Local synchronization of resting-state dynamics encodes Gray's trait Anxiety.
The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray's trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray's trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray's trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray's trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray's BIS.


Serological analysis of sensitization in allergic bronchopulmonary aspergillosis: a study on allergen components and interspecies relationships.
Background: Serological testing for immunoglobulin (Ig) E or IgG is useful for diagnosing allergic bronchopulmonary aspergillosis (ABPA), as it detects type I and III allergic reactions to Aspergillus species. However, few reports have investigated the allergen component and cross-reactivity among Aspergillus species. We aimed to measure and analyze the levels of IgGs specific to each Aspergillus species and investigate the prevalence of IgEs specific to each allergen component of A. fumigatus (Af) in ABPA patients.Methods: Serum samples were collected from 12 ABPA patients who visited our hospital between February and December 2017, and 16 with Af-sensitized asthma and 41 with Af-unsensitized asthma were controls. Immuno-CAP was performed to analyze the IgEs and IgGs specific to Af, A. niger, A flavus and A. terreus, and IgEs specific to allergen components Asp f 1, 2, 3, 4 and 6.Results: The ABPA group was significantly more frequently sensitized to Asp f 1 and 2 than the control groups. Af-specific IgEs were significantly positively correlated to the IgEs specific to A. flavus, A. niger and A. terreus. Af-specific IgGs were positively correlated to the IgGs specific to all the other species.Conclusions: Tests using allergen components were useful for ABPA diagnosis. Both IgE and IgG were highly cross-reactive among the Aspergillus species. There were many patients apart from asthmatic patients with ABPA, who displayed high Aspergillus IgG values.


Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells.
Renal angiomyolipomas (AML) contain an admixture of clonal tumour cells with features of several different mesenchymal lineages, implying the existence of an unidentified AML neoplastic stem cell. Biallelic inactivation of TSC2 or TSC1 is believed to represent the driving event in these tumours. Here we show that TSC2 knockdown transforms senescence-resistant cultured mouse and human renal epithelial cells into neoplastic stem cells that serially propagate renal AML-like tumours in mice. mTOR inhibitory therapy of mouse AML allografts mimics the clinical responses of human renal AMLs. Deletion of Tsc1 in mouse renal epithelia causes differentiation in vivo into cells expressing characteristic AML markers. Human renal AML and a renal AML cell line express proximal tubule markers. We describe the first mouse models of renal AML and provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells, uncovering an unexpected pathological differentiation plasticity of the proximal tubule.


Concurrent Guillain-Barré syndrome, transverse myelitis and encephalitis post-Zika: A case report and review of the pathogenic role of multiple arboviral immunity.
We review post-infectious and post-vaccination neurological syndromes involving peripheral and central nervous system (CNS) and report an illustrative case of simultaneous occurrence of Guillain-Barré syndrome (GBS), confirmed by nerve conduction velocities, plus MRI-demonstrated transverse myelitis (TM) and acute encephalitis [acute disseminated encephalomyelitis] (ADEM+GBS) affecting a 24-year-old woman from Cúcuta, Colombia, who developed acute Zika virus (ZIKV) infection confirmed by serum reverse transcriptase-polymerase chain reaction (RT-PCR) and convalescent ZIKV IgG antibodies. With intensive care treatment, respiratory support, steroids, and intravenous immunoglobulin (IVIg), patient survived with residual flaccid paraparesis. She had preexisting immunity against Chikungunya virus (CHIKV) and Dengue virus (DENV) acquired before the arrival of ZIKV in Colombia. From reports in the Caribbean, Central and South America we review 19 cases of ZIKV-associated TM, encephalitis and ADEM occurring after a mean latent period of 10.5 days (range 1-96) post-infection. Although GBS and ADEM are usually considered post-infectious and associated with development of antibodies against peripheral nerve and CNS epitopes, we postulate that our case of ADEM+GBS is para-infectious, induced by acute ZIKV neurotropism boosted by active immunity against other arboviruses. Animal models of ZIKV demonstrated strong viral neurotropism enhanced by passive immunity with antibodies against arboviruses such as West Nile virus, CHIKV, or DENV. These considerations are relevant to prevent potential ZIKV vaccine-induced reactions involving central and peripheral nervous system.


Developmental changes in the perception of visuotactile simultaneity.
A simultaneity judgment (SJ) task was used to measure the developmental trajectory of visuotactile simultaneity perception in children (aged 7, 9, 11, and 13 years) and adults. Participants were presented with a visual flash in the center of a computer monitor and a tap on their right index finger (located 20° below the flash) with 13 possible stimulus onset asynchronies (SOAs). Participants reported whether the flash and tap were presented at the same time. Compared with the adult group, children aged 7 and 9 years made more simultaneous responses when the tap led by more than 300 ms and when the flash led by more than 200 ms, whereas they made fewer simultaneous responses at the 0 ms SOA. Model fitting demonstrated that the window of visuotactile simultaneity became narrower with development and reached adult-like levels between 9 and 11 years of age. Response errors decreased continuously until 11 years of age. The point of subjective simultaneity (PSS) was located on the tactile-leading side in all participants tested, indicating that 7-year olds (the youngest age tested) are adult-like on this measure. In summary, the perception of visuotactile simultaneity is not fully mature until 11 years of age. The protracted development of visuotactile simultaneity perception may be related to the need for crossmodal recalibration as the body grows and to the developmental improvements in the ability to optimally integrate visual and tactile signals.


Consequences of seafood mislabeling for marine populations and fisheries management.
Over the past decade, seafood mislabeling has been increasingly documented, raising public concern over the identity, safety, and sustainability of seafood. Negative outcomes from seafood mislabeling are suspected to be substantial and pervasive as seafood is the world's most highly traded food commodity. Here we provide empirical systems-level evidence that enabling conditions exist for seafood mislabeling in the United States (US) to lead to negative impacts on marine populations and support consumption of products from poorly managed fisheries. Using trade, production, and mislabeling data, we determine that substituted products are more likely to be imported than the product listed on the label. We also estimate that about 60% of US mislabeled apparent consumption associated with the established pairs involves products that are exclusively wild caught. We use these wild-caught pairs to explore population and management consequences of mislabeling. We find that, compared to the product on the label, substituted products come from fisheries with less healthy stocks and greater impacts of fishing on other species. Additionally, substituted products are from fisheries with less effective management and with management policies less likely to mitigate impacts of fishing on habitats and ecosystems compared with the label product. While we provide systematic evidence of environmental impacts from food fraud, our results also highlight the current challenges with production, trade, and mislabeling data, which increase the uncertainty surrounding seafood mislabeling consequences. More integrated, holistic, and collaborative approaches are needed to understand mislabeling impacts and design interventions to minimize mislabeling.


C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis.
Hereditary angioedema (HAE) caused by functional deficiency of C1-inhibitor (C1-INH) is a rare disease that manifests with recurrent spontaneous nonallergic edema of the subcutaneous tissues and mucous membranes. In cases of laryngeal edema that are not treated immediately, HAE is associated with high mortality rates. Attenuated androgens (e.g., danazol) are usually administered for prophylaxis, but associated side effects may limit their use. This study investigated the efficacy, safety, and quality of life (QoL) associated with a pasteurized plasma-derived C1-inhibitor (pC1-INH) concentrate for individual replacement therapy (IRT) in patients with severe HAE suffering from frequent attacks who were intolerant or not responding to danazol. Twenty-two patients with severe HAE and danazol incompatibility or insufficient efficacy of danazol were recruited. Intraindividual comparisons of efficacy, safety, and QoL with pC1-INH concentrate IRT versus danazol treatment were made using retrospective and prospective patient data. Pharmacokinetic data were collected for 15 of the 22 patients. In patients receiving pC1-INH regularly, the median number of attacks per year decreased significantly compared to danazol prophylaxis (p < 0.001), and the 24 laryngeal edema episodes per year ceased. Superior efficacy of pC1-INH was found for all QoL variables (e.g., general condition, social activities). No transmission of human immunodeficiency virus or hepatitis A, B, or C was observed. In patients with severe HAE who experience severe side effects and/or lack of efficacy of danazol prophylaxis, very early substitution with pC1-INH can completely abolish the incidence of potentially fatal laryngeal edema and can reduce the incidence of acute attacks.


Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer.
Compared to patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism are more likely to develop recurrent venous thromboembolism (VTE). To compare the efficacy and safety of three types of parenteral anticoagulants for the initial treatment of VTE in patients with cancer. A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. Randomized clinical trials (RCTs) comparing low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux in patients with cancer and objectively confirmed VTE. Using a standardized data form, data was extracted in duplicate on methodological quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. Of 3986 identified citations, 16 RCTs were eligible: 13 compared LMWH to UFH, two compared fondaparinux to heparin, and one compared dalteparin to tinzaparin. Meta-analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow up with LMWH compared with UFH (relative risk (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodological quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of death (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63) or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin to tinzaparin did not find a statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73). LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient important outcomes will further inform the questions addressed in this review.


Globalization of stem cell science: an examination of current and past collaborative research networks.
Science and engineering research has becoming an increasingly international phenomenon. Traditional bibliometric studies have not captured the evolution of collaborative partnerships between countries, particularly in emerging technologies such as stem cell science, in which an immense amount of investment has been made in the past decade. Analyzing over 2,800 articles from the top journals that include stem cell research in their publications, this study demonstrates the globalization of stem cell science. From 2000 to 2010, international collaborations increased from 20.9% to 36% of all stem cell publications analyzed. The United States remains the most prolific and the most dominant country in the field in terms of publications in high impact journals. But Asian countries, particularly China are steadily gaining ground. Exhibiting the largest relative growth, the percent of Chinese-authored stem cell papers grew more than ten-fold, while the percent of Chinese-authored international papers increased over seven times from 2000 to 2010. And while the percent of total stem cell publications exhibited modest growth for European countries, the percent of international publications increased more substantially, particularly in the United Kingdom. Overall, the data indicated that traditional networks of collaboration extant in 2000 still predominate in stem cell science. Although more nations are becoming involved in international collaborations and undertaking stem cell research, many of these efforts, with the exception of those in certain Asian countries, have yet to translate into publications in high impact journals.


Features of Mobile Apps for People with Autism in a Post COVID-19 Scenario: Current Status and Recommendations for Apps Using AI.
The new 'normal' defined during the COVID-19 pandemic has forced us to re-assess how people with special needs thrive in these unprecedented conditions, such as those with Autism Spectrum Disorder (ASD). These changing/challenging conditions have instigated us to revisit the usage of telehealth services to improve the quality of life for people with ASD. This study aims to identify mobile applications that suit the needs of such individuals. This work focuses on identifying features of a number of highly-rated mobile applications (apps) that are designed to assist people with ASD, specifically those features that use Artificial Intelligence (AI) technologies. In this study, 250 mobile apps have been retrieved using keywords such as autism, autism AI, and autistic. Among 250 apps, 46 were identified after filtering out irrelevant apps based on defined elimination criteria such as ASD common users, medical staff, and non-medically trained people interacting with people with ASD. In order to review common functionalities and features, 25 apps were downloaded and analysed based on eye tracking, facial expression analysis, use of 3D cartoons, haptic feedback, engaging interface, text-to-speech, use of Applied Behaviour Analysis therapy, Augmentative and Alternative Communication techniques, among others were also deconstructed. As a result, software developers and healthcare professionals can consider the identified features in designing future support tools for autistic people. This study hypothesises that by studying these current features, further recommendations of how existing applications for ASD people could be enhanced using AI for (1) progress tracking, (2) personalised content delivery, (3) automated reasoning, (4) image recognition, and (5) Natural Language Processing (NLP). This paper follows the PRISMA methodology, which involves a set of recommendations for reporting systematic reviews and meta-analyses.


Gene regulation divergence is a major contributor to the evolution of Dobzhansky-Muller incompatibilities between species of Drosophila.
The Dobzhansky-Muller model denotes incompatible gene interactions between diverging populations/species and is recognized as the basis of postzygotic reproductive isolation. Little is known about the molecular nature of such gene interactions. We have carried out comparative gene expression analyses in the testes of 3 closely related species of the Drosophila melanogaster subgroup and their hybrids (all of which are sterile). We show that in hybrids 1) a higher proportion of male-biased genes (i.e., genes with a higher level of expression in males) are underexpressed (or not expressed) compared with non-sex-biased genes, 2) the majority of the underexpressed genes appear to be under stabilizing selection by virtue of showing similar levels of expression in the parental species, and only a small proportion of genes show signs of directional selection, 3) very few of the misexpressed genes are shared between species pairs, suggesting that there may not be a "common" set of "speciation genes," and 4) expression of non-testes-specific genes is observed in the testes of interspecific hybrids, and the number of such genes is positively correlated with divergence time. These results suggest that gene regulation divergence of sex- and reproduction-related genes is a major contributor to the evolution of Dobzhansky-Muller incompatibilities between species of Drosophila.


Surface analysis under ambient conditions using plasma-assisted desorption/ionization mass spectrometry.
A novel plasma-assisted desorption/ionization (PADI) method that can be coupled with atmospheric pressure sampling mass spectrometry to yield mass spectral information under ambient conditions of pressure and humidity from a range of surfaces without the requirement for sample preparation or additives is reported. PADI is carried out by generating a nonthermal plasma which interacts directly with the surface of the analyte. Desorption and ionization then occur at the surface, and ions are sampled by the mass spectrometer. The PADI technique is demonstrated and compared with desorption electrospray ionization (DESI) for the detection of active ingredients in a range of over-the-counter and prescription pharmaceutical formulations, including nonsterodial anti-inflammatory drugs (mefenamic acid, Ibugel, and ibuprofen), analgesics (paracetamol, Anadin Extra), and Beecham's "all in one" cold and flu remedy. PADI has also been successfully applied to the analysis of nicotine in tobacco and thiosulfates in garlic. PADI experiments have been performed using a prototype source interfaced with a Waters Platform LCZ single-quadrupole mass spectrometer with limited modifications and a Hiden Analytical HPR-60 molecular beam mass spectrometer (MBMS). The ability of PADI to rapidly detect active ingredients in pharmaceuticals without the need for prior sample preparation, solvents, or exposed high voltages demonstrates the potential of the technique for high-throughput screening in a pharmaceutical or forensic environment.


Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype.
Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.


On the effect of local sample slope during modulus measurements by contact-resonance atomic force microscopy.
Contact-resonance atomic force microscopy (CR-AFM) is of great interest and very valuable for a deeper understanding of the mechanics of biological materials with moduli of at least a few GPa. However, sample surfaces can present a high topography range with significant slopes, where the local angle can be as large as ± 50°. The non-trivial correlation between surface slope and CR-frequency hinders a straight-forward interpretation of CR-AFM indentation modulus measurements on such samples. We aim to demonstrate the significant influence of the surface slope on the CR-frequency that is caused by the local angle between sample surface and the AFM cantilever and present a practical method to correct the measurements. Based on existing analytical models of the effect of the AFM set-up's intrinsic cantilever tilt on CR-frequencies, we compute the non-linear variation of the first two (eigen)modes CR-frequency for a large range of surface angles. The computations are confirmed by CR-AFM experiments performed on a curved surface. Finally, the model is applied to directly correct contact modulus measurements on a durum wheat starch granule as an exemplary sample.


Three-dimensional hindlimb kinematics of water running in the plumed basilisk lizard (Basiliscus plumifrons).
Much of what is known about tetrapod locomotion is based upon movement over solid surfaces. Yet in the wild, animals are forced to move over substrates with widely varying properties. Basilisk lizards are unique in their ability to run across water from the time they hatch to adulthood. Previous studies have developed mechanical models or presented theoretical analyses of running across water, but no detailed kinematic descriptions of limb motion are currently available. The present study reports the first three-dimensional kinematic descriptions of plumed basilisk lizards (Basiliscus plumifrons) running across water, from hatchling (2.8 g) to adult (78 g) size range. Basilisks ran on a 4.6 m-long water track and were filmed with two synchronized high-speed cameras at 250 frames s(-1) and 1/1250 s shutter speed. All coordinates were transformed into three dimensions using direct linear transformation. Seventy-six kinematic variables and six morphological variables were measured or calculated to describe the motion of the hindlimb, but only 32 variables most relevant to kinematic motion are presented here. Kinematic variation among individuals was primarily related to size differences rather than sprint speed. Although basilisk lizards applied some of the same strategies to increase running velocity across water as other tetrapods do on land, their overall kinematics differ dramatically. The feet exhibit much greater medio-lateral excursions while running through water than do those of other lizards while running on land. Also, whereas the hindlimb kinematics of other lizards on land are typically symmetrical (i.e. limb excursions anterior to the hip are of similar magnitude to the limb excursions aft of the hip), basilisks running through water exhibit much greater excursions aft than they do anterior to the hip. Finally, ankle and knee flexion in early stance is a defining feature of a tetrapod step during terrestrial locomotion; yet this characteristic is missing in aquatic basilisk running. This may indicate that the basilisk limb acts primarily as a force producer - as opposed to a spring element - when locomoting on a highly damping surface such as water.


Current medication practice and tracheal intubation safety outcomes from a prospective multicenter observational cohort study.
Tracheal intubation in PICUs is often associated with adverse tracheal intubation-associated events. There is a paucity of data regarding medication selection for safe tracheal intubations in PICUs. Our primary objective was to evaluate the association of medication selection on specific tracheal intubation-associated events across PICUs. Prospective observational cohort study. Nineteen PICUs in North America. Critically ill children requiring tracheal intubation. None. Using the National Emergency Airway Registry for Children, tracheal intubation quality improvement data were prospectively collected from July 2010 to March 2013. Patient, provider, and practice characteristics including medications and dosages were collected. Adverse tracheal intubation-associated events were defined a priori. A total of 3,366 primary tracheal intubations were reported. Adverse tracheal intubation-associated events occurred in 593 tracheal intubations (18%). Fentanyl and midazolam were the most commonly used induction medications (64% and 58%, respectively). Neuromuscular blockade was used in 92% of tracheal intubation with the majority using rocuronium (64%) followed by vecuronium (20%). Etomidate and succinylcholine were rarely used (1.6% and 0.7%, respectively). Vagolytics were administered in 37% of tracheal intubations (51% in infants; 28% in > 1 yr old; p < 0.001). Ketamine was used in 27% of tracheal intubations but more often for tracheal intubations in patients with unstable hemodynamics (39% vs 25%; p < 0.001). However, ketamine use was not associated with lower prevalence of new hypotension (ketamine 8% vs no ketamine 14%; p = 0.08). In this large, pediatric multicenter registry, fentanyl, midazolam, and ketamine were the most commonly used induction agents, and the majority of tracheal intubations involved neuromuscular blockade. Ketamine use was not associated with lower prevalence of hypotension.


Measuring morale--does practice area deprivation affect doctors' well-being?
Morale is a perennial concern in general practice and, over the years, a variety of tools have been used to examine doctors' mental well-being in a range of psychological and sociological studies. Despite perceived associations between low morale and practice area deprivation, this has not been investigated previously. To devise and apply a measure of mental well-being in general practitioners, and to use this to investigate the effect of practice area deprivation. A questionnaire was devised and piloted, then used in an anonymous postal survey of a random sample of 500 London general practitioners, with questions on demography, workload, practice characteristics, patient centredness, and practice area deprivation. A total of 334 (68%) doctors replied to the questionnaire. Of these, 45% often feel exhausted, 46% are often frustrated by trivial consultations, and a third are seriously disenchanted with work. The resulting well-being score had a normal distribution, was reproducible (test-retest reliability = 0.91), and was internally consistent (Cronbach's alpha = 0.76). Comments from respondents suggested good face validity. Low well-being was not associated with practice area deprivation, but was associated with time stress, small practices and primary care teams, and lack of patient centredness. The instrument provided a useful tool for examining doctors' well-being and the associations thereof. Well-being was not associated with practice area deprivation. Help for small primary care teams and measures to reduce time stress should help to improve morale.


Camptothecin and khat (Catha edulis Forsk.) induced distinct cell death phenotypes involving modulation of c-FLIPL, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines.
An organic extract of the recreational herb khat (Catha edulis Forsk.) triggers cell death in various leukemia cell lines in vitro. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity. Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation. Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.


Care for the caregiver.
The issue of caring for the midwife caregiver is a complex issue when viewed within a global context. While national health-care systems vary significantly, midwives around the world are affected by the policies of economic globalisation. Caring for the caregiver must take place within the notion of a worldwide community of midwives, where caring for the caregiver is seen as caring for each other. In this address I examine the issue of caring for the caregiver from four perspectives: global, professional, workplace and personal. As midwives living and working in stressful environments, we are called upon to examine the ways in which we may be contributing to the systems that create the stresses. From the capabilities available to us through the International Confederation of Midwives to apply political pressure to global policies, to individual workplace conditions, midwives can affect change. By exploring alternative models and attitudes and challenging the status quo, we can apply our midwifery skills of caring to each other.


Differences in foot and forearm skin microcirculation in diabetic patients with and without neuropathy.
We have compared the hyperemic response to heat and the endothelium-dependent and endothelium-independent vasodilatation between the dorsum of the foot and the forearm in diabetic neuropathic and non-neuropathic patients and healthy control subjects. We studied the cutaneous microcirculation in the forearm and foot in 15 diabetic patients with neuropathy, in 14 diabetic patients without neuropathy, and in 15 control subjects matched for age, sex, BMI, and in the case of diabetic patients, for the duration of diabetes. Patients with peripheral vascular disease and/or renal impairment were excluded. The cutaneous microcirculation of the dorsum of the foot and the flexor aspect of the forearm was tested in all subjects. Single-point laser Doppler was employed to measure the maximal hyperemic response to heating of the skin to 44 degrees C and laser Doppler imaging scanner was used to evaluate the response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent response) and 1% sodium nitroprusside (NaNP) (endothelium-independent response). The transcutaneous oxygen tension was lower in the neuropathic group at both foot and forearm level, while the maximal hyperemic response to heat was similar at the foot and forearm level in all three groups. The endothelium-dependent vasodilation (percent increase over baseline) was lower in the foot compared to the forearm in the neuropathic group (23 +/- 4 vs. 55 +/- 10 [mean +/- SEM]; P < 0.01)], the non-neuropathic group (33 +/- 6 vs. 88 +/- 14; P < 0.01), and the control subjects (43 +/- 6 vs. 93 +/- 13; P < 0.001). Similar results were observed during the iontophoresis of NaNP (P < 0.05). No differences were found among the three groups when the ratio of the forearm:foot response was calculated for both the endothelium-dependent (neuropathic group, 2.25 +/- 0.24; non-neuropathic group, 2.55 +/- 0.35; and control subjects, 2.11 +/- 0.26; P = NS) and endothelium-independent vasodilation (neuropathic group, 1.54 +/- 0.27; non-neuropathic group, 2.08 +/- 0.33; and control subjects, 2.77 +/- 1.03; P = NS). The vasodilatory response, which is related to the C nociceptive fiber action, was reduced at the foot level during iontophoresis of Ach in the neuropathic group. In contrast, no difference was found during the iontophoresis of NaNP at the foot and forearm level and of Ach at the forearm level among all three groups. In healthy subjects, the endothelial-dependent and endothelial-independent vasodilatation is lower at the foot level when compared to the forearm, and a generalized impairment of the microcirculation in diabetic patients with neuropathy preserves this forearm-foot gradient. These changes may be a contributing factor for the early involvement of the foot with neuropathy when compared to the forearm.


Complete radiofrequency ablation of hepatolithiasis-associated cholangiocarcinoma and successful management of post-ablation bronchobiliary fistula.
This report documented the use of radiofrequency ablation (RFA) in the treatment of hepatolithiasis-associated cholangiocarcinoma and cyanoacrylate glue in the management of post-ablation bronchobiliary fistula. A 47-year-old Chinese woman with 20 years history of extrahepatic and intrahepatic cholangiolithiasis and multiple hepatic segmentectomy, developed hepatolithiasis-associated cholangiocarcinoma. The tumor was successfully treated with RFA but patient developed bronchobiliary fistula. Cyanoacrylate glue was used for occluding the bronchobiliary fistula. CT scan at 3 months showed complete restoration of physiological separation between the biliary and bronchial system. Repeat CT scan showed complete tumor ablation with no signs of tumor recurrence 10 months after RFA. In conclusion, RFA may be a safe and effective treatment option for patients with hepatolithiasis-associated cholangiocarcinoma who are poor candidates for surgical resection. Protection of the integrity of the bile duct and diaphragm during RFA can minimize postoperative complications. In case of development of post-ablation bronchobiliary fistula, cyanoacrylate glue can be used to occlude the fistula, before surgical resection is considered.


Regional phase unwrapping algorithm for photoelastic phase map.
In this paper, a simple isoclinic phase map unwrapping method is proposed to retrieve map with ambiguities at photoelastic isotropic points. Regional phase unwrapping method is also utilized to enhance the retrieving efficiency after all phase inconsistencies have been fully detected and branch cutting works have been properly done to ensure blockings of all the paths which could cause incorrect integrations while involuntarily crossing them. The correctly retrieved isoclinic data are then fed into isochromatic formulation, and as a consequence an inconsistency free isochromatic phase map will be obtained. This map can be unwrapped by any simple and fast unwrapping algorithm accurately and effectively. Circular disk and ring under diametric compression samples are both applied for the verification of the proposed algorithm. The experimental results show the proposed algorithm can successfully solve the annoying problems occurred at photoelastic isotropic points with a processing time of roughly 2 seconds for a 420 x 420 pixels map by a general personal computer.


Sulfated fucan oligosaccharides elicit defense responses in tobacco and local and systemic resistance against tobacco mosaic virus.
Sulfated fucans are common structural components of the cell walls of marine brown algae. Using a fucan-degrading hydrolase isolated from a marine bacterium, we prepared sulfated fucan oligosaccharides made of mono- and disulfated fucose units alternatively bound by alpha-1,4 and alpha-1,3 glycosidic linkages, respectively. Here, we report on the elicitor activity of such fucan oligosaccharide preparations in tobacco. In suspension cell cultures, oligofucans at the dose of 200 microg ml(-1) rapidly induced a marked alkalinization of the extracellular medium and the release of hydrogen peroxide. This was followed within a few hours by a strong stimulation of phenylalanine ammonia-lyase and lipoxygenase activities. Tobacco leaves treated with oligofucans locally accumulated salicylic acid (SA) and the phytoalexin scopoletin and expressed several pathogenesis-related (PR) proteins, but they displayed no symptoms of cell death. Fucan oligosaccharides also induced the systemic accumulation of SA and the acidic PR protein PR-1, two markers of systemic acquired resistance (SAR). Consistently, fucan oligosaccharides strongly stimulated both local and systemic resistance to tobacco mosaic virus (TMV). The use of transgenic plants unable to accumulate SA indicated that, as in the SAR primed by TMV, SA is required for the establishment of oligofucan-induced resistance.


Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich's ataxia.
Friedreich's ataxia (FRDA) is the most common hereditary ataxia in the caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia, hypertrophic cardiomyopathy and increased incidence of diabetes. FRDA is caused by impaired expression of the FXN gene coding for the mitochondrial protein frataxin. During the past ten years, the development of mouse models of FRDA has allowed better understanding of the pathophysiology of the disease. Among the mouse models of FRDA, the liver conditional mouse model pointed to a tumor suppressor activity of frataxin leading to the hypothesis that individuals with FRDA might be predisposed to cancer. In the present work, we investigated the presence and the incidence of neoplasia in the largest FRDA patient cohorts from the USA, Australia and Europe. As no predisposition to cancer could be observed in both cohorts, we revisited the phenotype of the liver conditional mouse model. Our results show that frataxin-deficient livers developed early mitochondriopathy, iron-sulfur cluster deficits and intramitochondrial dense deposits, classical hallmarks observed in frataxin-deficient tissues and cells. With age, a minority of mice developed structures similar to the ones previously associated with tumor formation. However, these peripheral structures contained dying, frataxin-deficient hepatocytes, whereas the inner liver structure was composed of a pool of frataxin-positive cells, due to inefficient Cre-mediated recombination of the Fxn gene, that contributed to regeneration of a functional liver. Together, our data demonstrate that frataxin deficiency and tumorigenesis are not associated.


Radiative Energy Budgets of Phototrophic Surface-Associated Microbial Communities and their Photosynthetic Efficiency Under Diffuse and Collimated Light.
We investigated the radiative energy budgets of a heterogeneous photosynthetic coral reef sediment and a compact uniform cyanobacterial biofilm on top of coastal sediment. By combining electrochemical, thermocouple and fiber-optic microsensor measurements of O2, temperature and light, we could calculate the proportion of the absorbed light energy that was either dissipated as heat or conserved by photosynthesis. We show, across a range of different incident light regimes, that such radiative energy budgets are highly dominated by heat dissipation constituting up to 99.5% of the absorbed light energy. Highest photosynthetic energy conservation efficiency was found in the coral sediment under low light conditions and amounted to 18.1% of the absorbed light energy. Additionally, the effect of light directionality, i.e., diffuse or collimated light, on energy conversion efficiency was tested on the two surface-associated systems. The effects of light directionality on the radiative energy budgets of these phototrophic communities were not unanimous but, resulted in local spatial differences in heat-transfer, gross photosynthesis, and light distribution. The light acclimation index, Ek, i.e., the irradiance at the onset of saturation of photosynthesis, was >2 times higher in the coral sediment compared to the biofilm and changed the pattern of photosynthetic energy conservation under light-limiting conditions. At moderate to high incident irradiances, the photosynthetic conservation of absorbed energy was highest in collimated light; a tendency that changed in the biofilm under sub-saturating incident irradiances, where higher photosynthetic efficiencies were observed under diffuse light. The aim was to investigate how the physical structure and light propagation affected energy budgets and light utilization efficiencies in loosely organized vs. compact phototrophic sediment under diffuse and collimated light. Our results suggest that the optical properties and the structural organization of phytoelements are important traits affecting the photosynthetic efficiency of biofilms and sediments.


Suppressing cascades of load in interdependent networks.
Understanding how interdependence among systems affects cascading behaviors is increasingly important across many fields of science and engineering. Inspired by cascades of load shedding in coupled electric grids and other infrastructure, we study the Bak-Tang-Wiesenfeld sandpile model on modular random graphs and on graphs based on actual, interdependent power grids. Starting from two isolated networks, adding some connectivity between them is beneficial, for it suppresses the largest cascades in each system. Too much interconnectivity, however, becomes detrimental for two reasons. First, interconnections open pathways for neighboring networks to inflict large cascades. Second, as in real infrastructure, new interconnections increase capacity and total possible load, which fuels even larger cascades. Using a multitype branching process and simulations we show these effects and estimate the optimal level of interconnectivity that balances their trade-offs. Such equilibria could allow, for example, power grid owners to minimize the largest cascades in their grid. We also show that asymmetric capacity among interdependent networks affects the optimal connectivity that each prefers and may lead to an arms race for greater capacity. Our multitype branching process framework provides building blocks for better prediction of cascading processes on modular random graphs and on multitype networks in general.


Mediterranean diet and hip fracture incidence among older adults: the CHANCES project.
The association between adherence to Mediterranean diet (MD) and hip fracture incidence is not yet established. In a diverse population of elderly, increased adherence to MD was associated with lower hip fracture incidence. Except preventing major chronic diseases, adhering to MD might have additional benefits in lowering hip fracture risk. Hip fractures constitute a major public health problem among older adults. Latest evidence links adherence to Mediterranean diet (MD) with reduced hip fracture risk, but still more research is needed to elucidate this relationship. The potential association of adherence to MD with hip fracture incidence was explored among older adults. A total of 140,775 adults (116,176 women, 24,599 men) 60 years and older, from five cohorts from Europe and the USA, were followed-up for 1,896,219 person-years experiencing 5454 hip fractures. Diet was assessed at baseline by validated, cohort-specific, food-frequency questionnaires, and hip fractures were ascertained through patient registers or telephone interviews/questionnaires. Adherence to MD was evaluated by a scoring system on a 10-point scale modified to be applied also to non-Mediterranean populations. In order to evaluate the association between MD and hip fracture incidence, cohort-specific hazard ratios (HR), adjusted for potential confounders, were estimated using Cox proportional-hazards regression and pooled estimates were subsequently derived implementing random-effects meta-analysis. A two-point increase in the score was associated with a significant 4% decrease in hip fracture risk (pooled adjusted HR 0.96; 95% confidence interval (95% CI) 0.92-0.99, pheterogeneity = 0.446). In categorical analyses, hip fracture risk was lower among men and women with moderate (HR 0.93; 95% CI 0.87-0.99) and high (HR 0.94; 95% CI 0.87-1.01) adherence to the score compared with those with low adherence. In this large sample of older adults from Europe and the USA, increased adherence to MD was associated with lower hip fracture incidence.


Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab.
Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.


Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2.
In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.


Kinetics of ketone body metabolism in fasting humans.
The rates of production of total ketone bodies (acetoacetate + beta-hydroxybutyrate) were determined using an isotope tracer technique in 23 obese subjects submitted to a fast of variable duration (15 hr--23 days). Constant infusions of 14C-acetoacetate were used in most studies, but similar results were obtained with pulse injections of this tracer or with constant infusions of 14C-D(-)-beta-hydroxybutyrate. Blood concentration, production rate, and urinary elimination of total ketones rose during approximately the first 3 days of fast and plateaued thereafter at values amounting, respectively, to 7.09 +/- 0.32 mumole/ml, 1908 +/- 80 mumole/min and 167 +/- 14 mumole/min. The rates of ketogenesis are significantly higher than those usually reported in the literature. Ketonemia was an exponential function of production rate suggesting that tissue uptake becomes progressively saturated as inflow rate rises. The same type of relationship between concentration and inflow rate was observed in nine control overnight fasted obese subjects rendered hyperketonemic with infusions of variable amounts of unlabeled acetoacetate. The comparison between the fasted and the control subjects at ketone concentrations of 3--10 mumole/ml showed that on an average, starvation is associated with a 35% decrease in the metabolic clearance rate of ketones. These data suggest that fasting is associated with an impairment of mechanisms for utilizing ketones, this defect contributing to the hyperketonemia of food deprivation.


Cyclic GMP: a potential mediator of neurally- and drug-induced relaxation of opossum lower esophageal sphincter.
Electrical field stimulation (EFS) of isolated strips of opossum lower esophageal sphincter (LES) produced a relaxation that was accompanied by an elevation of intracellular cyclic GMP content. In order to compare the time dependence of the EFS-induced relaxation with that of the elevation of cyclic GMP, the ability of EFS to produce relaxation and increase cyclic GMP was measured. The results of these experiments showed that cyclic GMP content increased before the onset of relaxation. Cumulative addition of atriopeptin II, an activator of particulate guanylate cyclase, produced a concentration-dependent relaxation of this tissue and increased cyclic GMP content. In other experiments, zaprinast, an inhibitor of a cyclic GMP selective-phosphodiesterase, produced a concentration-related relaxation of opossum LES and increased cyclic GMP content. However, pretreatment with zaprinast (3 microM) did not potentiate the EFS-induced relaxation or the increase in cyclic GMP content. At this concentration, however, zaprinast increased the basal content of cyclic GMP. Finally, 8-Br-cyclic GMP, a membrane-permeable analog of cyclic GMP, produced a concentration-dependent relaxation of isolated strips of opossum LES. In conclusion, these data extend the initial findings that an elevation in cyclic GMP content is associated with relaxation and suggest that cyclic GMP is a potential intracellular messenger of neurally- and drug-induced relaxation of opossum LES.


Correlation between Fatty Acid Profile and Anti-Inflammatory Activity in Common Australian Seafood by-Products.
Marine organisms are a rich source of biologically active lipids with anti-inflammatory activities. These lipids may be enriched in visceral organs that are waste products from common seafood. Gas chromatography-mass spectrometry and fatty acid methyl ester (FAME) analyses were performed to compare the fatty acid compositions of lipid extracts from some common seafood organisms, including octopus (Octopus tetricus), squid (Sepioteuthis australis), Australian sardine (Sardinops sagax), salmon (Salmo salar) and school prawns (Penaeus plebejus). The lipid extracts were tested for anti-inflammatory activity by assessing their inhibition of nitric oxide (NO) and tumor necrosis factor alpha (TNFα) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 mouse cells. The lipid extract from both the flesh and waste tissue all contained high amounts of polyunsaturated fatty acids (PUFAs) and significantly inhibited NO and TNFα production. Lipid extracts from the cephalopod mollusks S. australis and O. tetricus demonstrated the highest total PUFA content, the highest level of omega 3 (ω-3) PUFAs, and the highest anti-inflammatory activity. However, multivariate analysis indicates the complex mixture of saturated, monounsaturated, and polyunsaturated fatty acids may all influence the anti-inflammatory activity of marine lipid extracts. This study confirms that discarded parts of commonly consumed seafood species provide promising sources for the development of new potential anti-inflammatory nutraceuticals.


Impact of metabolic syndrome on the risk of atrial fibrillation recurrence after catheter ablation: systematic review and meta-analysis.
The impact of metabolic syndrome (MetS) on recurrence of atrial fibrillation (AF) after catheter ablation remains uncertain. We conducted a meta-analysis to summarize the relative risks (RR) of AF recurrence after catheter ablation in patients with vs. without MetS and its components. Among 839 articles identified from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, we included 23 studies with a total of 12,924 patients (7,594 with paroxysmal AF and 5,330 with nonparoxysmal AF) for analysis. Five of these had complete information on MetS components. Variables assessed comprised study design and population characteristics, AF ablation methods, use of anti-arrhythmic drugs, AF recurrence ascertainment methods, adjustment variables, and other quality indicators. Our meta-analysis found an elevated risk of AF recurrence after ablation in patients with vs. without MetS (pooled RR, 1.63; 95 % confidence interval (CI), 1.25-2.12). Among components of MetS, hypertension was a predictor of AF post-ablation recurrence in studies without adjustment for other MetS components (RR, 1.62; 95 % CI, 1.23-2.13) but not in those adjusting for two or more additional MetS components (RR, 1.03; 95 % CI, 0.88-1.20). There was a borderline association between overweight/obesity and AF recurrence after ablation (RR, 1.27; 95 % CI, 0.99-1.64). MetS is associated with an increased risk of AF recurrence after catheter ablation. Further study of the MetS and its components as determinants of AF risk could help refine patient selection and improve procedural outcomes.


PROSESS: a protein structure evaluation suite and server.
PROSESS (PROtein Structure Evaluation Suite and Server) is a web server designed to evaluate and validate protein structures generated by X-ray crystallography, NMR spectroscopy or computational modeling. While many structure evaluation packages have been developed over the past 20 years, PROSESS is unique in its comprehensiveness, its capacity to evaluate X-ray, NMR and predicted structures as well as its ability to evaluate a variety of experimental NMR data. PROSESS integrates a variety of previously developed, well-known and thoroughly tested methods to evaluate both global and residue specific: (i) covalent and geometric quality; (ii) non-bonded/packing quality; (iii) torsion angle quality; (iv) chemical shift quality and (v) NOE quality. In particular, PROSESS uses VADAR for coordinate, packing, H-bond, secondary structure and geometric analysis, GeNMR for calculating folding, threading and solvent energetics, ShiftX for calculating chemical shift correlations, RCI for correlating structure mobility to chemical shift and PREDITOR for calculating torsion angle-chemical shifts agreement. PROSESS also incorporates several other programs including MolProbity to assess atomic clashes, Xplor-NIH to identify and quantify NOE restraint violations and NAMD to assess structure energetics. PROSESS produces detailed tables, explanations, structural images and graphs that summarize the results and compare them to values observed in high-quality or high-resolution protein structures. Using a simplified red-amber-green coloring scheme PROSESS also alerts users about both general and residue-specific structural problems. PROSESS is intended to serve as a tool that can be used by structure biologists as well as database curators to assess and validate newly determined protein structures. PROSESS is freely available at http://www.prosess.ca.


Effect of nursing caries on body weight in a pediatric population.
A review of anesthesia and sedation records of children with nursing caries was undertaken. The weights of these 115 children with otherwise noncontributory medical histories were compared to subjects matched for age, gender, race, and socioeconomic status. Nursing caries children were treated using either sedation or general anesthesia and received treatment for at least one pulpally involved tooth. Comparison subjects had no gross carious lesions. The average age for both the comparison and test groups was 3.2 years (SD = 1.01 and 0.98, respectively). While comparison patients weighed 16.2 +/- 3.08 kg, patients with nursing caries weighed only 15.2 +/- 2.66 kg. This difference was statistically significant (P < 0.005). Of the nursing caries patients, 8.7% weighed less than 80% of their ideal weight, compared with only 1.7% of the comparison patients (P < 0.02). Of nursing caries children, 19.1% were in the 10th percentile or less for weight, compared with only 7.0% of comparison subjects (P < 0.01). The mean age of "low weight" patients with nursing caries was significantly greater than for patients at or above their ideal weights, indicating that progression of nursing caries may affect growth adversely.


Prosthesis and Hybrid Strategy Consideration for Treating Two-level Cervical Disc Degeneration in Hybrid Surgery.
Biomechanical analysis using a validated nonlinear finite element (FE) model. The aim of this study was to combine the strategy of two-level hybrid surgery (HS) to explore how prostheses affect cervical biomechanics. Few FE studies have explored differences in biomechanical behavior between combined and stand-alone structured prostheses with HS. No FE studies have considered whether the prosthesis type and hybrid strategy influence two-level HS. Three prostheses-Prodisc-C, PCM, and DCI-were analyzed in flexion and extension during HS at C4-C6. There were two HS constructs: anterior cervical discectomy and fusion (ACDF) conducted at the C4-C5 levels and anterior cervical disc replacement (ACDR) conducted at C5-C6 levels (ACDF/ACDR); ACDR/ACDF. Flexion motion at adjacent levels was greater than that of intact spine. A maximum increase of 80% was observed with PCM in the ACDF/ACDR group. Extension motion at adjacent levels for both hybrid strategies with PCM, however, was similar to that of intact spine (<10% change), whereas it increased by 14% to 32% with DCI. The strain energy-storing capability with DCI tended to be similar to that of normal discs. Facet stress at the infra-adjacent level, however, significantly increased with DCI in both groups, whereas it increased with PCM and Prodisc-C only in the ACDR/ACDF group. All prostheses produced overloads on cartilage at the arthroplasty level. Prodisc-C and PCM cores showed stress above the yield stress of ultrahigh-molecular-weight polyethylene. Each prosthesis had advantages and disadvantages. In extension, DCI (vs. Prodisc-C and PCM) exhibited more compensation at adjacent levels in terms of motion, moments, and facet stress. The biomechanical performance of Prodisc-C was easily affected by the hybrid strategy. Thus, if only a combined-structure prosthesis is available for two-level HS (C4-C6 level), the hybrid strategy should be carefully evaluated and the ACDF/ACDR construct is recommended to avoid accelerating degeneration of adjacent segments. 5.


Shaping veterinary health policies in a global and evolving context.
National animal health policies have at their foundation the overarching need to address society's concerns about animal disease control, the welfare of animals and the safety and security of the animal production food supply. However, in today's global, complex and interdependent context, national animal health policies also impact a broader range of policy outcomes, ranging from public health protection through ecosystem health and biodiversity to the economic well-being and performance of many countries. As a result, there are several fundamentally important elements that must be considered in the elaboration of effective and relevant animal health policies. Policies must be (i) proportionate to the risk to be managed, (ii) transparent (to ensure easy understanding and implementation), and (iii) responsive to constantly evolving and changing hazards and risk pathways. In addition, it is critical that there are sufficient resources and capacity to implement the policies as well as incentives for compliance on the part of affected parties.


Solid-State 31P Nuclear Magnetic Resonance Study of Interlayer Hydroxide Surfaces of Kaolinite Probed with an Interlayer Triethylphosphine Oxide Monolayer.
The solid acidity of the interlayer aluminol surfaces of kaolinite was explored by solid-state 31P nuclear magnetic resonance with magic angle spinning (MAS) using triethylphosphine oxide (TEPO), which formed a monolayer with a uniform orientation between the layers of kaolinite as a probe molecule. Intercalation of TEPO between the layers of kaolinite was achieved using methoxy-modified kaolinite as an intermediate. The presence of TEPO in the reaction products was revealed by the two signals at 21 and 7 ppm, which were assignable to ethyl groups in TEPO, in the solid-state 13C nuclear magnetic resonance with cross polarization and magic angle spinning techniques (13C CP/MAS NMR). The presence of TEPO between the layers of kaolinite was demonstrated by the expansion of basal spacing from 0.86 nm, the interlayer distance of methoxy-modified kaolinite to 1.16 nm, as shown by the X-ray diffraction patterns, suggesting the formation of a TEPO monolayer between the layers of kaolinite. The formation of hydrogen bonds between the P═O groups of TEPO and the aluminol groups on the interlayer surfaces of kaolinite was also revealed by the appearance of an additional OH stretching band at 3598 cm-1 in the Fourier-transform infrared spectrum and narrow solid-state 31P MAS NMR signals observed at 55-53 ppm which were shifted from the position of the physisorbed TEPO (50 ppm). These results clearly indicate that the solid acidity of interlayer aluminol groups of methoxy-modified kaolinite was probed using an interacted TEPO monolayer.


Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice.
Isolated perfused hearts from type 2 diabetic (db/db) mice show impaired ventricular function, as well as altered cardiac metabolism. Assessment of the relationship between myocardial oxygen consumption (MVO(2)) and ventricular pressure-volume area (PVA) has also demonstrated reduced cardiac efficiency in db/db hearts. We hypothesized that lowering the plasma fatty acid supply and subsequent normalization of altered cardiac metabolism by chronic treatment with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist will improve cardiac efficiency in db/db hearts. Rosiglitazone (23 mg/kg body weight/day) was administered as a food admixture to db/db mice for five weeks. Ventricular function and PVA were assessed using a miniaturized (1.4 Fr) pressure-volume catheter; MVO(2) was measured using a fibre-optic oxygen sensor. Chronic rosiglitazone treatment of db/db mice normalized plasma glucose and lipid concentrations, restored rates of cardiac glucose and fatty acid oxidation, and improved cardiac efficiency. The improved cardiac efficiency was due to a significant decrease in unloaded MVO(2), while contractile efficiency was unchanged. Rosiglitazone treatment also improved functional recovery after low-flow ischemia. In conclusion, the present study demonstrates that in vivo PPARgamma-treatment restores cardiac efficiency and improves ventricular function in perfused hearts from type 2 diabetic mice.


First Report of Powdery Mildew of Kenaf Caused by Leveillula taurica in South Africa.
Kenaf (Hibiscus cannabinus L.) is a fast-growing, bamboo-like annual plant belonging to the Malvaceae. The stem, which ranges from 1.5 to 4 m, presents a source of high-quality cellulose fibers. The plant is being investigated in South Africa with a view to commercial production. In April 2001, at least 50% of 4- to 5-month-old kenaf plants grown from seed in trials near Rustenburg, Northwest Province, South Africa, were observed as having powdery mildew. Signs included extensive growth of white, superficial mycelium and emergent conidiophores on the abaxial leaf surface, followed by partial defoliation. On older leaves, the abaxial leaf surface was completely covered by powdery mildew, and chlorotic and necrotic patches were clearly visible on the adaxial surface. Symptoms were observed on all five planted cultivars (Everglades 41, Cuba 108, El Salvador, SF459, and Tainung 2), and no difference in disease severity was noted among cultivars. Leveillula taurica (Lév.) Arnaud (anamorph Oidiopsis taurica [Lév.] Salmon) was subsequently identified by the presence of endophytic mycelia, often branched conidiophores, and dimorphic conidia borne singly or in short chains (1). In 100 measurements of each type, pyriform conidia averaged 69 ± 5 × 18 ± 2 μm and cylindrical conidia averaged 62 ± 6 × 16 ± 2 μm. The teleomorph was not observed. The source of L. taurica for this reported outbreak is unknown, and powdery mildew was not observed in a field of mature cotton (Gossypium hirsutum L.) growing within 10 m of the kenaf plot. L. taurica was reported on kenaf in Texas in 1992 (2) and in Italy in 1995 (3). The pathogen can cause significant losses in seed yield and reduce seed quality in susceptible kenaf cultivars. Although L. taurica has been reported from Hibiscus sabdariffa in Egypt (4), to our knowledge this is the first report of the pathogen occurring on kenaf in Africa. References: (1) H. J. Boesewinkel. Bot Rev. 46:167, 1980. (2) C. G. Cook and J. L. Riggs. Plant Dis. 79:968, 1995. (3) S. Frisullo et al. Inf. Fitopatol. 45:37-41, 1995. (4) M. Khairy, et al. Phytopathol. Medit. 10:269-271, 1971.


Relationship between leucocyte sodium content and high blood pressure during development and resolution of pre-eclampsia.
1. One hundred and five primigravidae were followed sequentially at 4-weekly intervals starting at gestational week 31. They were seen again at 6 weeks post partum. 2. At each visit measurements were made of blood pressure as well as of leucocyte and erythrocyte sodium and potassium content. 3. Eighty-five subjects completed the study. Seven developed pre-eclampsia. 4. In both controls and patients who developed pre-eclampsia, leucocyte and erythrocyte sodium content increased with gestational age and fell post partum. These changes were of greater magnitude in the patients with pre-eclampsia. Cell potassium fell in both groups, but to a greater extent in patients with pre-eclampsia. 5. These changes in cell sodium paralleled those in blood pressure in both groups. 6. These data suggest that the excessive blood pressure changes in pre-eclampsia might be related to similar changes in cell sodium content.


Evaluation of a university hospital trauma team activation protocol.
Admission with a multidisciplinary trauma team may be vital for the severely injured patient, as this facilitates rapid diagnosis and treatment. On the other hand, patients with minor injuries do not need the trauma team for adequate care. Correct triage is important for optimal resource utilization. The aim of the study was to evaluate our criteria for activating the trauma team, and identify suboptimal criteria that might be changed in the interest of precision. The study is an observational, retrospective cohort-study. All patients admitted with the trauma team (n = 382), all severely injured (Injury Severity Score (ISS) >15) (n = 161), and all undergoing an emergency procedure aimed at counteracting compromised airways, respiration or circulation at our hospital (n = 142) during 2006-2007 were included. Data were recorded from the admission records and the electronic patient records. The trauma team activation protocol was evaluated against the occurrence of severe injury and the occurrence of emergency procedures. A total of 441 patients were included. The overtriage was 71% and undertriage 32% when evaluating against ISS >15 as the standard of reference. When occurrence of emergency procedures was held as the standard of standard of reference, the over- and undertriage was 71% and 21%, respectively. Mechanism of injury-criteria for trauma team activation contributed the most to overtriage. The emergency procedures performed were mostly endotracheal intubation and external fixation of fractures. Less than 3% needed haemostatic laparotomy or thoracotomy. Approximately 2/3 of the overtriage represented isolated head or cervical spine injuries, and/or interhospital transfers. The over- and undertriage of our protocol are both too high. To decrease overtriage we suggest omissions and modifications of some of the criteria. To decrease undertriage, transferred patients and patients with head injuries should be more thoroughly assessed against the trauma team activation criteria.


Innovative Programmable Bio-Nano-Chip Digitizes Biology Using Sensors That Learn Bridging Biomarker Discovery and Clinical Implementation.
The lack of standard tools and methodologies and the absence of a streamlined multimarker approval process have hindered the translation rate of new biomarkers into clinical practice for a variety of diseases afflicting humankind. Advanced novel technologies with superior analytical performance and reduced reagent costs, like the programmable bio-nano-chip system featured in this article, have potential to change the delivery of healthcare. This universal platform system has the capacity to digitize biology, resulting in a sensor modality with a capacity to learn. With well-planned device design, development, and distribution plans, there is an opportunity to translate benchtop discoveries in the genomics, proteomics, metabolomics, and glycomics fields by transforming the information content of key biomarkers into actionable signatures that can empower physicians and patients for a better management of healthcare. While the process is complicated and will take some time, showcased here are three application areas for this flexible platform that combines biomarker content with minimally invasive or non-invasive sampling, such as brush biopsy for oral cancer risk assessment; serum, plasma, and small volumes of blood for the assessment of cardiac risk and wellness; and oral fluid sampling for drugs of abuse testing at the point of need.


Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.
We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).


Application of a non-linear dispersion model to analysis of the renal handling of p-aminohippurate in isolated perfused rat kidney.
To analyze the renal handling of therapeutic compounds observed as a non-linear process with a diffusion phenomenon, we employed a non-linear dispersion model described with a partial differential equation and solved it by using the finite difference method with an implicit scheme in a model dependent analysis. In this study, the renal handling of p-aminohippurate (PAH) was investigated in isolated perfused rat kidney, in which a 50 microl bolus of injection solution containing [3H]PAH and [14C]inulin was administered rapidly into the renal artery. The venous outflows were then collected for 15 min with a fraction collector. The renal extraction ratio of PAH was decreased from 65% to 18% as the PAH concentration in the injection solution was increased from 2 microM to 10 mM. The PAH outflow profile changed as the extraction process became saturated. With the non-linear dispersion model, the Michaelis-Menten parameters for the PAH extraction process were estimated by a model fitting calculation. The calculated values were 0.83 micromol/min/kidney for Vmax and 89 microM for Km. It was demonstrated that the model dependent analysis with a non-linear dispersion model is a useful approach to characterize renal drug handling, and is probably applicable for examining other non-linear processes which involve a diffusion phenomenon.


Efficient priming of CD8+ memory T cells specific for a subdominant epitope following Sendai virus infection.
The relationship between the primary effector CTL response to viral infection and the subsequent pool of memory CTL precursors (CTLp) is poorly understood. Here, we have analyzed the induction of both effector CTL and memory CTLp to dominant and subdominant epitopes following Sendai virus infection of C57BL/6 mice. A single peptide derived from the Sendai virus nucleoprotein (NP(324-332)) binds to both H-2 Kb and Db MHC class I molecules, generating both immunodominant (NP(324-332)/Kb) and subdominant (NP(324-332)/Db) epitopes. Following intranasal Sendai virus infection, NP(324-332)/Kb-specific CTL dominated the primary effector CTL response in the lung and were present at high frequency in the memory CTLp pool. In contrast, NP(324-332)/Db-specific CTL were not a detectable component of the effector response to primary Sendai virus infection. However, memory CTLp specific for this subdominant epitope were induced at frequencies approaching those of CTLp specific for the immunodominant epitope. These data indicate that memory CTLp specific for subdominant epitopes can be primed by Sendai virus infection in the absence of a detectable effector response. To determine whether CTLp memory to subdominant epitopes is functional in the context of Sendai virus infection, memory CTLp specific for a subdominant epitope were selectively primed by vaccination. These cells dominated the subsequent effector CTL response to Sendai virus infection, demonstrating that memory CTLp primed against subdominant epitopes can participate in an immune response and effectively compete with T cells specific for immunodominant epitopes. These data have implications for the development of vaccines designed to emphasize cellular immunity.


Emotion Socialization by Mothers and Fathers: Coherence among Behaviors and Associations with Parent Attitudes and Children's Social Competence.
This study examined interrelations among different types of parental emotion socialization behaviors in 88 mothers and 76 fathers (co-residing with participating mothers) of 8-year-old children. Parents completed questionnaires assessing emotion socialization behaviors, emotion-related attitudes, and their children's social functioning. An observed parent-child emotion discourse task and a child social-problem solving interview were also performed. Parent gender differences and concordance within couples in emotion socialization behaviors were identified for some but not all behaviors. Fathers' reactions to child emotion, family expressiveness, and fathers' emotion coaching during discussion cohered, and a model was supported in which the commonality among these behaviors was predicted by fathers' emotion-coaching attitudes, and was associated with children's social competence. A cohesive structure for the emotion socialization construct was less clear for mothers, although attitudes predicted all three types of emotion socialization behavior (reactions, expressiveness, and coaching). Implications for developmental theory and for parent-focused interventions are discussed.


Binding of dipeptidyl peptidase III to the oxidative stress cell sensor Kelch-like ECH-associated protein 1 is a two-step process.
This work is about synergy of theory and experiment in revealing mechanism of binding of dipeptidyl peptidase III (DPP III) and Kelch-like ECH-associated protein 1 (KEAP1), the main cellular sensor of oxidative stress. The NRF2 ̶ KEAP1 signaling pathway is important for cell protection, but it is also impaired in many cancer cells where NRF2 target gene expression leads to resistance to chemotherapeutic drugs. DPP III competitively binds to KEAP1 in the conditions of oxidative stress and induces release of NRF2 and its translocation into nucleus. The binding is established mainly through the ETGE motif of DPP III and the Kelch domain of KEAP1. However, although part of a flexible loop, ETGE itself is firmly attached to the DPP III surface by strong hydrogen bonds. Using combined computational and experimental study, we found that DPP III ̶ Kelch binding is a two-step process comprising the endergonic loop detachment and exergonic DPP III ̶ Kelch interaction. Substitution of arginines, which keep the ETGE motif attached, decreases the work needed for its release and increases DPP III ̶ Kelch binding affinity. Interestingly, mutations of one of these arginine residues have been reported in cBioPortal for cancer genomics, implicating its possible involvement in cancer development. Communicated by Ramaswamy H. Sarma.


The effect of smoke-free legislation on the mortality rate of acute myocardial infarction: a meta-analysis.
Several studies have demonstrated that smoke-free legislation is associated with a reduced risk of mortality from acute myocardial infarction (AMI). This study aimed to examine and quantify the potential effect of smoke-free legislation on AMI mortality rate in different countries. Studies were identified using a systematic search of the scientific literature from electronic databases, including PubMed, Web of Science, ScienceDirect, Embase, Google Scholar, and China National Knowledge Infrastructure (CNKI), from their inception through September 30, 2017. A random effects model was employed to estimate the overall effects of smoke-free legislation on the AMI mortality rate. Subgroup analysis was performed to explore the possible causes of heterogeneity in risk estimates based on sex and age. The results of meta-analysis after excluding the studies with a high risk of bias were reported in this study. A total of 10 eligible studies with 16 estimates of effect size were included in this meta-analysis. Significant heterogeneity in the risk estimates was identified (overall I2 = 94.6%, p < 0.001). Therefore, a random effects model was utilized to estimate the overall effect of smoke-free legislation. There was an 8% decline in AMI mortality after introducing smoke-free legislation (RR = 0.92, 95% confidence interval (CI): 0.90-0.94). The results of subgroup analyses showed that smoke-free legislation was significantly associated with lower rates of mortality for the following 5 diagnostic subgroups: smoke-free in workplaces, restaurants and bars (RR = 0.92, 95% CI: 0.90-0.95), smaller sample size (RR = 0.92, 95% CI: 0.89-0.95), study location in Europe (RR = 0.90, 95% CI: 0.85-0.94), regional study area (RR = 0.92, 95% CI: 0.89-0.94), and no previous local smoke-free legislation (RR = 0.91, 95% CI: 0.90-0.93). However, there was not much difference in AMI mortality rates after the legislation between the longer (RR = 0.92, 95% CI: 0.86-0.98) and shorter follow-up duration subgroups (RR = 0.92, 95% CI: 0.89-0.94). Smoke-free legislation could significantly reduce the AMI mortality rate by 8%. The reduction in the AMI mortality rate was more significant in studies with more comprehensive laws, without prior smoke-free bans, with a smaller sample size, at the regional level, and with a location in Europe.


Measurement invariance of the kidney disease and quality of life instrument (KDQOL-SF) across veterans and non-veterans.
Studies have demonstrated that perceived health-related quality of life (HRQOL) of patients receiving hemodialysis is significantly impaired. Since HRQOL outcome data are often used to compare groups to determine health care effectiveness it is imperative that measures of HRQOL are valid. However, valid HRQOL comparisons between groups can only be made if instrument invariance is demonstrated. The Kidney Disease Quality of Life-Short Form (KDQOL-SF) is a widely used HRQOL measure for patients with chronic kidney disease (CKD) however, it has not been validated in the Veteran population. Therefore, the purpose of this study was to examine the measurement invariance of the KDQOL-SF across Veterans and non-Veterans with CKD. Data for this study were from two large prospective observational studies of patients receiving hemodialysis: 1) Veteran End-Stage Renal Disease Study (VETERAN) (N = 314) and 2) Dialysis Outcomes and Practice Patterns Study (DOPPS) (N = 3,300). Health-related quality of life was measured with the KDQOL-SF, which consists of the SF-36 and the Kidney Disease Component Summary (KDCS). Single-group confirmatory factor analysis was used to evaluate the goodness-of-fit of the hypothesized measurement model for responses to the subscales of the KDCS and SF-36 instruments when analyzed together; and given acceptable goodness-of-fit in each group, multigroup CFA was used to compare the structure of this factor model in the two samples. Pattern of factor loadings (configural invariance), the magnitude of factor loadings (metric invariance), and the magnitude of item intercepts (scalar invariance) were assessed as well as the degree to which factors have the same variances, covariances, and means across groups (structural invariance). CFA demonstrated that the hypothesized two-factor model (KDCS and SF-36) fit the data of both the Veteran and DOPPS samples well, supporting configural invariance. Multigroup CFA results concerning metric and scalar invariance suggested partial strict invariance for the SF-36, but only weak invariance for the KDCS. Structural invariance was not supported. Results suggest that Veterans may interpret the KDQOL-SF differently than non-Veterans. Further evaluation of measurement invariance of the KDQOL-SF between Veterans and non-Veterans is needed using large, randomly selected samples before comparisons between these two groups using the KDQOL-SF can be done reliably.


Emerging antivirals for the treatment of hepatitis B.
Chronic infection with hepatitis B virus (HBV) constitutes a major global public health threat, causing substantial disease burdens such as liver cirrhosis and hepatocellular carcinoma, thus representing high unmet medical needs. Currently available therapies are safe, well tolerated, and highly effective in decreasing viremia and improving measured clinical outcomes with low rates of antiviral resistance. However, long-term management remains a clinical challenge, mainly due to the slow kinetics of HBV surface antigen clearance. In this article, we review emerging antivirals directed at novel targets derived from mechanisms of viral cellular entry, viral replication, viral assembly, and the host immune response, leading to preclinical and clinical trials for possible future therapeutic intervention. The recent therapeutic advances in the development of all categories of HBV inhibitors may pave the way for regimens of finite duration that result in long-lasting control of chronic hepatitis B infection.


Formulation of a microparticle carrier for oral polyplex-based DNA vaccines.
Oral induction of a disseminated mucosal immune response with polyplex-based DNA vaccines requires the delivery of intact polyplexes (polyelectrolyte complexes formed by self-assembly of plasmid DNA with a cationic polymer) to subepithelial lymphoid tissue (e.g. Peyer's patches) within the gastrointestinal tract. This work describes the formulation of a microparticle polyplex carrier allowing the potential of this approach to be realised. PEGylated PEI/DNA polyplexes (DNA concentration 20 microg/ml) formed at N/P 5:0 (defined as the ratio of polycation amino groups to DNA phosphates) were stable to salt-induced aggregation and could be concentrated to a final DNA concentration of 1 mg/ml without polyplex size increase. Polyplexes containing 1:1 polyethylene glycol (PEG)/polyethylenimine (PEI) ratio (mass/mass) gave similar levels of luciferase gene expression in B16F10 cells compared to non-PEG complexes. Poly-(D,L-lactide-co-glycolide) (PLGA) microparticles containing PEGylated polyplexes (approximately 17% DNA encapsulation efficiency) were formulated using a modified double emulsion solvent evaporation method. The microencapsulation and release of intact polyplexes from the microparticle carrier was demonstrated using polyanion (heparin sulfate and poly(aspartic acid) (PAA)) displacement techniques and electron microscopy. Microparticles containing PEGylated polyplexes (24 microg beta-galactosidase DNA) were given orally to Wistar rats. Significant transgene expression (compared to background) was found in peripheral tissue (spleen) 72 h after administration. This work demonstrates the potential application of microparticle carriers for mucosal polyplex-based vaccination.


Crystal structure of complete rhinovirus RNA polymerase suggests front loading of protein primer.
Picornaviruses utilize virally encoded RNA polymerase and a uridylylated protein primer to ensure replication of the entire viral genome. The molecular details of this mechanism are not well understood due to the lack of structural information. We report the crystal structure of human rhinovirus 16 3D RNA-dependent RNA polymerase (HRV16 3Dpol) at a 2.4-A resolution, representing the first complete polymerase structure from the Picornaviridae family. HRV16 3Dpol shares the canonical features of other known polymerase structures and contains an N-terminal region that tethers the fingers and thumb subdomains, forming a completely encircled active site cavity which is accessible through a small tunnel on the backside of the molecule. The small thumb subdomain contributes to the formation of a large cleft on the front face of the polymerase which also leads to the active site. The cleft appears large enough to accommodate a template:primer duplex during RNA elongation or a protein primer during the uridylylation stage of replication initiation. Based on the structural features of HRV16 3Dpo1 and the catalytic mechanism known for all polymerases, a front-loading model for uridylylation is proposed.


Evidence that the tandem-pleckstrin-homology-domain-containing protein TAPP1 interacts with Ptd(3,4)P2 and the multi-PDZ-domain-containing protein MUPP1 in vivo.
PtdIns(3,4,5)P3 is an established second messenger of growth-factor and insulin-induced signalling pathways. There is increasing evidence that one of the immediate breakdown products of PtdIns(3,4,5)P3, namely PtdIns(3,4)P2, whose levels are elevated by numerous extracellular agonists, might also function as a signalling molecule. Recently, we identified two related pleckstrin-homology (PH)-domain-containing proteins, termed 'tandem-PH-domain-containing protein-1' (TAPP1) and TAPP2, which interacted in vitro with high affinity with PtdIns(3,4)P2, but did not bind PtdIns(3,4,5)P3 or other phosphoinositides. In the present study we demonstrate that stimulation of Swiss 3T3 or 293 cells with agonists that stimulate PtdIns(3,4)P2 production results in the marked translocation of TAPP1 to the plasma membrane. This recruitment is dependent on a functional PtdIns(3,4)P2-binding PH domain and is inhibited by wortmannin, a phosphoinositide 3-kinase inhibitor that prevents PtdIns(3,4)P2 generation. A search for proteins that interact with TAPP1 identified the multi-PDZ-containing protein termed 'MUPP1', a protein possessing 13 PDZ domains and no other known modular or catalytic domains [PDZ is postsynaptic density protein (PSD-95)/Drosophila disc large tumour suppressor (dlg)/tight junction protein (ZO1)]. We demonstrate that immunoprecipitation of endogenously expressed TAPP1 from 293-cell lysates results in the co-immunoprecipitation of endogenous MUPP1, indicating that these proteins are likely to interact with each other physiologically. We show that TAPP1 and TAPP2 interact with the 10th and 13th PDZ domain of MUPP1 through their C-terminal amino acids. The results of the present study suggest that TAPP1 and TAPP2 could function in cells as adapter proteins to recruit MUPP1, or other proteins that they may interact with, to the plasma membrane in response to signals that elevate PtdIns(3,4)P2.


Carbon Capture Simulation Initiative: a case study in multiscale modeling and new challenges.
Advanced multiscale modeling and simulation have the potential to dramatically reduce the time and cost to develop new carbon capture technologies. The Carbon Capture Simulation Initiative is a partnership among national laboratories, industry, and universities that is developing, demonstrating, and deploying a suite of such tools, including basic data submodels, steady-state and dynamic process models, process optimization and uncertainty quantification tools, an advanced dynamic process control framework, high-resolution filtered computational-fluid-dynamics (CFD) submodels, validated high-fidelity device-scale CFD models with quantified uncertainty, and a risk-analysis framework. These tools and models enable basic data submodels, including thermodynamics and kinetics, to be used within detailed process models to synthesize and optimize a process. The resulting process informs the development of process control systems and more detailed simulations of potential equipment to improve the design and reduce scale-up risk. Quantification and propagation of uncertainty across scales is an essential part of these tools and models.


Quality and safety requirements for sustainable phage therapy products.
The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allows a timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.