded on the different sensors (i.e., conventional beamforming). Alternatively, beamforming can be applied to cross-correlations between the waveforms on the different sensors. We derive a kernel for beamforming cross-correlated data and call it cross-correlation beamforming (CCBF). We point out that CCBF has slightly better resolution and aliasing characteristics than conventional beamforming. When auto-correlations are added to CCBF, the array response functions are the same as for conventional beamforming. We show numerically that CCBF is more resilient to non-coherent noise. Furthermore, we illustrate that with CCBF individual receiver-pairs can be removed to improve mapping to the slowness domain. An additional flexibility of CCBF is that cross-correlations can be time-windowed prior to beamforming, e.g., to remove the directionality of a scattered wavefield. The observations on synthetic data are confirmed with field data from the SPITS array (Svalbard). Both when beamforming an earthquake arrival and when beamforming ambient noise, CCBF focuses more of the energy to a central beam. Overall, the main advantage of CCBF is noise suppression and its flexibility to remove station pairs that deteriorate the signal-related beampower. The online version of this article (doi:10.1007/s10950-016-9612-6) contains supplementary material, which is available to authorized users.


Overall water splitting by Pt/g-C3N4 photocatalysts without using sacrificial agents.
We report the direct splitting of pure water by light-excited graphitic carbon nitride (g-C3N4) modified with Pt, PtO x , and CoO x as redox cocatalysts, while pure g-C3N4 is virtually inactive for overall water splitting by photocatalysis. The novelty is in the selective creation of both H2 and O2 cocatalysts on surface active sites of g-C3N4via photodeposition triggering the splitting of water for the simultaneous evolution of H2 and O2 gases in a stoichiometric ratio of 2 : 1, irradiated with light, without using any sacrificial reagents. The photocatalyst was stable for 510 hours of reaction.


Ubiquitous expression of sevenless: position-dependent specification of cell fate.
Specification of cell fate in the compound eye of Drosophila appears to be controlled entirely by cell interactions. The sevenless gene is required for the correct determination of one of the eight photoreceptor cells (R7) in each ommatidium. It encodes a transmembrane protein with a tyrosine kinase domain and is expressed transiently on a subpopulation of ommatidial precursor cells including the R7 precursors. It is shown here that heat shock-induced indiscriminate expression of a sevenless complementary DNA throughout development can correctly specify R7 cell identity without affecting the development of other cells. Furthermore, discontinuous supply of sevenless protein during eye development leads to the formation of mosaic eyes containing stripes of sevenless+ and sevenless- ommatidia, suggesting that R7 cell fate can be specified only within a relatively short period during ommatidial assembly. These results support the hypothesis that the specification of cell fate by position depends on the interaction of a localized signal with a receptor present on many undifferentiated cells, and that the mere presence of the receptor alone is not sufficient to specify cell fate.


Importance of the Reactant-State Potentials of Chromium(V)-Oxo Complexes to Determine the Reactivity in Hydrogen-Atom Transfer Reactions.
A new chromium(V)-oxo complex, [CrV(O)(6-COO--py-tacn)]2+ (1; 6-COO--py-tacn = 1-(6-carboxylato-2-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane), was synthesized and characterized to evaluate the reactivity of CrV(O) complexes in a hydrogen-atom transfer (HAT) reaction by comparing it with that of a previously reported CrV(O) complex, [CrV(O)(6-COO--tpa)]2+ (2; 6-COO--tpa = N, N-bis(2-pyridylmethyl)- N-(6-carboxylato-2-pyridylmethyl)amine). Definitive differences of these two CrV(O) complexes were observed in resonance Raman scatterings of the Cr-O bond (ν = 911 cm-1 for 1 and 951 cm-1 for 2) and the reduction potential (0.73 V vs SCE for 1 and 1.23 V for 2); this difference should be derived from that of the ligand bound at the trans position to the oxo ligand, a tertiary amino group in 1, and a pyridine nitrogen in 2. When we employed 9,10-dihydroanthracene as a substrate, the second-order rate constant ( k) of 1 was 4000 times smaller than that of 2. Plots of normalized k values for both complexes relative to bond dissociation energies (BDEs) of C-H bonds to be cleaved in several substrates showed a pair of parallel lines with slopes of -0.91 for 1 and -0.62 for 2, indicating that the HAT reactions by the two complexes proceed via almost the same transition states. Judging from estimated BDEs of CrIV(OH)/CrV(O) (85-87 kcal mol-1 for 1 and 92-94 kcal mol-1 for 2) and the activation barrier in the HAT reaction of DHA ( Ea = 7.9 kcal mol-1 for 1 and Ea = 4.8 kcal mol-1 for 2), the reactivity of CrV(O) complexes in HAT reactions depends on the energy level of the reactant state rather than the product state.


Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma.
The phosphatidylinositol 3-kinase pathway is an important regulator of a wide spectrum of tumor-related biological processes, including cell proliferation, survival, and motility, as well as neovascularization. Protein kinase B/Akt is activated in a complex manner through the phosphorylation of protein kinase B/Akt on Thr308 and Ser473. Although protein-dependent kinase-1 has been shown to phosphorylate Akt at Thr308, it is not clear whether there is a distinct kinase that exclusively phosphorylates Akt at Ser473. A possible candidate is integrin-linked kinase (ILK), which has been shown to phosphorylate Akt at Ser473 in vitro. ILK is a multidomain focal adhesion protein that is believed to be involved in signal transmission from integrin and growth factor receptors. Further, ILK is implicated in the regulation of anchorage-dependent cell growth/survival, cell cycle progression, invasion and migration, and tumor angiogenesis. In this study, we tested the hypothesis that ILK inhibition would inhibit these processes in gliomas in which it is constitutively expressed. We found that a newly developed small-molecule compound (QLT0267) effectively inhibited signaling through the ILK/Akt cascade in glioma cells by blocking the phosphorylation of Akt and downstream targets, including mammalian target of rapamycin and glycogen synthase kinase-3beta. Treatment of glioma cells with 12.5 micromol/L QLT0267 inhibited cell growth by 50% at 48 hours. An anchorage-dependent cell growth assay confirmed the cell growth-inhibitory effect of QLT0267. Further, the decrease in cell growth was associated with a dramatic accumulation of cells in the G2-M phase of the cell cycle. Although the cell growth-inhibitory effects of the ILK inhibitor were achieved only at a high concentration, the QLT0267 was able to reduce cellular invasion and angiogenesis at much lower concentrations as shown by in vitro invasion assays and vascular endothelial growth factor secretion. Thus, blocking the ILK/Akt pathway is a potential strategy for molecular targeted therapy for gliomas.


Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging.
Although optical absorption is strongly associated with the physiological status of biological tissue, existing high-resolution optical imaging modalities, including confocal microscopy, two-photon microscopy and optical coherence tomography, do not sense optical absorption directly. Furthermore, optical scattering prevents these methods from imaging deeper than approximately 1 mm below the tissue surface. Here we report functional photoacoustic microscopy (fPAM), which provides multiwavelength imaging of optical absorption and permits high spatial resolution beyond this depth limit with a ratio of maximum imaging depth to depth resolution greater than 100. Reflection mode, rather than orthogonal or transmission mode, is adopted because it is applicable to more anatomical sites than the others. fPAM is demonstrated with in vivo imaging of angiogenesis, melanoma, hemoglobin oxygen saturation (sO2) of single vessels in animals and total hemoglobin concentration in humans.


The Hirschsprung's-multiple endocrine neoplasia connection.
The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2-Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease-medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both "switch off" and "switch on" of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET620 (the "Janus gene"). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a "hot spot". The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of "risk" by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.


A multi-stage stochastic programming approach to epidemic resource allocation with equity considerations.
Existing compartmental models in epidemiology are limited in terms of optimizing the resource allocation to control an epidemic outbreak under disease growth uncertainty. In this study, we address this core limitation by presenting a multi-stage stochastic programming compartmental model, which integrates the uncertain disease progression and resource allocation to control an infectious disease outbreak. The proposed multi-stage stochastic program involves various disease growth scenarios and optimizes the distribution of treatment centers and resources while minimizing the total expected number of new infections and funerals. We define two new equity metrics, namely infection and capacity equity, and explicitly consider equity for allocating treatment funds and facilities over multiple time stages. We also study the multi-stage value of the stochastic solution (VSS), which demonstrates the superiority of the proposed stochastic programming model over its deterministic counterpart. We apply the proposed formulation to control the Ebola Virus Disease (EVD) in Guinea, Sierra Leone, and Liberia of West Africa to determine the optimal and fair resource-allocation strategies. Our model balances the proportion of infections over all regions, even without including the infection equity or prevalence equity constraints. Model results also show that allocating treatment resources proportional to population is sub-optimal, and enforcing such a resource allocation policy might adversely impact the total number of infections and deaths, and thus resulting in a high cost that we have to pay for the fairness. Our multi-stage stochastic epidemic-logistics model is practical and can be adapted to control other infectious diseases in meta-populations and dynamically evolving situations.


Relation Between Insulin Sensitivity and Metabolic Abnormalities in Japanese Men With BMI of 23-25 kg/m2.
Although metabolic abnormalities are often developed in Asians with body mass index (BMI) of 23-25 kg/m2, the characteristics of the nonobese Asians with metabolic abnormality have not been fully understood. The aim of this study was to investigate the clinical significance of insulin sensitivity in Japanese men with BMI of 23-25 kg/m2. In this study, we defined hypertension, hyperglycemia, and dyslipidemia as cardiometabolic risk factors (CMRFs). We recruited subjects who met the following selection criteria: men with BMI of 21-23 kg/m2 and no CMRF (n = 24); men with BMI of 23-25 kg/m2 and no CMRF (n = 28), or one CMRF (n = 28), or at least two CMRFs (n = 14); and overweight men with metabolic syndrome (n = 20). Insulin sensitivity (IS) and ectopic fat content in muscle and liver were measured by two-step hyperinsulinemic-euglycemic clamp and 1H-magnetic resonance spectroscopy, respectively. Among subjects with BMI of 23-25 kg/m2, impaired IS in muscle, but not in liver, was found in those with even one CMRF, whereas impaired IS in both muscle and liver was observed in overweight men with metabolic syndrome. Liver fat accumulation and elevated liver enzymes were associated with impaired IS in both muscle and liver in those subjects. Among Japanese men with BMI of 23-25 kg/m2, muscle insulin resistance was present in those with even one CMRF. In this population, liver fat accumulation and/or elevated liver enzymes could be a good marker for impaired IS in both muscle and liver.


Novel designs and end points for phase II clinical trials.
The large number of negative phase III trials in oncology over the last several years has renewed interest in refining phase II oncology clinical trials to maximize the chances of success in phase III testing. More efficient phase II study designs will improve our ability to identify promising agents for testing while accurately identifying nonefficacious agents. Recognizing that new paradigms of phase II trial designs need to be developed, the Clinical Trial Design Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee has tackled the question of improving efficiency of phase II clinical trials. In this issue of CCR Focus, four of the major topics discussed are presented. First, the task force recommended that alternate phase II end points should be studied. Second, depending on the characteristics of the specific trial and study population, historical controls or a randomized design may be more appropriate. Third, rational incorporation of biomarkers into phase II trials should be encouraged. Last, novel imaging modalities will be critical in evaluating the clinical benefit of new cytostatic agents.


Breast cancer risk and exposure in early life to polycyclic aromatic hydrocarbons using total suspended particulates as a proxy measure.
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous in the environment. We hypothesized that early life exposure to PAHs may have particular importance in the etiology of breast cancer. We conducted a population-based, case-control study of ambient exposure to PAHs in early life in relation to the risk of breast cancer. Total suspended particulates (TSP), a measure of ambient air pollution, was used as a proxy for PAHs exposure. Cases (n = 1,166) were women with histologically confirmed, primary, incident breast cancer. Controls (n = 2,105) were frequency matched by age, race, and county of residence to cases. Annual average TSP concentrations (1959-1997) by location were obtained from the New York State Department of Environmental Conservation for Erie and Niagara Counties. Based on the monitor readings, prediction maps of TSP concentrations were generated with ArcGIS 8.0 (ESRI, Inc., Redlands, CA) using inverse distance squared weighted interpolation. Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals. In postmenopausal women, exposure to high concentrations of TSP (>140 microg/m(3)) at birth was associated with an adjusted odds ratio of 2.42 (95% confidence interval, 0.97-6.09) compared with exposure to low concentrations (<84 microg/m(3)). However, in premenopausal women, where exposures were generally lower, the results were inconsistent with our hypothesis and in some instances were suggestive of a reduction in the risk of breast cancer. Our study suggests that exposure in early life to high levels of PAHs may increase the risk of postmenopausal breast cancer; however, other confounders related to geography cannot be ruled out.


Nonlinear Hebbian Learning as a Unifying Principle in Receptive Field Formation.
The development of sensory receptive fields has been modeled in the past by a variety of models including normative models such as sparse coding or independent component analysis and bottom-up models such as spike-timing dependent plasticity or the Bienenstock-Cooper-Munro model of synaptic plasticity. Here we show that the above variety of approaches can all be unified into a single common principle, namely nonlinear Hebbian learning. When nonlinear Hebbian learning is applied to natural images, receptive field shapes were strongly constrained by the input statistics and preprocessing, but exhibited only modest variation across different choices of nonlinearities in neuron models or synaptic plasticity rules. Neither overcompleteness nor sparse network activity are necessary for the development of localized receptive fields. The analysis of alternative sensory modalities such as auditory models or V2 development lead to the same conclusions. In all examples, receptive fields can be predicted a priori by reformulating an abstract model as nonlinear Hebbian learning. Thus nonlinear Hebbian learning and natural statistics can account for many aspects of receptive field formation across models and sensory modalities.


Brief mindfulness meditation improves mental state attribution and empathizing.
The ability to infer and understand the mental states of others (i.e., Theory of Mind) is a cornerstone of human interaction. While considerable efforts have focused on explicating when, why and for whom this fundamental psychological ability can go awry, considerably less is known about factors that may enhance theory of mind. Accordingly, the current study explored the possibility that mindfulness-based meditation may improve people's mindreading skills. Following a 5-minute mindfulness induction, participants with no prior meditation experience completed tests that assessed mindreading and empathic understanding. The results revealed that brief mindfulness meditation enhanced both mental state attribution and empathic concern, compared to participants in the control group. These findings suggest that mindfulness may be a powerful technique for facilitating core aspects of social-cognitive functioning.


Comparison in the Management of Respiratory Failure due to Bronchiolitis in a Pediatric ICU Between 2010 and 2016.
In recent years, respiratory support in severe bronchiolitis has changed in several aspects: increased use of noninvasive ventilation, new equipment, and implementation of high-flow nasal cannula therapy. To analyze the effectiveness of the changes progressively introduced in the respiratory support of patients with bronchiolitis to reduce the intubation rate. This was a retrospective, observational, descriptive study. Patients admitted to the pediatric ICU of Hospital Sant Joan de Déu (Barcelona, Spain) with respiratory failure due to bronchiolitis in the 2010-2011 and 2016-2017 periods were included. Exclusion criteria were the following: patients who were previously intubated and tracheostomized and patients > 1 y. Data collected were demographic, clinical, and ventilatory variables, including the type, equipment used, and length of the respiratory support received. A total of 161 subjects were included: 53 in the 2010-2011 period and 108 in the 2016-2017 period. No clinical differences were observed except the incidence of previous apnea, a diagnosis of sepsis, and procalcitonin values on admission that were higher in the first period. High-flow nasal cannula use before pediatric ICU admission was significantly higher in 2016-2017. A significant increase in the use of the total face mask was observed. The need for invasive ventilation decreased from 37.7% to 17.5%. In the multivariate study, use of interfaces other than the total face mask was identified as the only independent predictive factor for noninvasive ventilation failure, with an odds ratio of 2.5, 95% CI 1.04-6.2 (P = .040). An important reduction in invasive ventilation was observed. An independent predictive factor for noninvasive ventilation failure was in using an interface other than the total face mask. Implementation of high-flow nasal cannula has not been identified as an independent protective factor for intubation.


Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window.
We examined the neuroprotective efficacy of moderate-dose human albumin therapy in acute focal ischemic stroke and defined the therapeutic window after stroke onset, within which this therapy would confer neurobehavioral and histopathological neuroprotection. Sprague-Dawley rats were anesthetized with halothane/nitrous oxide and received 2-hour middle cerebral artery occlusion (MCAo) by a poly-L-lysine-coated intraluminal suture. Neurological status was evaluated during occlusion (60 minutes) and daily for 3 days after MCAo. In the dose-response study, human albumin doses of either of 0.63 or 1.25 g/kg or saline vehicle (5 mL/kg) were given intravenously immediately after suture removal. In the therapeutic window study, a human albumin dose of 1.25 g/kg was administered intravenously at 2 hours, 3 hours, 4 hours, or 5 hours after onset of MCAo. Three days after MCAo, brains were perfusion-fixed, and infarct volumes and brain swelling were determined. Moderate-dose albumin therapy significantly improved the neurological score at 24 hours, 48 hours, and 72 hours and significantly reduced total infarct volume (by 67% and 58%, respectively, at the 1.25- and 0.63-g/kg doses). Cortical and striatal infarct volumes were also significantly reduced by both doses. Brain swelling was virtually eliminated by albumin treatment. Even when albumin therapy (1.25 g/kg) was initiated as late as 4 hours after onset of MCAo, it improved the neurological score and markedly reduced infarct volumes in cortex (by 68%), subcortical regions (by 52%), and total infarct (by 61%). Moderate-dose albumin therapy markedly improves neurological function and reduces infarction volume and brain swelling, even when treatment is delayed up to 4 hours after onset of ischemia.


Assembly mechanism of the contractile ring for cytokinesis by fission yeast.
Animals and fungi assemble a contractile ring of actin filaments and the motor protein myosin to separate into individual daughter cells during cytokinesis. We used fluorescence microscopy of live fission yeast cells to observe that membrane-bound nodes containing myosin were broadly distributed around the cell equator and assembled into a contractile ring through stochastic motions, after a meshwork of dynamic actin filaments appeared. Analysis of node motions and numerical simulations supported a mechanism whereby transient connections are established when myosins in one node capture and exert force on actin filaments growing from other nodes.


Dopamine Alters the Fidelity of Working Memory Representations according to Attentional Demands.
Capacity limitations in working memory (WM) necessitate the need to effectively control its contents. Here, we examined the effect of cabergoline, a dopamine D2 receptor agonist, on WM using a continuous report paradigm that allowed us to assess the fidelity with which items are stored. We assessed recall performance under three different gating conditions: remembering only one item, being cued to remember one target among distractors, and having to remember all items. Cabergoline had differential effects on recall performance according to whether distractors had to be ignored and whether mnemonic resources could be deployed exclusively to the target. Compared with placebo, cabergoline improved mnemonic performance when there were no distractors but significantly reduced performance when distractors were presented in a precue condition. No significant difference in performance was observed under cabergoline when all items had to be remembered. By applying a stochastic model of response selection, we established that the causes of drug-induced changes in performance were due to changes in the precision with which items were stored in WM. However, there was no change in the extent to which distractors were mistaken for targets. Thus, D2 agonism causes changes in the fidelity of mnemonic representations without altering interference between memoranda.


Impedance plethysmography. A noninvasive screening method to detect deep-vein thrombosis.
Impedance plethysmography (IPG) is a useful noninvasive detection of proximal segment thrombosis. Seven hundred patients treated with total hip arthroplasty were examined preoperatively and several times postoperatively using this technique. Twenty-one abnormal IPG results were obtained, and venography confirmed that 12 of these patients had proximal segment thrombi and five had evidence of calf thrombi. Four venograms were completely clear, demonstrating a false-positive rate of 1.3% (including calf thrombi). Six patients with normal IPG results had calf thrombi. All positive venograms indicating a thrombus in the proximal venous segment were indicated with a positive IPG result, giving a sensitivity of 100%. The standardization of the procedure involving constant leg elevation has assisted in the accuracy of this screening system.


Educational preparation for maternal, child and family health nurses in Australia.
The study aims to map and critique the current postgraduate educational nursing programmes offered to nurses and midwives in maternal, child and family health in Australia. Nursing specialties that focus on the early years of child health and development are based on international recognition of the developmental needs of the growing infant and of the social, health and economic consequences of failing to support families to raise their children in optimal environments. Little is known whether the educational programmes that prepare maternal, child and family health nurses (MCFHNs) for practice in Australia have kept up with new knowledge and understanding of the early years of life. A survey of all maternal, child and family health education programmes offered in Australia was undertaken. Marked variations in course titles, length, content, clinical exposure and award exist across the 12 institutions offering such programmes in Australia. Many institutions provide inadequate preparation in some of the core skills required of the workforce. The establishment of minimum standards for the education of MCFHNs across Australia is required. This study also highlights the need for further research around the scope of practice of MCFHNs, and the role of midwives who are not nurses, in this specialty area.


Active interaction switching controls the dynamic heterogeneity of soft colloidal dispersions.
We employ Reactive Dynamical Density Functional Theory (R-DDFT) and Reactive Brownian Dynamics (R-BD) simulations to investigate the dynamics of a suspension of active soft Gaussian colloids with binary interaction switching, i.e., a one-component colloidal system in which every particle stochastically switches at predefined rates between two interaction states with different mobility. Using R-DDFT we extend a theory previously developed to access the dynamics of inhomogeneous liquids [Archer et al., Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2007, 75, 040501] to study the influence of the switching activity on the self and distinct part of the Van Hove function in bulk solution, and determine the corresponding mean squared displacement of the switching particles. Our results demonstrate that, even though the average diffusion coefficient is not affected by the switching activity, it significantly modifies the non-equilibrium dynamics and diffusion coefficients of the individual particles, leading to a crossover from short to long times, with a regime for intermediate times showing anomalous diffusion. In addition, the self-part of the van Hove function has a Gaussian form at short and long times, but becomes non-Gaussian at intermediates ones, having a crossover between short and large displacements. The corresponding self-intermediate scattering function shows the two-step relaxation patters typically observed in soft materials with heterogeneous dynamics such as glasses and gels. We also introduce a phenomenological Continuous Time Random Walk (CTRW) theory to understand the heterogeneous diffusion of this system. R-DDFT results are in excellent agreement with R-BD simulations and the analytical predictions of CTRW theory, thus confirming that R-DDFT constitutes a powerful method to investigate not only the structure and phase behavior, but also the dynamical properties of non-equilibrium active switching colloidal suspensions.


A dominant bursting electromyograph pattern in dystonic conditions predicts an early response to pallidal stimulation.
Although chronic pallidal deep brain stimulation (DBS) is effective in the treatment of medically intractable dystonia, there is no way of predicting the variations in clinical outcome, partly due to our limited understanding of the pathophysiological mechanisms underlying this condition. We recorded electromyographic (EMG) activity from the most severely affected muscle groups in seven dystonia patients before and after pallidal DBS. Patient EMG recordings could be classified into two groups: one consisting of patients who at rest demonstrated a dominant low frequency component of activity on power spectral analysis (ranging from 2 to 5 Hz), and one group in which this dominant pattern was absent. Early postoperative improvements (within 2-3 days) were observed in the former group, whereas the latter group benefited more gradually (over several months). Analysis of EMG activity may provide a sensitive means of identifying dystonic patients who are likely to be most responsive to functional neurosurgical intervention.


The Sch9 protein kinase in the yeast Saccharomyces cerevisiae controls cAPK activity and is required for nitrogen activation of the fermentable-growth-medium-induced (FGM) pathway.
In cells of the yeast Saccharomyces cerevisiae, trehalase activation, repression of CTT1 (catalase), SSA3 (Hsp70) and other STRE-controlled genes, feedback inhibition of cAMP synthesis and to some extent induction of ribosomal protein genes is controlled by the Ras-adenylate cyclase pathway and by the fermentable-growth-medium-induced pathway (FGM pathway). When derepressed cells are shifted from a non-fermentable carbon source to glucose, the Ras-adenylate cyclase pathway is transiently activated while the FGM pathway triggers a more lasting activation of the same targets when the cells become glucose-repressed. Activation of the FGM pathway is not mediated by cAMP but requires catalytic activity of cAMP-dependent protein kinase (cAPK; Tpk1, 2 or 3). This study shows that elimination of Sch9, a protein kinase with homology to the catalytic subunits of cAPK, affects all target systems in derepressed cells in a way consistent with higher activity of cAPK in vivo. In vitro measurements with trehalase and kemptide as substrates confirmed that elimination of sch9 enhances cAPK activity about two- to threefold, in both the absence and presence of cAMP. In vivo it similarly affected the basal and final level but not the extent of the glucose-induced responses in derepressed cells. The reduction in growth rate caused by deletion of SCH9 is unlikely to be responsible for the increase in cAPK activity since reduction of growth rate generally leads to lower cAPK activity in yeast. On the other hand, deletion of SCH9 abolished the responses of the protein kinase A targets in glucose-repressed cells. Re-addition of nitrogen to cells starved for nitrogen in the presence of glucose failed to trigger activation of trehalase, caused strongly reduced and aberrant repression of CTT1 and SSA3, and failed to induce the upshift in RPL25 expression. From these results three conclusions can be drawn: (1) Sch9 either directly or indirectly reduces the activity of protein kinase A; (2) Sch9 is not required for glucose-induced activation of the Ras-adenylate cyclase pathway; and (3) Sch9 is required for nitrogen-induced activation of the FGM pathway. The latter indicates that Sch9 might be the target of the FGM pathway rather than cAPK itself.


Rating the certainty in evidence in the absence of a single estimate of effect.
When studies measure or report outcomes differently, it may not be feasible to pool data across studies to generate a single effect estimate (ie, perform meta-analysis). Instead, only a narrative summary of the effect across different studies might be available. Regardless of whether a single pooled effect estimate is generated or whether data are summarised narratively, decision makers need to know the certainty in the evidence in order to make informed decisions. In this guide, we illustrate how to apply the constructs of the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to assess the certainty in evidence when a meta-analysis has not been performed and data were summarised narratively.


Matting of scalp hair during shampooing--a new look.
We present a new case of irreversible hair matting, a rare, but important and alarming, acquired hair disorder. This case was investigated to test the causal hypothesis proposed in 1984. At the same time four other specimens of matted hair from patients and tangles from normal individuals were also examined. Light and electron microscopy showed dramatic permanent twisting and bending of the hairs through 180 degrees. There was marked variation in the fibre width of hairs from matted samples, with some longitudinally split along a considerable length. This bending and entanglement of hairs of varying widths (felting) seemed to be the main reason for the hairs becoming so dramatically knotted together in four of the cases. In only one case was there any evidence of a viscous fluid binding the hair together. This finding suggests that there may be two different mechanisms involved in hair matting.


"You Can't Just Walk Down the Street and Meet Someone": The Intersection of Social-Sexual Networking Technology, Stigma, and Health Among Gay and Bisexual Men in the Small City.
Social-sexual networking technologies have been reported to yield both psychosocial benefits and sexual risks for gay and bisexual men, yet little research has explored how technology interacts with the social-geographical environment to shape the health of gay and bisexual men in the relatively understudied environment of small cities. This article draws on 29 semistructured interviews examining the use of social-sexual networking technologies among racially diverse gay and bisexual men in two small cities. Questions probed participants' use of technology to meet sexual partners, engagement in the gay community, and the role of virtual and nonvirtual spaces in relation to health. Findings suggest that social networking technologies can help men navigate the challenges of small cities, including small and insular gay communities, lack of dedicated gay spaces, and sexual minority stigma. However, participants also describe declines in gay community visibility and cohesion, which they attribute to technology use. The article concludes by discussing the intersections of virtual and physical space in small cities as sites for the production of health and illness.


Network dynamics for optimal compressive-sensing input-signal recovery.
By using compressive sensing (CS) theory, a broad class of static signals can be reconstructed through a sequence of very few measurements in the framework of a linear system. For networks with nonlinear and time-evolving dynamics, is it similarly possible to recover an unknown input signal from only a small number of network output measurements? We address this question for pulse-coupled networks and investigate the network dynamics necessary for successful input signal recovery. Determining the specific network characteristics that correspond to a minimal input reconstruction error, we are able to achieve high-quality signal reconstructions with few measurements of network output. Using various measures to characterize dynamical properties of network output, we determine that networks with highly variable and aperiodic output can successfully encode network input information with high fidelity and achieve the most accurate CS input reconstructions. For time-varying inputs, we also find that high-quality reconstructions are achievable by measuring network output over a relatively short time window. Even when network inputs change with time, the same optimal choice of network characteristics and corresponding dynamics apply as in the case of static inputs.


Interspecies and Intrastrain Interplay among Leishmania spp. Parasites.
Leishmania parasites present astonishing adaptative abilities that represent a matter of life or death within disparate environments during the heteroxenous parasite life cycle. From an evolutionary perspective, organisms develop methods of overcoming such challenges. Strategies that extend beyond the genetic diversity have been discussed and include variability between parasite cells during the infections of their hosts. The occurrence of Leishmania subpopulation fluctuations with variable structural genomic contents demonstrates that a single strain might shelter the variability required to overcome inconsistent environments. Such intrastrain variability provides parasites with an extraordinary ability to adapt and thus survive and propagate. However, different perspectives on this evolution have been proposed. Strains or species living in the same environment can cooperate but also compete. These interactions might increase the replication rate of some parasites but cause the loss of more aggressive competitors for others. Adaptive responses to intra- and interspecific competition can evolve as a fixed strategy (replication is adapted to the average genetic complexity of infections) or an optional strategy (replication varies according to the genetic complexity of the current infection). This review highlights the complexity of interspecies and intrastrain interactions among Leishmania parasites as well as the different factors that influence this interplay.


Acute Effects of Energy Deficit Induced by Moderate-Intensity Exercise or Energy-Intake Restriction on Postprandial Lipemia in Healthy Girls.
Eleven healthy girls (mean ± SD: age 12.1 ± 0.6 years) completed three 2-day conditions in a counterbalanced, crossover design. On day 1, participants either walked at 60 (2)% peak oxygen uptake (energy deficit 1.55[0.20] MJ), restricted food energy intake (energy deficit 1.51[0.25] MJ) or rested. On day 2, capillary blood samples were taken at predetermined intervals throughout the 6.5 hr postprandial period before, and following, the ingestion of standardized breakfast and lunch meals. Fasting plasma triacylglycerol concentrations (TAG) was 29% and 13% lower than rest control in moderate-intensity exercise (effect size [ES] = 1.39, p = .01) and energy-intake restriction (ES = 0.57, p = .02) respectively; moderate-intensity exercise was 19% lower than energy-intake restriction (ES = 0.82, p = .06). The moderate-intensity exercise total area under the TAG versus time curve was 21% and 13% lower than rest control (ES = 0.71, p = .004) and energy-intake restriction (ES = 0.39, p = .06) respectively; energy-intake restriction was marginally lower than rest control (-10%; ES = 0.32, p = .12). An exercise-induced energy deficit elicited a greater reduction in fasting plasma TAG with a trend for a larger attenuation in postprandial plasma TAG than an isoenergetic diet-induced energy deficit in healthy girls.


Efficacy of paced breathing for insomnia: enhances vagal activity and improves sleep quality.
Fourteen self-reported insomniacs (SRI) and 14 good sleepers (GS) had their cardiac neuronal activity assessed by heart rate variability (HRV) under controlled respiration at a slow frequency rate of 0.1 Hz, and a forced rate of 0.2 Hz during daytime rest. Nighttime sleep was measured by polysomnography. The SRI showed depressed high frequency power of HRV compared to the GS. An increased total power of HRV was observed among the SRI during slow, paced breathing compared with spontaneous breathing and 0.2 Hz. Sleep onset latency, number of awakenings, and awakening time during sleep were decreased and sleep efficiency was increased if SRI practiced slow, paced breathing exercises for 20 min before going to sleep. Our results indicate that there is autonomic dysfunction among insomniacs, especially in relation to vagal activity; however, this decreased vagal activity can be facilitated by practicing slow, paced breathing, thereby improving sleep quality.


Back pain in patients with degenerative spine disease and intradural spinal tumor: what to treat? when to treat?
Back pain is common in industrialized countries and one of the most frequent causes of work incapacity. Successful treatment is, therefore, not only important for improving the symptoms and the quality of life of these patients but also for socioeconomic reasons. Back pain is frequently caused by degenerative spine disease. Intradural spinal tumors are rare with an annual incidence of 2-4/1,00,000 and are mostly associated with neurological deficits and radicular and nocturnal pain. Back pain is not commonly described as a concomitant symptom, such that in patients with both a tumor and degenerative spine disease, any back pain is typically attributed to the degeneration rather than the tumor. The aim of the present retrospective investigation was to study and analyze the impact of microsurgery on back/neck pain in patients with intradural spinal tumor in the presence of degenerative spinal disease in adjacent spinal segments. Fifty-eight consecutive patients underwent microsurgical, intradural tumor surgery using a standardized protocol assisted by multimodal intraoperative neuromonitoring. Clinical symptoms, complications and surgery characteristics were documented. Standardized questionnaires were used to measure outcome from the surgeon's and the patient's perspectives (Spine Tango Registry and Core Outcome Measures Index). Follow-up included clinical and neuroradiological examinations 6 weeks, 3 months and 1 year postoperatively. Back/neck pain as a leading symptom and coexisting degenerative spine disease was present in 27/58 (47 %) of the tumor patients, and these comprised to group under study. Patients underwent tumor surgery only, without addressing the degenerative spinal disease. Remission rate after tumor removal was 85 %. There were no major surgical complications. Back/neck pain as the leading symptom was eradicated in 67 % of patients. There were 7 % of patients who required further invasive therapy for their degenerative spinal disease. Intradural spinal tumor surgery improves back/neck pain in patients with coexisting severe degenerative spinal disease. Intradural spinal tumors seem to be the only cause of back/neck pain more often than appreciated. In these patients suffering from both pathologies, there is a higher risk of surgical overtreatment than undertreatment. Therefore, elaborate clinical and radiological examinations should be performed preoperatively and the indication for stabilization/fusion should be discussed carefully in patients foreseen for first time intradural tumor surgery.


Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells.
Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. This seminal work was followed by numerous studies reporting alternative (noninsertional) reprogramming methods and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency. Here we report that inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition, the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. We further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin), and an activating adenosine monophosphate-activated protein kinase activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. Our results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity based on the regulation of cellular reprogramming.


Sr-fresnoite determined from synchrotron X-ray powder diffraction data.
The fresnoite-type compound Sr2TiO(Si2O7), distrontium oxidotitanium disilicate, has been prepared by high-temperature solid-state synthesis. The results of a Rietveld refinement study, based on high-resolution synchrotron X-ray powder diffraction data, show that the title compound crystallizes in the space group P4bm and adopts the structure of other fresnoite-type mineral samples with general formula A2 TiO(Si2O7) (A = alkaline earth metal cation). The structure consists of titanosilicate layers composed of corner-sharing SiO4 tetra-hedra (forming Si2O7 disilicate units) and TiO5 square-based pyramids. These layers extend parallel to the ab plane and are stacked along the c axis. Layers of distorted SrO6 octa-hedra lie between the titanosilicate layers. The Sr(2+) ion, the SiO4 tetra-hedron and the bridging O atom of the disilicate unit are located on mirror planes whereas the TiO5 square-based pyramid is located on a fourfold rotation axis.


Irsogladine activates gap-junctional intercellular communication through M1 muscarinic acetylcholine receptor.
Irsogladine, an agent that protects gastric mucosa against various ulcerogenic stimuli through increasing cyclic AMP in surface mucous cells, has been reported to dose-dependently (10(-7) to 10(-5) M) facilitate gap-junctional intercellular communication (GJIC) in gastric epithelial cells. The beta adrenergic agonist, isoproterenol, stimulates GJIC in resting cells and inhibits GJIC in cells activated by 3-isobutyl-1-methylxanthine. In this study, we investigated whether irsogladine acts on GJIC in a manner similar to that shown by isoproterenol. Irsogladine, which bound to M1 muscarinic acetylcholine receptors (mAChR), did not inhibit, but failed to further facilitate the 3-isobutyl-1-methylxanthine-enhanced GJIC, measured by Lucifer yellow transfer. The enhancement of GJIC by irsogladine was inhibited by the M1 mAChR antagonist, pirenzepine. A selective M1 mAChR agonist, McN-A-343, enhanced GJIC. Isoproterenol (10(-8) to 10(-6) M), which alone did not affect GJIC, inhibited the GJIC enhanced by 10(-5) M irsogladine. Conversely, 10(-10) to 10(-6) M irsogladine, which alone did not affect GJIC, inhibited the GJIC enhanced by 10(-5) M isoproterenol. McN-A-343 also converted the action of 10(-5) M isoproterenol from facilitation to inhibition of GJIC. These results indicate that GJIC is heterologously down-regulated by cross-talk between M1 mAChR and beta adrenergic receptors. In addition, the effects of irsogladine and isoproterenol at low concentrations suggest the involvement of another mechanism for down-regulating GJIC.


The impact of electronic health record (EHR) interoperability on immunization information system (IIS) data quality.
Objectives: To evaluate the impact of electronic health record (EHR) interoperability on the quality of immunization data in the North Dakota Immunization Information System (NDIIS). Methods: NDIIS doses administered data was evaluated for completeness of the patient and dose-level core data elements for records that belong to interoperable and non-interoperable providers. Data was compared at three months prior to electronic health record (EHR) interoperability enhancement to data at three, six, nine and twelve months post-enhancement following the interoperability go live date. Doses administered per month and by age group, timeliness of vaccine entry and the number of duplicate clients added to the NDIIS was also compared, in addition to, immunization rates for children 19 - 35 months of age and adolescents 11 - 18 years of age. Results: Doses administered by both interoperable and non-interoperable providers remained fairly consistent from pre-enhancement through twelve months post-enhancement. Comparing immunization rates for infants and adolescents, interoperable providers had higher rates both pre- and post-enhancement than non-interoperable providers for all vaccines and vaccine series assessed. The overall percentage of doses entered into the NDIIS within one month of administration varied slightly between interoperable and non-interoperable providers; however, there were significant changes between the percentage of doses entered within one day and within one week with the percentage entered within one day increasing and within one week decreasing with interoperability. The number of duplicate client records created by interoperable providers increased from 94 duplicates pre-enhancement to 10,552 at twelve months post-enhancement, while the duplicates from non-interoperable providers only increased from 300 to 637 over the same period. Of the 40 core data elements in the NDIIS, there was some difference in completeness between the interoperable versus non-interoperable providers. Only middle name, sex, county, phone number, mother's maiden name, vaccine manufacturer, lot number and expiration date were significantly (>=5%) different between the two provider groups. Conclusions: Interoperability with provider EHRs has had an impact on NDIIS data quality. Timeliness of data entry has improved and overall doses administered have remained fairly consistent, as have the immunization rates for the providers assessed. There are more technical and non-technical interventions that will need to be accomplished by NDIIS staff and vendor to help reduce the negative impact of duplicate record creation, as well as, data completeness.


The Impact of Pharmacist Interventions on Quality Use of Medicines, Quality of Life, and Health Outcomes in People with Dementia and/or Cognitive Impairment: A Systematic Review.
Medication use in people with dementia and/or cognitive impairment (PWD/CI) is challenging. As medication experts, pharmacists have an important role in improving care of this vulnerable population. Systematically review evidence for the effectiveness of pharmacist-led interventions on quality use of medicines, quality of life, and health outcomes of PWD/CI. A systematic review was conducted using MEDLINE, EMBASE, PsycINFO, Allied and Complementary Medicine (AMED) and Cumulative index to Nursing and Allied Health Literature (CINAHL) databases from conception to 20 March 2017. Full articles published in English were included. Data were synthesized using a narrative approach. Nine studies were eligible for inclusion. All studies were from high-income countries and assessed pharmacist-led medication management services. There was great variability in the content and focus of services described and outcomes reported. Pharmacists were found to provide a number of cognitive services including medication reconciliation, medication review, and medication adherence services. These services were generally effective with regards to improving quality use of medicines and health outcomes for PWD/CI and their caregivers, and for saving costs to the healthcare system. Pharmacist-led medication and dementia consultation services may also improve caregiver understanding of dementia and the different aspects of pharmacotherapy, thus improving medication adherence. Emerging evidence suggests that pharmacist-led medication management services for PWD/CI may improve outcomes. Future research should confirm these findings using more robust study designs and explore additional roles that pharmacists could undertake in the pursuit of supporting PWD/CI.


Enhancing Primary School Children's Knowledge of Online Safety and Risks with the CATZ Cooperative Cross-Age Teaching Intervention: Results from a Pilot Study.
Children are heavy users of the Internet and prior studies have shown that many of them lack a good understanding of the risks of doing so and how to avoid them. This study examined if the cross-age teaching zone (CATZ) intervention could help children acquire important knowledge of online risks and safety. It allowed older students to act as CATZ tutors to design and deliver a lesson to younger schoolmates (tutees), using content material about online risks and safety provided by adults. Students in Year 6 (mean age = 11.5 years) were randomly assigned to act as either CATZ tutors (n = 100) or age-matched controls (n = 46) and students in Year 4 (mean age = 9.5 years) acted as either CATZ tutees (n = 117) or age-matched controls (n = 28) (total N = 291). CATZ tutors, but not matched controls scored significantly higher on objective measures of knowledge of both online risks and safety, and CATZ tutees, but not matched controls did so for online safety. Effect sizes were moderate or large. CATZ was highly acceptable to participants. The results suggest that CATZ is a viable way to help school students learn about online dangers and how to avoid them.


Pediatric brain injuries: the nature, clinical course, and early outcomes in a defined United States' population.
Acute brain injury is the cause of approximately 100,000 pediatric hospital admissions per year in the United States. This report examines the nature of the brain injury, clinical diagnosis, hospital course, and discharge outcome of all pediatric cases in the population of San Diego County, California, for 1981 (N = 709). Brain-injured children were identified from hospital records, death certificates, and coroners' records. Severity of injury was determined using the Abbreviated Injury Scale and the Glasgow Coma Scale. Three percent of brain-injured children died at the accident site; an additional 3% died in the hospital. All in-hospital deaths occurred among the 5% of children with Glascow Coma Scale scores of 8 or less, and in this group the case fatality rate was 59%. Fractures of the skull, present in 23% of cases, seemed to be associated with excess mortality even after type of lesion was considered. Type of lesion, but not presence or absence of a skull fracture, had some predictive power for disability among survivors. Concussion was the most frequent diagnosis. Mildly brain-injured children accounted for 93% of all cases and about 90% of all hospital days.


Hazard and mode of action of disinfection by-products (DBPs) in water for human consumption: Evidences and research priorities.
Disinfection of water system is an essential strategy to protect human health from pathogens and prevent their regrowth during water distribution, but the reaction of disinfectant agents with organic matter can lead to the formation of disinfection by-products (DBPs). Given their widespread occurrence, potential human health impacts and (eco)toxicity associated with exposure to DBPs are of particular interest due to their potential carcinogenicity and vary non-carcinogenic effects, such as endocrine disruption. Understanding the public health implications of this emerging issue is crucial for societies and decision-makers, supporting more effective water safety plans. Here, we review the recent literature on the effects of DBPs presented in drinking water and treated swimming pools water, focusing particularly in unregulated compounds and the putative underlying mode of action, linking the available data with adverse health outcomes. Overall, the majority of studies highlight the limited knowledge in the understanding of the underlying mode of action of DBPs. Yet, available evidences indicate that different signaling pathways seem to be involved in the adverse outcomes associated with distinct DBPs classes. The main knowledge gaps in this field are also identified, and future research priorities discussed.


Factors associated with the implementation of quality and safety requirements for cross-border care in acute myocardial infarction: Results from 315 hospitals in four countries.
Cross-border patients have specific quality and safety requirements for hospital care. Little is known to what extent hospitals meet these requirements. We aim to assess their current level, and the factors associated with their implementation. A cross-sectional survey of 315 hospitals and cardiology departments in the Czech Republic, France, Poland and Spain. Employing bi-variate statistics and logistic regression analysis, we assess quality and safety requirements for cross-border patients and their association with hospital characteristics, cross-border care arrangements, proximity to EU borders, the hospital's quality improvement system, and country. Certain quality and safety requirements are frequently met (administrative support or informed consent using forms in various EU languages) while others are widely absent (case-managers, contacts to patients' general practitioners). Due to communication problems, it is often not possible to inform patients about their condition and treatment. Discharge summaries are rarely available in other than the vernacular languages, and medication upon discharge and arranging back-transfer occur occasionally only. Logistic regression analysis suggests a strong effect of country-level covariates (followed by type of hospital, hospital size and hospital's quality improvement system), but covariates are not consistently associated with higher rates of implementation. Hospitals with existing cross-border care collaboration do not differ substantially from hospitals without such arrangements. Cross-border patients have specific quality and safety requirements that are not always met. Various factors are associated with these requirements; however, the trend is not systematic and the underlying mechanisms need to be studied further to inform policy decisions.


Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy.
Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt-/-mice, the glomerular hypertrophy and albuminuria in Pemt-/- mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt-/- diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.


Guidelines for management of idiopathic normal pressure hydrocephalus: second edition.
Among the various disorders manifesting dementia, gait disturbance, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. After the publication of the first edition of the Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus in 2004 (the English version was published in 2008), clinical awareness of iNPH has risen dramatically, and the number of shunt surgeries has increased rapidly across Japan. Clinical and basic research on iNPH has increased significantly, and more high-level evidence has since been generated. The second edition of the Japanese Guidelines was thus published in July 2011, to provide a series of timely evidence-based recommendations related to iNPH. The revision of the Guidelines has been undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project on "Studies on the epidemiology, pathophysiology, and treatment of normal pressure hydrocephalus." This English version of the second edition of the Guidelines was made to share these ideas with the international community and to promote international research on iNPH.


Mixed-methods evaluation of a telehealth collaborative care program for persons with HIV infection in a rural setting.
Delivery of comprehensive care for persons with human immunodeficiency virus (HIV) infection in rural and low prevalence settings presents many challenges. We developed and evaluated a telehealth collaborative care (TCC) program for persons with HIV in a rural area. To determine the feasibility of TCC, and identify factors influencing implementation in rural settings. Mixed methods evaluation of a quality improvement program with pre-measures and post-measures. Veterans with HIV infection in Iowa and Illinois. TCC integrated HIV specialty care delivered by clinical video telehealth, with primary care delivered by generalist providers, in seven Community Based Outpatient Clinics (CBOCs) serving rural areas. Principles guiding TCC design were: 1) clear delineation of specialty and primary care clinic roles in co-managed care; 2) creation of processes to improve care coordination between specialty and primary care teams; and 3) use of a patient registry for population management across sites. Veterans Affairs (VA) healthcare system performance measures for care for HIV infection and common comorbidities, patient travel time to obtain care, and patient satisfaction. Qualitative evaluation involved semi-structured telephone interviews with patients. Thirty of 32 eligible patients chose TCC over traveling to the HIV clinic for all care. Among 24 patients in TCC during the June 2011-May 2012 evaluation period, median age was 54 (range, 40-79), most (96 %) were men, and median CD4 count was 707 cells/cm(3) (range, 233-1307). VA performance measures were met for > 90 % of TCC patients. Median yearly travel time decreased from 320 min per patient prior to TCC to 170 min during TCC (p < 0.001). Interview themes included: 1) overcoming privacy concerns during care in local primary care clinics; 2) tradeoffs between access, continuity, and care coordination; and 3) the role of specialist involvement in collaborative care. Telehealth Collaborative Care is a feasible approach to providing accessible and comprehensive care for persons with HIV in rural settings.


Antioxidant, antimicrobial and antiproliferative activities of five lichen species.
The antioxidative, antimicrobial and antiproliferative potentials of the methanol extracts of the lichen species Parmelia sulcata, Flavoparmelia caperata, Evernia prunastri, Hypogymnia physodes and Cladonia foliacea were evaluated. The total phenolic content of the tested extracts varied from 78.12 to 141.59 mg of gallic acid equivalent (GA)/g of extract and the total flavonoid content from 20.14 to 44.43 mg of rutin equivalent (Ru)/g of extract. The antioxidant capacities of the lichen extracts were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals scavenging. Hypogymnia physodes with the highest phenolic content showed the strongest DPPH radical scavenging effect. Further, the antimicrobial potential of the lichen extracts was determined by a microdilution method on 29 microorganisms, including 15 strains of bacteria, 10 species of filamentous fungi and 4 yeast species. A high antimicrobial activity of all the tested extracts was observed with more potent inhibitory effects on the growth of Gram (+) bacteria. The highest antimicrobial activity among lichens was demonstrated by Hypogymnia physodes and Cladonia foliacea. Finally, the antiproliferative activity of the lichen extracts was explored on the colon cancer adenocarcinoma cell line HCT-116 by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) viability assay and acridine orange/ethidium bromide staining. The methanol extracts of Hypogymnia physodes and Cladonia foliacea showed a better cytotoxic activity than the other extracts. All lichen species showed the ability to induce apoptosis of HCT-116 cells.


A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas.
A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, clonogenicity, and induction of histone deacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma cell lines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion–mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets.


A data-driven approach for studying the role of body mass in multiple diseases: a phenome-wide registry-based case-control study in the UK Biobank.
Mendelian randomisation allows for the testing of causal effects in situations where clinical trials are challenging to do. In this hypothesis-free, data-driven phenome-wide association study (PheWAS), we sought to assess possible associations of high body-mass index (BMI) with multiple disease outcomes. For this registry-based case-control PheWAS, we used genome-wide data available from the UK Biobank to construct a genetic risk score of 76 variants related to BMI. Eligible UK Biobank participants were aged 37-73 years during recruitment, were white British, were unrelated to each other, and had available genetic information. Disease outcomes from these participants were mapped to a phenotype code (phecode). Participants with a phecode of interest were recoded as cases, whereas participants without a phecode of interest or any codes under a parent phecode were classified as controls. We did a PheWAS to analyse possible associations between the BMI genetic risk score and a range of disease outcomes. Disease associations passing stringent correction for multiple testing (Bonferroni corrected threshold p<5·4 × 10-5, false discovery rate corrected p<0·0074) were assessed for causal association with use of inverse-variance weighted mendelian randomisation. We did sensitivity analyses to assess pleiotropy and stability of estimation with use of weighted median, weighted mode, Egger regression, and mendelian randomisation pleiotropy residual sum and outlier methods. Our study population comprised 337 536 UK Biobank participants, and analyses were done for 925 unique phecodes from 17 different disease categories. After Bonferroni correction, PheWAS identified that BMI genetic risk score was associated with hospital-diagnosed obesity and 58 other outcomes; 30 distinct disease associations were supported by the mendelian randomisation analyses. 30 distinct disease associations were supported by the mendelian randomisation analyses. In inverse-variance weighted mendelian randomisation, genetically determined BMI was associated with endocrine disorders (odds ratio per one SD or 4·1 kg/m2 higher BMI 2·72, 95% CI 2·33-3·29 for type 2 diabetes; 2·11, 1·62-2·76 for type 1 diabetes; and 1·46, 1·25-1·70 for hypothyroidism), circulatory diseases (1·96, 1·53-2·51 for phlebitis and thrombophlebitis; 1·89, 1·39-2·57 for cardiomegaly; 1·68, 1·35-2·09 for congestive heart failure; 1·55, 1·37-1·76 for hypertension; 1·31, 1·13-1·52 for ischaemic heart disease; and 1·25, 1·14-1·37 for cardiac dysrhythmias), and inflammatory or dermatological conditions (2·00, 1·72-2·23 for superficial cellulitis and abscess; 3·37, 2·17-5·25 for chronic ulcers of leg and foot; 4·99, 2·54-9·82 for gangrene; and 2·24, 1·53-3·28 for atopy). Mendelian randomisation analyses provided further support for a causal effect of BMI on renal failure, osteoarthrosis, neurological (insomnia and peripheral nerve disorders) and respiratory diseases (asthma and chronic bronchitis), structural problems (hernias and knee derangement), and chemotherapy treatment. Mendelian randomisation with Egger regression produced consistently wider CIs compared with those of other methods. 26 of 72 distinct diseases detected under false discovery rate correction produced consistent estimates across at least four mendelian randomisation methods, and consistent evidence across all five approaches was obtained for 14 diseases. Our data-driven approach identified a range of diseases as possibly affected by high BMI. This population-level screening approximated the accumulated consequences of high BMI, whereas the true effects might be more complex and vary by life stage. Our results highlight the importance of obesity prevention and effective management of obesity-related comorbidities. National Health and Medical Research Council of Australia.


What is the perceived impact of Alexander technique lessons on health status, costs and pain management in the real life setting of an English hospital? The results of a mixed methods evaluation of an Alexander technique service for those with chronic back pain.
Randomised controlled trial evidence indicates that Alexander Technique is clinically and cost effective for chronic back pain. The aim of this mixed methods evaluation was to explore the role and perceived impact of Alexander Technique lessons in the naturalistic setting of an acute hospital Pain Management Clinic in England. To capture changes in health status and resource use amongst service users, 43 service users were administered three widely used questionnaires (Brief Pain Inventory, MYMOP and Client Service Resource Inventory) at three time points: baseline, six weeks and three months after baseline. We also carried out 27 telephone interviews with service users and seven face-to-face interviews with pain clinic staff and Alexander Technique teachers. Quantitative data were analysed using descriptive statistics and qualitative data were analysed thematically. Those taking Alexander Technique lessons reported small improvements in health outcomes, and condition-related costs fell. However, due to the non-randomised, uncontrolled nature of the study design, changes cannot be attributed to the Alexander Technique lessons. Service users stated that their relationship to pain and pain management had changed, especially those who were more committed to practising the techniques regularly. These changes may explain the reported reduction in pain-related service use and the corresponding lower associated costs. Alexander Technique lessons may be used as another approach to pain management. The findings suggests that Alexander Technique lessons can help improve self-efficacy for those who are sufficiently motivated, which in turn may have an impact on service utilisation levels.


Philip Harker Newman (1911-1994): Dunkirk hero, war psychologist and orthopaedic surgeon to Sir Winston Churchill.
Philip Harker Newman an orthopaedic surgeon and a major in the Royal Army Medical Corps was left behind to man a casualty clearing station during the evacuation of Dunkrik in 1940. Newman was made a Prisoner of War and studied the adverse psychological effects of incarceration on his fellow officers. He escaped from Germany eventually returning to Europe for its liberation in 1944. He was awarded the Distinguished Service Order and Military Cross for his bravery. In 1946, Philip Newman was appointed consultant orthopaedic surgeon to The Middlesex Hospital and The Royal National orthopaedic Hospital, London. He became an internationally recognised authority on the management of spinal conditions including spondylolisthesis. In 1962, he operated with Sir Herbert Seddon (1903-1977) on Sir Winston Churchill who had sustained a fractured neck of femur following a fall in the South of France. Newman became President of The British Orthopaedic Association in 1976 and chairman of the Editorial Board of The Journal of Bone and Joint Surgery. In 1976, he was also awarded a CBE and wrote his wartime memoirs, Safer than a Known Way published in 1983.


Telomere length control and transcriptional regulation of subtelomeric adhesins in Candida glabrata.
The pathogenic yeast Candida glabrata is able to bind in vitro to human epithelial cells. This interaction depends on expression of the adhesin Epa1p. The genome contains a number of EPA1 paralogues which localize to the subtelomeric regions of the C. glabrata. We have identified three hyperadherent mutants of C. glabrata. The first has an insertion adjacent to EPA7, an EPA1-related adhesin. The others disrupt the SIR3 and RIF1 genes of C. glabrata. We show that SIR3 and RIF1 are required for subtelomeric silencing in C. glabrata and that RIF1 regulates telomere length in C. glabrata. We show that the hyperadherent phenotype of the sir3Delta and rif1Delta deletion strains depends primarily on derepression of two novel members of the EPA gene family -EPA6 and EPA7. The sir3Delta and rif1Delta mutants show increased colonization of the kidney in a murine model of disseminated infection and this hypercolonization depends, at least in part, on derepression of EPA6 and EPA7. The analysis here is the first evidence that multiple EPA genes encode adhesins and demonstrates that transcription of at least two of these adhesins is regulated by subtelomeric silencing.


Amino acid architecture that influences dNTP insertion efficiency in Y-family DNA polymerase V of E. coli.
Y-family DNA polymerases (DNAPs) are often required in cells to synthesize past DNA-containing lesions, such as [+ta]-B[a]P-N(2)-dG, which is the major adduct of the potent mutagen/carcinogen benzo[a]pyrene. The current model for the non-mutagenic pathway in Escherichia coli involves DNAP IV inserting deoxycytidine triphosphate opposite [+ta]-B[a]P-N(2)-dG and DNAP V doing the next step(s), extension. We are investigating what structural differences in these related Y-family DNAPs dictate their functional differences. X-ray structures of Y-family DNAPs reveal a number of interesting features in the vicinity of the active site, including (1) the "roof-amino acid" (roof-aa), which is the amino acid that lies above the nucleobase of the deoxynucleotide triphosphate (dNTP) and is expected to play a role in dNTP insertion efficiency, and (2) a cluster of three amino acids, including the roof-aa, which anchors the base of a loop, whose detailed structure dictates several important mechanistic functions. Since no X-ray structures existed for UmuC (the polymerase subunit of DNAP V) or DNAP IV, we previously built molecular models. Herein, we test the accuracy of our UmuC(V) model by investigating how amino acid replacement mutants affect lesion bypass efficiency. A ssM13 vector containing a single [+ta]-B[a]P-N(2)-dG is transformed into E. coli carrying mutations at I38, which is the roof-aa in our UmuC(V) model, and output progeny vector yield is monitored as a measure of the relative efficiency of the non-mutagenic pathway. Findings show that (1) the roof-aa is almost certainly I38, whose beta-carbon branching R-group is key for optimal activity, and (2) I38/A39/V29 form a hydrophobic cluster that anchors an important mechanistic loop, aa29-39. In addition, bypass efficiency is significantly lower both for the I38A mutation of the roof-aa and for the adjacent A39T mutation; however, the I38A/A39T double mutant is almost as active as wild-type UmuC(V), which probably reflects the following. Y-family DNAPs fall into several classes with respect to the [roof-aa/next amino acid]: one class has [isoleucine/alanine] and includes UmuC(V) and DNAP eta (from many species), while the second class has [alanine (or serine)/threonine] and includes DNAP IV, DNAP kappa (from many species), and Dpo4. Thus, the high activity of the I38A/A39T double mutant probably arises because UmuC(V) was converted from the V/eta class to the IV/kappa class with respect to the [roof-aa/next amino acid]. Structural and mechanistic aspects of these two classes of Y-family DNAPs are discussed.


Baseline characteristics and patterns of care in testicular cancer patients: first data from the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS).
The majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations. The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment. Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 2.5¬‒5.0 and 2.3‒4.5 in seminoma and non-seminoma, respectively) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21 (19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Eleven patients did not receive therapy that conformed with guidelines. It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures. NCT02229916 (Clinicaltrials.gov).


Probability characteristics of nonlinear dynamical systems driven by δ-pulse noise.
For a nonlinear dynamical system described by the first-order differential equation with Poisson white noise having exponentially distributed amplitudes of δ pulses, some exact results for the stationary probability density function are derived from the Kolmogorov-Feller equation using the inverse differential operator. Specifically, we examine the "effect of normalization" of non-Gaussian noise by a linear system and the steady-state probability density function of particle velocity in the medium with Coulomb friction. Next, the general formulas for the probability distribution of the system perturbed by a non-Poisson δ-pulse train are derived using an analysis of system trajectories between stimuli. As an example, overdamped particle motion in the bistable quadratic-cubic potential under the action of the periodic δ-pulse train is analyzed in detail. The probability density function and the mean value of the particle position together with average characteristics of the first switching time from one stable state to another are found in the framework of the fast relaxation approximation.


[Comparison [corrected] of Chiari I malformation treatment using suboccipital craniectomy and posterior arch of C1 resection with or without dural graft].
There are various surgical approaches to treat Chiari I malformation. In spite of the good clinical results that are reported with most of them, there is still controversy about the optimal treatment of this pathology. To compare the clinical and radiological results of surgical treatment of the Chiari I malformation with suboccipital craniectomy, posterior arch of C1 resection with or without dural graft, analyzing clinical and radiological findings and describing the complications. Retrospectively clinical cases series of patients who underwent Chiari I malformation surgery between 1998 and 2006 in the Hospital Germans Trias i Pujol in Badalona. The inclusion criteria consisted in: patients older than 18 years, who have had surgery in our hospital, detailed neurological examination before and after surgery (calculating the EDSS scale punctuation), craniospinal magnetic resonance imaging before and after surgery and minimal follow up period of 6 months. The election of the surgical approach was left to the discretion of the main surgeon. Patients were divided in two groups depending of the surgical technique: Group A (with dural graft) and Group B (without dural graft). To evaluate the morphological results in both groups, measurements of the position of the fastigium above a basal line in the midsagittal T1 weighted magnetic resonance images were obtained. In patients with syringomyelia, siringo-to-cord ratio was measured before and after surgery. To evaluate the clinical results, neurological examination was recorded in both groups before and after surgery. The mean age of Group A patients was 47 (-/+12.89) years, and of Group B was 38.3 (-/+7.77) years. Mean follow up period was 2.48 (-/+2.44) years in Group A and 4.2 (-/+4.46) in Group B. Creation of an artificial cisterna magna was observed en 35.7% of Group A patients and only in 3.5% of Group B patients (p=0.022). In 8 patients front Group A, 8 patients (28.6%) an upward migration of the cerebellum was seen, whereas any of the Group B patients presented it (p=0.022) Siringo-to-cord ratios were decreased in both groups without significant differences. All of the Group A patients improved their clinical exploration. In Group B, 60% of the patients improved and the 40% left maintained clinical stability. Any patient worsened. All patients that maintained clinical stability belonged to Group B, the differences between the two groups were statistically significant (p=0.04). Five patients presented immediate surgical complications (2 pseudomeningoceles, 2 meningitis and 1 hydrocephalus). All this patients where operated with dural graft (p=0.049). According to our study, suboccipital craniectomy with resection of the posterior arch of C1 and dural graft shows better clinical and radiological results than without dural graft. Nevertheless this technique can increase the incidence of surgical complications.


Prevalence and predictors of insomnia in women with invasive ovarian cancer: anxiety a major factor.
The estimated prevalence of insomnia in cancer patients varies between 20% and 50%, which is substantially higher than the general population. To date, little is known about the risk factors for insomnia in patients with cancer. This study examines the prevalence and predictors of insomnia in a population-based sample of women with ovarian cancer. Participants were 772 women participating in the Australian Ovarian Cancer Study - Quality of Life Study. Insomnia was assessed using the Insomnia Severity Index (ISI). Demographic, disease and treatment variables, and psychosocial variables, including anxiety and depression, support care needs and social support and coping, were investigated as potential predictors of insomnia. Twenty-seven percent of women reported sub-clinical symptoms of insomnia (ISI score 8-14) and 17% reported clinically significant insomnia (ISI score 15-28). Three variables were significant predictors of clinically significant insomnia: young age (<50 years: Odds Ratio (OR)=2.36; Confidence Interval (CI) 1.06-5.26; 50-59 years: OR=2.73; CI 1.33-5.64) relative to 70+ years; higher unmet needs in the physical/daily living domain (OR=1.02; CI 1.01-1.03) and elevated anxiety (sub-clinical anxiety (Hospital Anxiety and Depression Scale (HADS) score 8-10): OR=1.83; CI 1.04-3.24; clinical anxiety (HADS score 11-21): OR=2.03; CI 1.08-3.85). In contrast to predictors of primary insomnia, women with cancer aged <60 years were more likely to report clinical levels of insomnia than women of 70+ years. Consistent with primary insomnia, elevated anxiety predicted insomnia in women with ovarian cancer. Given that both anxiety and insomnia are relatively common, and the relationship may potentially be bi-directional, the efficacy of interventions targeting insomnia and anxiety, rather than insomnia alone, is worthy of consideration.


Unintended pregnancy and taxpayer spending.
Nearly half of all pregnancies in the United States are unintended. These pregnancies likely represent a substantial cost to taxpayers, but national-level estimates of these public costs have been lacking. Taxpayer spending on unintended pregnancy is measured by multiplying estimates of the 2001 incidence of publicly financed unintended pregnancy outcomes (abortions, fetal losses, births and need for infant medical care) by average per-incident costs. Public savings that would result from preventing unintended pregnancies are estimated by assuming that the prevention of an unwanted pregnancy would save the full cost of financing the pregnancy, while the prevention of a mistimed pregnancy would save the cost of financing the pregnancy today minus the present value of the cost of financing the pregnancy when it eventually occurs. Lower-bound, mean and upper-bound estimates of the annual cost of unintended pregnancy are, respectively, $9.6 billion, $11.3 billion and $12.6 billion. Corresponding estimates of the savings that would accrue to taxpayers by preventing unintended pregnancies are $4.7 billion, $5.6 billion and $6.2 billion. The mean estimate of the taxpayer cost per publicly subsidized unintended pregnancy is $9,000; the prevention of such a pregnancy would save taxpayers about half that amount. The prevention of unintended pregnancy represents an important opportunity for the public to reap substantial savings, especially given the current fiscal climate. The enactment or expansion of cost-effective policies to prevent unintended pregnancies is therefore a timely and sensible strategy.


Elizabethkingia meningoseptica: emerging multidrug resistance in a nosocomial pathogen.
A 46-year-old male patient presented with complaints of burning micturition for 2 days. Initial history, physical examination and laboratory investigations were consistent with the diagnosis of congestive cardiac failure (CCF) and concomitant urinary tract infection. CCF was treated with diuretics and a urine culture/sensitivity (C/S) was sent which returned growing Elizabethkingia meningoseptica resistant to all tested drugs. Intravenous cefotaxime which had been started empirically 3 days earlier was withheld at this point, and a repeat urine C/S was sent revealing resistance to all tested drugs (including reserved drugs) barring minocycline. The patient was treated with oral minocycline for 14 days after which he was symptomatically better with sterile urine. The patient was subsequently discharged.


Identification of c-di-GMP-Responsive Riboswitches.
Bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is an important signaling molecule for community behavior control, cell morphogenesis, and virulence in bacteria. In addition to protein effectors, this second messenger binds RNA molecules that act as riboswitches to control target gene expression. In this chapter, we describe a method for experimental validation of the functionality of c-di-GMP-responsive riboswitches and the analysis of c-di-GMP control of target gene expression by qRT-PCR and Northern blot. This procedure can be used for the studies of in silico-predicted riboswitch candidates, as well as a targeted experimental approach for exploring the data from next-generation sequencing. The examples on the analysis of type I and type II c-di-GMP-responsive riboswitches in Clostridium difficile are provided to illustrate the application of the method.


1H CSA parameters by ultrafast MAS NMR: Measurement and applications to structure refinement.
A 1H anisotropic-isotropic chemical shift correlation experiment which employs symmetry-based recoupling sequences to reintroduce the chemical shift anisotropy in ν1 and ultrafast MAS to resolve 1H sites in ν2 is described. This experiment is used to measure 1H shift parameters for L-ascorbic acid, a compound with a relatively complex hydrogen-bonding network in the solid. The 1H CSAs of hydrogen-bonded sites with resolved isotropic shifts can be extracted directly from the recoupled lineshapes. In combination with DFT calculations, hydrogen positions in crystal structures obtained from X-ray and neutron diffraction are refined by comparison with simulations of the full two-dimensional NMR spectrum. The improved resolution afforded by the second dimension allows even unresolved hydrogen-bonded sites 1H to be assigned and their shift parameters to be obtained.


Three-dimensional grain boundary spectroscopy in transparent high power ceramic laser materials.
Using confocal Raman and fluorescence spectroscopic imaging in 3-dimensions, we show direct evidence of inhomogeneous Nd(3+) distribution across grain boundaries (GBs) in Nd(3+):YAG laser ceramics. It is clearly shown that Nd(3+) segregation takes place at GBs leading to self-fluorescence quenching which affects a volume fraction as high as 20%. In addition, we show a clear trend of increasing spatial inhomogeneities in Nd(3+) concentration when the doping levels exceeds 3 at%, which is not detected by standard spectrometry techniques. These results could point the way to further improvements in what is already an impressive class of ceramic laser materials.


Controlling the morphology and crystallization of a thiophene-based all-conjugated diblock copolymer by solvent blending.
We report the crystallization and microphase separation behavior of an all-conjugated poly(3-hexylthiophene)-b-poly[3-(6-hydroxy)hexylthiophene] (P3HT-b-P3HHT) block copolymer in mixed solvents and demonstrate how the conformations of P3HT and P3HHT chains influence the photophysical properties of the copolymer. It is shown that the balance among π-π stacking of P3HT, P3HHT and microphase separation of the copolymer can be dynamically shifted by controlling the rod-rod interactions of the copolymer via changing the block ratio and solvent blending. A series of nanostructures such as well-ordered nanofibers, spheres and lamellar structures are formed and their formation mechanisms and kinetics are discussed in detail. The variations in P3HT-b-P3HHT conformations are concomitant with a hybrid photophysical property depending on the competition between intrachain and interchain excitonic coupling, resulting in the transformation between J- and H-aggregation. Overall, this work demonstrates how the P3HT-b-P3HHT conformations crystallize and phase-separate in the solution and solid state, and the correlation between their structures and photophysical properties, which improves our understanding of all-conjugated rod-rod block copolymer systems.