IDEAL-D Framework for Device Innovation: A Consensus Statement on the Preclinical Stage.
To extend the IDEAL framework for device innovation, IDEAL-D, to include the preclinical stage of development (stage 0). In previous work, the IDEAL collaboration has proposed frameworks for new surgical techniques and complex therapeutic technologies, the central tenet being that development and evaluation can and should proceed together in an ordered and logical manner that balances innovation and safety. Following agreement at the IDEAL Collaboration Council, a multidisciplinary working group was formed comprising 12 representatives from healthcare, academia, industry, and a patient advocate. The group conducted a series of discussions following the principles used in the development of the original IDEAL framework. Importantly, IDEAL aims for maximal transparency, optimal validity in the evaluation of primary effects, and minimization of potential risk to patients or others. The proposals were subjected to further review and editing by members of the IDEAL Council before a final consensus version was adopted. In considering which studies are required before a first-in-human study, we have: (1) classified devices according to what they do and the risks they carry, (2) classified studies according to what they show about the device, and (3) made recommendations based on the principle that the more invasive and high risk a device is, the greater proof required of their safety and effectiveness before progression to clinical studies (stage 1). The proposed recommendations for preclinical evaluation of medical devices represent a proportionate and pragmatic approach that balances the de-risking of first-in-human translational studies against the benefits of rapid translation of new devices into clinical practice.


A multiphase model for chemically- and mechanically- induced cell differentiation in a hollow fibre membrane bioreactor: minimising growth factor consumption.
We present a simplified two-dimensional model of fluid flow, solute transport, and cell distribution in a hollow fibre membrane bioreactor. We consider two cell populations, one undifferentiated and one differentiated, with differentiation stimulated either by growth factor alone, or by both growth factor and fluid shear stress. Two experimental configurations are considered, a 3-layer model in which the cells are seeded in a scaffold throughout the extracapillary space (ECS), and a 4-layer model in which the cell-scaffold construct occupies a layer surrounding the outside of the hollow fibre, only partially filling the ECS. Above this is a region of free-flowing fluid, referred to as the upper fluid layer. Following previous models by the authors (Pearson et al. in Math Med Biol, 2013, Biomech Model Mechanbiol 1-16, 2014a, we employ porous mixture theory to model the dynamics of, and interactions between, the cells, scaffold, and fluid in the cell-scaffold construct. We use this model to determine operating conditions (experiment end time, growth factor inlet concentration, and inlet fluid fluxes) which result in a required percentage of differentiated cells, as well as maximising the differentiated cell yield and minimising the consumption of expensive growth factor.


Survival, plasma HIV-1 RNA concentrations and drug resistance in HIV-1-infected Haitian adolescents and young adults on antiretrovirals.
To assess outcomes after antiretroviral therapy (ART) in adolescents and youth in Haiti, a country with a generalized epidemic of infection with HIV-1. An assessment was made of survival, plasma HIV-1 ribonucleic acid (RNA) concentrations and HIV-1 drug resistance patterns after 12 months of ART in patients aged 13-25 years who presented to a clinic in Port-au-Prince, Haiti, with AIDS between 1 March 2003 and 31 December 2005. Participants received ART in accordance with WHO guidelines. Kaplan-Meier analysis was used to estimate survival probabilities and their 95% confidence intervals (CI) for the period from ART initiation to death. Of a total of 146 patients, 96 (66%) were female; the median CD4+ T-cell count at baseline was 129 cells/ml. By Kaplan-Meier analysis, 13% of the patients had died at 12 months, 17% at 24 months and 20% at 36 months. A plasma HIV-1 RNA concentration > or = 50 copies/ml was seen in 40 (51%) of 79 patients 12 months after treatment initiation and was associated with poor ART adherence. Among 29 patients with > 1000 copies/ml at 12 months, resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 23 cases (79%); to both NNRTIs and lamivudine in 21 (72%) cases; and to NNRTIs, lamivudine and other nucleoside reverse transcriptase inhibitors in 10 (35%) cases. One hundred and six participants (73%) reported sexual intercourse without condoms, and 35 of the 96 women (36%) were pregnant during follow-up. Adolescents and youth with AIDS receiving ART are at risk of virologic failure and disease progression and can therefore transmit HIV-1 to sexual partners and infants. Strategies to target the special needs of this age group are urgently needed.


Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia.
Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.


Macrocyclic Antimicrobial Peptides Engineered from ω-Conotoxin.
The potent calcium channel blocker ω-conotoxin MVIIA is a linear cystine-knot peptide with multiple basic amino acids at both termini. This work shows that macrocyclization of MVIIA linking two positive-charge terminal clusters as a contiguous segment converts a conotoxin into an antimicrobial peptide. In addition, conversion of disulfide bonds to amino butyric acids improved the antimicrobial activity of the cyclic analogs. Ten macrocyclic analogs, with or without disulfide bonds, were prepared by both Boc and Fmoc chemistry using native chemical ligation. All cyclic analogs were active against selected Gram-positive and Gram-negative bacteria with minimal inhibitory concentrations in a low μM range. In contrast, MVIIA and its linear analog were inactive at concentrations up to 0.5 mM. The cyclic analogs also showed 2 to 3-fold improved chemotactic activity against human monocytes THP-1 compared with MVIIA. Reduction of molecular stability against thermal and acid treatment due to the reduced number of disulfide crosslinks can be partly restored by backbone cyclization. Together, these results show that macrocyclization and side chain modification of a linear conopeptide lead to a gain-of-function, which brings a new perspective in designing and engineering of peptidyl therapeutics.


Comparative immunogenicity and thrombolytic properties toward arterial and venous thrombi of streptokinase and recombinant staphylokinase in baboons.
Streptokinase is a routinely used thrombolytic agent that is immunogenic and relatively inefficient toward platelet-rich thrombus, whereas staphylokinase is a poorly studied fibrinolytic agent. Here, the comparative immunogenicity and thrombolytic properties toward arterial platelet-rich thrombus and venous whole blood clots of streptokinase and recombinant staphylokinase were studied in baboons. The inhibitory capacity of baboon plasma (in a human plasma-based clot lysis assay) was 0.39 +/- 0.25 microgram streptokinase and 0.04 +/- 0.05 microgram recombinant staphylokinase per milliliter of plasma (mean +/- SD, n = 9). Intravenous infusion over 1 hour of 0.300 mg/kg of streptokinase at 0, 1, 2, 3, and 5 weeks in five baboons given heparin and the antiplatelet agent ridogrel increased the streptokinase-neutralizing titer from 0.22 +/- 0.18 microgram/mL plasma at baseline to 3.8 +/- 4.4 micrograms/mL after 2 weeks (p = 0.043 versus baseline by Wilcoxon signed rank test) and to 4.4 +/- 4.6 micrograms/mL after 5 weeks, whereas the thrombolytic potency toward a 125I-fibrin-labeled plasma clot inserted into an extracorporeal arteriovenous loop was reduced from 84 +/- 7% at baseline to 45 +/- 8% after 2 weeks and to 36 +/- 8% after 5 weeks (p < 0.01 versus baseline). Administration over 1 hour of 0.065 mg/kg recombinant staphylokinase at 0, 1, 2, 3, and 5 weeks in four baboons did not induce measurable staphylokinase-neutralizing activity in three of the four animals after 5 weeks. In the fourth baboon, a staphylokinase-neutralizing activity of 0.8 and 1.5 micrograms/mL was found at 3 and 5 weeks, respectively. Repeated staphylokinase administration was not associated with inhibition of clot lysis (43 +/- 4% lysis at baseline, 52 +/- 9% at 3 weeks, and 61 +/- 14% at 5 weeks; p = NS versus baseline). Repeated administration of streptokinase but not of staphylokinase caused a marked (> 50%) decrease in blood pressure, requiring administration of steroids and intravenous fluids, and a marked increase in leukocyte count and hemoglobin concentration. Intravenous infusion of streptokinase or recombinant staphylokinase over 1 hour in doses ranging between 0 and 1.0 mg/kg in three groups of four baboons each induced dose-dependent lysis of a 125I-fibrin-labeled autologous jugular vein blood clot (50% lysis requiring 0.140 mg/kg streptokinase and 0.058 mg/kg recombinant staphylokinase, representing equimolar amounts of 3.25 nmol/kg) without systemic fibrinogen depletion. The thrombolytic potency toward platelet-rich arterial thrombus of streptokinase and recombinant staphylokinase were studied in a femoral arterial eversion graft model. Arterial recanalization with recombinant staphylokinase was more frequent and more persistent than with streptokinase (all p < 0.05). Intravenous infusion of 1.0 mg/kg streptokinase or 0.25 mg/kg recombinant staphylokinase in two groups of four baboons each given intravenous heparin (200-unit bolus and 50 units.kg-1 x hr-1) and aspirin (10 mg/kg) did not produce a significant prolongation of the median template bleeding time. Recombinant staphylokinase has a thrombolytic potency toward jugular vein blood clots in baboons comparable to that of streptokinase, but it is less immunogenic and less allergenic and it does not induce resistance to lysis upon repeated administration; it is significantly more efficient than streptokinase for the dissolution of platelet-rich arterial eversion graft thrombi. Recombinant staphylokinase, which can be easily obtained in active form by expression in Escherichia coli, may constitute a potentially useful alternative to streptokinase for the treatment of acute myocardial infarction.


Collective motion of self-propelled particles with memory.
We show that memory, in the form of underdamped angular dynamics, is a crucial ingredient for the collective properties of self-propelled particles. Using Vicsek-style models with an Ornstein-Uhlenbeck process acting on angular velocity, we uncover a rich variety of collective phases not observed in usual overdamped systems, including vortex lattices and active foams. In a model with strictly nematic interactions the smectic arrangement of Vicsek waves giving rise to global polar order is observed. We also provide a calculation of the effective interaction between vortices in the case where a telegraphic noise process is at play, explaining thus the emergence and structure of the vortex lattices observed here and in motility assay experiments.


Development of a Microscopic Colitis Disease Activity Index: a prospective cohort study.
Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI). Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated. Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57-73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R2=0.80). A 1-unit decrease in disease activity (ΔMCDAI) was associated with a 9-unit increase in quality of life (ΔIBDQ). The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC.


K+ efflux in NIH mouse 3T3 cells and transformed derivatives: dependence on extracellular Ca2+ and phorbol esters.
In culture medium deficient in Ca2+, NIH mouse 3T3 cells lose K+, gain Na+, and stop growing. A marked increase in the rate of K+ efflux accounts for this loss; Na+, K+-ATPase pump activity increases but does not fully compensate for enhanced K+ efflux. Phorbol esters and cycloheximide inhibit K+ loss in Ca2+-deficient medium. Phorbol esters inhibit K+ efflux from human fibroblasts as well, even at physiological levels of Ca2+. Two cell lines derived from NIH-3T3, one transformed by a simian virus 40 deletion mutant, the other by the polyoma virus oncogene encoding the middle-sized tumor antigen, retain K+ and can multiply in medium with low Ca2+. Efflux of K+ from these cells is relatively insensitive to reduced Ca2+ concentration, phorbol esters, and cycloheximide. The results suggest the following hypothesis: a channel, nonselective for K+ and Na+, opens when NIH-3T3 cells are in Ca2+-deficient medium; the channel is controlled by the receptor for phorbol ester (protein kinase C) and may also be regulated by a short-lived protein.


Utilization of biomarker data for clinical and environmental intervention.
Of the 189 air toxics listed in the Clean Air Act, a substantial number are important in potentially causing adverse health effects in several organ systems. Although the major health effects are manifested as respiratory diseases, especially airways disease, these agents may cause cancer and premature mortality, probably from cardiopulmonary disease. Validated biologic markers may be useful in identifying early effects to improve our understanding of exposure-response relationships and clarify susceptibility. However, the knowledge obtained from epidemiologic studies utilizing these new molecular tools will reduce morbidity and mortality from air toxics only when they can be applied effectively in the prevention and control of disease. Intervention strategies using these markers can be used to identify etiologic factors and assess the effectiveness of exposure reduction, and, in some instances, chemoprevention. This paper illustrates examples of these intervention strategies and reviews the current strengths and limitations of environmental molecular epidemiology in controlling disease caused by air toxics.


Cross-cultural adaptation, reliability and validity of the Spanish version of the Quality of Life in Adult Cancer Survivors (QLACS) questionnaire: application in a sample of short-term survivors.
The aim of this study was to validate the Quality of Life in Adult Cancer Survivors (QLACS) in short-term Spanish cancer survivor's patients. Patients with breast, colorectal or prostate cancer that had finished their initial cancer treatment 3 years before the beginning of this study completed QLACS, WHOQOL, Short Form-36, Hospital Anxiety and Depression Scale, EORTC-QLQ-BR23 and EQ-5D. Cultural adaptation was made based on established guidelines. Reliability was evaluated using internal consistency and test-retest. Convergent validity was studied by mean of Pearson's correlation coefficient. Structural validity was determined by a second-order confirmatory factor analysis (CFA) and Rasch analysis was used to assess the unidimensionality of the Generic and Cancer-specific scales. Cronbach's alpha were above 0.7 in all domains and summary scales. Test-retest coefficients were 0.88 for Generic and 0.82 for Cancer-specific summary scales. QLACS generic summary scale was correlated with other generic criterion measures, SF-36 MCS (r = - 0.74) and EQ-VAS (r = - 0.63). QLACS cancer-specific scale had lower values with the same constructs. CFA provided satisfactory fit indices in all cases. The RMSEA value was 0.061 and CFI and TLI values were 0.929 and 0.925, respectively. All factor loadings were higher than 0.40 and statistically significant (P < 0.001). Generic summary scale had eight misfitting items. In the remaining 20 items, the unidimensionality was supported. Cancer Specific summary scale showed four misfitting items, the remaining showed unidimensionality. The findings support the validity and reliability of QLACS questionnaire to be used in short-term cancer survivors.


Parity derived for pregnant women using historical administrative hospital data: accuracy varied among patient groups.
Understanding patterns of maternity care requires knowing which women have given birth previously, but this information is typically unavailable in administrative hospital data sets. We assessed how well parity can be derived using linked historical records. Using Hospital Episode Statistics data, we identified records of women who gave birth between April 2009 and March 2010 in English National Health Service hospitals. The parity coded in these records was compared with an estimate derived from deliveries identified in previous hospital admissions between April 2000 and March 2009. We identified 358,849 eligible deliveries with complete parity data in the 2009-10 birth records. The historical data classified 168,041 women as multiparous; of whom, 98% were coded as multiparous in their birth record. Among 190,798 women classified as primiparous using historical data, 72% were coded as primiparous in their birth record. The proportion of accurate predictions about primiparous status from historical data varied with age, ranging from 89% for 15-18 year olds to 50% for women aged more than 35 years. Historical records in administrative hospital data sets give accurate information on multiparous status of women. There is some misclassification of primiparous status, and error rates differ among subgroups of women.


Total-Body PET and Highly Stable Chelators Together Enable Meaningful 89Zr-Antibody PET Studies up to 30 Days After Injection.
The use of 89Zr-antibody PET imaging to measure antibody biodistribution and tissue pharmacokinetics is well established, but current PET systems lack the sensitivity needed to study 89Zr-labeled antibodies beyond 2-3 isotope half-lives (7-10 d), after which a poor signal-to-noise ratio is problematic. However, studies across many weeks are desirable to better match antibody circulation half-life in human and nonhuman primates. These studies investigated the technical feasibility of using the primate mini-EXPLORER PET scanner, making use of its high sensitivity and 45-cm axial field of view, for total-body imaging of 89Zr-labeled antibodies in rhesus monkeys up to 30 d after injection. Methods: A humanized monoclonal IgG antibody against the herpes simplex viral protein glycoprotein D (gD) was radiolabeled with 89Zr via 1 of 4 chelator-linker combinations (benzyl isothiocyanate-DFO [DFO-Bz-NCS], where DFO is desferrioxamine B; DFO-squaramide; DFO*-Bz-NCS, where DFO* is desferrioxamine*; and DFO*-squaramide). The pharmacokinetics associated with these 4 chelator-linker combinations were compared in 12 healthy young male rhesus monkeys (∼1-2 y old, ∼3 ± 1 kg). Each animal was initially injected intravenously with unlabeled antibody in a peripheral vessel in the right arm (10 mg/kg, providing therapeutic-level antibody concentrations), immediately followed by approximately 40 MBq of one of the 89Zr-labeled antibodies injected intravenously in a peripheral vessel in the left arm. All animals were imaged 6 times over a period of 30 d, with an initial 60-min dynamic scan on day 0 (day of injection) followed by static scans of 30-45 min on approximately days 3, 7, 14, 21, and 30, with all acquired using a single bed position and images reconstructed using time-of-flight list-mode ordered-subsets expectation maximization. Activity concentrations in various organs were extracted from the PET images using manually defined regions of interest. Results: Excellent image quality was obtained, capturing the initial distribution phase in the whole-body scan; later time points showed residual 89Zr mainly in the liver. Even at 30 d after injection, representing approximately 9 half-lives of 89Zr and with a total residual activity of only 20-40 kBq in the animal, the image quality was sufficient to readily identify activity in the liver, kidneys, and upper and lower limb joints. Significant differences were noted in late time point liver uptake, bone uptake, and whole-body clearance between chelator-linker types, whereas little variation (±10%) was observed within each type. Conclusion: These studies demonstrate the ability to image 89Zr-radiolabeled antibodies up to 30 d after injection while maintaining satisfactory image quality, as provided by the primate mini-EXPLORER with high sensitivity and long axial field of view. Quantification demonstrated potentially important differences in the behavior of the 4 chelators. This finding supports further investigation.


Effects of Reduced Tillage, Resistant Cultivars, and Reduced Fungicide Inputs on Progress of Early Leaf Spot of Peanut (Arachis hypogaea).
Field experiments were conducted in 2000 and 2001 on Georgia Green, Florida MDR-98, and C-99R peanut (Arachis hypogaea) cultivars in Tifton, GA, to determine the effects of tillage practices on early leaf spot (Cercospora arachidicola) epidemics under standard fungicide regimes and fungicide regimes with fewer applications. Leaf spot epidemics were suppressed in reduced tillage (strip-till) plots compared with conventional tillage plots and were suppressed in MDR-98 and C-99R cultivars compared with the standard runner-type cultivar, Georgia Green. Within tillage and cultivar combinations, leaf spot intensity typically was lower in plots treated with fungicides at standard intervals (seven total applications) than in those treated at extended intervals (four total applications). However, in most cases, leaf spot control in extended interval treatments in the strip-till system was comparable to that in the standard interval treatments in conventional tillage. Based on these results, the number of fungicide applications could be reduced without compromising control of leaf spot when reduced tillage is used, especially if combined with moderately resistant cultivars. Suppression of leaf spot epidemics in the strip-till plots did not coincide with higher yields in either year. In 2001, yields were lower in strip-till plots than in conventional tillage plots. Yields were typically higher in the cultivar C-99R than in Georgia Green, regardless of the tillage treatment.


An optimized electroporation approach for efficient CRISPR/Cas9 genome editing in murine zygotes.
Electroporation of zygotes represents a rapid alternative to the elaborate pronuclear injection procedure for CRISPR/Cas9-mediated genome editing in mice. However, current protocols for electroporation either require the investment in specialized electroporators or corrosive pre-treatment of zygotes which compromises embryo viability. Here, we describe an easily adaptable approach for the introduction of specific mutations in C57BL/6 mice by electroporation of intact zygotes using a common electroporator with synthetic CRISPR/Cas9 components and minimal technical requirement. Direct comparison to conventional pronuclear injection demonstrates significantly reduced physical damage and thus improved embryo development with successful genome editing in up to 100% of living offspring. Hence, our novel approach for Easy Electroporation of Zygotes (EEZy) allows highly efficient generation of CRISPR/Cas9 transgenic mice while reducing the numbers of animals required.


Robust effects of affective person learning on evaluation of faces.
People form impressions of others from multiple sources of information. Facial appearance is one such source and judgments based on facial appearance are made after minimal exposure to faces. A more reliable source of information is affective person learning based on others' past actions. Here we investigated whether the effects of such appearance-independent learning on face evaluation emerge after rapid face exposure, a response deadline procedure, and a lack of explicit recognition of the faces. In three experiments, participants learned to associate novel faces with negative and positive behaviors, and then evaluated the faces presented on their own, without the behaviors. Even after extremely brief exposures (e.g., 35 ms), participants evaluated faces previously associated with negative behaviors more negatively than those associated with positive behaviors (Experiment 1). The learning effect persisted when participants were asked to evaluate briefly presented faces before a response deadline (Experiment 2), although the effect was diminished. Finally, although this learning effect increased as a function of face recognition (Experiment 3), it was present with only minimal recognition, suggesting that participants do not need to deliberately retrieve behavioral information for it to influence face evaluation. Together, the findings suggest that person learning unrelated to facial appearance is a powerful determinant of face evaluation. (PsycINFO Database Record


Electrochemical noise and impedance of Au electrode/electrolyte interfaces enabling extracellular detection of glioma cell populations.
Microelectrode arrays (MEA) record extracellular local field potentials of cells adhered to the electrodes. A disadvantage is the limited signal-to-noise ratio. The state-of-the-art background noise level is about 10 μVpp. Furthermore, in MEAs low frequency events are filtered out. Here, we quantitatively analyze Au electrode/electrolyte interfaces with impedance spectroscopy and noise measurements. The equivalent circuit is the charge transfer resistance in parallel with a constant phase element that describes the double layer capacitance, in series with a spreading resistance. This equivalent circuit leads to a Maxwell-Wagner relaxation frequency, the value of which is determined as a function of electrode area and molarity of an aqueous KCl electrolyte solution. The electrochemical voltage and current noise is measured as a function of electrode area and frequency and follow unambiguously from the measured impedance. By using large area electrodes the noise floor can be as low as 0.3 μVpp. The resulting high sensitivity is demonstrated by the extracellular detection of C6 glioma cell populations. Their minute electrical activity can be clearly detected at a frequency below about 10 Hz, which shows that the methodology can be used to monitor slow cooperative biological signals in cell populations.


Skin conditions in a South African tuberculosis hospital: Prevalence, description, and possible associations.
The current pandemic of tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection, the modern era of antiretroviral therapy, and the rising incidence of multidrug-resistant TB have led to a broader spectrum of skin conditions in patients hospitalized with TB. These factors also influence investigations into possible causal relationships with TB. The aim of this study was to describe mucocutaneous conditions found in patients hospitalized with TB and to report associated factors. A cross-sectional observational study examining the spectrum of skin manifestations found in 105 patients hospitalized with TB was conducted. All relevant demographic and clinical data were collected. Possible associations were evaluated by making use of statistical analysis. Seventy-four (70%) of the investigated population were HIV-positive, and 46 (44%) patients were being treated for drug-resistant TB. The most prevalent dermatosis was xerosis (n = 83, 79%), followed by oral candidiasis (n = 33, 31%) and scars (n = 33, 31%), finger clubbing (n = 31, 29%), leukonychia (n = 29, 28%), striae (n = 25, 24%), and facial hyperpigmentation (n = 22, 21%). Anemia was detected in 90 (86%) patients, and 75 (71%) were classified as being underweight. Three patients were diagnosed with cutaneous TB. Patients hospitalized with TB have on average four different dermatoses, but xerosis remains the leading dermatological finding, irrespective of HIV status or TB drug sensitivity. Anemia and malnutrition are associated with numerous skin conditions found in this population. The prevalence of cutaneous TB among patients hospitalized with TB remains low, despite the high rate of TB and HIV co-infection.


Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice.
Bone development is a multistep process that includes patterning of skeletal elements, commitment of hematopoietic and/or mesenchymental cells to chondrogenic and osteogenic lineages, and further differentiation into three specialized cell types: chondrocytes in cartilage and osteoblasts and osteoclasts in bone. Although PRL has a multitude of biological actions in addition to its role in the mammary gland, very little is known about its effect on bone. Mice carrying a germline null mutation for the PRL receptor gene have been produced in our laboratory and used to study the role of PRL in bone formation. In -/- embryos, we observed an alteration in bone development of calvaria. In adults, histomorphometric analysis showed that the absence of PRL receptors leads to a decrease in bone formation rate using double calcein labeling and a reduction of bone mineral density, measured by dual energy x-ray absorptiometry. In addition, serum estradiol, progesterone, testosterone, and PTH levels were analyzed. We also established that osteoblasts, but not osteoclasts, express PRL receptors. This suggests that an effect of PRL on osteoblasts could be required for normal bone formation and maintenance of bone mass. Thus, the PRL receptor knockout mouse model provides a new tool to investigate the involvement of PRL in bone metabolism.


Surface-coupling of Cerenkov radiation from a modified metallic metamaterial slab via Brillouin-band folding.
Metallic metamaterials with positive dielectric responses are promising as an alternative to dielectrics for the generation of Cerenkov radiation [J.-K. So et al., Appl. Phys. Lett. 97(15), 151107 (2010)]. We propose here by theoretical analysis a mechanism to couple out Cerenkov radiation from the slab surfaces in the transverse direction. The proposed method based on Brillouin-zone folding is to periodically modify the thickness of the metamaterial slab in the axial direction. Moreover, the intensity of the surface-coupled radiation by this mechanism shows an order-of-magnitude enhancement compared to that of ordinary Smith-Purcell radiation.


Improvements in health parameters of a diabetic and hypertensive patient with only 40 minutes of exercise per week: a case study.
Purpose: The present study aimed to report the effects of 15 weeks of a minimal dose resistance training on blood glucose levels, blood pressure, heart rate, physical capacity, and quality of life of a 67 old woman with type 2 diabetes mellitus, cardiopathy and hypertension.Method: The Patient was sedentary with a family history of heart failure and coronary artery disease. She suffered a heart attack in 2013 and was submitted to six cardiac catheterizations and one angioplasty between the 2015 and 2017. On April 2017, she was initially untrained in resistance training and was followed for 15 weeks with the performance of 31 resistance training sessions. Resistance training followed a minimal dose approach with 4 exercises performed with 2 sets to muscle failure, twice a week.Results: After follow up, the Patient presented a reduction in blood glucose, systolic and diastolic blood pressure, and heart rate at rest. There were also improvements on body mass index, cardiorespiratory fitness and quality of life. These results were accompanied by a reduction in the amount of antihypertensive and anti-diabetic medications.Conclusions: These results suggest that only 40 min of resistance training per week might help to improve general health and quality of life in a patient with hypertension and type 2 diabetes mellitus.Implications for RehabilitationMinimal dose resistance training improved health parameters in a diabetic and hypertensive patient.Resistance training promoted a reduction in the drugs used to control blood pressure and blood glucose levels.


Exogenous administration of immunomodulatory therapies in hematopoietic cell transplantation: an infectious diseases perspective.
In contrast to the recipient of a solid organ transplantation, the immunological competence of recipients of hematopoietic cell transplantation does not correlate well with the administration of non-corticosteroid immunosuppressive agents. This apparent paradox reflects the unique and dynamic conglomeration of factors that affect immune reconstitution after hematopoietic cell transplantation. The following is the second part of a review of the recent primary literature regarding exogenous immunomodulatory influences as they pertain to infections in the setting of hematopoietic cell transplantation. The main themes of published primary research from 2004 to the present include the influence of exogenously administered immunomodulatory agents on infectious complications after hematopoietic cell transplantation. The use of immunomodulatory agents such as monoclonal antibodies directed against lymphocyte antigens in the treatment of hematopoietic malignancy has greatly expanded during the past decade. Separate trials of the potential utility of these agents, particularly in the reduction of graft-versus-host disease, in the setting of hematopoietic cell transplantation have yielded encouraging results. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens such as cytomegalovirus as probes of the functional reconstitution of immunity.


Prevalence and predictors of falls and dizziness in people younger and older than 80 years of age--a longitudinal cohort study.
The objectives were to investigate the prevalence and predictors for falls and dizziness among people younger and older than 80 years of age. The sample was drawn from the Swedish National study on Aging and Care (SNAC) and comprised 973 and 1273 subjects with data on the occurrence of falls and dizziness respectively at baseline. Follow-ups were made after 3- and 6-years. Data included socio-demographics, physical function, health complaints, cognition, quality of life and medications. The prevalence of falls was 16.5% in those under aged 80 and 31.7% in those 80+ years while dizziness was reported by 17.8% and 31.0% respectively. Predictors for falls in those under aged 80 were neuroleptics, dependency in personal activities of daily living (PADL), a history of falling, vision impairment and higher age, and in those 80+ years a history of falling, dependency in instrumental activities of daily living (IADL), fatigue and higher age. Factors predicting dizziness in those under aged 80 were a history of dizziness, feeling nervous and reduced grip strength and in those 80+ years a history of dizziness and of falling. Predictors for falls and dizziness differed according to age. Specific factors were identified in those under aged 80. In those 80+ years more general factors were identified implying the need for a comprehensive investigation to prevent falls. This longitudinal study also showed that falling and dizziness in many older people are persistent and therefore should be treated as chronic conditions.


β-caryophyllene, a dietary cannabinoid, complexed with β-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn.
Evaluate the anti-hyperalgesic effect of the complex containing β-caryophyllene (βCP) and β-cyclodextrin (βCD) in a non-inflammatory chronic muscle pain mice model and investigated its action on superficial dorsal horn of the lumbar spinal cord. The βCP-βCD complex were prepared and characterized through the DSC, TG/DTG, FTIR, XRD and SEM. The model of chronic muscle pain was induced by two injections of pH4.0 saline (20μL) into left gastrocnemius 5days apart. After confirming hyperalgesia, male mice were treated with βCP-βCD (10 or 20mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 9days. 1h after, the mechanical hyperalgesia, muscle withdrawal thresholds and motor performance were evaluated. To evaluate the βCP-βCD action on spinal cord, animals induced with chronic muscle pain were treated with βCP-βCD (20mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) and 90min. after, were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein. The characterization tests indicated that βCP were efficiently incorporated into βCD. The oral treatment with βCP-βCD, at all doses tested, produced a significant (p<0.05) reduction on mechanical hyperalgesia and a significant (p<0.05) increase in muscle withdrawal thresholds, without produce any alteration in force. In addition, βCP-βCD was able to significantly (p<0.05) decrease Fos expression in the superficial dorsal horn. Thus, βCP-βCD attenuates the non-inflammatory chronic muscle pain in mice and inhibits the Fos expression in the lumbar spinal cord.


Gynecologic Cancer InterGroup (GCIG) consensus review for high-grade undifferentiated sarcomas of the uterus.
High-grade undifferentiated sarcomas (HGUSs) are rare uterine malignancies arising from the endometrial stroma. They are poorly differentiated sarcomas composed of cells that do not resemble proliferative-phase endometrial stroma. High-grade undifferentiated sarcomas are characterized by aggressive behavior and poor prognosis. Cyclin D1 has been reported as a diagnostic immunomarker for high-grade endometrial stromal sarcoma with an YWHAE-FAM22 rearrangement. YWHAE-FAM22 endometrial stromal sarcomas (ESS) represent a clinically aggressive subtype of ESS classified as high-grade endometrial sarcomas, and its distinction from the usual low-grade ESS with JAZF1 rearrangement and from HGUS with no identifiable molecular aberration may be important in guiding clinical management. Median age of the patients is between 55 and 60 years. The most common symptoms are vaginal bleeding, abdominal pain, and increasing abdominal girth.Disease is usually advanced with approximately 70% of the patients staged III to IV according to the International Federation of Gynecology and Obstetrics classification. Preferential metastatic locations include peritoneum, lungs, intra-abdominal lymph nodes, and bone. Median progression-free survival ranged from 7 to 10 months, and median overall survival ranged from 11 to 23 months. There is no clear prognostic factor identified for HGUS, not even stage. The standard management for HGUS consists of total hysterectomy and bilateral salpingo-oophorectomy. Systematic lymphadenectomy is not recommended. Adjuvant therapies, such as chemotherapy and radiotherapy, have to be discussed in multidisciplinary staff meetings.


A person-centred approach to family carer needs assessment and support in dementia community care in Western Australia.
This feasibility study aimed to identify and address the support needs of family carers (FCs) of people living with dementia and to assess whether the use of the Carer Support Needs Assessment Tool (CSNAT) intervention in home-based care was acceptable and relevant to FCs. The CSNAT intervention comprised two FC support needs assessment visits, 7 weeks apart, plus associated actions addressing prioritised needs by the Client Care Advisors of a community care service in Western Australia in 2015. Telephone interviews were conducted with FCs on their experience using the CSNAT at the end of the intervention. Twenty-one FCs were involved in the intervention and 15 of them completed the feedback interviews. Care recipients had moderate to severe dementia. The top five support needs reported by FCs were: having time to yourself in the day; knowing what to expect in the future; practical help in the home; looking after your own health and dealing with your feelings and worries. Three themes summarised their experience: a straightforward structured approach; awareness, acknowledgement and acceptance of their situation; and provision of support. FCs appreciated the opportunity to be heard and acknowledged, to have their practical and psychosocial support needs facilitated, to identify what is important to them and to receive a response in a timely manner. The CSNAT approach offered a structured carer-led, person-centred, supportive intervention that facilitated discussion between the family carer and the service provider about support needs and strategies to address them.


Morphological and AFLP-based differentiation within the taxonomical complex section Caninae (subgenus Rosa).
The taxonomical structure of the polymorphic subgenus Rosa section Caninae is highly complex due to the combination of some unusual features: the unique polyploid chromosomal constitution, the heterogamic canina meiosis, the ability to hybridize interspecifically, and the predominantly matroclinal inheritance. Although most taxonomists agree on the subdivision of the section into three morphologically well-defined groups (Rubigineae, Vestitae, and Caninae), they disagree on the existence of smaller groups such as Tomentellae. The aim was to gain insight in the taxonomical structure and investigate the interpopulation differentiation of the polymorphic section Caninae by analysing morphological and AFLP-based characters of the seven most common Belgian dog-rose taxa. The intersubsectional and -specific relationships within the dog-roses were examined using morphological and molecular-genetic markers. AFLP data were analysed with basic descriptive genetic statistics because of the lack of Hardy-Weinberg equilibrium due to the polyploid genetic structure and heterogamic meiosis. Both the morphological and AFLP-based analyses supported the subdivision of the dog-roses in three well-defined though partly overlapping groups, Rubigineae, Vestitae and Caninae. However, it was not possible to distinguish between the morphologically well-defined taxa within the same subsection using AFLP-based data. In addition, the results suggested a high similarity of Rosa balsamica with subsection Caninae taxa. Small-scale geographical AFLP-based differentiation was observed within several dog-rose taxa. Surprisingly, individuals sampled at one locality and belonging to morphologically distinct dog-rose taxa displayed higher genetic similarities in comparison to their congeners sampled at different localities. The hybridogenic character of the dog-roses was reflected in the vague boundaries between the subsections and on the species level within the subsections. Indications were found for current or historical hybridization on the genetic structure of the population. No morphological or AFLP-based evidence was obtained to support the existence of the separate subsection Tomentellae.


First Report of Zonate Leaf Spot Caused by Hinomyces moricola on Japanese Hop in Korea.
Japanese hop (Humulus japonicus Siebold & Zucc. = H. scandens (Lour.) Merr.), native to East Asia, is an annual, climbing or trailing vine. The vines can spread to cover large areas of open ground or low vegetation, eventually blanketing the land and vegetation. Pollen of H. japonicus is allergenic, and this species is considered as one of the important causes of pollinosis in Korea and China. It is a notorious invasive weed in the United States and also in France, Hungary, and Italy (1). In September 2012, zonate leaf spots were observed on Japanese hops growing in wetlands in Yeongdong County of Korea. A voucher specimen was preserved in the Korea University Herbarium (KUS-F26901). Initial symptoms included grayish-green to grayish-brown spots without border lines. As the lesions enlarged, they coalesced, leading to leaf blight. Sporophores on the leaf lesions were dominantly hypophyllous, rarely epiphyllous, solitary, erect, easily detachable, and as long as 700 μm. The upper portion of the sporophores consisted of a pyramidal head was ventricose, 320 to 520 μm long and 110 to 150 μm wide. The fungus was isolated from leaf lesions and maintained on potato dextrose agar (PDA). Sclerotia were produced on PDA after 4 to 5 weeks at 18°C without light, but conidia were not observed in culture. These morphological and cultural characteristics were consistent with those of Hinomyces moricola (I. Hino) Narumi-Saito & Y. Harada (= Cristulariella moricola (I. Hino) Redhead) (3,4). An isolate was preserved in the Korean Agricultural Culture Collection (Accession No. KACC46955). Genomic DNA was extracted using the DNeasy Plant Mini DNA Extraction Kit (Qiagen Inc., Valencia, CA). The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced. The resulting sequence of 452 bp was deposited in GenBank (Accession No. KC460209). A BLAST search in GenBank revealed that the sequence showed an exact match with those of C. moricola (JQ036181 ex Acer negundo and JQ036182 ex Glycine max). To determine the pathogenicity of the fungus, according to the procedure of Cho et al. (2), sporophores with the pyramidal head were carefully detached from a lesion on the naturally infected leaf using a needle. Each sporophore was transferred individually onto five places of four detached healthy leaves. The leaves were placed in dew chambers and incubated at 16°C. Symptoms were observed after 2 days on all inoculated leaves. A number of sporophores and immature sclerotia which were morphologically identical to the ones observed in the field were formed on the abaxial surface of the leaf 2 weeks after inoculation. The pathogen was reisolated from lesions on the inoculated leaves, confirming Koch's postulates. No symptoms were observed on the control leaves kept in humid chambers for 2 weeks. H. moricola was known to cause zonate leaf spots and defoliation on a wide range of woody and annual plants (3). To the best of our knowledge, this is the first report of Hinomyces infection on Japanese hops in Korea. References: (1) Anonymous. Humulus japonicus (Cannabaceae): Japanese hop. Eur. Medit. Plant Prot. Org. (EPPO). 2012. (2) S. E. Cho et al. Plant Dis. 96:906, 2012. (3) D. F. Farr and A. Y. Rossman. Fungal Databases. Syst. Mycol. Microbiol. Lab., Online publication, ARS, USDA, Retrieved December 8, 2012. (4) S. A. Redhead. Can. J. Bot. 53:700, 1975.


Critical review of economic evaluations in multiple myeloma: an overview of the economic evidence and quality of the methodology.
Continued expansion in the availability of costly alternative therapies in multiple myeloma will enhance the role of economic evaluations in reimbursement decisions and amendments to the treatment guidelines. The quality of economic evaluations should be taken into account by clinicians involved in decision-making. A systematic review and critique of the methodology was performed to assess the trends and quality in economic evaluations in multiple myeloma to date. A literature search was conducted to identify full economic evaluations in multiple myeloma as of December 2009. Details of the economic evaluation methods applied were extracted. Each study underwent a quality assessment based on the Drummond checklist for appraisal of high-quality economic evaluations in health care. Eighteen published economic evaluations were identified. Stem cell transplantation in combination with intensive chemotherapy has been demonstrated to be cost-effective, while interferon alpha is generally ineffective at additional costs. Evaluations have become less frequent in the last decade, especially for newer therapies despite their important contribution to improvements in outcomes. The quality of the methodology applied and its documentation can be improved in many aspects. As users of the results of economic evaluations, clinicians involved in guiding decision-making should be critical of the quality of economic evaluations in multiple myeloma. To ensure access to and identification of high-quality studies, researchers conducting economic evaluations of future advances should strive towards evaluations that fulfil the Drummond criteria and are properly documented.


CATAN: Chart-aware temporal attention network for adverse outcome prediction.
There is an increased adoption of electronic health record systems by a variety of hospitals and medical centers. This provides an opportunity to leverage automated computer systems in assisting healthcare workers. One of the least utilized but rich source of patient information is the unstructured clinical text. In this work, we develop CATAN, a chart-aware temporal attention network for learning patient representations from clinical notes. We introduce a novel representation where each note is considered a single unit, like a sentence, and composed of attention-weighted words. The notes in turn are aggregated into a patient representation using a second weighting unit, note attention. Unlike standard attention computations which focus only on the content of the note, we incorporate the chart-time for each note as a constraint for attention calculation. This allows our model to focus on notes closer to the prediction time. Using the MIMIC-III dataset, we empirically show that our patient representation and attention calculation achieves the best performance in comparison with various state-of-the-art baselines for one-year mortality prediction and 30-day hospital readmission. Moreover, the attention weights can be used to offer transparency into our model's predictions.


ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) is a highly invasive and metastatic malignancy. The nerve growth factor receptor (NGFR) has been observed to be expressed on a subset of cells in OSCC, and NGFR+ cells have greater tumor-initiating capacity in vivo. Further, inhibition of NGFR reduces tumor growth, indicating a functional role of this receptor; however, the mechanisms by which NGFR confers enhanced tumor formation are not known. Here, we used an established murine model of OSCC and gene expression array analysis to identify ESM1 as a downstream target gene of NGFR, critical for tumor invasion and metastasis. ESM1 encodes a protein called endocan, which has the property of regulating proliferation, differentiation, migration, and adhesion of different cell types. Incubation of NGFR+ murine OSCC cells with nerve growth factor resulted in increased expression of ESM1. Importantly, ESM1 overexpression conferred an enhanced migratory, invasive, and metastatic phenotype, similar to what has been correlated with NGFR expression. Conversely, shRNA knockdown of ESM1 in NGFR overexpressing OSCC cells abrogated the tumor growth kinetics and the invasive and metastatic properties associated with NGFR. Together, our data indicate that NGFR plays an important role in the pathogenesis and progression of OSCC via regulation of ESM1.


Gender and estrogen supplementation increases severity of experimental choroidal neovascularization.
Observational clinical studies suggest that post-menopausal women may be at risk for more severe age-related macular degeneration, and that estrogen loss due to menopause may contribute. We sought to determine the effect of gender and estrogen status on the severity of choroidal neovascularization (CNV) in a mouse model for experimental choroidal neovascularization. Laser-induced CNV was performed in mice with or without estrogen supplementation. At various times, eyes were removed for analysis of severity of CNV lesions or for extraction of choroidal mRNA to evaluate iNOS, TNF-alpha, MMP-9, and ER-alpha expression, which are molecules relevant to angiogenic processes. Also, splenic macrophages were analysed for iNOS to determine the effect of estrogen treatment in vitro. Finally, laser-induced CNV was performed in iNOS -/- mice. Our result showed that aged female mice had significantly larger CNV than age-matched males. Ovariectomy in adult mice did not increase severity, but paradoxically estrogen supplementation after ovariectomy did increase CNV severity. More severe CNV were associated with a significant decrease in choroidal iNOS mRNA. Splenic macrophages from estrogen supplemented mice showed a significant increased in TNF-alpha mRNA expression (eight fold difference compared to the control) but only a mild change in iNOS mRNA levels (2-3 fold difference). In vitro data further showed that nitric oxide production in splenic macrophages at different estrogen levels was not different from controls. Finally, CNV severity was significantly more severe in iNOS -/- mice, compared to iNOS +/+ mice after laser treatment. In conclusion, aged female mice developed more severe CNV than do males. Estrogen replacement seems to increase severity, possibly by suppressing the upregulation of choroidal iNOS and activating macrophages. The putative beneficial or detrimental role of estrogen biology in age-related macular degeneration must be more carefully evaluated and may vary with the stage of age-related macular degeneration (atrophic or neovascular) as well as with the specific target cell type (monocytes vs. endothelial cell or vascular smooth muscle cell).


Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients.
Multiplex digital PCR (dPCR) enables noninvasive and sensitive detection of circulating tumor DNA with performance unachievable by current molecular-detection approaches. Furthermore, picodroplet dPCR facilitates simultaneous screening for multiple mutations from the same sample. We investigated the utility of multiplex dPCR to screen for the 7 most common mutations in codons 12 and 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) oncogene from plasma samples of patients with metastatic colorectal cancer. Fifty plasma samples were tested from patients for whom the primary tumor biopsy tissue DNA had been characterized by quantitative PCR. Tumor characterization revealed that 19 patient tumors had KRAS mutations. Multiplex dPCR analysis of the plasma DNA prepared from these samples identified 14 samples that matched the mutation identified in the tumor, 1 sample contained a different KRAS mutation, and 4 samples had no detectable mutation. Among the tumor samples that were wild type for KRAS, 2 KRAS mutations were identified in the corresponding plasma samples. Duplex dPCR (i.e., wild-type and single-mutation assay) was also used to analyze plasma samples from patients with KRAS-mutated tumors and 5 samples expected to contain the BRAF (v-raf murine sarcoma viral oncogene homolog B) V600E mutation. The results for the duplex analysis matched those for the multiplex analysis for KRAS-mutated samples and, owing to its higher sensitivity, enabled detection of 2 additional samples with low levels of KRAS-mutated DNA. All 5 samples with BRAF mutations were detected. This work demonstrates the clinical utility of multiplex dPCR to screen for multiple mutations simultaneously with a sensitivity sufficient to detect mutations in circulating DNA obtained by noninvasive blood collection.


Effect of endometrial thickness on ectopic pregnancy in frozen embryo transfer cycles: an analysis including 17,244 pregnancy cycles.
To investigate whether endometrial thickness (EMT) influences the incidence of ectopic pregnancy (EP) in frozen embryo transfer (FET) cycles. Retrospective cohort study. Academic tertiary-care medical center. A total of 16,556 patients were enrolled between January 2010 and December 2017, comprising 16,701 intrauterine, 488 ectopic, and 45 heterotopic pregnancy cycles after FET. None. EP was the primary outcome. EMT was the main measured variable. Data were analyzed with the binary logistic general estimating equations model to calculate the adjusted odds ratio (aOR) for EP. After adjusting for confounders, EMT remained statistically significant as an independent risk factor for EP. Compared with women with an EMT of ≥14 mm, the aORs for women with EMT in the ranges 7-7.9, 8-9.9, and 10-11.9 mm were 2.70 (95% confidence interval [CI], 1.65-4.40), 2.06 (95% CI, 1.33-3.20), and 1.66 (95% CI, 1.07-2.58), respectively. Hormone replacement treatment for endometrial preparation during FET increased the risk of EP after adjustment for confounding variables. EMT is inversely proportional to EP rate in FET cycles and is therefore a potential quantitative marker of endometrial receptivity and uterine contractibility in an FET cycle. The predictive validity of EMT value must be evaluated in further studies.


Seasonal variation in the incidence of spontaneous pneumothorax and its association with climate: a nationwide population-based study.
This study investigated seasonal variation in the incidence of spontaneous pneumothorax (SP) among young adults aged 15-44 years, in order to identify possible associations with meteorological parameters in a subtropical Asian climate. Neither particular months nor seasons of the year were significantly associated with the incidence of SP. While links between meteorological conditions and the incidence of spontaneous pneumothorax (SP) have been postulated, the findings are controversial. In this first large-scale, nationwide, population-based study, seasonal variation in the incidence of SP among young adults aged 15-44 years was investigated, in order to identify possible associations with meteorological parameters (rainfall, ambient temperature, relative humidity, atmospheric pressure, hours of sunshine) in a subtropical Asian climate. Data (2001-2005) from the National Health Insurance Research Database were used to identify a total of 8575 patients who had been hospitalized with a principal diagnosis of SP. The autoregressive integrated moving average method was used to evaluate the effects of seasonality and monthly climatic factors on the incidence of SP. The incidence of SP was not significantly associated with either particular months of the year or seasons. After adjusting for seasonality, month and time trends, relative humidity was positively associated with the monthly incidence of SP among men, while ambient temperature and rainfall were significantly associated with SP events among women. However, changes in monthly atmospheric pressure did not appear to influence the monthly risk of SP. These results do not support the premise that seasonal factors are involved in precipitating SP, although certain climatic parameters showed weak associations with the incidence of SP. Future studies should investigate other combinations of weather phenomena and potential triggering factors, in order to shed light on the occurrence of SP in various regions and climatic conditions, and among both men and women.


Dynamic assessment of learning ability improves outcome prediction following acquired brain injury.
There is a need to improve the prediction of outcome following acquired brain injury. The previous focus has been on specifying the relative contribution of such variables as pre-morbid intellectual ability, socioeconomic status, severity of injury and performance on neuropsychological assessments. To date, findings remain discrepant and often inconclusive. The present study examined whether dynamic assessment testing scores predict outcome. Both standard and dynamic assessment of 77 individuals with acquired brain injury was performed. Dynamic assessment identifies the learning potential of the individual, rather than measuring their statically assessed cognitive ability. The individual's potential to learn the Wisconsin Card Sorting Task (WCST), with guided instruction and feedback, was assessed and compared with standardized static measures. Using Rasch analysis, individual learning potential was determined and, unlike the standard WCST scores, was predictive of integration into the community following brain injury. It is concluded that dynamic testing potentially may offer advantages over the traditional standard cognitive tests in predicting the outcome for people with brain injuries.


Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.


Rosacea: clinical presentation and pathophysiology.
Acne rosacea is one of the most common diagnoses seen in the clinical dermatologic practice. The classic presentation of rosacea, acneiform papules, and pustules on a background of telangiectasia, is often easily identified by primary care physicians, patients, or their similarly afflicted friends or family members. However, rosacea actually represents a spectrum of disease from chronic skin hypersensitivity and flushing to rhinophyma. Although the pathogenesis of rosacea remains unknown, it is important to understand its various presentations and possible etiologies prior to developing individualized treatment protocols.


Adherence of catheterization laboratory cardiologists to American College of Cardiology/American Heart Association guidelines for percutaneous coronary interventions and coronary artery bypass graft surgery: what happens in actual practice?
The American College of Cardiology and the American Heart Association have issued guidelines for the use of coronary artery bypass graft surgery (CABG) and percutaneous coronary interventions (PCI) for many years, but little is known about the impact of these evidence-based guidelines on referral decisions. A cardiac catheterization laboratory database used by 19 hospitals in New York State was used to identify treatment (CABG surgery, PCI, medical treatment, or nothing) recommended by the catheterization laboratory cardiologist for patients undergoing catheterization with asymptomatic/mild angina, stable angina, and unstable angina/non-ST-elevation myocardial infarction between January 1, 2005, and August 31, 2007. The recommended treatment was compared with indications for these patients based on American College of Cardiology/American Heart Association guidelines. Of the 16 142 patients undergoing catheterization who were found to have coronary artery disease, the catheterization laboratory cardiologist was the final source of recommendation for 10 333 patients (64%). Of these 10 333 patients, 13% had indications for CABG surgery, 59% for PCI, and 17% for both CABG surgery and PCI. Of the patients who had indications for CABG surgery, 53% were recommended for CABG and 34% for PCI. Of the patients with indications for PCI, 94% were recommended for PCI. For the patients who had indications for both CABG surgery and PCI, 93% were recommended for PCI and 5% for CABG surgery. Catheterization laboratory cardiologists in hospitals with PCI capability were more likely to recommend patients for PCI than hospitals in which only catheterization was performed. Patients with coronary artery disease receive more recommendations for PCI and fewer recommendations for CABG surgery than indicated in the American College of Cardiology/American Heart Association guidelines.


Adenosine triphosphatase activity of streptozotocin-induced diabetic rat brain microsomes. Effect of vitamin E.
Hyperglycemia causes protein glycosylation, oxidation and alterations in enzyme activities, which are the underlying causes of diabetic complications. This study was undertaken to test the role of vitamin E treatment on Ca2+-ATPase activity, protein glycosylation and lipid peroxidation in the brain of streptozotocin (STZ)-induced diabetic rats. Male rats weighing about 250-300 g were rendered diabetic by a single STZ injection of 50 mg/kg via the tail vein. Both the diabetic and non-diabetic rats were fed a vitamin E supplemented diet (500 IU/kg/day). Ca2+-ATPase activity was significantly reduced at week 10 of diabetes compared to the control group (p < 0.05), with 0.225+/-0.021 U/I (mean +/- S.E.M.) in the control group and 0.072 +/- 0.008 U/l (mean +/- S.E.M.) in the diabetic group. Vitamin E treatment prevented the enzyme activity from decreasing. The activities observed were 0.226 +/- 0.020 U/l and 0.172 +/- 0.011 U/I (mean +/- S.E.M.) in the vitamin E-treated control and diabetic group, respectively. STZ-induced diabetes resulted in an increased protein glycosylation and lipid peroxidation. Vitamin E treatment led to a significant inhibition in blood glucose, protein glycosylation and lipid peroxidation, which in turn prevented abnormal activity of the enzyme in the brain. This study indicates that vitamin E supplementation may reduce complications of diabetes in the brain.


Slow swimming, fast strikes: effects of feeding behavior on scaling of anaerobic metabolism in epipelagic squid.
Many pelagic fishes engage prey at high speeds supported by high metabolic rates and anaerobic metabolic capacity. Epipelagic squids are reported to have among the highest metabolic rates in the oceans as a result of demanding foraging strategies and the use of jet propulsion, which is inherently inefficient. This study examined enzymatic proxies of anaerobic metabolism in two species of pelagic squid, Dosidicus gigas and Doryteuthis pealeii (Lesueur 1821), over a size range of six orders of magnitude. We hypothesized that activity of the anaerobically poised enzymes would be high and increase with size as in ecologically similar fishes. In contrast, we demonstrate that anaerobic metabolic capacity in these organisms scales negatively with body mass. We explored several cephalopod-specific traits, such as the use of tentacles to capture prey, body morphology and reduced relative prey size of adult squids, that may create a diminished reliance on anaerobically fueled burst activity during prey capture in large animals.


Estrogen promotes the development of mouse cumulus cells in coordination with oocyte-derived GDF9 and BMP15.
The differentiation and function of cumulus cells depend upon oocyte-derived paracrine factors, but studies on the estrogen receptor knockout mice suggested that estrogen also participates in these processes. This study investigates the possible coordination of estrogen and oocytes in the development and function of cumulus cells using cumulus expansion and the expression of transcripts required for expansion as functional endpoints. Preantral granulosa cell-oocyte complexes developed in vitro with 17β-estradiol (E2) exhibited increased levels of cumulus expansion and Has2 transcripts, encoding hyaluronan synthase 2, compared with those developed without E2. Moreover, cumulus cell-oocyte complexes (COCs) isolated from antral follicles and maintained in culture without E2 exhibited reduced cumulus expansion and Has2 mRNA levels compared with freshly isolated COCs. Exogenous E2, provided during the maintenance culture, alleviated these deficiencies. However, when oocytes were removed from COCs, E2 supplementation did not maintain competence to undergo expansion; the presence in culture of either fully grown oocytes or recombinant growth differentiation factor 9 (GDF9) was required. Recombinant bone morphogenetic protein 15, but not fibroblast growth factor 8, augmented the GDF9 effect. Oocytes or GDF9 suppressed cumulus cell levels of Nrip1 transcripts encoding nuclear receptor-interacting protein 1, a potential inhibitor of estrogen receptor signals. Therefore, E2 and oocyte-derived paracrine factors GDF9 and bone morphogenetic protein 15 coordinate to promote the development of cumulus cells and maintain their competence to undergo expansion. Furthermore, suppression of Nrip1 expression in cumulus cells by oocyte may be one mechanism mediating cross talk between oocyte and E2 signals that promotes follicular development.


Monte Carlo simulations of the static friction between two grafted polymer brushes.
A configurational bias Monte Carlo method has been developed to study the static friction between grafted polymers immersed in a good solvent. Simple models using the soft quadratic potential from a dissipative particle dynamics study have been used to model polyzwitterionic brushes at physiological pressures (up to 7.5 MPa). Three models of decreasing rigidity have been used to model the friction between the brushes by calculating the tangential component of the pressure induced by a mismatch in the registry of the two grafting surfaces. The static friction coefficient can be calculated for three model systems and the slip between the layers occurs at a much lower values of shear force for the more flexible polymer layer. A moderate increase in the flexibility of the chains reduces the friction coefficient by a factor of ca. 20. Tilting the layer directors of the brushes also increases the static friction between the layer when the top, tilted layer is displaced in the direction away from the tilt. Non-equilibrium dynamics techniques for the same model were performed using dissipative particle dynamics and the limiting extremes of the Stribeck curve corresponding to the boundary lubrication regime and the hydrodynamic lubrication regime were observed for these flat surfaces. As expected, μk is significantly lower than μs for the same system. The dynamical friction coefficients in the model are in good agreement with those observed in the experiment and the ratio of μk/μs of between 0.11 and 0.5 observed in the simulations is in reasonable agreement with the value of 0.5 normally observed for these seen for these systems.


Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.
Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.


Retail Pharmacy Policy to End the Sale of Tobacco Products: What Is the Impact on Disparity in Neighborhood Density of Tobacco Outlets?
Population-level research on the implications of retail pharmacy policies to end the sale of tobacco products is scant, and the impact of such policies on racial/ethnic and socioeconomic disparities across neighborhoods in access to tobacco products remains unexplored. We investigated the association between neighborhood sociodemographic characteristics and tobacco retail density in Rhode Island (RI; N = 240 census tracts). We also investigated whether the CVS Health (N = 60) policy to end the sale of tobacco products reduces the disparity in the density of tobacco retail across neighborhoods, and we conducted a prospective policy analysis to determine whether a similar policy change in all pharmacies in RI (N = 135) would reduce the disparity in tobacco retail density. The results revealed statistically significant associations between neighborhood sociodemographic characteristics and tobacco retail outlet density across RI neighborhoods. The results when excluding the CVS Health locations, as well as all pharmacies as tobacco retailers, revealed no change in the pattern for this association. The results of this study suggest that while a commendable tobacco control policy, the CVS Health policy appears to have no impact on the neighborhood racial/ethnic and socioeconomic disparities in the density of tobacco retailers in RI. Prospective policy analyses showed no impact on this disparity even if all other pharmacies in the state adopted a similar policy. Policy efforts aimed at reducing the disparity in access to tobacco products should focus on reducing the density of tobacco outlets in poor and racial/ethnic neighborhoods. Cancer Epidemiol Biomarkers Prev; 25(9); 1305-10. ©2016 AACR.


Effect of Chlorophytum Borivilianum Santapau and Fernandes on sexual dysfunction in hyperglycemic male rats.
To investigate the effects of Chlorophytum borivilianum (CB) on sexual dysfunction, loss of body weight, and lack of libido in hyperglycemic rats induced with streptozotocin or alloxan. Wistar strain male albino rats were divided into five groups of six animals each: the control group (2% polyvinylpyrollidone solution), the streptozotocin control group (50 mg/kg), the alloxan control group (100 mg/kg), the streptozotocin + CB treated group (200 mg/kg), and the alloxan + CB treated group (200 mg/kg). Only after confirming the induction of diabetes, the animals of test groups were treated with CB. The sexual behavior of male rats of in presence of female rat in a special cage was recorded. The effects of induced diabetes in control groups and on simultaneous extract treatment in CB treated groups were tested for sexual parameters. The parameters evaluated included mount, ejaculation, and intromission latencies/frequencies, hesitation time, and penile erection index. Parallel to this, using a separate set of similarly treated animals, the influence of diabetes and CB treatment on anabolism and weight of secondary sexual organs were determined on day 0 and day 28 of the treatment. CB extract treatment ameliorated the diabetes-induced dysfunction at 200 mg/kg dose. There was very low weight loss (P<0.05) in CB-treated animals as compared to the diabetic control. There was a very high latency time (P<0.05) in the diabetic animals, whereas the latency time was very low in CB-treated animals. Mount, intromission, and ejaculation frequencies were very high (P<0.01) in CB-treated animals, while streptozotocin and alloxan groups animals had a very significantly lower sexual behavior (P<0.05) compared to the normo-glycemic control group animals. CB can significantly ameliorate diabetes-induced sexual dysfunction. Polysaccharide and saponin-rich aqueous extract appears to have the most suitable effects on diabetes and its associated effects on sexual functionality.


Implementation of the Bamako Initiative: strategies in Benin and Guinea.
Two West African countries, Benin and Guinea, have been reorganizing their peripheral health systems since 1986, with the goal of improving access to primary health care (PHC). A comprehensive approach evolve, based on improving effectiveness, optimizing efficiency, ensuring financial variability and promoting equity. These strategies were launched as the Bamako Initiative by the World Health Organization's Regional Assembly in 1987. This is the first in a series of five articles on the Bamako Initiative in Benin and Guinea. The strategies implemented in these two countries are discussed. Subsequent articles discuss the improved health indicators, impact on service costs efficiency, and community empowerment through local cost recovery and equity implications. The health center is the basis for a revitalized primary care system. From here, an integrated minimum health care package is readily accessible to meet basic community health needs. Through the Bamako Initiative program, drugs and other essential resources are always available, regular contract between the community health service providers and communities has increased, and the quality of care has improved while also becoming more efficient. Community health resources are managed locally through joint microplanning and monitoring, involving health personnel and village committees. Community ownership, fostered by local budgeting and decision making, is an essential pillar for the success of the system.


Gas exchange responses to constant work-rate exercise in patients with glycogenosis type V and VII.
During constant work-rate exercise above the lactic acidosis threshold, oxygen consumption fails to plateau by 3 minutes, but continues to rise slowly. This slow component correlates closely with the rise in lactate in normal subjects. We investigated if oxygen consumption during constant work-rate exercise could rise after 3 minutes in the absence of a rise in lactate. We studied five patients with McArdle's disease, one patient with phosphofructokinase deficiency and six normal subjects. Subjects performed two 6-minute duration constant work-rate exercise tests at 40 and 70% of peak oxygen consumption. During low-intensity exercise, oxygen consumption reached steady state by 3 minutes in both groups. Lactate rose slightly in control subjects but not in patients. During high-intensity exercise, oxygen consumption rose from the third to the sixth minute by 144 (21-607) ml/minute (median and range) in control subjects and by 142 (73-306) ml/minute in patients (p = not significant, Mann-Whitney U test). Over the same period, lactate (geometric mean and range) rose from 2.68 (1.10-5.00) to 5.39 (2.70-10.00) mmol/L in control subjects, but did not rise in patients (1.20 [0.64-1.60] to 0.70 [0.57-1.20] mmol/L). We conclude that the slow component of oxygen consumption during heavy exercise is not dependent on lactic acidosis.


The ATR-WEE1 kinase module inhibits the MAC complex to regulate replication stress response.
DNA damage response is a fundamental mechanism to maintain genome stability. The ATR-WEE1 kinase module plays a central role in response to replication stress. Although the ATR-WEE1 pathway has been well studied in yeasts and animals, how ATR-WEE1 functions in plants remains unclear. Through a genetic screen for suppressors of the Arabidopsis atr mutant, we found that loss of function of PRL1, a core subunit of the evolutionarily conserved MAC complex involved in alternative splicing, suppresses the hypersensitivity of atr and wee1 to replication stress. Biochemical studies revealed that WEE1 directly interacts with and phosphorylates PRL1 at Serine 145, which promotes PRL1 ubiquitination and subsequent degradation. In line with the genetic and biochemical data, replication stress induces intron retention of cell cycle genes including CYCD1;1 and CYCD3;1, which is abolished in wee1 but restored in wee1 prl1. Remarkably, co-expressing the coding sequences of CYCD1;1 and CYCD3;1 partially restores the root length and HU response in wee1 prl1. These data suggested that the ATR-WEE1 module inhibits the MAC complex to regulate replication stress responses. Our study discovered PRL1 or the MAC complex as a key downstream regulator of the ATR-WEE1 module and revealed a novel cell cycle control mechanism.


Focal periocular carboplatin chemotherapy avoids systemic chemotherapy for unilateral, progressive retinoblastoma.
The purpose of this study was to report a case of a boy with unilateral, multifocal retinoblastoma who was successfully treated with periocular carboplatin injections for a tumor that progressed despite focal laser ablation. This is an interventional case report. A boy with a paternal history of retinoblastoma and in utero identification of an RB1 mutation was monitored beginning at 2 weeks of age. When the patient was 6 months old, the first tumor was detected and treatment with a direct, ablative, large spot-size diode laser was initiated. During a 38-month period of follow-up, the patient received 23 laser treatments and 3 periocular carboplatin injections (20 mg in 2 mL) to treat 3 tumors in 1 eye. Initially, diode laser ablation of the tumors produced a favorable involutional response of the tumors, associated with a decrease in size and vascularity. Despite aggressive treatment with 12 consecutive laser treatments for 9.7 months, progressive tumor growth was observed in the superonasal tumor, whereas the other 2 tumors remained quiescent. At that time, a series of three focal periocular injections of carboplatin were administered in combination with continued laser ablation. The tumor regressed with type 4 chorioretinal scarring. No systemic chemotherapy or radiation was required. This case of unilateral, multifocal retinoblastoma was successfully treated solely with diode laser ablation and rescue periocular injections of carboplatin after the failure of laser alone. A trial of periocular carboplatin with laser may be considered in cases of unilateral retinoblastoma that are resistant to laser ablation therapy alone.


Multiple plant diversity components drive consumer communities across ecosystems.
Humans modify ecosystems and biodiversity worldwide, with negative consequences for ecosystem functioning. Promoting plant diversity is increasingly suggested as a mitigation strategy. However, our mechanistic understanding of how plant diversity affects the diversity of heterotrophic consumer communities remains limited. Here, we disentangle the relative importance of key components of plant diversity as drivers of herbivore, predator, and parasitoid species richness in experimental forests and grasslands. We find that plant species richness effects on consumer species richness are consistently positive and mediated by elevated structural and functional diversity of the plant communities. The importance of these diversity components differs across trophic levels and ecosystems, cautioning against ignoring the fundamental ecological complexity of biodiversity effects. Importantly, plant diversity effects on higher trophic-level species richness are in many cases mediated by modifications of consumer abundances. In light of recently reported drastic declines in insect abundances, our study identifies important pathways connecting plant diversity and consumer diversity across ecosystems.


Cost-benefit analysis of investment in occupational health and safety in Colombian companies.
To determine whether investment in preventive measures by a Colombian insurer reduces rates of work-related injuries and results in positive returns from these investments. The study is based on monthly panel data of 2011-2015 of 303 medium and large companies affiliated with a private insurer in Colombia. We undertook regression modeling analysis to assess the effectiveness of incremental investments in occupational health and safety (OHS) prevention measures. The cost-benefit analysis is from the insurer's perspective. Investment in OHS per full-time equivalent was statistically significant at the 1% level. We estimated that 4919 injuries were averted through these investments, resulting in the avoidance of $3 949 957 in costs. Our results suggest that the investments were worth undertaking from the insurer's perspective. This paper provides new empirical evidence on the effectiveness and cost-benefit of OHS investments in a middle-income country. Incremental investment in OHS can be effective and cost-beneficial.


Nurse prescribing by children's nurses: views of doctors and clinical leads in one specialist children's hospital.
To explore the views of doctors and clinical leads (CLs), who care for children and young people, on nurse prescribing in one specialist children's hospital. Nearly 14,000 nurses in the UK have virtually the same prescribing rights as doctors. Benefits of nurses adopting this role have been reported, but doctors do have some concerns. Increasing numbers of specialist nurses involved in the care of children in the hospital setting are undertaking prescribing training. No research has explored the views of health care professionals on nurse prescribing in this setting. A subset of qualitative data taken from a larger study that adopted an intrinsic case study design. Interviews were conducted between October 2006-July 2007 with 11 doctors and three clinical leads in one specialist children's hospital. A thematic analysis was conducted on the interview data. Nurse prescribing improved access to medicines and continuity of care. Concerns included the need for doctors to have confidence in the ability of the nurse who wanted to become a prescriber, the selection of nurses for prescribing training, the effects of nurse prescribing on the individual roles and responsibilities of doctors and nurses' clinical skills. Doctors and clinical leads working in a specialist children's hospital in the UK recognise that nurse prescribing makes a positive contribution to the delivery of services. However, it is important that nurses have the appropriate clinical skills and doctors understand nurse prescribing. This will only take place if there is good communication across professional boundaries. Selection processes for the prescribing programmes must ensure that students have the necessary course prerequisites. Communication across professional boundaries is crucial to the successful implementation of nurse prescribing in the care of children and young people in the hospital setting.


Estimation of optical constants of thin film by the use of artificial neural networks.
A system for analyzing single-layer optical thin films has been formulated by the use of artificial neural networks. The training data sets stem from the computational results of the physical model of thin films, and they are used to train the artificial neural network, which, when done, can give values of film parameters in the millisecond time regime. The fast backpropagation algorithm is employed during training. The results of training are also given.


Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines.
The normal process of epithelial mesenchymal transition (EMT) is subverted by carcinoma cells to facilitate metastatic spread. Cancer cells rarely undergo a full conversion to the mesenchymal phenotype, and instead adopt positions along the epithelial-mesenchymal axis, a propensity we refer to as epithelial mesenchymal plasticity (EMP). EMP is associated with increased risk of metastasis in breast cancer and consequent poor prognosis. Drivers towards the mesenchymal state in malignant cells include growth factor stimulation or exposure to hypoxic conditions. We have examined EMP in two cell line models of breast cancer: the PMC42 system (PMC42-ET and PMC42-LA sublines) and MDA-MB-468 cells. Transition to a mesenchymal phenotype was induced across all three cell lines using epidermal growth factor (EGF) stimulation, and in MDA-MB-468 cells by hypoxia. We used RNA sequencing to identify gene expression changes that occur as cells transition to a more-mesenchymal phenotype, and identified the cell signalling pathways regulated across these experimental systems. We then used inhibitors to modulate signalling through these pathways, verifying the conclusions of our transcriptomic analysis. We found that EGF and hypoxia both drive MDA-MB-468 cells to phenotypically similar mesenchymal states. Comparing the transcriptional response to EGF and hypoxia, we have identified differences in the cellular signalling pathways that mediate, and are influenced by, EMT. Significant differences were observed for a number of important cellular signalling components previously implicated in EMT, such as HBEGF and VEGFA. We have shown that EGF- and hypoxia-induced transitions respond differently to treatment with chemical inhibitors (presented individually and in combinations) in these breast cancer cells. Unexpectedly, MDA-MB-468 cells grown under hypoxic growth conditions became even more mesenchymal following exposure to certain kinase inhibitors that prevent growth-factor induced EMT, including the mTOR inhibitor everolimus and the AKT1/2/3 inhibitor AZD5363. While resulting in a common phenotype, EGF and hypoxia induced subtly different signalling systems in breast cancer cells. Our findings have important implications for the use of kinase inhibitor-based therapeutic interventions in breast cancers, where these heterogeneous signalling landscapes will influence the therapeutic response.


"If you do vasectomy and come back here weak, I will divorce you": a qualitative study of community perceptions about vasectomy in Southern Ghana.
Male involvement in contraceptive use is increasingly becoming a global reproductive health issue. Vasectomy is one of the two male modern contraceptive methods espoused by the National Family Planning Policy in Ghana. Despite these advocacies, there are reports of low patronage of this method in Ghana. This study adhering to RATS guidelines on qualitative research therefore explored the social and cultural factors that may be affecting the low vasectomy uptake in Southern Ghana. The study was conducted in Sefwi Bibiani-Ahwiaso Bekwai (SBAB) District and Komenda-Edina-Eguafo-Abrem (KEEA) Municipal area in the Western and Central regions of Ghana respectively. Twelve Focus Group Discussions were held with both male and female community members. In-depth interviews were also carried out with Community Health Officers (CHOs), Community Health Volunteers (CHVs) and health managers at both the district and regional levels. The discussions and interviews were recorded, transcribed verbatim and analysed using Nvivo 10. The study revealed that vasectomy was perceived as an act against God, which was punishable either by death or answerable on judgement day. Vasectomy was also perceived to be a form of castration, which can make men weak and incapable, thereby unable to satisfy their wives sexually, leading to marital conflicts. Women were more concerned about the negative effects of vasectomy on men. Cafalgin and panacin which are locally manufactured analgesics were perceived to have contraceptive abilities and therefore used by men as an alternative to modern contraceptive methods. Stigma and the misconceptions in the community may be accounting for the low vasectomy uptake in Ghana despite several advocacy strategies. Women were highly influential in a man's decision on vasectomy. This calls for the need to increase health education to demystify the misconceptions about vasectomy. Vasectomy-related campaign messages should target both men and women.


Store-operated calcium entry: Pivotal roles in renal physiology and pathophysiology.
Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid-base homeostasis. Many of these cells are regulated by Ca2+ signaling. Recent evidence demonstrates that SOCCs are major Ca2+ entry portals in several renal cell types. SOCC is activated by depletion of Ca2+ stores in the sarco/endoplasmic reticulum, which communicates with plasma membrane SOCC via the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Orai1 is recognized as the main pore-forming subunit of SOCC in the plasma membrane. Orai proteins alone can form highly Ca2+ selective SOCC channels. Also, members of the Transient Receptor Potential Canonical (TRPC) channel family are proposed to form heteromeric complexes with Orai1 subunits, forming SOCC with low Ca2+ selectivity. Recently, Ca2+ entry through SOCC, known as store-operated Ca2+ entry (SOCE), was identified in glomerular mesangial cells, tubular epithelium, and renovascular smooth muscle cells. The physiological and pathological relevance and the characterization of SOCC complexes in those cells are still unclear. In this review, we summarize the current knowledge of SOCC and their roles in renal glomerular, tubular and vascular cells, including studies from our laboratory, emphasizing SOCE regulation of fibrotic protein deposition. Understanding the diverse roles of SOCE in different renal cell types is essential, as SOCC and its signaling pathways are emerging targets for treatment of SOCE-related diseases.