What causes medication administration errors in a mental health hospital? A qualitative study with nursing staff.
Medication administration errors (MAEs) are a common risk to patient safety in mental health hospitals, but an absence of in-depth studies to understand the underlying causes of these errors limits the development of effective remedial interventions. This study aimed to investigate the causes of MAEs affecting inpatients in a mental health National Health Service (NHS) hospital in the North West of England. Registered and student mental health nurses working in inpatient psychiatric units were identified using a combination of direct advertisement and incident reports and invited to participate in semi-structured interviews utilising the critical incident technique. Interviews were designed to capture the participants' experiences of inpatient MAEs. All interviews were transcribed verbatim and subject to framework analysis to illuminate the underlying active failures, error/violation-provoking conditions and latent failures according to Reason's model of accident causation. A total of 20 participants described 26 MAEs (including 5 near misses) during the interviews. The majority of MAEs were skill-based slips and lapses (n = 16) or mistakes (n = 5), and were caused by a variety of interconnecting error/violation-provoking conditions relating to the patient, medicines used, medicines administration task, health care team, individual nurse and working environment. Some of these local conditions had origins in wider organisational latent failures. Recurrent and influential themes included inadequate staffing levels, unbalanced staff skill mix, interruptions/distractions, concerns with how the medicines administration task was approached and problems with communication. To our knowledge this is the first published in-depth qualitative study to investigate the underlying causes of specific MAEs in a mental health hospital. Our findings revealed that MAEs may arise due to multiple interacting error and violation provoking conditions and latent 'system' failures, which emphasises the complexity of this everyday task facing practitioners in clinical practice. Future research should focus on developing and testing interventions which address key local and wider organisational 'systems' failures to reduce error.


Self-feeding system for an adult with head injury and severe ataxia.
This report describes a customized self-feeding system designed to increase the independence of a person with a head injury who is unable to use his arm for self-feeding. The client has spastic hemiparesis in the right upper extremity and profound ataxia in the left upper extremity. Due to the severity of these disabilities, the client required total assistance at every meal since his injury 6.5 years ago. The self-feeding system described consists of an adapted spoon, a spoon holder, a scoop dish, and a dish stand. The client scoops food from the scoop dish with the adapted spoon held in his mouth and then transfers the spoon to a magnetic holder for positioning. This adaptation allows the client to position the spoon with his chin without demanding fine motor coordination. The self-feeding system is evaluated with a BAB single case research withdrawal design. Results indicate that this self-feeding system provides a viable alternative to assisting independence in self-feeding as measured by the cost-benefit ratio and nutrition intake. The client used the self-feeding system for 12 months at the rehabilitation center and has continued using the equipment at his nursing home.


Route infrastructure and the risk of injuries to bicyclists: a case-crossover study.
We compared cycling injury risks of 14 route types and other route infrastructure features. We recruited 690 city residents injured while cycling in Toronto or Vancouver, Canada. A case-crossover design compared route infrastructure at each injury site to that of a randomly selected control site from the same trip. Of 14 route types, cycle tracks had the lowest risk (adjusted odds ratio [OR] = 0.11; 95% confidence interval [CI] = 0.02, 0.54), about one ninth the risk of the reference: major streets with parked cars and no bike infrastructure. Risks on major streets were lower without parked cars (adjusted OR = 0.63; 95% CI = 0.41, 0.96) and with bike lanes (adjusted OR = 0.54; 95% CI = 0.29, 1.01). Local streets also had lower risks (adjusted OR = 0.51; 95% CI = 0.31, 0.84). Other infrastructure characteristics were associated with increased risks: streetcar or train tracks (adjusted OR = 3.0; 95% CI = 1.8, 5.1), downhill grades (adjusted OR = 2.3; 95% CI = 1.7, 3.1), and construction (adjusted OR = 1.9; 95% CI = 1.3, 2.9). The lower risks on quiet streets and with bike-specific infrastructure along busy streets support the route-design approach used in many northern European countries. Transportation infrastructure with lower bicycling injury risks merits public health support to reduce injuries and promote cycling.


The neurobiology of stress management.
Stress is natural and belongs to life itself. To sustain it and even grow with it biology invented different mechanisms, since stress resistance is obligatory. These pathways, we surmise, can be activated and learned intentionally, through professional stress management training or 'mind-body medicine', or endogenously and automatically through autoregulation. Since the primary goal of various stress-reducing approaches is corresponding, we expect to find an overlapping physiology and neurobiological principle of stress reduction. These common pathways, as we speculate, involve some of the very same signalling molecules and structures. Concepts of stress and stress management are described and then associated with underlying molecular and neurobiological pathways. Evidence is gathered from different sources to substantiate the hypothesis of an overlapping neurobiological principle in stress autoregulation. Stress describes the capacity and mechanisms to sustain and adjust to externally or internally challenging situations. Therefore, organisms can rely on the endogenous ability to self-regulate stress and stressors, i.e., autoregulatory stress management. Stress management usually consists of one to all of the following instruments and activities: behavioral or cognitive, exercise, relaxation and nutritional or food interventions (BERN), including social support and spirituality. These columns can be analyzed for their underlying neurobiological and autoregulatory pathways, thereby revealing a close connection to the brain's pleasure, reward and motivation circuits that are particularly bound to limbic structures and to endogenous dopamine, morphine, and nitric oxide (NO) signalling. Within this work, we demonstrate the existence of opioid, opiate, dopamine and related pathways for each of the selected stress management columns. Stress management techniques may possess specific and distinct physiological effects. However, beneficial behaviors and strategies to overcome stress are, as a more general principle, neurobiologically rewarded by pleasure induction, yet positively and physiologically amplified and reinforced, and this seems to work via dopamine, endorphin and morphine release, apart from other messenger molecules. These latter effects are unspecific, however, down-regulatory and clearly stress-reducing by their nature. There seems to exist a common neurobiological mechanism, i.e., limbic autoregulation, that involves dopamine, morphine and other endogenous signalling molecules, e.g., other opioid receptor agonists, endocannabinoids, oxytocin or serotonin, many of which act via NO release, and this share seems to be of critical importance for the self-regulation and management of stress: stress management is an endogenous potential.


Structure, Function and Inhibition of Poly(ADP-ribose)polymerase, Member 14 (PARP14).
Poly(ADP-ribose)polymerase, member 14 (PARP14, alternatively named ARTD8, BAL2, and COAST6) is an intracellular mono(ADP-ribosyl) transferase. PARP14 transfers a negatively charged ADP-ribose unit from a donor NAD+ molecule onto a target protein, post-translationally. PARP14's domain architecture consists of three macrodomains (Macro1, Macro2 and Macro3), a WWE domain and an ARTD (or catalytic domain). The Macro2 and Macro3 domains bind ADPribose (ADPr) with high affinity, whereas the WWE domain stabilizes the protein structure by binding to ADPr derivatives. The catalytic domain is involved in binding the NAD+ and catalyzing the mono- ADP-ribosylation reaction. PARP14 has been identified as a possible anti-cancer and antiinflammatory target. Acting as a transcriptional co-activator for STAT6, PARP14 acts to promote the over activation of the Th2 immune response, thus promoting the metabolic change to an anaerobic state (Warburg effect) and activation of cell survival pathways through JNK2 and the PGI/AMF complex. These changes are consistent with the metabolic sophistication observed in cancer, and the immune imbalance in inflammatory diseases. Current literature on selective and unselective PARP14 inhibitors are reviewed and discussed. Although there is no evidence that selective PARP inhibitors would be advantageous we have proposed some strategies for future design of selective PARP14 inhibitors.


Enhanced narrow-bandwidth emission during high-order harmonic generation from aligned molecules.
We theoretically investigate the selective enhancement of high-harmonic generation (HHG) in a small spectral range when an orthogonal-polarized two-color laser field interacts with aligned O(2) molecules. It is shown clearly that the enhanced narrow-bandwidth emission near the cutoff of the HHG spectrum can be effectively controlled by the molecular alignment angle, laser intensity and the relative phase of two-color laser fields. Furthermore, the strong dependence of narrow-bandwidth HHG on molecular alignment angle indicates that it encodes information about O(2) molecular orbitals, so it may be an alternative method for reconstruction of O(2) molecular orbitals.


Sensory-motor transformations for speech occur bilaterally.
Historically, the study of speech processing has emphasized a strong link between auditory perceptual input and motor production output. A kind of 'parity' is essential, as both perception- and production-based representations must form a unified interface to facilitate access to higher-order language processes such as syntax and semantics, believed to be computed in the dominant, typically left hemisphere. Although various theories have been proposed to unite perception and production, the underlying neural mechanisms are unclear. Early models of speech and language processing proposed that perceptual processing occurred in the left posterior superior temporal gyrus (Wernicke's area) and motor production processes occurred in the left inferior frontal gyrus (Broca's area). Sensory activity was proposed to link to production activity through connecting fibre tracts, forming the left lateralized speech sensory-motor system. Although recent evidence indicates that speech perception occurs bilaterally, prevailing models maintain that the speech sensory-motor system is left lateralized and facilitates the transformation from sensory-based auditory representations to motor-based production representations. However, evidence for the lateralized computation of sensory-motor speech transformations is indirect and primarily comes from stroke patients that have speech repetition deficits (conduction aphasia) and studies using covert speech and haemodynamic functional imaging. Whether the speech sensory-motor system is lateralized, like higher-order language processes, or bilateral, like speech perception, is controversial. Here we use direct neural recordings in subjects performing sensory-motor tasks involving overt speech production to show that sensory-motor transformations occur bilaterally. We demonstrate that electrodes over bilateral inferior frontal, inferior parietal, superior temporal, premotor and somatosensory cortices exhibit robust sensory-motor neural responses during both perception and production in an overt word-repetition task. Using a non-word transformation task, we show that bilateral sensory-motor responses can perform transformations between speech-perception- and speech-production-based representations. These results establish a bilateral sublexical speech sensory-motor system.


Testing the neutral theory of molecular evolution using genomic data: a comparison of the human and bovine transcriptome.
Despite growing evidence of rapid evolution in protein coding genes, the contribution of positive selection to intra- and interspecific differences in protein coding regions of the genome is unclear. We attempted to see if genes coding for secreted proteins and genes with narrow expression, specifically those preferentially expressed in the mammary gland, have diverged at a faster rate between domestic cattle (Bos taurus) and humans (Homo sapiens) than other genes and whether positive selection is responsible. Using a large data set, we identified groups of genes based on secretion and expression patterns and compared them for the rate of nonsynonymous (dN) and synonymous (dS) substitutions per site and the number of radical (Dr) and conservative (Dc) amino acid substitutions. We found evidence of rapid evolution in genes with narrow expression, especially for those expressed in the liver and mammary gland and for genes coding for secreted proteins. We compared common human polymorphism data with human-cattle divergence and found that genes with high evolutionary rates in human-cattle divergence also had a large number of common human polymorphisms. This argues against positive selection causing rapid divergence in these groups of genes. In most cases dN/dS ratios were lower in human-cattle divergence than in common human polymorphism presumably due to differences in the effectiveness of purifying selection between long-term divergence and short-term polymorphism.


Reconstructing unknown wavefronts by use of diffraction-intensity pattern subtraction.
We propose an easy method for unknown wavefront reconstruction by a typical Fourier transform system based on an amplitude-only spatial light modulator (SLM). The Fourier transform of the diffraction intensity pattern on the backfocal plane is the autocorrelation of the wavefront-transmitted SLM. Two intensity patterns were recorded when we set the transmittance of one corner pixel on the SLM as 0 and 1, separately, under the condition that the transmittances of the other pixels equal 1. The complex amplitude of the wavefront-transmitted SLM can be extracted from the Fourier transform of the diffraction intensity pattern subtraction without complicated calculations. The simulation results certifying our theories are also given. Our method provides us with an easy way for detecting the wavefront with high speed and high quality in real time without the reference wave.


Improving Depression Care Through an Online Learning Collaborative.
Depression is a leading cause of disability worldwide, and many internists diagnose and treat depression. This study aimed to examine the impact of a practice improvement intervention on screening and managing patients with depression in primary care. This pre-post study design included a physician practice survey designed to capture what the physicians believed they were doing in practice, a chart audit tool to capture what physicians were actually doing in practice, and an intervention that included an evidence-based educational program, online toolkit, and practice improvement coaching conference calls that promoted group learning. Following completion of the intervention, participants increasingly used the Patient Health Questionnaire-9 to detect, diagnose, and gauge treatment success for depression and reported increased use of guidelines and team-based care. Although barriers to improving depression care exist, this study suggests that evidence-based quality improvement programs can positively affect practice.


Therapy-Induced Plasticity in Chronic Aphasia Is Associated with Behavioral Improvement and Time Since Stroke.
Cortical reorganization after stroke is thought to underlie functional improvement. Patterns of reorganization may differ depending on the amount of time since the stroke or the degree of improvement. We investigated these issues in a study of brain connectivity changes with aphasia therapy. Twelve individuals with chronic aphasia participated in a 6-week trial of imitation-based speech therapy. We assessed improvement on a repetition test and analyzed effective connectivity during functional magnetic resonance imaging of a speech observation task before and after therapy. Using structural equation modeling, patient networks were compared with a model derived from healthy controls performing the same task. Independent of the amount of time since the stroke, patients demonstrating behavioral improvement had networks that reorganized to be more similar to controls in two functional pathways in the left hemisphere. Independent of behavioral improvement, patients with remote infarcts (2-7 years poststroke; n = 5) also reorganized to more closely resemble controls in one of these pathways. Patients with far removed injury (>10 years poststroke; n = 3) did not show behavioral improvement and, despite similarities to the normative model and overall network heterogeneity, reorganized to be less similar to controls following therapy in a distinct right-lateralized pathway. Behavioral improvement following aphasia therapy was associated with connectivity more closely approximating that of healthy controls. Individuals who had a stroke more than a decade before testing also showed plasticity, with a few pathways becoming less like controls, possibly representing compensation. Better understanding of these mechanisms may help direct targeted brain stimulation.


Class III beta-tubulin expression and in vitro resistance to microtubule targeting agents.
Class III beta-tubulin overexpression is a marker of resistance to microtubule disruptors in vitro, in vivo and in the clinic for many cancers, including breast cancer. The aims of this study were to develop a new model of class III beta-tubulin expression, avoiding the toxicity associated with chronic overexpression of class III beta-tubulin, and study the efficacy of a panel of clinical and pre-clinical drugs in this model. MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) were either transfected with pALTER-TUBB3 or siRNA-tubb3 and 24 h later exposed to test compounds for a further 96 h for proliferation studies. RT-PCR and immunoblotting were used to monitor the changes in class III beta-tubulin mRNA and protein expression. The model allowed for subtle changes in class III beta-tubulin expression to be achieved, which had no direct effect on the viability of the cells. Class III beta-tubulin overexpression conferred resistance to paclitaxel and vinorelbine, whereas downregulation of class III beta-tubulin rendered cells more sensitive to these two drugs. The efficacy of the colchicine-site binding agents, 2-MeOE2, colchicine, STX140, ENMD1198 and STX243 was unaffected by the changes in class III beta-tubulin expression. These data indicate that the effect of class III beta-tubulin overexpression may depend on where the drug's binding site is located on the tubulin. Therefore, this study highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.


External quality assessment of point-of-care International Normalized Ratio (INR) testing in Europe.
Point-of-care testing (POCT) of prothrombin time, expressed as International Normalized Ratio (INR), is widely used to monitor patients in oral anticoagulation treatment. Guidelines recommend that POCT users should participate in an external quality assessment (EQA) scheme whenever available. The aim of this study was to investigate which European countries provide EQA for POCT INR and to compare how these schemes are organized. Thirty European countries were invited to participate in this study. Those who reported that they provide EQA for POCT INR filled in a questionnaire dealing with different aspects of their schemes. Nineteen countries reported that they do not provide EQA for POCT INR, while 12 organizations from nine countries reported that they provide this service. Most of these countries circulate lyophilized samples with for the participants unknown target values. Samples with certified INR values and procedures using split samples with fresh patient samples are also used. The acceptability limits vary from 15% to 30%, and the total number of samples circulated per year varies from 1 to 12. Most of the countries organize educational activities together with their schemes. This study demonstrates that there is a wide variation in the way EQA for POCT INR is performed in Europe and that there are many European countries that do not provide this service. Even though our findings indicate that EQA for POCT INR draws some challenges, especially in providing suitable control materials, participation in such schemes is considered useful.


Alien animal introductions in Iberian inland waters: An update and analysis.
Inland waters provide innumerable ecosystem services and for this reason are among the most negatively impacted ecosystems worldwide. This is also the case with invasive alien species, which have enormous economic and ecological impacts in freshwater ecosystems. The pace of alien introductions has not decreased in recent years and the first step to their management is to update checklists and to determine introduction pathways and origins of species. This study updates the list of alien animal species introduced and naturalised in inland waters of the Iberian Peninsula. Additionally, the most relevant characteristics and association patterns of these species (region of origin, taxonomic group, introduction pathway and main habitat) and introduction trends in the Iberian Peninsula, mainland Portugal and Galicia are analysed. We identified 125 alien animal species introduced in Iberian inland waters (increase of 30% compared to previous reviews) whereas 24 additional species have uncertain establishment or native status. We found marked associations among taxonomic groups and their region of origin, introduction pathway and main habitat used but less relationship between these three latter features. Considering the whole territory of the Iberian Peninsula, the introduction rates seem to be experiencing a decrease or to have achieved stabilization. However, this is not applicable to mainland Portugal and Galicia for which the historical delay in the first record dates for alien species is fading-out, suggesting increasing spread rates. Our results should facilitate early detections and the design of prevention protocols and taxon-specific management plans.


Tissue and exosomal miRNA editing in Non-Small Cell Lung Cancer.
RNA editing in microRNAs has been recently proposed as a novel biomarker in cancer. Here, we investigated RNA editing by leveraging small-RNA sequencing data from 87 NSCLC (Non-Small Cell Lung Cancer) samples paired with normal lung tissues from The Cancer Genome Atlas (TCGA) combined with 26 plasma-derived exosome samples from an independent cohort. Using both the editing levels and microRNA editing expression, we detected deregulated microRNA editing events between NSCLC tumor and normal tissues. Interestingly, and for the first time, we also detected editing sites in the microRNA cargo of circulating exosomes, providing the potential to non-invasively discriminate between normal and tumor samples. Of note, miR-411-5p edited in position 5 was significantly dysregulated in tissues as well as in exosomes of NSCLC patients, suggesting a potential targetome shift relevant to lung cancer biology.


Glutamate excitotoxicity induced by orally administered propionic acid, a short chain fatty acid can be ameliorated by bee pollen.
Rodent models may guide investigations towards identifying either environmental neuro-toxicants or drugs with neuro-therapeutic effects. This work aims to study the therapeutic effects of bee pollen on brain glutamate excitotoxicity and the impaired glutamine-glutamate- gamma amino butyric acid (GABA) circuit induced by propionic acid (PPA), a short chain fatty acid, in rat pups. Twenty-four young male Western Albino rats 3-4 weeks of age, and 45-60 g body weight were enrolled in the present study. They were grouped into four equal groups: Group 1, the control received phosphate buffered saline at the same time of PPA adminstration; Group 2, received 750 mg/kg body weight divided into 3 equal daily doses and served as acute neurotoxic dose of PPA; Group 3, received 750 mg/kg body weight divided in 10 equal doses of 75 mg/kg body weight/day, and served as the sub-acute group; and Group 4, the therapeutic group, was treated with bee pollen (50 mg/kg body weight) for 30 days after acute PPA intoxication. GABA, glutamate and glutamine were measured in the brain homogenates of the four groups. The results showed that PPA caused multiple signs of excitotoxicity, as measured by the elevation of glutamate and the glutamate/glutamine ratio and the decrease of GABA, glutamine and the GABA/glutamate ratio. Bee pollen was effective in counteracting the neurotoxic effects of PPA to a certain extent. In conclusion, bee pollen demonstrates ameliorating effects on glutamate excitotoxicity and the impaired glutamine-glutamate-GABA circuit as two etiological mechanisms in PPA-induced neurotoxicity.


Size-specific optimization of CT protocols based on minimum detectability.
To develop a comprehensive model of task-based performance of CT across a broad library of CT protocols, so that radiation dose and image quality can be optimized within a large multivendor clinical facility. Eighty adult CT protocols from the Duke University Medical Center were grouped into 23 protocol groups with similar acquisition characteristics. A size-based image quality phantom (Duke Mercury Phantom 2.0) was imaged using these protocol groups for a range of clinically relevant dose levels on two CT manufacturer platforms (Siemens SOMATOM Definition Flash and GE CT750 HD). For each protocol group, phantom size, and dose level, the images were analyzed to extract task-based image quality metrics, the task transfer function (TTF), and the noise power spectrum (NPS). The TTF and NPS were further combined with generalized models of lesion task functions to predict the detectability of the lesions in terms of areas under the receiver operating characteristic curve (Az ). A graphical user interface (GUI) was developed to present Az as a function of lesion size and contrast, dose, patient size, and protocol, as well as to derive the necessary dose to achieve a detection threshold for a targeted lesion. The GUI provided the prediction of Az values modeling detection confidence for a targeted lesion, patient size, and dose. As an example, an abdomen pelvis exam for one scanner, with a reference task size/contrast of 5-mm/50-HU, and an Az of 0.9 indicated a dose requirement of 4.0, 8.9, and 16.9 mGy for patient diameters of 25, 30, and 35 cm, respectively. For a constant patient diameter of 30 cm and 50-HU lesion contrast, the minimum detected lesion size at those dose levels were predicted to be 8.4, 5.0, and 3.9 mm, respectively. A CT protocol optimization platform was developed by combining task-based detectability calculations with a GUI that demonstrates the tradeoff between dose and image quality. The platform can be used to improve individual protocol dose efficiency, as well as to improve protocol consistency across various patient sizes and CT scanners.


Prevalence of atopy and respiratory allergic diseases in the elderly SAPALDIA population.
Because of changing world demographics, the elderly population is steadily increasing. Few studies have assessed the prevalence of atopy and allergic diseases in elderly persons with objective measures. The aim of this paper is to describe the prevalence of atopy, self-reported allergic rhinitis and doctor's diagnosed asthma in persons over the age of 60 in Switzerland. The cross-sectional examination of the Swiss Study on Air Pollution and Health in Adults (SAPALDIA 1), performed in 1991, included 9,651 adults aged 18-60 years. In 2001-2002 the same subjects were invited for a follow-up examination (SAPALDIA 2). Serum samples collected at baseline and follow-up were tested for specific IgE sensitization with the Phadiatop® (Phadia, Uppsala, Sweden, now Thermo Fisher Scientific) assay containing a mixture of common respiratory allergens (grass, birch, mugwort, Parietaria and olive pollen, dog, cat, horse, Cladosporium herbarum, house dust mite and flour mite). Atopy was defined as a positive result in the Phadiatop test according to guidelines by the manufacturer. The prevalence rates of atopy, self-reported allergic rhinitis and doctor's diagnosed asthma were evaluated by sex and age group (≤60 or >60 years). 7,667 subjects (men = 3,692/women = 3,975) participated in the follow-up by responding to a detailed questionnaire (80% of SAPALDIA 1 participants). Phadiatop results were available for 5,835 participants (men = 2,839/women = 2,996). Prevalence rates of atopy (Phadiatop positive) were 36.4% in men aged ≤60 years versus 26.2% in men aged >60 years and 30.6 and 18.1% in women, respectively (both p < 0.001). Prevalence rates of self-reported allergic rhinitis in subjects >60 years old were 13.0% for men and 15.4% for women (p = 0.12), and for doctor's diagnosed asthma 6.6% versus 7.6%, respectively (p = 0.40). Both rhinitis and asthma prevalences were higher in persons <60 years. The results were not sensitive to potential bias from nonparticipation at follow-up as demonstrated by imputation of sex- and age-specific allergic rhinitis and asthma among nonparticipants. According to our estimates, the prevalence of allergic rhinitis among persons aged between 60 and 70 years in Switzerland in the present cohort is of the order of 13-15% and should not be underestimated, although it is lower than in age groups ≤60 years.


Measuring data reliability for preventive services in electronic medical records.
Improvements in the quality of health care services are often measured using data present in medical records. Electronic Medical Records (EMRs) contain potentially valuable new sources of health data. However, data quality in EMRs may not be optimal and should be assessed. Data reliability (are the same data elements being measured over time?) is a prerequisite for data validity (are the data accurate?). Our objective was to measure the reliability of data for preventive services in primary care EMRs during the transition to EMR. Our data sources were randomly selected eligible patients' medical records and data obtained from provincial administrative datasets. Eighteen community-based family physicians in Toronto, Ontario that implemented EMRs starting in 2006 participated in this study. We measured the proportion of patients eligible for a service (Pap smear, screening mammogram or influenza vaccination) that received the service. We compared the change in rates of selected preventive services calculated from the medical record audits with the change in administrative datasets. In the first year of EMR use (2006) services decreased by 8.7% more (95% CI -11.0%- - 6.4%, p < 0.0001) when measured through medical record audits as compared with administrative datasets. Services increased by 2.4% more (95% CI 0%-4.9%, p = 0.05) in the medical record audits during the second year of EMR use (2007). There were differences between the change measured through medical record audits and administrative datasets. Problems could include difficulties with organizing new data entry processes as well as continued use of both paper and EMRs. Data extracted from EMRs had limited reliability during the initial phase of EMR implementation. Unreliable data interferes with the ability to measure and improve health care quality.


The Lognormal Lung: A new approach to quantifying lung inhomogeneity in COPD.
Early diagnosis and disease phenotyping in COPD are currently limited by the use of spirometry, which may remain normal despite significant small-airways disease and which may not fully capture a patient's underlying pathophysiology. In this study we explored the use of a new non-invasive technique that assesses gas-exchange inhomogeneity in patients with COPD of varying disease severity (according to GOLD Stage), compared with age-matched healthy controls. The technique, which combines highly accurate measurement of respiratory gas exchange using a bespoke molecular flow sensor and a mechanistic mathematical model of the lung, provides new indices of lung function: the parameters σCL, σCd, and σVD represent the standard deviations of distributions for alveolar compliance, anatomical deadspace and vascular conductance relative to lung volume, respectively. It also provides parameter estimates for total anatomical deadspace and functional residual capacity (FRC). We demonstrate that these parameters are robust and sensitive, and that they can distinguish between healthy individuals and those with mild-moderate COPD (stage 1-2), as well as distinguish between mild-moderate COPD (stage 1-2) and more severe (stage 3-4) COPD. In particular, σCL, a measure of unevenness in lung inflation/deflation, could represent a more sensitive non-invasive marker of early or mild COPD. In addition, by providing a multi-dimensional assessment of lung physiology, this technique may also give insight into the underlying pathophysiological phenotype for individual patients. These preliminary results warrant further investigation in larger clinical research studies, including interventional trials.


Policy Challenges and Opportunities to Address Changing Paradigms in Cancer Care Delivery.
Multiple factors are forcing the healthcare delivery system to change. A movement toward value-based payment models is shifting these systems to team-based integration and coordination of care for better efficiencies and outcomes. Workforce shortages are stressing access and quality of care for patients with cancer and survivors, and their families and caregivers. Innovative therapies are expensive, forcing payers and employers to prioritize resources. Patients are advocating for care models centered on their needs rather than those of providers. In response, payment policies have recently focused on the promotion of alternative payment models that incentivize coordinated, high-quality care with consideration for value and controlling the increasing overall costs associated with cancer and its treatment. Given the multitude of factors confounding cancer care, NCCN convened a multistakeholder working group to examine the challenges and opportunities presented by changing paradigms in cancer care delivery. The group identified key challenges and developed policy recommendations to address 4 high-visibility topics in cancer care delivery. The findings and recommendations were then presented at the NCCN Policy Summit: Policy Challenges and Opportunities to Address Changing Paradigms in Cancer Care Delivery in September 2018, and multistakeholder roundtable panel discussions explored these findings and recommendations along with additional items. This article encapsulates the discussion from the NCCN Working Group meetings and the NCCN Policy Summit, including multistakeholder policy recommendations on delivery issues in cancer care designed to help inform national policies moving forward.


The effects of vascular access types on the survival and quality of life and depression in the incident hemodialysis patients.
Background: Although arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD), the association between vascular access types and quality of life is not well-known. We investigated the relationships between HD vascular access types and all-cause mortality, health-related quality of life (HRQOL) and the degree of depression in a large prospective cohort.Methods: A total of 1461 patients who newly initiated HD were included. The initial vascular access types were classified into AVF, arteriovenous graft (AVG), and central venous catheter (CVC). The primary outcomes were all-cause mortality and HRQOL and depression. The secondary outcome was all-cause hospitalization. Kidney Disease Quality of Life Short Form 36 (KDQOL-36) and Beck's depression inventory (BDI) scores were measured to assess HRQOL and depression.Results: Among 1461 patients, we identified 314 patients who started HD via AVF, 76 via AVG, and 1071 via CVC. In the survival analysis, patients with AVF showed significantly better survival compared with patients with other accesses (p < .001). The AVF and AVG group had higher KDQOL-36 score and lower BDI score than CVC group at 3 months and 12 months after the initiation of HD. The frequency of hospitalization was higher in patients with AVG compared to those with AVF (AVF 0.7 vs. AVG 1.1 times per year) (p = .024).Conclusions: The patients with AVF had better survival rate and low hospitalization rate, and the patients with AVF or AVG showed both higher HRQOL and lower depression scores than those with CVC.


The prevalence and awareness of sleep apnea in patients suffering chronic pain: an assessment using the STOP-Bang sleep apnea questionnaire.
Some patient subsets are at higher risk of sleep apnea, including patients with chronic pain. However, it is unclear whether patients and their caregivers are aware of the possibly increased risk of sleep apnea in this population. Chronic pain is often treated with opioids which may decrease both the central respiratory drive and the patency of the upper airway, potentially contributing to this sleep disorder. Using a self-reporting questionnaire approach in the chronic pain population, this study surveyed patient and caregiver awareness surrounding the risk of sleep apnea. In addition, we looked at the influence of opioid therapy on the prevalence of sleep apnea. Consecutive patients presenting to a pain clinic were invited to participate anonymously in a survey that included the STOP-Bang sleep apnea questionnaire, which assesses patients' knowledge, testing, diagnosis, or treatment of sleep apnea and whether their caregivers had discussed with them their increased risk of sleep apnea and opioid use. Among 305 participating patients, 58.2% (n=173) screened positive for sleep apnea. Among the 202 patients on opioid therapy, 59.2% (116/202) were STOP-Bang positive (score ≥3). However, only 37.5% (n=72/173) of these patients had discussed their risk of sleep apnea with a caregiver and only 30.7% (n=59) underwent testing. Against expectation, opioids did not increase the prevalence of sleep apnea in our study population. Chronic pain patients had a high risk of sleep apnea, regardless of opioid prescription. Most patients were unaware of their increased risk and denied undergoing the necessary testing. Greater attention to screening, testing, and education for sleep apnea needs to be paid in chronic pain patients, especially given the potentially dangerous ramifications of opioid-induced sleep apnea.


Preparation and characterization of carbon nanofluid by a plasma arc nanoparticles synthesis system.
Heat dissipation from electrical appliances is a significant issue with contemporary electrical devices. One factor in the improvement of heat dissipation is the heat transfer performance of the working fluid. In this study, we used plasma arc technology to produce a nanofluid of carbon nanoparticles dispersed in distilled water. In a one-step synthesis, carbon was simultaneously heated and vaporized in the chamber, the carbon vapor and particles were then carried to a collector, where cooling furnished the desired carbon/water nanofluid. The particle size and shape were determined using the light-scattering size analyzer, SEM, and TEM. Crystal morphology was examined by XRD. Finally, the characterization include thermal conductivity, viscosity, density and electric conductivity were evaluated by suitable instruments under different temperatures. The thermal conductivity of carbon/water nanofluid increased by about 25% at 50°C compared to distilled water. The experimental results demonstrated excellent thermal conductivity and feasibility for manufacturing of carbon/water nanofluids.


Endocrine and milt responses of male crucian carp (Carassius carassius L.) to periovulatory females under field conditions.
Laboratory studies in domesticated goldfish (Carassius auratus) show that, during the preovulatory luteinizing hormone (LH) surge, females release a complex steroidal pheromone that induces in males a rapid increase of plasma LH, which in turn increases strippable milt (sperm and seminal fluid) prior to ovulation and spawning. The objective of this study was to determine if the same phenomenon occurs in a wild congener, the crucian carp (Carassius carassius), under field conditions where fish are held in natural waters under ambient temperature and photoperiod. During the spawning season in June 2003, crucian carp were trapped in a small pond near Uppsala, Sweden, and held separately by sex in floating net pens. Addition of untreated females to male pens did not change male LH concentrations or milt volume during the 17 h sampling period. In contrast, addition of females injected with Ovaprim (to induce an LH surge and ovulation) increased male LH concentrations at all sample times (5, 9, 13, and 17h) following female addition and increased milt volumes at all but the first (5h) sample time. Similar increases in male LH and milt that also occurred when untreated females ovulated spontaneously after addition to male pens suggest it is female ovulatory condition, rather than injection of ovaprim per se, that induced male LH and milt responses. Males also increased LH and milt 9h after addition of females injected with the goldfish pheromonal steroid 4-pregnen-17,20beta-diol-3-one (17,20betaP), suggesting that similar responses to ovaprim-injected females were due, at least in part, to release of preovulatory pheromonal steroid(s). The clear and consistent effects of ovulatory females on male LH and milt, and the fact that crucian carp adapted well to confinement, ovulated spontaneously, and exhibited apparently normal spawning behavior, all suggest that this species can serve as a useful cyprinid model to study reproductive processes in natural conditions.


Glazed lunar rocks: origin by impact.
The glassy coating of lunar rock 12017 is enriched in 15 trace elements relative to the crystalline interior. It apparently consists chiefly of shock-melted rock, somewhat richer in rare earth elements and alkali metals than rock 12017 itself. The glass has been contaminated by about 0.5 percent carbonaceous-chondrite-like material or, alternatively, by a mixture of 0.06 to 0.3 percent fractionated meteoritic material and approximately 10 to 15 percent local soil. The glazing seems to represent molten material splashed from a nearby meteorite impact and not in situ melting by a sudden increase in solar luminosity.


Statistical models to evaluate invertebrate-plant trophic interactions in arable systems.
Over the past 40 years there have been marked shifts in arable farmland management that are widely believed to have had a considerable impact on flowering plants and invertebrates and the small mammals and birds that rely upon them. It is not yet possible to predict the dynamics of plants and invertebrates either with past or future changes in farmland management. This study investigates whether a basic invertebrate classification, formed of broad trophic groups, can be used to describe interactions between invertebrates and their resource plants and evaluate management impacts for genetically modified, herbicide-tolerant (GMHT) and conventional herbicide management in both spring- and winter-sown oilseed rape. It is argued that the analyses validate trophic-based approaches for describing the dynamics of invertebrates in farmland and that linear models might be used to describe the changes in invertebrate trophic group abundance in farmland when driven by primary producer abundance or biomass and interactions between invertebrates themselves. The analyses indicate that invertebrate dynamics under GMHT management are not unique, but similar to conventional management occurring over different resource ranges, and that dynamics differed considerably between spring- and winter-sown oilseed rape. Thus, herbicide management was of much lower impact on trophic relationships than sowing date. Results indicate that invertebrate dynamics in oilseed rape are regulated by a combination of top-down and bottom-up trophic processes.


Multi-functionalization of lithographically designed gold nanodisks by plasmon-mediated reduction of aryl diazonium salts.
Plasmon-driven surface functionalization of nanoparticles is receiving increasing attention as it allows locally tailored chemical reactivity to be generated on the nanoparticle surface. The extension to surface multi-functionalization still represents a major breakthrough in chemistry. We address this issue by triggering regiospecific surface double-functionalization under plasmon excitation, using diazonium salts as surface functionalization agents.


Novel targets and approaches in advanced prostate cancer.
The development of therapeutic resistance is the underlying cause for most cancer deaths. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in prostate cancer, the rational design of targeted therapeutics is possible. We review new treatment options for men with advanced prostate cancer. Although the taxanes currently represent the most active chemotherapeutic agents and standard of care for first-line treatment of metastatic hormone-refractory prostate cancer, most patients eventually progress because of intrinsic or acquired drug resistance. In recent years, increased knowledge of cancer progression and therapeutic resistance has identified many gene targets that regulate apoptosis, proliferation, and cell signalling. To date, numerous novel compounds have entered clinical trials as either single agents or in combination with cytotoxic chemotherapy. Even though hormone-refractory prostate cancer is still incurable, it is not untreatable. As cancer cells are proficient at adapting to therapeutic stressors, a combination regimen with drugs that target crucial cellular networks like the apoptotic rheostat may be more promising than treatment with highly selective single-target agents. Recent findings are very hopeful, but challenges remain to demonstrate effective antitumour activity in phase III trials with survival as the principal endpoint.


Expression of the neural RNA-binding protein Musashi1 in human gliomas.
Tumor cells arising from a particular tissue may exhibit the same gene expression patterns as their precursor cells. To test this proposition, we have analyzed the expression of a neural RNA-binding protein, Musashi1, in primary human central nervous system (CNS) tumors. In rodents, Musashi1 is expressed predominantly in proliferating multipotent neural precursor cells, but not in newly generated postmitotic neurons. The expression of Musashi1 is downregulated with the successive progression of neurogenesis. In normal adult human tissues, we detected low levels of Musashi1 expression in brain and testis by RT-PCR analysis. In an RNA panel of 32 cancer tissues and cell lines, elevated expression of Musashi1 was seen in all five malignant gliomas studied, in contrast to the slight expression seen in other tumor cells, including those in several melanomas and a prostate cancer. Western blot analysis showed strong Musashi1 expression in malignant gliomas compared with nonneoplastic brain tissue. Glioblastomas, the most malignant form of glioma, showed higher Musashi1 expression than less malignant gliomas by immunohistochemical analysis. Tumors with strong Musashi1 expression tended to have high proliferative activity. Thus, the expression of Musashi1 correlated with the grade of the malignancy and proliferative activity in gliomas. These results suggest that primary CNS tumors may share gene expression patterns with primitive, undifferentiated CNS cells and that Musashi1 may be a useful marker for the diagnosis of CNS tumors.


Exoplanet Biosignatures: A Review of Remotely Detectable Signs of Life.
In the coming years and decades, advanced space- and ground-based observatories will allow an unprecedented opportunity to probe the atmospheres and surfaces of potentially habitable exoplanets for signatures of life. Life on Earth, through its gaseous products and reflectance and scattering properties, has left its fingerprint on the spectrum of our planet. Aided by the universality of the laws of physics and chemistry, we turn to Earth's biosphere, both in the present and through geologic time, for analog signatures that will aid in the search for life elsewhere. Considering the insights gained from modern and ancient Earth, and the broader array of hypothetical exoplanet possibilities, we have compiled a comprehensive overview of our current understanding of potential exoplanet biosignatures, including gaseous, surface, and temporal biosignatures. We additionally survey biogenic spectral features that are well known in the specialist literature but have not yet been robustly vetted in the context of exoplanet biosignatures. We briefly review advances in assessing biosignature plausibility, including novel methods for determining chemical disequilibrium from remotely obtainable data and assessment tools for determining the minimum biomass required to maintain short-lived biogenic gases as atmospheric signatures. We focus particularly on advances made since the seminal review by Des Marais et al. The purpose of this work is not to propose new biosignature strategies, a goal left to companion articles in this series, but to review the current literature, draw meaningful connections between seemingly disparate areas, and clear the way for a path forward. Key Words: Exoplanets-Biosignatures-Habitability markers-Photosynthesis-Planetary surfaces-Atmospheres-Spectroscopy-Cryptic biospheres-False positives. Astrobiology 18, 663-708.


Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms.
Primary cilia are microtubule-based organelles involved in signal transduction and project from the surface of most vertebrate cells. Proteins that can localize to the cilium, for example, Inversin and Bardet-Biedl syndrome (BBS) proteins, are implicated in both beta-catenin-dependent and -independent Wnt signalling. Given that Inversin and BBS proteins are found both at the cilium and elsewhere in the cell, the role of the cilium itself in Wnt signalling is not clear. Using three separate mutations that disrupt ciliogenesis (affecting Kif3a, Ift88 and Ofd1), we show in this study that the primary cilium restricts the activity of the canonical Wnt pathway in mouse embryos, primary fibroblasts, and embryonic stem cells. Interestingly, unciliated cells activate transcription only in response to Wnt stimulation, but do so much more robustly than ciliated cells. Loss of Kif3a, but not other ciliogenic genes, causes constitutive phosphorylation of Dishevelled (Dvl). Blocking the activity of casein kinase I (CKI) reverses this constitutive Dvl phosphorylation and abrogates pathway hyper-responsiveness. These results suggest that Kif3a restrains canonical Wnt signalling both by restricting the CKI-dependent phosphorylation of Dvl and through a separate ciliary mechanism. More generally, these findings reveal that, in contrast to its role in promoting Hedgehog (Hh) signalling, the cilium restrains canonical Wnt signalling.


Pluronic-g-poly(acrylic acid) copolymers as novel excipients for site specific, sustained release tablets.
Potential utility of copolymers comprising Pluronic (PEO-PPO-PEO) surfactants covalently conjugated with poly(acrylic acid) (PAA) as excipients for sustained-release tablets was explored. Apparent particle density, particle size distribution, Carr index, thermal stability, and compression behavior of the Pluronic-PAA copolymers were characterized. Tablets prepared by direct compression of blends of Pluronic-PAA copolymers were evaluated on the basis of their thermomechanical profile, crushing strength, friability, and drug release properties. Small molecular weight drugs of aqueous solubility decreasing in the order theophylline>hydrochlorothiazide>nitrofurantoin were incorporated to the tablets. For comparison purposes, tablets were also prepared from PAA of Carbopol 71G (C71G), and mixtures of C71G and Pluronic F127, with each of the above three drugs. The Pluronic-PAA aggregates are stabilized by hydrophobic associations between poly(propylene oxide) (PPO) segments in aqueous solutions, and thus require higher ionization of the carboxylic groups to overcome the associations and swell. The swelling pattern of the Pluronic-PAA copolymers is more dramatically pH-dependent than that of Carbopol lacking any hydrophobic associations. The drug retention in and release from the Pluronic-PAA based tablets is profoundly pH-dependent and hence specific to the pH exceeding that of the pK(a)>5 of these copolymers. Theophylline- and hydrochlorotiazide-containing tablets made with Pluronic-PAA copolymers showed a reduced release rate under acidic conditions compared to the neutral or alkaline conditions, while the opposite pattern was observed with the Carbopol-based tablets due to the different pH-dependent swelling behavior of the polymers. Nitrofurantoin-containing tablets showed a remarkably low drug release rate owing to the strong hydrophobic character of nitrofurantoin and of its complexes with the copolymers. Integrity of the nitrofurantoin-containing tablets was maintained during the 24h release test. Zero-order kinetics of the cumulative release profile of all drugs under study was observed with the Pluronic-PAA as a tablet excipient. Adequate mechanical properties, the self-assembling behavior, and the pH-sensitiveness of the Pluronic-PAA copolymers make them promising excipients for tablets with preferential delivery into a neutral to alkaline pH environment.


Utility of total lymphocyte count as a surrogate marker for CD4 counts in HIV-1 infected children in Kenya.
In resource-limited settings, such as Kenya, access to CD4 testing is limited. Therefore, evaluation of less expensive laboratory diagnostics is urgently needed to diagnose immuno-suppression in children. To evaluate utility of total lymphocyte count (TLC) as surrogate marker for CD4 count in HIV-infected children. This was a hospital based retrospective study conducted in three HIV clinics in Kisumu and Nairobi in Kenya. TLC, CD4 count and CD4 percent data were abstracted from hospital records of 487 antiretroviral-naïve HIV-infected children aged 1 month--12 years. TLC and CD4 count were positively correlated (r = 0.66, p < 0.001) with highest correlation seen in children with severe immuno-suppression (r = 0.72, p < 0.001) and children >59 months of age (r = 0.68, p < 0.001). Children were considered to have severe immuno-suppression if they met the following WHO set CD4 count thresholds: age below 12 months (CD4 counts < 1500 cells/mm(3)), age 12-35 months (CD4 count < 750 cells/mm(3)), age 36-59 months (CD4 count < 350 cells/mm(3), and age above 59 months (CD4 count < 200 cells/mm(3)). WHO recommended TLC threshold values for severe immuno-suppression of 4000, 3000, 2500 and 2000 cells/mm(3) for age categories <12, 12-35, 36-59 and >59 months had low sensitivity of 25%, 23%, 33% and 62% respectively in predicting severe immuno-suppression using CD4 count as gold standard. Raising TLC thresholds to 7000, 6000, 4500 and 3000 cells/mm3 for each of the stated age categories increased sensitivity to 71%, 64%, 56% and 86%, with positive predictive values of 85%, 61%, 37%, 68% respectively but reduced specificity to 73%, 62%, 54% and 68% with negative predictive values of 54%, 65%, 71% and 87% respectively. TLC is positively correlated with absolute CD4 count in children but current WHO age-specific thresholds had low sensitivity to identify severely immunosuppressed Kenyan children. Sensitivity and therefore utility of TLC to identify immuno-suppressed children may be improved by raising the TLC cut off levels across the various age categories.


Evaluation of chiropractic management of pediatric patients with low back pain: a prospective cohort study.
Recent epidemiologic studies have estimated that the lifetime prevalence of low back pain (LBP) in children is approximately 50%, with almost 15% of children experiencing frequent or continual pain. A literature search revealed no published studies addressing conservative treatment of childhood LBP. To describe chiropractic management of LBP in patients between the ages of 4 and 18 years, as well as outcomes and factors associated with the outcomes. Prospective cohort study of consecutive pediatric patients with LBP seeing randomly selected chiropractors within the cities of Calgary, Alberta, and Toronto, Ontario, Canada. Follow-up data collection included the type and extent of treatment rendered and its outcome, which was measured with a 5-point subjective rating scale and a self-report pediatric visual analogue scale. Fifteen chiropractors provided data on 54 consecutive pediatric patients with LBP. The average age of the patients was 13.1 years, 57% were male, 61% were acute, with 47% attributing onset to a traumatic event (most commonly sports-related); 24% reported an episode duration of greater than 3 months. Almost 90% of cases presented with uncomplicated mechanical LBP, most frequently diagnosed as lumbar facet dysfunction or subluxation. Patients were managed with manipulation, with a minority (7.7%) receiving some form of active management. "Important" improvement was seen in 62% and 87% on the visual analogue and subjective scales, respectively, within a 6-week course of management (Kaplan-Meier survival analysis). Patients with chronic LBP were less likely to respond within the median number of treatments (relative risk = 2.1). Patients responded favorably to chiropractic management, and there were no reported complications. Future investigations should establish the natural history and compare chiropractic management with other forms of treatment to gain knowledge about the effectiveness of chiropractic in managing pediatric LBP.


Molecular analysis of the gene cluster involved in the production and secretion of enterocins 1071A and 1071B and of the genes responsible for the replication and transfer of plasmid pEF1071.
Plasmid pEF1071 (9328 bp), bearing the structural genes of enterocins 1071A and 1071B, had been sequenced and nine genes were identified. The genes responsible for the production and transfer of enterocins 1071A and 1071B are arranged in two operons. The first operon (EntABI) contains the genes ent1071A, ent1071B and entI that encodes enterocin 1071A, enterocin 1071B and immunity to these bacteriocins, respectively. The second operon (EntTD) contains two genes, viz. abc (also named entT) and entD, encoding a putative ABC transporter (697 aa) and an accessory protein (697 aa), respectively. Three genes (mobC, mobA and mobX), situated downstream of the second operon, encode proteins of 127, 346 and 224 amino acids, respectively, and are presumably involved in the mobilization of plasmid pEF1071. The ninth gene was identified as a putative repA gene encoding a protein of 327 amino acids. The transcription initiation sites of the genes ent1071A, abc, mobA, mobX and repA were determined by primer extension. By inserting the cat gene into the ent1071B gene, and thereby disrupting the operon structure, we have shown that bacteriocins Ent1071A and Ent1071B act independently against target bacteria.


The syndapin protein family: linking membrane trafficking with the cytoskeleton.
Syndapins--also called PACSINs--are highly conserved Src-homology 3 (SH3)-domain-containing proteins that seem to exist in all multicellular eukaryotes. They interact with the large GTPase dynamin and several other proteins implicated in vesicle trafficking. Syndapin-dynamin complexes appear to play an important role in vesicle fission at different donor membranes, including the plasma membrane (endocytosis) and Golgi membranes. In addition, syndapins are implicated in later steps of vesicle cycling in neuronal and non-neuronal cells. Syndapins also interact with N-WASP, a potent activator of the Arp2/3 complex that forms a critical part of the actin polymerization machinery. Syndapin oligomers can thereby couple bursts of actin polymerization with the vesicle fission step involving dynamins. This allows newly formed vesicles to move away from the donor membrane driven by actin polymerization. Syndapins also engage in additional interactions with molecules involved in several signal transduction pathways, producing crosstalk at the interface between membrane trafficking and the cytoskeleton. Given the distinct expression patterns of the different syndapins and their splice forms, these proteins could have isoform-specific functions.


Super-elasticity of three-dimensionally cross-linked graphene materials all the way to deep cryogenic temperatures.
Until now, materials with high elasticity at deep cryogenic temperatures have not been observed. Previous reports indicated that graphene and carbon nanotube-based porous materials can exhibit reversible mechano-elastic behavior from liquid nitrogen temperature up to nearly a thousand degrees Celsius. Here, we report wide temperature-invariant large-strain super-elastic behavior in three-dimensionally cross-linked graphene materials that persists even to a liquid helium temperature of 4 K, a property not previously observed for any other material. To understand the mechanical properties of these graphene materials, we show by in situ experiments and modeling results that these remarkable properties are the synergetic results of the unique architecture and intrinsic elastic/flexibility properties of individual graphene sheets and the covalent junctions between the sheets that persist even at harsh temperatures. These results suggest possible applications for such materials at extremely low temperature environments such as those in outer space.


Expert opinion in melanoma: the sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the microanatomic location of metastases and metastatic tumour burden.
The sentinel node (SN) status has been recognised to be the most important prognostic factor in melanoma. Many studies have investigated additional factors to further predict survival/lymph node involvement. The EORTC Melanoma Group (MG) has formulated the following question: How should we report the microanatomic location and SN tumour burden? The EORTC MG recommends the following: the EORTC MG SN pathology protocol or a similarly extensive protocol, which has also been proven to be accurate, should be used. Only measure what you can see not what you presume. Cumulative measurements decrease the accuracy and reproducibility of measuring. The most reproducible measure is a single measurement of the maximum diameter of the largest lesion in any direction (1-D). If there is any infiltration into the parenchyma, this lesion can no longer be considered solely subcapsular. Reporting of the microanatomic location of metastases should be an assessment of the entire sentinel node, not only of the largest lesion. Multifocality reflects a scattered metastatic pattern, not to be confused with multiple cohesive foci, which fall under the regular location system. A subcapsular metastasis should have a smooth usually curved outline, not ragged or irregular. We recommend all pathologists to report the following items per positive SN for melanoma patients: the microanatomic location of the metastases according to Dewar et al. for the entire node, the SN Tumour Burden according to the Rotterdam Criteria for the maximum diameter of the largest metastasis expressed as an absolute number, and the SN Tumour Burden stratified per category; <0.1mm or 0.1-1.0mm or >1.0mm.


Costs and economies of scale in the accelerated program for prevention of mother-to-child transmission of HIV in Zimbabwe.
Despite a growing body of literature on HIV service costs in sub-Saharan Africa, only a few studies have estimated the facility-level cost of prevention of Mother-to-Child Transmission (PMTCT) services, and even fewer provide insights into the variation of PMTCT costs across facilities. In this study, we present the first empirical costs estimation of the accelerated program for the prevention of mother-to-child transmission of HIV in Zimbabwe and investigate the determinants of heterogeneity of the facility-level average cost per service. To understand such variation, we explored the association between average costs per service and supply-and demand-side characteristics, and quality of services. One aspect of the supply-side we explore carefully is the scale of production-which we define as the annual number of women tested or the yearly number of HIV-positive women on prophylaxis. We collected rich data on the costs and PMTCT services provided by 157 health facilities out of 699 catchment areas in five provinces in Zimbabwe for 2013. In each health facility, we measured total costs and the number of women covered with PMTCT services and estimated the average cost per woman tested and the average cost per woman on either ARV prophylaxis or ART. We refer to these facility-level average costs per service as unitary costs. We also collected information on potential determinants of the variation of unitary costs. On the supply-side, we gathered data on the scale of production, staff composition and on the types of antenatal and family planning services provided. On the demand side, we measured the total population at the catchment area and surveyed eligible pairs of mothers and infants about previous use of HIV testing and prenatal care, and on the HIV status of both mothers and infants. We explored the determinants of unitary cost variation using a two-stage linear regression strategy. The average annual total cost of the PMTCT program per facility was US$16,821 (median US$8,920). The average cost per pregnant woman tested was US$80 (median US$47), and the average cost per HIV-positive pregnant woman initiated on ARV prophylaxis or treatment was US$786 annually (median US$420). We found substantial heterogeneity of unitary costs across facilities regardless of facility type. The scale of production was a strong predictor of unitary costs variation across facilities, with a negative and statistically significant correlation between the two variables (p<0.01). These findings are the first empirical estimations of PMTCT costs in Zimbabwe. Unitary costs were found to be heterogeneous across health facilities, with evidence consistent with economies of scale.


Constitutive expression of interferon gamma-inducible protein 10 in lymphoid organs and inducible expression in T cells and thymocytes.
Interferon gamma-inducible protein 10 (IP-10), a member of a family of small proinflammatory chemotactic polypeptides, is expressed in interferon gamma-stimulated keratinocytes, macrophages, fibroblasts, and endothelial cells. Here we report that IP-10 is also expressed by activated but not resting T hybridoma cells, normal T cells, and thymocytes. Although resting lymphocytes did not synthesize IP-10, surprisingly high levels of IP-10 transcripts were found in lymphoid organs (spleen, thymus, and lymph nodes). Thymic and splenic stromal cells were found to express constitutively high levels of both IP-10 mRNA and protein, accounting for the high level of spontaneous expression in lymphoid tissue. Therefore, in addition to its role as a proinflammatory cytokine, IP-10 may participate in T cell effector function and perhaps T cell development.


The DREAM complex promotes gene body H2A.Z for target repression.
The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle genes, but its mechanism of action is poorly understood. Here we show that Caenorhabditis elegans DREAM targets have an unusual pattern of high gene body HTZ-1/H2A.Z. In mutants of lin-35, the sole p130/Rb-like gene in C. elegans, DREAM targets have reduced gene body HTZ-1/H2A.Z and increased expression. Consistent with a repressive role for gene body H2A.Z, many DREAM targets are up-regulated in htz-1/H2A.Z mutants. Our results indicate that the DREAM complex facilitates high gene body HTZ-1/H2A.Z, which plays a role in target gene repression.


Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer's disease.
Deregulation of metal ion homeostasis has been assumed as one of the key factors in the progression of neurodegenerative diseases. Aluminium (Al) has been believed as a major risk factor for the cause and progression of Alzheimer's disease (AD). In our lab, we have previously reported that hesperidin, a citrus bioflavonoid reversed memory loss caused by aluminium intoxication through attenuating acetylcholine esterase activity and the expression of Amyloid β biosynthesis related markers. Al has been reported to cause oxidative stress associated apoptotic neuronal loss in the brain. So in the present study, protective effect of hesperidin against aluminium chloride (AlCl3) induced cognitive impairment, oxidative stress and apoptosis was studied. Male Wistar rats were divided into control, AlCl3 treated (100 mg/kg., b.w.), AlCl3 and hesperidin (100 mg/kg., b.w.) co-treated and hesperidin alone treated groups. In control and experimental rats, learning and memory impairment were measured by radial arm maze, elevated plus maze and passive avoidance tests. In addition, oxidative stress and expression of pro and anti-apoptotic markers were also evaluated. Intraperitoneal injection of AlCl3 (100 mg/kg., b.w.) for 60 days significantly enhanced the learning and memory deficits, levels of thiobarbituric acid reactive substances and the expression of Bax and diminished the levels of reduced glutathione, activities of enzymatic antioxidants and the expression of B-cell lymphoma-2 (Bcl-2) as compared to control group in the hippocampus, cortex, and cerebellum. Coadministration of hesperidin (100 mg/kg., b.w. oral) for 60 days prevented the cognitive deficits, biochemical anomalies and apoptosis induced by AlCl3 treatment. Results of the present study demonstrated that hesperidin could be a potential therapeutic agent in the treatment of oxidative stress and apoptosis associated neurodegenerative diseases including AD.


Genetic population substructure in bison at Yellowstone National Park.
The Yellowstone National Park bison herd is 1 of only 2 populations known to have continually persisted on their current landscape since pre-Columbian times. Over the last century, the census size of this herd has fluctuated from around 100 individuals to over 3000 animals. Previous studies involving radiotelemetry, tooth wear, and parturition timing provide evidence of at least 2 distinct groups of bison within Yellowstone National Park. To better understand the biology of Yellowstone bison, we investigated the potential for limited gene flow across this population using multilocus Bayesian clustering analysis. Two genetically distinct and clearly defined subpopulations were identified based on both genotypic diversity and allelic distributions. Genetic cluster assignments were highly correlated with sampling locations for a subgroup of live capture individuals. Furthermore, a comparison of the cluster assignments to the 2 principle winter cull sites revealed critical differences in migration patterns across years. The 2 Yellowstone subpopulations display levels of differentiation that are only slightly less than that between populations which have been geographically and reproductively isolated for over 40 years. The identification of cryptic population subdivision and genetic differentiation of this magnitude highlights the importance of this biological phenomenon in the management of wildlife species.


Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models.
Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes PKD1 or PKD2 (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by PKHD1 (encoding fibrocystin/polyductin [FPC]). Primary cilia have been considered central to PKD pathogenesis due to protein localization and common cystic phenotypes in syndromic ciliopathies, but their relevance is questioned in the simple PKDs. ARPKD's mild phenotype in murine models versus in humans has hampered investigating its pathogenesis. To study the interaction between Pkhd1 and Pkd1, including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes. The genetic interaction was synergistic in both species, with digenic animals exhibiting phenotypes of rapidly progressive PKD and early lethality resembling classic ARPKD. Genetic interaction between Pkhd1 and Pkd1 depended on dosage in the digenic murine models, with no significant enhancement of the monogenic phenotype until a threshold of reduced expression at the second locus was breached. Pkhd1 loss did not alter expression, maturation, or localization of the ADPKD polycystin proteins, with no interaction detected between the ARPKD FPC protein and polycystins. RNA-seq analysis in the digenic and monogenic mouse models highlighted the ciliary compartment as a common dysregulated target, with enhanced ciliary expression and length changes in the digenic models. These data indicate that FPC and the polycystins work independently, with separate disease-causing thresholds; however, a combined protein threshold triggers the synergistic, cystogenic response because of enhanced dysregulation of primary cilia. These insights into pathogenesis highlight possible common therapeutic targets.


Biological application of microelectrode arrays in drug discovery and basic research.
Electrical activity of electrogenic cells in neuronal and cardiac tissue can be recorded by means of microelectrode arrays (MEAs) that offer the unique possibility for non-invasive extracellular recording from as many as 60 sites simultaneously. Since its introduction 30 years ago, the technology and the related culture methods for electrophysiological cell and tissue assays have been continually improved and have found their way into many academic and industrial laboratories. Currently, this technology is attracting increased interest owing to the industrial need to screen selected compounds against ion channel targets in their native environment at organic, cellular, and sub-cellular level. As the MEA technology can be applied to any electrogenic tissue (i.e., central and peripheral neurons, heart cells, and muscle cells), the MEA biosensor is an ideal in vitro system to monitor both acute and chronic effects of drugs and toxins and to perform functional studies under physiological or induced pathophysiological conditions that mimic in vivo damages. By recording the electrical response of various locations on a tissue, a spatial map of drug effects at different sites can be generated, providing important clues about a drug's specificity. In this survey, examples of MEA biosensor applications are described that have been developed for drug screening and discovery and safety pharmacology in the field of cardiac and neural research. Additionally, biophysical basics of recording and concepts for analysis of extracellular electrical signals are presented.


Dysuria in the emergency department: missed diagnosis of Chlamydia trachomatis.
The clinical presentation of genital Chlamydia trachomatis infection (chlamydia) in women is often indistinguishable from a urinary tract infection. While merited in the setting of dysuria, emergency department (ED) clinicians do not routinely test for chlamydia in women. The primary aim of our study was to evaluate the frequency of chlamydia testing among women presenting to the ED with dysuria. We conducted a retrospective chart review of women 19-25 years of age presenting with dysuria to an urban ED and who had been coded with urinary tract infection (UTI) as their primary diagnosis (ICD-9 599.0) from October 2005 to March 2011. We excluded women who were pregnant, had underlying anatomical or neurological urinary system pathology, had continuation of symptoms from UTI or a sexually transmitted infection (STI) diagnosed elsewhere, or were already on antibiotics for a UTI or STI. We identified the rates of sexual history screening, pelvic examination and chlamydia assay testing and evaluated predictors using univariate and multivariate analyses. Of 280 women with dysuria and a UTI diagnosis, 17% were asked about their sexual history, with 94% reporting recent sexual activity. Pelvic examination was performed in 23%. We were unable to determine the overall chlamydia prevalence as only 20% of women in the cohort were tested. Among the 20% of women tested for chlamydia infection, 21% tested positive. Only 42% of chlamydia-positive women were prescribed treatment effective for chlamydia (azithromycin or doxycycline) at their visit; the remaining were prescribed UTI treatment not effective against chlamydia. Predictors of sexual history screening included vaginal bleeding (OR 5.4, 95% CI=1.5 to 19.6) and discharge (OR 2.8, 95% CI=1.1 to 6.9). Predictors of a pelvic examination being performed included having a complaint of vaginal discharge (OR 11.8, 95% CI=4.2 to 32.9), a sexual history performed (OR 2.5, 95% CI=1.1 to 5.8), abdominal pain (OR 2.2, 95% CI=1.1 to 4.4), or pelvic pain (OR 15.3, 95% CI=2.5 to 92.2); a complaint of urinary frequency was associated with a pelvic examination not being performed (OR 0.34, 95% CI=0.13 to 0.86). Sexual histories, pelvic examinations, and chlamydia testing were not performed in the majority of women presenting with dysuria and diagnosed with UTI in the ED. The performance of a sexual history along with the availability of self-administered vaginal swab and first-void urine-based chlamydia tests may increase identification of chlamydia infection in women with dysuria.


Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is classically assumed to be a neurodegenerative disorder. Inflammation has been observed in CNS tissue in ALS patients. We investigated the expression and prognostic relevance of proinflammatory chemokines in ALS. We analyzed nine chemokines, eotaxin, eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, macrophage derived chemokine (MDC), macrophage inflammatory protein-1beta (MIP-1beta), and serum thymus and activation- regulated chemokine (TARC) in serum and cerebrospinal fluid (CSF) of 20 ALS- and 20 non-inflammatory neurological disease (NIND)-patients. MCP-1 and IL-8 levels in CSF in ALS were significantly higher than in NIND (1304 pg/ml vs. 1055 pg/ml, P = 0.013 and 22.7 pg/ml vs. 18.6 pg/ml, P = 0.035). The expression of MCP-1 and IL-8 were higher in CSF than in serum (P < 0.001). There was a trend towards higher MCP-1 CSF levels in ALS patients with shorter time between first symptoms and diagnosis (r = -0.407; P = 0.075). We confirmed previous findings of increased MCP-1 levels in CSF of ALS patients. Furthermore, increased levels of IL-8 in CSF suggest a stimulation of a proinflammatory cytokine cascade after microglia activation. We found a tendency for higher MCP-1 values in patients with a shorter diagnostic delay, who are known to have also a shorter survival. This may suggest an association of higher MCP-1 levels with rapidly progressing disease.


Differential effects of nitric oxide synthase inhibitors in an in vivo allergic rat model.
The in vivo role of nitric oxide in inflammatory cell migration, vascular permeability and the development of hyperresponsiveness to methacholine (MCh) was studied in rats 24 h following ovalbumin (OVA) challenge. The NO synthase (NOS) inhibitors N(G)-mono-methyl-L-arginine (L-NMMA; nonselective), aminoguanidine (two-fold inducible NOS-selective), N(omega)-nitro-L-arginine methyl ester (L-NAME; 2000-fold endothelial cell NOS-selective) or S-methyl-L-thiocitrulline (100-fold neuronal NOS-selective) were administered (100 mg x kg(-1) s.c.) to OVA-sensitized Piebald-Virol-Glaxo rats on 3 consecutive days during which they were challenged with allergen (1% OVA). Responses to inhaled MCh were measured in anaesthetized animals 24 h after OVA challenge. Cellular inflammation and vascular permeability were assessed using bronchoalveolar lavage (BAL) fluid collected 30 min after administration of Evans blue (50 mg x kg(-1) i.v.). OVA challenge in sensitized animals induced hyperresponsiveness to MCh, inflammatory cell influx and increased leakage of Evans blue into the BAL fluid (n=9, p<0.001). Aminoguanidine was effective in inhibiting the allergen-induced cellular influx and microvascular leakage (n=9, p<0.001) without altering responses to MCh. This effect was reserved by L-arginine. L-NAME (n=5, p<0.01) and S-methyl-L-thiocitrulline (n=6, p<0.001) further potentiated the allergen-induced hyperresponsiveness without altering cellular inflammation. L-NMMA attenuated both the OVA-induced cellular influx and Evans blue leakage (n=8, p<0.001) as well as further potentiating the hyperresponsiveness to MCh (p<0.05). From these studies, it is suggested that, in allergic Piebald-Virol-Glaxo rats, nitric oxide production by inducible nitric oxide synthase plays a role in the migration of inflammatory cells and increase in vascular permeability following allergen challenge, whereas nitric oxide produced by the constitutively expressed neuronal nitric oxide synthase limits hyperresponsiveness to methacholine.


Epidemiology of single and multiple species of helminth infections among school children in Busia District, Kenya.
To describe the patterns of single and multiple helminth infection in school children from Busia District, Kenya. A cross-sectional school survey using a randomly selected sample, forming part of an evaluation study of an ongoing deworming project. Budalangi and Funyula divisions of Busia District, Western Province, Kenya. One thousand seven hundred and thirty eight school children aged 8-20 years randomly selected from those enrolled in standards 3-8 in 25 randomly selected primary schools. Overall, 91.7% of children were infected with either hookworm, Ascaris lumbricoides, Trichuris trichiura or Schistosoma mansoni. Infection prevalence of each species varied considerably among schools, being most marked for S. mansoni, where prevalence was highest in lakeshore schools. Children were typically infected with two or more species of helminth. Infection intensity of each geohelminth species was higher in school children infected with multiple species than in school children with single species infections, and intensity increased with the number of concurrent infections. Helminth infections are exceptionally common among school children in Busia district, thus confirming the good sense of the school-based approach adopted by the control programme. The study also shows that there is an association between concurrent infection and the intensity of infection, which may have consequences for nutritional and educational status.


The central kink region of fowlicidin-2, an alpha-helical host defense peptide, is critically involved in bacterial killing and endotoxin neutralization.
Fowlicidins are a group of newly identified chicken cathelicidin host defense peptides. We have shown that the putatively mature fowlicidin-2 of 31 amino acid residues possesses potent antibacterial and lipopolysaccharide (LPS)- neutralizing activities, but with a noticeable toxicity to mammalian cells. As a first step in exploring the structure-activity relationships of fowlicidin-2, in this study we determined its tertiary structure by nuclear magnetic resonance spectroscopy. Unlike the majority of cathelicidins, which are composed of a predominant alpha-helix with a short hinge sequence near the center, fowlicidin-2 consists of 2 well-defined alpha-helical segments (residues 6-12 and 23-27) connected by a long extensive kink (residues 13-20) induced by proline. To further investigate the functional significance of each of these structural components, several N- and C-terminal deletion analogs of fowlicidin-2 were synthesized and analyzed for their antibacterial, cytotoxic and LPS-neutralizing activities. Our results indicated that neither the N- nor C-terminal alpha-helix alone is sufficient to confer any function. Rather, fowlicidin-2(1-18) and fowlicidin-2(15-31), 2 alpha-helical segments with inclusion of the central cationic kink region, retained substantial capacities to kill bacteria and neutralize the LPS-induced proinflammatory response, relative to the parent peptide. More desirably, these 2 peptide analogs showed substantially reduced toxicity to human erythrocytes and epithelial cells, indicative of improved potential as antibacterial and antisepsis agents. To our knowledge, fowlicidin-2 is the first alpha-helical cathelicidin, with the central kink region shown to be critically important in killing bacteria and neutralizing LPS.


Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements.
Recent assays for individual-specific genome-wide DNA methylation profiles have enabled epigenome-wide association studies to identify specific CpG sites associated with a phenotype. Computational prediction of CpG site-specific methylation levels is critical to enable genome-wide analyses, but current approaches tackle average methylation within a locus and are often limited to specific genomic regions. We characterize genome-wide DNA methylation patterns, and show that correlation among CpG sites decays rapidly, making predictions solely based on neighboring sites challenging. We built a random forest classifier to predict methylation levels at CpG site resolution using features including neighboring CpG site methylation levels and genomic distance, co-localization with coding regions, CpG islands (CGIs), and regulatory elements from the ENCODE project. Our approach achieves 92% prediction accuracy of genome-wide methylation levels at single-CpG-site precision. The accuracy increases to 98% when restricted to CpG sites within CGIs and is robust across platform and cell-type heterogeneity. Our classifier outperforms other types of classifiers and identifies features that contribute to prediction accuracy: neighboring CpG site methylation, CGIs, co-localized DNase I hypersensitive sites, transcription factor binding sites, and histone modifications were found to be most predictive of methylation levels. Our observations of DNA methylation patterns led us to develop a classifier to predict DNA methylation levels at CpG site resolution with high accuracy. Furthermore, our method identified genomic features that interact with DNA methylation, suggesting mechanisms involved in DNA methylation modification and regulation, and linking diverse epigenetic processes.


Selection of bacteriophage T4 antimutator DNA polymerases: a link between proofreading and sensitivity to phosphonoacetic acid.
During DNA replication, DNA polymerases alternate between DNA synthesis and proofreading the newly synthesized DNA. In order to understand the molecular details of how DNA polymerases determine the balance between polymerase and proofreading activities, it would be useful to have mutants which switch between the two activities either more or less frequently. Antimutator DNA polymerases switch more frequently and thus have more opportunity for proofreading. We have observed that mutant DNA polymerases which proofread less frequently have a mutator phenotype and are inhibited by the pyrophosphate analogue phosphonoacetic acid. Sensitivity to phosphonoacetic acid can be used to isolate second-site suppressor mutations. These suppressor mutations encode amino acid substitutions which produce antimutator DNA polymerases.


Effects of salinity on olfactory toxicity and behavioral responses of juvenile salmonids from copper.
Dissolved copper is one of the more pervasive and toxic constituents of stormwater runoff and is commonly found in stream, estuary, and coastal marine habitats of juvenile salmon. While stormwater runoff does not usually carry copper concentrations high enough to result in acute lethality, they are of concern because sublethal concentrations of copper exposure have been shown to both impair olfactory function and alter behavior in various species in freshwater. To compare these results to other environments that salmon are likely to encounter, experiments were conducted to evaluate the effects of salinity on the impairment of olfactory function and avoidance of copper. Copper concentrations well within the range of those found in urban watersheds, have been shown to diminish or eliminate the olfactory response to the amino acid, l-serine in freshwater using electro-olfactogram (EOG) techniques. The olfactory responses of both freshwater-phase and seawater-phase coho and seawater-phase Chinook salmon, were tested in freshwater or seawater, depending on phase, and freshwater-phase coho at an intermediate salinity of 10‰. Both 10‰ salinity and full strength seawater protected against the effects of 50μg copper/L. In addition to impairing olfactory response, copper has also been shown to alter salmon behavior by causing an avoidance response. To determine whether copper will cause avoidance behavior at different salinities, experiments were conducted using a multi-chambered experimental tank. The circular tank was divided into six segments by water currents so that copper could be contained within one segment yet fish could move freely between them. The presence of individual fish in each of the segments was counted before and after introduction of dissolved copper (<20μg/L) to one of the segments in both freshwater and seawater. To address whether use of preferred habitat is altered by the presence of copper, experiments were also conducted with a submerged structural element. The presence of sub-lethal levels of dissolved copper altered the behavior of juvenile Chinook salmon by inducing an avoidance response in both freshwater and seawater. While increased salinity is protective against loss of olfactory function from dissolved copper, avoidance could potentially affect behaviors beneficial to growth, survival and reproductive success.


Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain.
CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the "glymphatic" system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ~50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ~60%. When paravascular CSF-ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF-ISF exchange, while dobutamine increased the rate of paravascular CSF-ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.


The end of gating? An introduction to automated analysis of high dimensional cytometry data.
Ever since its invention half a century ago, flow cytometry has been a major tool for single-cell analysis, fueling advances in our understanding of a variety of complex cellular systems, in particular the immune system. The last decade has witnessed significant technical improvements in available cytometry platforms, such that more than 20 parameters can be analyzed on a single-cell level by fluorescence-based flow cytometry. The advent of mass cytometry has pushed this limit up to, currently, 50 parameters. However, traditional analysis approaches for the resulting high-dimensional datasets, such as gating on bivariate dot plots, have proven to be inefficient. Although a variety of novel computational analysis approaches to interpret these datasets are already available, they have not yet made it into the mainstream and remain largely unknown to many immunologists. Therefore, this review aims at providing a practical overview of novel analysis techniques for high-dimensional cytometry data including SPADE, t-SNE, Wanderlust, Citrus, and PhenoGraph, and how these applications can be used advantageously not only for the most complex datasets, but also for standard 14-parameter cytometry datasets.


Visual attention and flexible normalization pools.
Attention to a spatial location or feature in a visual scene can modulate the responses of cortical neurons and affect perceptual biases in illusions. We add attention to a cortical model of spatial context based on a well-founded account of natural scene statistics. The cortical model amounts to a generalized form of divisive normalization, in which the surround is in the normalization pool of the center target only if they are considered statistically dependent. Here we propose that attention influences this computation by accentuating the neural unit activations at the attended location, and that the amount of attentional influence of the surround on the center thus depends on whether center and surround are deemed in the same normalization pool. The resulting form of model extends a recent divisive normalization model of attention (Reynolds & Heeger, 2009). We simulate cortical surround orientation experiments with attention and show that the flexible model is suitable for capturing additional data and makes nontrivial testable predictions.


Assessing allergenicity in urban parks: A nature-based solution to reduce the impact on public health.
Urban parks play a key role in the provision of ecosystem services, actively participating in improving the quality of life and welfare of local residents. This paper reports on the application of an index designed to quantify the allergenicity of urban parks in a number of Spanish cities. The index, which records biological and biometric parameters for the tree species growing there, classifies parks in terms of the risk they pose for allergy sufferers, graded as null, low, moderate or high. In this initial phase, the index was applied to 26 green areas in 24 Spanish cities; green areas varied in type (urban park, historical or modern garden, boulevard, square or urban forest), size 1-100 ha), geographical location, species richness, number of trees and tree density (number of trees / ha.). The data obtained were used to calculate the percentage of allergenic species in each park, which varied between 17-67%; density ranged from 100 to 300 trees/ha. The index values recorded ranged from a minimum of .07 to a maximum of .87; a significant correlation was found between index value and both number of trees and tree density. Taking an index value of .30 as the threshold considered sufficient to trigger allergy symptoms in the sensitive population, 12 of the parks studied may be regarded as unhealthy at any time of the year. Corrective measures to mitigate the impact of pollen emissions include the implementation of nature-based solutions at various levels: planning and design, handling and management, and strengthening of urban green-infrastructure elements. The index proved to be a useful tool for environmental analysis, and complies with the principles of portability and scalability central to current and horizon scientific research.


[Asbestosis still exists…].
A diagnosis of asbestosis, lung fibrosis due to asbestos exposure, was proposed in 2003 in a 64-year-old woman on the basis of the history, computed tomography appearances, lung function studies, and biometric data. This diagnosis was confirmed by the pathological examination of a lung lobe resected surgically for bronchial carcinoma in 2010. The diagnosis of asbestosis is now rarely made as a result of a substantial decrease in dust exposure over the past decades and mainly because of the interdiction of asbestos use in western countries. Currently, the most frequent thoracic manifestations of asbestos exposure are benign pleural lesions and mesothelioma. It has also become exceptional to have pathological confirmation of the diagnosis, obtained in this woman thanks to the surgical treatment of another complication of her occupational exposure.