Electrodiagnostic study of peripheral nerves in high-voltage electrical injury.
It is well known that peripheral nerves are very vulnerable to electricity. However, only a small portion of individuals who have had high-voltage electrical injury exhibit peripheral nerve damage. The aim of this study was to investigate peripheral nerve damage in high-voltage electrical injury, which often occurs in the industrial field. The authors reviewed the medical records of patients who were admitted to their hospital from January 2009 to December 2011, because of electrical injuries. The results of nerve conduction studies (NCSs) were reviewed retrospectively. NCS data of the injured site were compared with those of the opposite noninjured site and follow-up data. Thirty-seven extremities were reviewed. The authors found that 18 of 33 median nerves (48.6%) showed abnormalities in at least one parameter and 15 of 36 ulnar nerves (41.7%) exhibited abnormalities. There was no evidence of demyelination. Eight patients had undergone NCS on the opposite normal extremities. The compound muscle action potential and nerve conduction velocity were higher at the normal site. Follow-up NCS were performed in 14 patients: the compound muscle action potential and nerve conduction velocity values of all patients were improved. High-voltage electricity damaged peripheral nerves by causing axonal injury rather than demyelinating injury. Hence, even if NCSs yield normal findings, peripheral nerves may be damaged. F/U studies and opposite examinations are required for the exact evaluation of peripheral nerve damage.


Indirect decoding edges for one-shot shape acquisition.
Determining the correspondence in coded structured light is challenging, but it is very important in one-shot techniques for 3D shape reconstruction. The problem of decoding stripe patterns can be modeled as matching two code sequences. We propose decoding edges indirectly based on the property of the stripe pattern, which can be represented as edge code, color code, or mixed code sequences. While traditional methods match two edge code sequences, indirect decoding matches two color sequences or mixed code sequences. The advantages of the proposed method, including a higher Hamming distance, enforced local coherence, and more code information, make indirect decoding excellent in performance. Previously, the lack of ground truth has prevented direct comparisons of different decoding algorithms. Here we obtain six benchmark datasets using the robust space-time analysis. Five decoding methods are quantitatively evaluated using the ground truth. The comparison results show that our method is robust for complex code situations and that it outperforms the state-of-the-art technique in this area.


[Hormonal contraception: a comparison between patients of the private and public health network].
The aim of this paper is to assess the profile of patients using hormonal contraceptives in the public health network and a comparison with the private health service, as well as the frequency of side effects and adherence to treatment. A cross-sectional study was conducted with 240 patients, namely 120 patients from the private health service and 120 patients from the public health network. The most commonly prescribed hormonal dosage on the private group (36.7%) was 15 or 20 micrograms of ethinyl estradiol (EE), associated with gestodene, desogestrel or levonorgestrel. On the other hand, the prescribed hormonal dosage in the public group was a combination of 30 micrograms of EE associated with gestodene, levonorgestrel or desogestrel (48.3%). There was no difference between the frequency of side effects in both groups surveyed (p>0.05). Meanwhile, adherence to treatment was higher in patients of the private group. The authors concluded that the most widely used contraceptive method was a low oral dose of ethinyl estradiol and there is no difference between the frequency of side effects. However, adherence to treatment was higher in the private group, which may be associated with social and cultural aspects of the patients surveyed.


Lung biopsy in rheumatoid arthritis.
Forty open lung biopsies from patients with rheumatoid arthritis and possible "rheumatoid lung disease" were reviewed in an attempt to correlate histology with radiologic, physiologic, and prognostic variables. A wide variety of histopathologic features was seen, and primary and secondary patterns of injury were recognized. Five different groups based on histologic patterns were identified: pulmonary rheumatoid nodules, usual interstitial pneumonia (UIP), bronchiolitis obliterans with patchy organizing pneumonia (BOOP), lymphoid hyperplasia, and cellular interstitial infiltrates. The finding of rheumatoid nodules as the primary pattern imparted a uniformly good prognosis, whereas the pattern of UIP indicated a poor one. Patients with BOOP had a more favorable prognosis than did patients with UIP, as did patients with lymphoid hyperplasia and/or nonspecific cellular interstitial infiltrates. Consistent correlations between pulmonary function testing and roentgenographic and histologic findings were not found. The term "rheumatoid lung disease" is of no use as a histologic diagnosis because it encompasses a broad spectrum of morphologic changes that carry significantly different prognoses.


Development of a simple score based on HBeAg and ALT for selecting patients for HBV treatment in Africa.
To eliminate hepatitis B virus (HBV) infection, it is essential to scale up antiviral treatment through decentralized services. However, access to the conventional tools to assess treatment eligibility (liver biopsy/Fibroscan®/HBV DNA) is limited and not affordable in resource-limited countries. We developed and validated a simple score to easily identify patients in need of HBV treatment in Africa. As a reference, we used treatment eligibility determined by the European Association for the Study of the Liver based on alanine aminotransferase (ALT), liver histology and/or Fibroscan and HBV DNA. We derived a score indicating treatment eligibility by a stepwise logistic regression using a cohort of chronic HBV infection in The Gambia (n = 804). We subsequently validated the score in an external cohort of HBV-infected Africans from Senegal, Burkina Faso, and Europe (n = 327). Out of several parameters, two remained in the final model, namely HBV e antigen (HBeAg) and ALT level, constituting a simple score (treatment eligibility in Africa for the hepatitis B virus: TREAT-B). The score demonstrated a high area under the receiver operating characteristic curve (0.85, 95% CI 0.79-0.91) in the validation set. The score of 2 and above (HBeAg-positive and ALT ≥20 U/L or HBeAg-negative and ALT ≥40 U/L) had a sensitivity and specificity for treatment eligibility of 85% and 77%, respectively. The sensitivity and specificity of the World Health Organization criteria based on the aspartate aminotransferase-to-platelet ratio index (APRI) and ALT were 90% and 40%, respectively. A simple score based on HBeAg and ALT had a high diagnostic accuracy for the selection of patients for HBV treatment. This score could be useful in African settings. Limited access to the diagnostic tools used to assess treatment eligibility (liver biopsy/Fibroscan/hepatitis B virus DNA) has been an obstacle to the scale up of hepatitis B treatment programs in low- and middle-income countries. Using the data from African patients with chronic HBV infection, we developed and validated a new simple diagnostic score for treatment eligibility, which only consists of hepatitis B virus e antigen and alanine aminotransferase level. The diagnostic accuracy of the score for selecting patients for HBV treatment was high and could be useful in African settings.


Percutaneous screw fixation or cast immobilization for nondisplaced scaphoid fractures.
Nondisplaced scaphoid fractures treated with prolonged cast immobilization may result in temporary joint stiffness and muscle weakness in addition to a delay in return to sports or work. Fixation of scaphoid fractures with a percutaneous cannulated screw has resulted in a shorter time to union and to return to work or sports. The purpose of this prospective, randomized study was to compare cast immobilization with percutaneous cannulated screw fixation of nondisplaced scaphoid fractures with respect to time to radiographic union and to return to work. Twenty-five full-time military personnel with an acute nondisplaced fracture of the scaphoid waist consented to be randomized to either cast immobilization or fixation with a percutaneous cannulated Acutrak screw (Acumed, Beaverton, Oregon) for the purpose of this study. Time to fracture union, wrist motion, grip strength, and return to work as well as overall patient satisfaction at the time of a two-year follow-up were evaluated. Eleven patients were randomized to percutaneous cannulated screw fixation, and fourteen were randomized to cast immobilization. The average time to fracture union in the screw fixation group was seven weeks compared with twelve weeks in the cast immobilization group (p = 0.0003). The average time until the patients returned to work was eight weeks compared with fifteen weeks in the cast immobilization group (p = 0.0001). There was no significant difference in the range of motion of the wrist or in grip strength at the two-year follow-up evaluation. Overall patient satisfaction was high in both groups. Percutaneous cannulated screw fixation of nondisplaced scaphoid fractures resulted in faster radiographic union and return to military duty compared with cast immobilization. The specific indications for and the risks and benefits of percutaneous screw fixation of such fractures must be determined in larger randomized, prospective studies.


Risk of bias: a simulation study of power to detect study-level moderator effects in meta-analysis.
There are both theoretical and empirical reasons to believe that design and execution factors are associated with bias in controlled trials. Statistically significant moderator effects, such as the effect of trial quality on treatment effect sizes, are rarely detected in individual meta-analyses, and evidence from meta-epidemiological datasets is inconsistent. The reasons for the disconnect between theory and empirical observation are unclear. The study objective was to explore the power to detect study level moderator effects in meta-analyses. We generated meta-analyses using Monte-Carlo simulations and investigated the effect of number of trials, trial sample size, moderator effect size, heterogeneity, and moderator distribution on power to detect moderator effects. The simulations provide a reference guide for investigators to estimate power when planning meta-regressions. The power to detect moderator effects in meta-analyses, for example, effects of study quality on effect sizes, is largely determined by the degree of residual heterogeneity present in the dataset (noise not explained by the moderator). Larger trial sample sizes increase power only when residual heterogeneity is low. A large number of trials or low residual heterogeneity are necessary to detect effects. When the proportion of the moderator is not equal (for example, 25% 'high quality', 75% 'low quality' trials), power of 80% was rarely achieved in investigated scenarios. Application to an empirical meta-epidemiological dataset with substantial heterogeneity (I(2) = 92%, τ(2) = 0.285) estimated >200 trials are needed for a power of 80% to show a statistically significant result, even for a substantial moderator effect (0.2), and the number of trials with the less common feature (for example, few 'high quality' studies) affects power extensively. Although study characteristics, such as trial quality, may explain some proportion of heterogeneity across study results in meta-analyses, residual heterogeneity is a crucial factor in determining when associations between moderator variables and effect sizes can be statistically detected. Detecting moderator effects requires more powerful analyses than are employed in most published investigations; hence negative findings should not be considered evidence of a lack of effect, and investigations are not hypothesis-proving unless power calculations show sufficient ability to detect effects.


Disabling stroke in persons already with a disability: Ethical dimensions and directives.
Stroke is the second leading cause of death worldwide and a leading cause of adult disability worldwide. More than a third of individuals presenting with strokes are estimated to have a preexisting disability. Despite unprecedented advances in stroke research and clinical practice over the past decade, approaches to acute stroke care for persons with preexisting disability have received scant attention. Current standards of research and clinical practice are influenced by an underexplored range of biases that may hinder acute stroke care for persons with disability. These trends may exacerbate unequal health outcomes by rendering novel stroke therapies inaccessible to many persons with disabilities. Here, we explore the underpinnings and implications of biases involving persons with disability in stroke research and practice. Recent insights from bioethics, disability rights, and health law are explained and critically evaluated in the context of prevailing research and clinical practices. Allowing disability to drive decisions to withhold acute stroke interventions may perpetuate disparate health outcomes and undermine ethically resilient stroke care. Advocacy for inclusion of persons with disability in future stroke trials can improve equity in stroke care delivery.


Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex.
The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for IL-4, IL-7, IL-9, and IL-15 as well as IL-2. Here we show that the gamma(c) is also shared with the IL-21R complex. Although IL-21 binds to the IL-21R expressed on gamma(c)-deficient ED40515(-) cells, IL-21 is unable to transduce any intracytoplasmic signals. However, in EDgamma-16 cells, a gamma(c)-transfected ED40515(-) cell line, IL-21 binds to the IL-21R and can activate Janus kinase (JAK)1, JAK3, STAT1, and STAT3. The chemical cross-linking study reveals the direct binding of IL-21 to the gamma(c). These data clearly demonstrate that the gamma(c) is an indispensable subunit of the functional IL-21R complex.


A Highly Effective and Robust Membrane Potential-Driven Supervised Learning Method for Spiking Neurons.
Spiking neurons are becoming increasingly popular owing to their biological plausibility and promising computational properties. Unlike traditional rate-based neural models, spiking neurons encode information in the temporal patterns of the transmitted spike trains, which makes them more suitable for processing spatiotemporal information. One of the fundamental computations of spiking neurons is to transform streams of input spike trains into precisely timed firing activity. However, the existing learning methods, used to realize such computation, often result in relatively low accuracy performance and poor robustness to noise. In order to address these limitations, we propose a novel highly effective and robust membrane potential-driven supervised learning (MemPo-Learn) method, which enables the trained neurons to generate desired spike trains with higher precision, higher efficiency, and better noise robustness than the current state-of-the-art spiking neuron learning methods. While the traditional spike-driven learning methods use an error function based on the difference between the actual and desired output spike trains, the proposed MemPo-Learn method employs an error function based on the difference between the output neuron membrane potential and its firing threshold. The efficiency of the proposed learning method is further improved through the introduction of an adaptive strategy, called skip scan training strategy, that selectively identifies the time steps when to apply weight adjustment. The proposed strategy enables the MemPo-Learn method to effectively and efficiently learn the desired output spike train even when much smaller time steps are used. In addition, the learning rule of MemPo-Learn is improved further to help mitigate the impact of the input noise on the timing accuracy and reliability of the neuron firing dynamics. The proposed learning method is thoroughly evaluated on synthetic data and is further demonstrated on real-world classification tasks. Experimental results show that the proposed method can achieve high learning accuracy with a significant improvement in learning time and better robustness to different types of noise.


Benefits of healthy adipose tissue in the treatment of diabetes.
The major malfunction in diabetes mellitus is severe perturbation of glucose homeostasis caused by deficiency of insulin. Insulin deficiency is either absolute due to destruction or failure of pancreatic β cells, or relative due to decreased sensitivity of peripheral tissues to insulin. The primary lesion being related to insulin, treatments for diabetes focus on insulin replacement and/or increasing sensitivity to insulin. These therapies have their own limitations and complications, some of which can be life-threatening. For example, exogenous insulin administration can lead to fatal hypoglycemic episodes; islet/pancreas transplantation requires life-long immunosuppressive therapy; and anti-diabetic drugs have dangerous side effects including edema, heart failure and lactic acidosis. Thus the need remains for better safer long term treatments for diabetes. The ultimate goal in treating diabetes is to re-establish glucose homeostasis, preferably through endogenously generated hormones. Recent studies increasingly show that extra-pancreatic hormones, particularly those arising from adipose tissue, can compensate for insulin, or entirely replace the function of insulin under appropriate circumstances. Adipose tissue is a versatile endocrine organ that secretes a variety of hormones with far-reaching effects on overall metabolism. While unhealthy adipose tissue can exacerbate diabetes through limiting circulation and secreting of pro-inflammatory cytokines, healthy uninflamed adipose tissue secretes beneficial adipokines with hypoglycemic and anti-inflammatory properties, which can complement and/or compensate for the function of insulin. Administration of specific adipokines is known to alleviate both type 1 and 2 diabetes, and leptin mono-therapy is reported to reverse type 1 diabetes independent of insulin. Although specific adipokines may correct diabetes, administration of individual adipokines still carries risks similar to those of insulin monotherapy. Thus a better approach is to achieve glucose homeostasis with endogenously-generated adipokines through transplantation or regeneration of healthy adipose tissue. Our recent studies on mouse models show that type 1 diabetes can be reversed without insulin through subcutaneous transplantation of embryonic brown adipose tissue, which leads to replenishment of recipients' white adipose tissue; increase of a number of beneficial adipokines; and fast and long-lasting euglycemia. Insulin-independent glucose homeostasis is established through a combination of endogenously generated hormones arising from the transplant and/or newly-replenished white adipose tissue. Transplantation of healthy white adipose tissue is reported to alleviate type 2 diabetes in rodent models on several occasions, and increasing the content of endogenous brown adipose tissue is known to combat obesity and type 2 diabetes in both humans and animal models. While the underlying mechanisms are not fully documented, the beneficial effects of healthy adipose tissue in improving metabolism are increasingly reported, and are worthy of attention as a powerful tool in combating metabolic disease.


Telomerase Activation to Reverse Immunosenescence in Elderly Patients With Acute Coronary Syndrome: Protocol for a Randomized Pilot Trial.
Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia-reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. The TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. The study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. The study received National Health Service (NHS) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and NHS Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. This pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients. ISRCTN Registry ISRCTN16613292; http://www.isrctn.com/ISRCTN16613292 and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), European Union Clinical Trials Register 2017-002876-26; https://tinyurl.com/y4m2so8g. DERR1-10.2196/19456.


Histogram-based normalization technique on human brain magnetic resonance images from different acquisitions.
Intensity normalization is an important preprocessing step in brain magnetic resonance image (MRI) analysis. During MR image acquisition, different scanners or parameters would be used for scanning different subjects or the same subject at a different time, which may result in large intensity variations. This intensity variation will greatly undermine the performance of subsequent MRI processing and population analysis, such as image registration, segmentation, and tissue volume measurement. In this work, we proposed a new histogram normalization method to reduce the intensity variation between MRIs obtained from different acquisitions. In our experiment, we scanned each subject twice on two different scanners using different imaging parameters. With noise estimation, the image with lower noise level was determined and treated as the high-quality reference image. Then the histogram of the low-quality image was normalized to the histogram of the high-quality image. The normalization algorithm includes two main steps: (1) intensity scaling (IS), where, for the high-quality reference image, the intensities of the image are first rescaled to a range between the low intensity region (LIR) value and the high intensity region (HIR) value; and (2) histogram normalization (HN),where the histogram of low-quality image as input image is stretched to match the histogram of the reference image, so that the intensity range in the normalized image will also lie between LIR and HIR. We performed three sets of experiments to evaluate the proposed method, i.e., image registration, segmentation, and tissue volume measurement, and compared this with the existing intensity normalization method. It is then possible to validate that our histogram normalization framework can achieve better results in all the experiments. It is also demonstrated that the brain template with normalization preprocessing is of higher quality than the template with no normalization processing. We have proposed a histogram-based MRI intensity normalization method. The method can normalize scans which were acquired on different MRI units. We have validated that the method can greatly improve the image analysis performance. Furthermore, it is demonstrated that with the help of our normalization method, we can create a higher quality Chinese brain template.


Dream-recall frequency and waking imagery.
The purpose was to investigate the relationship between dream-recall frequency and waking imagery, so 323 undergraduates completed four imagery tests: (1) Sheehan's modified version of Betts' Questionnaire on Mental Imagery, (2) Marks' Vividness of Visual Imagery Questionnaire, (3) the Gordon Test of Visual Imagery Control, (4) Richardson's Verbalizer Visualizer Questionnaire, and a dream-recall questionnaire which contained a question about dream-recall frequency. When scores on the four imagery tests and the seven sensory subscales of the Questionnaire on Mental Imagery were compared for the n = 82 frequent and n = 80 infrequent dream recallers, higher recall was associated with more vivid voluntary images and more frequent use of visual imagery; however, control visual imagery as measured by the Test of Visual Imagery Control was not associated with dream-recall frequency. Scores for frequent use of visual imagery on dream-recall frequency might have been due to the two items of the Verbalizer-Visualizer Questionnaire which asked about dream experiences. The results for the seven sensory subscales of the Betts' questionnaire indicated that the frequency of dream recall was significantly related to scores on visual, cutaneous, and organic but not on auditory, gustatory, kinaesthetic, and olfactory subscales. No significant differences were found between males and females. Present findings indicated that forming vivid mental images in the waking state is related to frequency of dream recall and support Cohen's salience theory of dream recall, i.e., that evoking vivid waking mental images voluntarily may play an important role in retrieving dream images or saving them during wakefulness. All sensory modalities should be considered in study of dream recall.


The hedgehog-related gene wrt-5 is essential for hypodermal development in Caenorhabditis elegans.
The Caenorhabditis elegans genome encodes a series of hedgehog-related genes, which are thought to have evolved and diverged from an ancestral Hh gene. They are classified into several families based on their N-terminal domains. Here, we analyze the expression and function of a member of the warthog gene family, wrt-5, that lacks the Hint/Hog domain. wrt-5 is expressed in seam cells, the pharynx, pharyngeal-intestinal valve cells, neurons, neuronal support cells, the excretory cell, and the reproductive system. WRT-5 protein is secreted into the extracellular space during embryogenesis. Furthermore, during larval development, WRT-5 protein is secreted into the pharyngeal lumen and the pharyngeal expression changes in a cyclical manner in phase with the molting cycle. Deletion mutations in wrt-5 cause embryonic lethality, which are temperature sensitive and more severe at 15 degrees C than at 25 degrees C. Animals that hatch exhibit variable abnormal morphology, for example, bagging worms, blistering, molting defects, or Roller phenotypes. We examined hypodermal cell junctions using the AJM-1Colon, two colonsGFP marker in the wrt-5 mutant background and observed cell boundary abnormalities in the arrested embryos. AJM-1Colon, two colonsGFP protein is also misplaced in pharyngeal muscle cells in the absence of WRT-5. In conclusion, we show that wrt-5 is an essential gene that - despite its lack of a Hint domain - has multiple functions in C. elegans and is implicated in cell shape integrity.


Cellular and proteomic events associated with the localized formation of smut-gall during Zizania latifolia-Ustilago esculenta interaction.
The perennial wild rice Zizania latifolia is confined in the swampy habitat and wetland of the Indo-Burma biodiversity hotspot of India and infection by the biotrophic fungus Ustilago esculenta is hallmarked by swellings that develop to form localized smut-gall at the topmost internodal region. The cellular and proteomic events involved in the non-systemic colonization of Z. latifolia by U. esculenta leading to smut-gall formation is poorly understood. Proteins were extracted from the smut-gall region at the topmost internodal region below the apical meristematic tissue from the infected and uninfected parts of Z. latifolia. By combining transmission electron microscopy (TEM) and fluorescent microscopy (FM), we showed that U. esculenta hyphal morphological transitions and movement occurred both intercellularly and intracellularly while sporulation occurred intracellularly in selective cells. Following proteome profiling using two dimensional SDS-PAGE at different phenological phases of smut-gall development and U. esculenta infection, differentially expressed proteins bands and their relative abundance were detected and subjected to liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. Importantly, the fungus explores at least 7 metabolic pathways and 5 major biological processes to subdue the host defense and thrive successfully on Z. latifolia. The fungus U. esculenta produces proteases and energy acquisition proteins those enhance it's defensive and survival mode in the host. The identified differentially regulated proteins shed-light into why inflorescence is being replaced by bulbous smut-gall at late stages of the disease, as well as the development of resistance in some Z. latifolia plants against U. esculenta infection.


Macrocyclic fragrance materials--a screening-level environmental assessment using chemical categorization.
A screening-level aquatic environmental risk assessment for macrocyclic fragrance materials using a "group approach" is presented using data for 30 macrocyclic fragrance ingredients. In this group approach, conservative estimates of environmental exposure and ecotoxicological effects thresholds for compounds within two subgroups (15 macrocyclic ketones and 15 macrocyclic lactones/lactides) were used to estimate the aquatic ecological risk potential for these subgroups. It is reasonable to separate these fragrance materials into the two subgroups based on the likely metabolic pathway required for biodegradation and on expected different ecotoxicological modes of action. The current volumes of use for the macrocyclic ketones in both Europe and North America ranges from <1 (low kg quantities) to no greater than 50 metric tonnes in either region and for macrocyclic lactones/lactides the volume of use range for both regions is <1 to no greater than 1000 metric tonnes in any one region. Based on these regional tonnages, biodegradability of these two subgroups of materials, and minimal in stream dilution (3:1), the conservatively predicted exposure concentrations for macrocyclic ketones would range from <0.01 to 0.05 μg/L in Europe and from <0.01 to 0.03 μg/L in North America. For macrocyclic lactones/lactides, the concentration within the mixing zone would range from <0.01 to 0.7 μg/L in Europe and from <0.01 to 1.0 μg/L in North America. The PNECs derived for the macrocyclic ketones is 0.22 μg/L and for macrocyclic lactones/lactides is 2.7 μg/L. The results of this screening-level aquatic ecological risk assessment indicate that at their current tonnage, often referred to as volumes of use, macrocyclic fragrance materials in Europe and North America, pose a negligible risk to aquatic biota; with no PEC/PNEC ratio exceeding 1 for any material in any subgroup.


Balloon dilation in the management of severe airway stenosis in children and adolescents.
Children and adolescents with airway stenosis pose a clinical challenge. Recently, balloon dilation has been described, primarily for the treatment of early, immature, less severe airway stenosis. We describe our experience with 8 children and adolescents managed with balloon dilation, including severe, mature subglottic and tracheal stenosis. This is a case series of 8 children and adolescents with acquired subglottic and tracheal stenosis treated by the primary author with balloon dilation between August 2006 and April 2010 at an academic tertiary care center. In the four patients who were tracheotomy-dependent at the time of presentation, suprastomal stents or Montgomery T-tubes were used. In 1 patient with 99% subglottic stenosis (SGS), balloon dilation and stenting were used to create a lumen prior to laryngotracheal reconstruction (LTR). All 4 patients with tracheotomy were decannulated. The remaining 4 patients were successfully managed without tracheotomy. Mature, severe laryngeal and tracheal stenosis in pediatric patients can be successfully managed with balloon dilation. In the most severe cases with prior tracheotomy, stenting is necessary. Balloon dilation with stenting can also facilitate LTR. In patients without prior tracheotomy, tracheotomy and stenting can often be safely avoided with appropriate postoperative management.


Nutritional Control of Cell Size by the Greatwall-Endosulfine-PP2A·B55 Pathway.
Proliferating cells adjust their cell size depending on the nutritional environment. Cells are large in rich media and small in poor media. This physiological response has been demonstrated in both unicellular and multicellular organisms. Here we show that the greatwall-endosulfine (Ppk18-Igo1 in fission yeast) pathway couples the nutritional environment to the cell-cycle machinery by regulating the activity of PP2A·B55. In the presence of nutrients, greatwall (Ppk18) protein kinase is inhibited by TORC1 and PP2A·B55 is active. High levels of PP2A·B55 prevent the activation of mitotic Cdk1·Cyclin B, and cells increase in size in G2 before they undergo mitosis. When nutrients are limiting, TORC1 activity falls off, and the activation of greatwall (Ppk18) leads to the phosphorylation of endosulfine (Igo1) and inhibition of PP2A·B55, which in turn allows full activation of Cdk1·CyclinB and entry into mitosis with a smaller cell size. Given the conservation of this pathway, it is reasonable to assume that this mechanism operates in higher eukaryotes, as well.


Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport.
With a small amount of maleimide modification on the liposome surface, enhanced cellular uptake of liposomes and drug-delivery efficiency can be obtained both in vitro and in vivo. Herein, we describe the mechanisms underlying this enhanced cellular uptake. Suppression of the cellular uptake of maleimide-modified liposomes (M-GGLG, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate [GGLG]/cholesterol/poly(ethylene glycol) - 1,2-distearoyl-sn-glycero-3-phosphoethanolamine [PEG₅₀₀₀-DSPE]/maleimide [M]-PEG₅₀₀₀-Glu2C18 at a molar ratio of 5:5:0.03:0.03) caused by temperature block and addition of serum was alleviated compared with that of liposomes without maleimide modification (GGLG liposomes, composed of GGLG/cholesterol/PEG₅₀₀₀-DSPE/PEG₅₀₀₀-Glu2C₁₈ at a molar ratio of 5:5:0.03:0.03). When 0.01 nM N-ethylmaleimide was used to pre-block cellular thiols, the cellular uptake of M-GGLG liposomes was decreased to approximately 70% in HeLa, HCC1954, MDA-MB-468, and COS-7 cell lines. Moreover, inhibition of a thiol-related reductase such as protein disulfide isomerase resulted in a 15%-45% inhibition of the cellular uptake of M-GGLG liposomes, whereas GGLG liposomes were not influenced. Further, single and mixed inhibitors of clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis did not efficiently inhibit the cellular uptake of M-GGLG liposomes. Using confocal microscopy, we verified that M-GGLG liposomes were localized partially in lysosomes after inhibition of the mentioned conventional endocytic pathways. Therefore, it was hypothesized that the mechanisms underlying the enhanced cellular uptake of liposomes by maleimide modification was thiol-mediated membrane trafficking, including endocytosis and energy-independent transport.


Skills for Growing Up-Epilepsy: An exploratory mixed methods study into a communication tool to promote autonomy and empowerment of youth with epilepsy.
The consequences of having epilepsy seriously hamper the development of autonomy for youth with epilepsy (YWE) and limit their social participation. This study was designed to provide insight into the impact of epilepsy on autonomy and empowerment and to evaluate the use of the Skills for Growing Up (SGU-Epilepsy) communication tool in pediatric epileptic care. A mixed methods design was used to examine the impact of epilepsy on autonomy and empowerment and to evaluate the feasibility and use of the SGU-Epilepsy. Six focus groups with YWE and their parents were organized (N = 27), and the benefits of the SGU-Epilepsy were evaluated (N = 72). Youth with epilepsy struggled with social participation. Beliefs of YWE and their parents on managing daily life and taking medication were not always similar. Parents worried about the passive attitude of YWE, but autonomy of YWE seemed to be constrained by parents. The SGU-Epilepsy seemed to be feasible. It facilitated the communication on development and empowerment although it was sometimes confronting for parents. Not all YWE were motivated to use and discuss the tool. In the evaluation, no differences in perceived autonomy and empowerment between YWE who used SGU-Epilepsy and received usual care appeared. On the short-term, a beneficial effect of using the SGU-Epilepsy on autonomy and empowerment for YWE and their parents was not shown. The SGU-Epilepsy seemed to be a feasible instrument, however, to address nonmedical issues during pediatric consultations.


RNA-binding properties of HCF152, an Arabidopsis PPR protein involved in the processing of chloroplast RNA.
The nonphotosynthetic mutant of Arabidopsis hcf152 is impaired in the processing of the chloroplast polycistronic transcript, psbB-psbT-psbH-petB-petD, resulting in nonproduction of the essential photosynthetic cytochrome b6f complex. The nucleus-encoded HCF152gene was identified to encode a pentatricopeptide repeat (PPR) protein composed primarily of 12 PPR motifs, similar to other proteins of this family that were identified in mutants defected in chloroplast gene expression. To understand the molecular mechanism of how HCF152 modulates chloroplast gene expression, the molecular and biochemical properties should be revealed. To this end, HCF152 and several truncated versions were produced in bacteria and analyzed for RNA-binding and protein-protein interaction. It was found that two HCF152 polypeptides bind to form a homodimer, and that this binding is impaired by a single amino acid substitute near the carboxyl terminus, replacing leucine with proline. Recombinant HCF152 bound with higher affinity RNA molecules, resembling the petB exon-intron junctions, as well as several other molecules. The highest affinity was found to RNA composed of the poly(A) sequence. When truncated proteins composed of different numbers of PPR motifs were analyzed for RNA-binding, it was found that two PPR motifs were required for RNA-binding, but had very low affinity. The affinity to RNA increased significantly when proteins composed of more PPR motifs were analyzed, displaying the highest affinity with the full-length protein composed of 12 PPR motifs. Together, our data characterized the nuclear-encoded HCF152 to be a chloroplast RNA-binding protein that may be involved in the processing or stabilization of the petB transcript by binding to the exon-intron junctions.


Novel reconstruction of the extrahepatic biliary tree with a biosynthetic absorbable graft.
The reference standard technique for the reconstruction of the extrahepatic biliary tree is Roux-en-Y hepaticojejunostomy. This procedure is not without complications and may not be feasible in some patients. This project sought to evaluate a novel approach for repairing common bile duct injuries with a biosynthetic graft. This allows for the reconstruction of the anatomy without necessitating an intestinal bypass. Study subjects were 11 mongrel hounds. Utilizing an open approach, the common bile duct was transected in each animal. A 1-cm graft of a synthetic bioabsorbable prosthesis was interposed over a 5-Fr pancreatic stent and sewn in place as an interposition tube graft with absorbable sutures. Intraoperative cholangiograms and monthly liver function tests were completed. Animals were killed at 6, 7, 8, 10 and 12 months. The first five animals were killed early in the process of protocol development. One animal developed obstructive symptoms and was killed on postoperative day 14. The next five animals were longterm survivors without evidence of clinically significant graft stenosis. Mean alkaline phosphatase and total bilirubin were normal, at 140 U/l and 0.2 mg/dl, respectively. Histology showed the complete replacement of the graft with native tissue at 6 months. Biliary reconstruction using a synthetic bioabsorbable prosthetic as an interposition tube graft is feasible based on initial results.


Purification and characterization of a transcription factor which appears to regulate cAMP responsiveness of the human CYP21B gene.
A unique cAMP regulatory sequence, -129/-96 base pairs (bp), associated with the gene encoding human cytochrome P450C21 (CYP21B) binds a nuclear protein designated ASP, as described previously (Kagawa, N., and Waterman, M. R. (1991) J. Biol. Chem. 266, 11199-11204). This putative transcription factor required for cAMP-dependent transcription of the human CYP21B gene has been purified from the nuclear extracts of mouse Y1 cells by using sequence-specific DNA-affinity chromatography. The purified ASP is 78 kDa as estimated by SDS-polyacrylamide gel electrophoresis and binds to its specific recognition site, -126/-113-bp CACTCTGTGGGCGG, which has been demonstrated to be the minimum cAMP regulatory sequence of the human CYP21B gene. To characterize ASP more precisely, an antibody was raised against the 78-kDa protein. This antibody led to a supershift of the DNA.ASP complex on gel shift analysis and inhibition of in vitro transcription promoted by the ASP binding sequence, thereby indicating that ASP is a 78-kDa transcription factor. Upon DNase I footprinting experiments, ASP showed a characteristic footprint which very closely resembles but is distinct from that of Sp1 which also occupies a binding site within -129/-96 bp. Furthermore, the addition of purified ASP enhanced the mRNA synthesis promoted by the minimum cAMP regulatory sequence in a cell-free transcription system using HeLa cell extracts, whereas added Sp1 does not. These results indicate that ASP is a primary transcription factor for the cAMP-dependent regulation of the human CYP21B gene.


Promoting clinically effective practice: general practitioners' awareness of sources of research evidence.
Practitioners are being encouraged to base their clinical practice on research evidence. In order to do this, they must be aware of and use the sources of evidence. A questionnaire survey was undertaken to establish GPs' awareness of research evidence in their clinical practice and, in fundholding practices, its influence on purchasing plans. Questionnaires were sent to 360 lead fundholders in North Thames Region and 440 of a random sample of the remaining general practitioners in the region for comparison. Questionnaires were returned by 62% of lead fundholders and 63% of GPs in the random sample. There was limited use of the electronic sources of clinical effectiveness. There was greater reported awareness of published sources of research evidence and fundholding GPs were significantly more likely to have referred to publications summarizing research evidence. GPs seem to make more use of published clinical effectiveness sources than the electronic databases. Consequently, they need educational and technical support if they are to make full use of the available sources of research evidence available in other media.


Weak synchronization and large-scale collective oscillation in dense bacterial suspensions.
Collective oscillatory behaviour is ubiquitous in nature, having a vital role in many biological processes from embryogenesis and organ development to pace-making in neuron networks. Elucidating the mechanisms that give rise to synchronization is essential to the understanding of biological self-organization. Collective oscillations in biological multicellular systems often arise from long-range coupling mediated by diffusive chemicals, by electrochemical mechanisms, or by biomechanical interaction between cells and their physical environment. In these examples, the phase of some oscillatory intracellular degree of freedom is synchronized. Here, in contrast, we report the discovery of a weak synchronization mechanism that does not require long-range coupling or inherent oscillation of individual cells. We find that millions of motile cells in dense bacterial suspensions can self-organize into highly robust collective oscillatory motion, while individual cells move in an erratic manner, without obvious periodic motion but with frequent, abrupt and random directional changes. So erratic are individual trajectories that uncovering the collective oscillations of our micrometre-sized cells requires individual velocities to be averaged over tens or hundreds of micrometres. On such large scales, the oscillations appear to be in phase and the mean position of cells typically describes a regular elliptic trajectory. We found that the phase of the oscillations is organized into a centimetre-scale travelling wave. We present a model of noisy self-propelled particles with strictly local interactions that accounts faithfully for our observations, suggesting that self-organized collective oscillatory motion results from spontaneous chiral and rotational symmetry breaking. These findings reveal a previously unseen type of long-range order in active matter systems (those in which energy is spent locally to produce non-random motion). This mechanism of collective oscillation may inspire new strategies to control the self-organization of active matter and swarming robots.


Measurement of Physiological Monitor Alarm Accuracy and Clinical Relevance in Intensive Care Units.
Alarm fatigue threatens patient safety by delaying or reducing clinician response to alarms, which can lead to missed critical events. Interventions to reduce alarms without jeopardizing patient safety target either inaccurate or clinically irrelevant alarms, so assessment of alarm accuracy and clinical relevance may enhance the rigor of alarm intervention studies done in clinical units. To (1) examine approaches used to measure accuracy and/or clinical relevance of physiological monitor alarms in intensive care units and (2) compare the proportions of inaccurate and clinically irrelevant alarms. An integrative review was used to systematically search the literature and synthesize resulting articles. Twelve studies explicitly measuring alarm accuracy and/or clinical relevance on a clinical unit were identified. In the most rigorous studies, alarms were annotated retrospectively by obtaining alarm data and parameter waveforms rather than being annotated in real time. More than half of arrhythmia alarms in recent studies were inaccurate. However, contextual data were needed to determine alarms' clinical relevance. Proportions of clinically irrelevant alarms were high, but definitions of clinically irrelevant alarms often included inaccurate alarms. Future studies testing interventions on clinical units should include alarm accuracy and/or clinical relevance as outcome measures. Arrhythmia alarm accuracy should improve with advances in technology. Clinical interventions should focus on reducing clinically irrelevant alarms, with careful consideration of how clinical relevance is defined and measured.


Induction of pre-infection thread structures in the leguminous host plant by mitogenic lipo-oligosaccharides of Rhizobium.
Root nodules of leguminous plants are symbiotic organs in which Rhizobium bacteria fix nitrogen. Their formation requires the induction of a nodule meristem and the formation of a tubular structure, the infection thread, through which the rhizobia reach the nodule primordium. In the Rhizobium host plants pea and vetch, pre-infection thread structures always preceded the formation of infection threads. These structures consisted of cytoplasmic bridges traversing the central vacuole of outer cortical root cells, aligned in radial rows. In vetch, the site of the infection thread was determined by the plant rather than by the invading rhizobia. Like nodule primordia, pre-infection thread structures could be induced in the absence of rhizobia provided that mitogenic lipo-oligosaccharides produced by Rhizobium leguminosarum biovar viciae were added to the plant. In this case, cells in the two outer cortical cell layers containing cytoplasmic bridges may have formed root hairs. A common morphogenetic pathway may be shared in the formation of root hairs and infection threads.


Progressive intellectual impairment in children with Encephalopathy related to Status Epilepticus during slow Sleep.
We investigated whether Encephalopathy related to Status Epilepticus during slow Sleep (ESES) in childhood was associated with progressive intellectual decline. Participants were identified from the caseload of a single paediatric neurosciences centre and EEG department. A retrospective review of overnight sleep EEG reports (n=2200) over a five-year period identified twenty-two children as having the neurophysiological characteristics of ESES. All had repeat neuropsychological assessment using the WISC-III (UK) and/or WPPSI-R (UK). There was a statistically significant reduction in Full-Scale IQ and Performance IQ across a mean and median time interval of two years. Around a third of the participants showed a clinically significant regression in intellectual functioning evidenced by =>12-point reduction in IQ. These patients were not distinguishable from the rest of the cohort in terms of clinical history, imaging or duration of ESES. The reduction in IQ reflected reduced processing speed, working memory and overall cognitive efficiency. Children with a history of ESES require close monitoring in order to support educational planning and provide families with accurate information about prognosis.


Effects of phthalic acid esters on the liver and thyroid.
The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P-450 isoenzyme(s) catalyzing omega oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fail to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid. The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.


TRPV1 expression level in isolectin B₄-positive neurons contributes to mouse strain difference in cutaneous thermal nociceptive sensitivity.
Differential thermal nociception across inbred mouse strains has genetic determinants. Thermal nociception is largely attributed to the heat/capsaicin receptor transient receptor potential vanilloid 1 (TRPV1); however, the contribution of this channel to the genetics of thermal nociception has not been revealed. In this study we compared TRPV1 expression levels and electrophysiological properties in primary sensory neurons and thermal nociceptive behaviors between two (C57BL/6 and BALB/c) inbred mouse strains. Using immunofluorescence and patch-clamp physiology methods, we demonstrated that TRPV1 expression was significantly higher in isolectin B4 (IB4)-positive trigeminal sensory neurons of C57BL/6 relative to BALB/c; the expression in IB4-negative neurons was similar between the strains. Furthermore, using electrophysiological cell classification (current signature method), we showed differences between the two strains in capsaicin sensitivity in IB4-positive neuronal cell types 2 and 13, which were previously reported as skin nociceptors. Otherwise electrophysiological membrane properties of the classified cell types were similar in the two mouse strains. In publicly available nocifensive behavior data and our own behavior data from the using the two mouse strains, C57BL/6 exhibited higher sensitivity to heat stimulation than BALB/c, independent of sex and anatomical location of thermal testing (the tail, hind paw, and whisker pad). The TRPV1-selective antagonist JNJ-17203212 inhibited thermal nociception in both strains; however, removing IB4-positive trigeminal sensory neurons with IB4-conjugated saporin inhibited thermal nociception on the whisker pad in C57BL/6 but not in BALB/c. These results suggest that TRPV1 expression levels in IB4-positive type 2 and 13 neurons contributed to differential thermal nociception in skin of C57BL/6 compared with BALB/c.


Unveiling the diversification dynamics of Australasian predaceous diving beetles in the Cenozoic.
During the Cenozoic, Australia experienced major climatic shifts that have had dramatic ecological consequences for the modern biota. Mesic tropical ecosystems were progressively restricted to the coasts and replaced by arid-adapted floral and faunal communities. Whilst the role of aridification has been investigated in a wide range of terrestrial lineages, the response of freshwater clades remains poorly investigated. To gain insights into the diversification processes underlying a freshwater radiation, we studied the evolutionary history of the Australasian predaceous diving beetles of the tribe Hydroporini (147 described species). We used an integrative approach including the latest methods in phylogenetics, divergence time estimation, ancestral character state reconstruction, and likelihood-based methods of diversification rate estimation. Phylogenies and dating analyses were reconstructed with molecular data from seven genes (mitochondrial and nuclear) for 117 species (plus 12 outgroups). Robust and well-resolved phylogenies indicate a late Oligocene origin of Australasian Hydroporini. Biogeographic analyses suggest an origin in the East Coast region of Australia, and a dynamic biogeographic scenario implying dispersal events. The group successfully colonized the tropical coastal regions carved by a rampant desertification, and also colonized groundwater ecosystems in Central Australia. Diversification rate analyses suggest that the ongoing aridification of Australia initiated in the Miocene contributed to a major wave of extinctions since the late Pliocene probably attributable to an increasing aridity, range contractions and seasonally disruptions resulting from Quaternary climatic changes. When comparing subterranean and epigean genera, our results show that contrasting mechanisms drove their diversification and therefore current diversity pattern. The Australasian Hydroporini radiation reflects a combination of processes that promoted both diversification, resulting from new ecological opportunities driven by initial aridification, and a subsequent loss of mesic adapted diversity due to increasing aridity.


Efficient targeted multiallelic mutagenesis in tetraploid potato (Solanum tuberosum) by transient CRISPR-Cas9 expression in protoplasts.
Altered starch quality with full knockout of GBSS gene function in potato was achieved using CRISPR-Cas9 technology, through transient transfection and regeneration from isolated protoplasts. Site-directed mutagenesis (SDM) has shown great progress in introducing precisely targeted mutations. Engineered CRISPR-Cas9 has received increased focus compared to other SDM techniques, since the method is easily adapted to different targets. Here, we demonstrate that transient application of CRISPR-Cas9-mediated genome editing in protoplasts of tetraploid potato (Solanum tuberosum) yielded mutations in all four alleles in a single transfection, in up to 2 % of regenerated lines. Three different regions of the gene encoding granule-bound starch synthase (GBSS) were targeted under different experimental setups, resulting in mutations in at least one allele in 2-12 % of regenerated shoots, with multiple alleles mutated in up to 67 % of confirmed mutated lines. Most mutations resulted in small indels of 1-10 bp, but also vector DNA inserts of 34-236 bp were found in 10 % of analysed lines. No mutations were found in an allele diverging one bp from a used guide sequence, verifying similar results found in other plants that high homology between guide sequence and target region near the protospacer adjacent motif (PAM) site is essential. To meet the challenge of screening large numbers of lines, a PCR-based high-resolution fragment analysis method (HRFA) was used, enabling identification of multiple mutated alleles with a resolution limit of 1 bp. Full knockout of GBSS enzyme activity was confirmed in four-allele mutated lines by phenotypic studies of starch. One remaining wild-type (WT) allele was shown sufficient to maintain enough GBSS enzyme activity to produce significant amounts of amylose.


INTER-HEART: A global study of risk factors for acute myocardial infarction.
Although declines in mortality rates have occurred in most developed countries, increases are being seen in developing countries. Our knowledge of risk factors for acute myocardial infarction (AMI) is largely derived from studies in the former. Applicability of these results to other populations is unknown. The objectives of INTER-HEART are to determine the association between risk factors and AMI within populations defined by ethnicity and/or geographic region and to assess the relative importance of risk factors across these populations. INTER-HEART is a study of 14,000 cases of AMI and 16,000 matched control patients from 46 countries, which was conducted with a standardized protocol. Questionnaires were translated into 11 languages; physical measurements were obtained, and 20 mL of blood was drawn and shipped frozen to a central laboratory in Canada. The study will evaluate the importance of conventional and emerging risk factors within each geographic region and whether their impact varies by region. INTER-HEART is sponsored by the World Health Organization and the World Heart Federation and has received funding from several peer-reviewed agencies and many different pharmaceutical companies. A vanguard phase (February 1999 to 2000) enrolled 4000 subjects from 41 countries. Full data collection started in April 2000 and is expected to be completed by October 2002. Several years of targeted work have allowed the development of the concepts that were tested in the pilot studies. This has ensured the feasibility of INTER-HEART. This study has the potential to have a major impact in developing a worldwide strategy for cardiovascular disease prevention, especially in developing countries and nonwhite populations.


Detection and genotype analysis of Giardia duodenalis from asymptomatic Hungarian inhabitants and comparative findings in three distinct locations.
The transmission route of giardiasis not yet understood and why some infected individuals remain asymptomatic while others become quite ill. The drinking water quality is supposedly responsible for the prevalence of asymptomatic Giardia duodenalis infections in different areas, therefore asymptomatic giardiasis has been investigated in three water supply areas of Hungary: three hundred stool samples from inhabitants of Budapest, Füzér and Mátrafüred were examined by immunological and molecular methods for the presence of G. duodenalis infections. Individuals were asked to fill out a validated questionnaire at the time of stool collection and the interview covered demographic data, family life, education and travel history.In Budapest and in Mátrafüred in one stool sample G. duodenalis Assemblage A, whereas in Füzér once G. duodenalis Assemblage A, once Assemblage B and twice mixed infection were detected. We found higher prevalence rate of 4% of G. duodenalis infections of asymptomatic people in the village Füzér, where the removal of the Giardia cysts of the drinking water treatment plant was not effective. This study throws a light the need to look into the possibility of other risks of Giardia infections such as water transmission routes. To our knowledge, this is the first study evaluating the prevalence of G. duodenalis infections in asymptomatic persons in Hungary.


Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.
Published data on treatment of fatty acid oxidation defects are scarce. Treatment recommendations have been developed on the basis of observations in 75 patients with long-chain fatty acid oxidation defects from 18 metabolic centres in Central Europe. Recommendations are based on expert practice and are suggested to be the basis for further multicentre prospective studies and the development of approved treatment guidelines. Considering that disease complications and prognosis differ between different disorders of long-chain fatty acid oxidation and also depend on the severity of the underlying enzyme deficiency, treatment recommendations have to be disease-specific and depend on individual disease severity. Disorders of the mitochondrial trifunctional protein are associated with the most severe clinical picture and require a strict fat-reduced and fat-modified (medium-chain triglyceride-supplemented) diet. Many patients still suffer acute life-threatening events or long-term neuropathic symptoms despite adequate treatment, and newborn screening has not significantly changed the prognosis for these severe phenotypes. Very long-chain acyl-CoA dehydrogenase deficiency recognized in neonatal screening, in contrast, frequently has a less severe disease course and dietary restrictions in many patients may be loosened. On the basis of the collected data, recommendations are given with regard to the fat and carbohydrate content of the diet, the maximal length of fasting periods and the use of l-carnitine in long-chain fatty acid oxidation defects.


Optimal fits of diffusion constants from single-time data points of Brownian trajectories.
Experimental methods based on single particle tracking (SPT) are being increasingly employed in the physical and biological sciences, where nanoscale objects are visualized with high temporal and spatial resolution. SPT can probe interactions between a particle and its environment but the price to be paid is the absence of ensemble averaging and a consequent lack of statistics. Here we address the benchmark question of how to accurately extract the diffusion constant of one single Brownian trajectory. We analyze a class of estimators based on weighted functionals of the square displacement. For a certain choice of the weight function these functionals provide the true ensemble averaged diffusion coefficient, with a precision that increases with the trajectory resolution.


Nutrition impacts the prevalence of peripheral arterial disease in the United States.
Traditional recommendations for peripheral arterial disease (PAD) risk factor reduction include smoking cessation, low-fat/low-salt diet, exercise, and optimal medical management of chronic disease. Little attention has been paid to the role of dietary supplementation of specific nutrients in the prevention of PAD. This cross-sectional study used the National Health and Nutrition Examination Survey (NHANES) to determine specific nutrients that are associated with prevalent PAD in the United States (US) population. NHANES data include nationwide sampling of the US population, using physical examination, questionnaire, and laboratory testing. PAD status was defined by an ankle-brachial index (ABI) of <0.9. Nutritional information was collected by 24-hour dietary recall using the US Department of Agriculture dietary collection instrument. Data were linked to a database of foods and their nutrient composition. Univariate and multivariate logistic regression analyses were performed to evaluate associations between specific nutrient intake and the presence of PAD. Multivariate models adjusted for the effects of age, gender, hypertension, coronary vascular disease, diabetes, and smoking. NHANES data for 1999 to 2004 included 7203 lower extremity examinations, of which 422 individuals had prevalent PAD (5.9%). Examinees with PAD had significantly higher rates of hypertension, coronary artery disease, diabetes, and smoking than those without PAD. Univariate analysis revealed that consumption of all nutrients considered were associated with lower odds of PAD, including antioxidants (vitamins A, C, and E), folate, other B vitamins (B(6), B(12)), fiber, and polyunsaturated and saturated fatty acids. After adjustment for traditional risk factors, nutrients associated with reduced prevalence of PAD were vitamin A (odds ratio [OR], 0.79; P = .036), vitamin C (OR, 0.84; P < .001), vitamin E (OR, 0.78; P = .011), vitamin B(6) (OR, 0.71; P = .023), fiber (OR, 0.65; P < .001), folate (OR, 0.67; P = .006), and omega-3 (alpha-linolenic) fatty acid (OR, 0.79; P = .028). Improved nutrition is associated with a reduced prevalence of PAD in the US population. Higher consumption of specific nutrients, including antioxidants (vitamin A, C, and E), vitamin B(6), fiber, folate, and omega-3 fatty acids have a significant protective effect, irrespective of traditional cardiovascular risk factors. These findings suggest specific dietary supplementation may afford additional protection, above traditional risk factor modification, for the prevention of PAD.


An automated, pre-programmed, multiplexed, hydraulic microvalve.
An automated, pre-programmed, multiplexed hydraulic valve actuator is described. The valve is membrane-based and normally open. In contrast to the membrane-based pneumatic valve, the hydraulic valve uses hydraulic liquid to exert the control pressure. The line pressure is controlled with a roller moving over a prefabricated topology. Multiple rollers, each traversing its own track, are assembled into a single carriage, which can be actuated either manually or with a single computer-controlled motor. A valve manifold and roller actuators are designed, fabricated, and tested to demonstrate three-way valve actuation in a pre-determined sequence. The performance of the valve is evaluated and the utility of the valve in the operation of a micro thermal cycler was demonstrated. Hydraulic controllers of the type described here can be operated either manually or under computer control and provide an inexpensive means of controlling flow in lab-on-a-chip devices.


Radiographic anatomy of the foot and ankle--part 1: the distal leg.
The normal radiographic anatomy of the foot and ankle, aside from my previous work, has been addressed only superficially or sparingly in the medical literature. This project correlates the detailed radiographic anatomy of the entire adult foot and ankle (two-dimensional) to osteology (three-dimensional). Each bone's position was determined after meticulous examination and correlation to an articulated skeleton relative to the image receptor and direction of the x-ray beam, with correlation to the radiograph for confirmation. Images of each foot and distal leg bone ("front" and "back" perspectives) are presented alongside a corresponding radiographic image for comparison. The normal gross and radiographic anatomy is correlated and described for each radiographic positioning technique. Foundational knowledge is provided that future researchers can use as a baseline ("normal") and that students and practitioners can use for comparison when interpreting radiographs and distinguishing abnormal findings. The findings from the original project, owing to its broad scope, have been divided into five parts: the lower leg (the focus of this paper), the greater tarsus, the lesser tarsus, the metatarsals, and the phalanges.


Outcome of the HORIZONS-AMI trial: bivalirudin enhances long-term survival in patients with ST-elevation myocardial infarction undergoing angioplasty.
Cardiovascular disease is the leading cause of death in the US. For patients with ST-elevation myocardial infarction (STEMI), urgent reperfusion of the culprit arterial occlusion, often achieved via primary percutaneous coronary intervention (PCI), reduces post-MI mortality and other major adverse cardiovascular events (MACE). Adjunctive antithrombotic and antiplatelet therapies are used during PCI to reduce MACE rates. Currently, a variety of antithrombotic options are available for peri-procedural use. The most commonly used agents include unfractionated heparin or low molecular weight heparin ± glycoprotein IIb/IIIa inhibitors (GPI). These agents reduce the rates of peri-procedural ischemic and thrombotic events, though these benefits come at the cost of an increase in bleeding complications. Bivalirudin is a direct thrombin inhibitor with a short half-life and linear pharmacokinetics, which results in predictable serum concentrations and anticoagulant effect. Bivalirudin has emerged as an efficacious and safe alternative to heparin plus GP IIb/IIIa inhibitors in both stable coronary artery disease and acute coronary syndrome patients. In the HORIZONS-AMI trial, monotherapy with bivalirudin was compared with the combination of heparin and a GPI in a large population of patients with STEMI who underwent primary PCI. Bivalirudin treatment was associated with improved event-free survival at 30 days and reduced rates of major bleeding. Based on the results of the trial, the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines have incorporated recommendations for bivalirudin use in the setting of STEMI. Recently, 3-year follow-up data from the HORIZONS-AMI cohort were published, demonstrating sustained benefits in patients treated with bivalirudin, including reduced rates of mortality, cardiovascular mortality, reinfarction, and major bleeding events. These results further support the use of bivalirudin in the setting of primary PCI for STEMI given that its benefits are maintained through long-term follow-up.


Nutritional policies and standards for snacks served in after-school programmes: a review.
To review and synthesize existing national and state organizations' policies related to the nutritional quality of snacks served in after-school programmes (ASP; 15.00-18.00 hours) in the USA. Systematic review of websites and corresponding documentation describing national and state-level ASP organizations' policies, standards, guidelines and/or recommendations for the nutritional quality of snacks served within the ASP setting. ASP can play a critical role in a child's daily dietary intake. State and national organizations have developed policies to assist ASP in selecting nutritionally appropriate snacks, yet no widely accepted standards exist. By reviewing the extent of existing policies, recommendations for uniform policies can be made. Policy documentation. A total of seventeen organizations representing five unique snack policies comprised of thirteen different food items were identified. The most widely recognized snack policy, which the majority of state and national ASP organizations endorsed and upon which other snack policies were modelled, was the US Department of Agriculture reimbursement programmes. Consistently, policies endorsed serving fruits/vegetables, whole grains and milk/dairy products, and limiting foods high in fats/sugar/energy (calories). Two policies focused predominantly on total energy and macronutrient composition of snacks, a single policy suggested limits on sugar-sweetened beverages, and three endorsed serving water daily. A proposed set of general guidelines for ASP was developed based on uniformity in recommendations across policies. The proposed set of nutritional guidelines will assist policy makers and ASP providers in selecting and serving nutritionally appropriate snacks that contribute to a child's overall healthful daily dietary intake.


Managing health care decisions and improvement through simulation modeling.
Simulation modeling is a way to test changes in a computerized environment to give ideas for improvements before implementation. This article reviews research literature on simulation modeling as support for health care decision making. The aim is to investigate the experience and potential value of such decision support and quality of articles retrieved. A literature search was conducted, and the selection criteria yielded 59 articles derived from diverse applications and methods. Most met the stated research-quality criteria. This review identified how simulation can facilitate decision making and that it may induce learning. Furthermore, simulation offers immediate feedback about proposed changes, allows analysis of scenarios, and promotes communication on building a shared system view and understanding of how a complex system works. However, only 14 of the 59 articles reported on implementation experiences, including how decision making was supported. On the basis of these articles, we proposed steps essential for the success of simulation projects, not just in the computer, but also in clinical reality. We also presented a novel concept combining simulation modeling with the established plan-do-study-act cycle for improvement. Future scientific inquiries concerning implementation, impact, and the value for health care management are needed to realize the full potential of simulation modeling.


Tetrasomy 18p: report of the molecular and clinical findings of 43 individuals.
Thus far, the phenotype of tetrasomy 18p has been primarily delineated by published case series and reports. Findings reported in more than 25% of these cases include neonatal feeding problems, growth retardation, microcephaly, strabismus, muscle tone abnormalities, scoliosis/kyphosis, and variants on brain MRI. Developmental delays and cognitive impairment are universally present. The purpose of this study was to more fully describe tetrasomy 18p at both the genotypic and the phenotypic levels. Array CGH was performed on 43 samples from individuals with tetrasomy 18p diagnosed via routine karyotype. The medical records of 42 of these 43 individuals were reviewed. In order to gain additional phenotypic data, 31 individuals with tetrasomy 18p underwent a series of clinical evaluations at the Chromosome 18 Clinical Research Center. Results from the molecular analysis indicated that 42 of 43 samples analyzed had 4 copies of the entire p arm of chromosome 18; one individual was also trisomic for a section of proximal 18q. The results of the medical records review and clinical evaluations expand the phenotypic description of tetrasomy 18p to include neonatal jaundice and respiratory distress; recurrent otitis media; hearing loss; seizures; refractive errors; constipation and gastroesophageal reflux; cryptorchidism; heart defects; and foot anomalies. Additional findings identified in a small number of individuals include hernias, myelomeningocele, kidney defects, short stature, and failure to respond to growth hormone stimulation testing. Additionally, a profile of dysmorphic features is described. Lastly, a series of clinical evaluations to be considered for individuals with tetrasomy 18p is suggested.


Light-activated self-propelled colloids.
Light-activated self-propelled colloids are synthesized and their active motion is studied using optical microscopy. We propose a versatile route using different photoactive materials, and demonstrate a multiwavelength activation and propulsion. Thanks to the photoelectrochemical properties of two semiconductor materials (α-Fe2O3 and TiO2), a light with an energy higher than the bandgap triggers the reaction of decomposition of hydrogen peroxide and produces a chemical cloud around the particle. It induces a phoretic attraction with neighbouring colloids as well as an osmotic self-propulsion of the particle on the substrate. We use these mechanisms to form colloidal cargos as well as self-propelled particles where the light-activated component is embedded into a dielectric sphere. The particles are self-propelled along a direction otherwise randomized by thermal fluctuations, and exhibit a persistent random walk. For sufficient surface density, the particles spontaneously form 'living crystals' which are mobile, break apart and reform. Steering the particle with an external magnetic field, we show that the formation of the dense phase results from the collisions heads-on of the particles. This effect is intrinsically non-equilibrium and a novel principle of organization for systems without detailed balance. Engineering families of particles self-propelled by different wavelength demonstrate a good understanding of both the physics and the chemistry behind the system and points to a general route for designing new families of self-propelled particles.


Creating chronicity.
An authentic sickness history is the vantage point for juxtaposing a biomedical and a biographical-phenomenological reading. What, in a biomedical framework, appears to be a longstanding state of comorbidity of different and unrelated types of diseases is rendered transparent in a biographical reading. This particular reading, evidencing the shortcomings of a biomedical framework regarding identifying the social sources of an increasingly complex burden of disease, is reflected upon in light of recent research in the neurosciences. Thus, the biomedical contribution to a sickness history is demonstrated, with its resultant multimorbidity, chronification, and complete incapacitation of a woman despite the continuing and nearly excessive involvement of the health care system.


The Role of Civil Society Organizations in Monitoring the Global AIDS Response.
Civil society organizations (CSOs) are recognized as playing an exceptional role in the global AIDS response. However, there is little detailed research to date on how they contribute to specific governance functions. This article uses Haas' framework on global governance functions to map CSO's participation in the monitoring of global commitments to the AIDS response by institutions and states. Drawing on key informant interviews and primary documents, it focuses specifically on CSO participation in Global AIDS Response Progress Reporting and in Global Fund to Fight AIDS, Tuberculosis and Malaria processes. It argues that the AIDS response is unique within global health governance, in that CSOs fulfill both formal and informal monitoring functions, and considers the strengths and weaknesses of these contributions. It concludes that future global health governance arrangements should include provisions and resources for monitoring by CSOs because their participation creates more inclusive global health governance and contributes to strengthening commitments to human rights.


Preventive care delivered within Public Dental Service after caries risk assessment of young adults.
To study preventive care provided to young adults in relation to their estimated risk category over a 3-year period. The amount and type of preventive treatment during 3 years was extracted from the digital dental records of 982 patients attending eight public dental clinics. The baseline caries risk assessment was carried out by the patient's regular team in four classes according to a predetermined model, and the team was responsible for all treatment decisions. Based on the variables 'oral health information', 'additional fluoride' and 'professional tooth cleaning', a cumulative score was constructed and dichotomized to 'basic prevention' and 'additional prevention'. More additional preventive care was provided to the patients in the 'low-risk' and 'some risk' categories than to those classified as 'high' or 'very high' risk (OR = 2.0, 95% CI 1.4-3.0; P < 0.05). Professional tooth cleaning and additional fluorides were most frequently employed in the 'low-risk' and 'some risk' categories, respectively. Around 15% of the patients in the high-risk categories did not receive additional preventive measures over the 3-year period. There was an insignificant tendency that patients with additional prevention developed less caries than those that received basic prevention in all risk categories except for the 'very high-risk' group. The caries risk assessment process was not accompanied by a corresponding targeted individual preventive care in a cohort of young adults attending public dental service. Further research is needed how to reach those with the greatest need of primary and secondary prevention.


Anthropogenic electromagnetic fields (EMF) influence the behaviour of bottom-dwelling marine species.
Many marine animals have evolved sensory abilities to use electric and magnetic cues in essential aspects of life history, such as to detect prey, predators and mates as well as to orientate and migrate. Potential disruption of vital cues by human activities must be understood in order to mitigate potential negative influences. Cable deployments in coastal waters are increasing worldwide, in capacity and number, owing to growing demands for electrical power and telecommunications. Increasingly, the local electromagnetic environment used by electro- and magneto-sensitive species will be altered. We quantified biologically relevant behavioural responses of the presumed, magneto-receptive American lobster and the electro-sensitive Little skate to electromagnetic field (EMF) emissions of a subsea high voltage direct current (HVDC) transmission cable for domestic electricity supply. We demonstrate a striking increase in exploratory/foraging behaviour in skates in response to EMF and a more subtle exploratory response in lobsters. In addition, by directly measuring both the magnetic and electric field components of the EMF emitted by HVDC cables we found that there were DC and unexpectedly AC components. Modelling, restricted to the DC component, showed good agreement with measured results. Our cross-disciplinary study highlights the need to integrate an understanding of the natural and anthropogenic EMF environment together with the responses of sensitive animals when planning future cable deployments and predicting their environmental effects.


Parental or Teacher Education and Coaching to Support Function and Participation of Children and Youth With Sensory Processing and Sensory Integration Challenges: A Systematic Review.
This systematic review examines the literature published from January 2007 through May 2015 related to the effectiveness of occupational therapy interventions using parental or teacher education and coaching with children with challenges in sensory processing and sensory integration (SP-SI). Of more than 11,000 abstracts and 86 articles that were considered, only 4 met the criteria and were included in this review. Studies of parental training and coaching for children with challenges in SP-SI and comorbid autism spectrum disorder have suggested that educational or coaching programs could result in positive outcomes for both parents and children, often in a relatively short time period. Recommendations include a greater focus on providing educational interventions for parents and teachers and including specific assessment of SP-SI before implementing interventions meant to address those issues. Specific recommendations for future research are provided.


Fabrication and Properties of a Free-Standing Two-Dimensional Titania.
The synthesis of free-standing two-dimensional titania (2-D TiO2) with a reduced band gap presents complex challenges to synthetic chemists. Here, we report a free-standing 2-D TiO2 sheet synthesized via a one-step solvothermal methodology, with a measured optical onset at ∼1.84 eV. Using first-principles calculations in combination with experiment, we propose that the as-formed 2-D TiO2 sheets are layers of the lepidocrocite TiO2 structure, but with large nonuniform strains consistent with its crumpled morphology. These strains cause a significant change in the quasiparticle band structure and optical absorption spectra, resulting in large absorption in the visible-light region. This narrow band gap 2-D TiO2 can catalyze the formation of singlet oxygen and the degradation of dye pollutants with low-energy photons of solar light. Our work demonstrates that lattice strains intrinsic to 2-D materials, especially its crumpled, free-standing forms, can result in new and useful properties.


Genetic variants of coagulation factor XI show association with ischemic stroke up to 70 years of age.
Coagulation factor XI (FXI) has an important role in the propagation and stabilization of a thrombus upon vessel injury. High FXI levels have been implicated in thrombotic diseases including ischemic stroke. The aim of our study was to investigate whether FXI gene (F11) variants are associated with ischemic stroke. The discovery sample, the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), included 844 patients with ischemic stroke and 668 controls, all aged 18-70 years. Replication was performed in the Lund Stroke Register (LSR) and Malmö Diet and Cancer study (MDC), together including 1213 patients and 788 controls up to 70 years of age, and in total 3145 patients and 1793 controls (18-102 years). Seven F11 single-nucleotide polymorphisms (SNPs) were selected using a tagging approach. The SNPs rs3733403, rs925451, and rs1593 showed independent associations with overall ischemic stroke in SAHLSIS, ORs of 0.74 (95% CI 0.59-0.94), 1.24 (95% CI 1.06-1.46), and 0.70 (95% CI 0.55-0.90), respectively. The association for rs925451 was replicated in the LSR and MDC sample in a pre-specified analysis of subjects aged 70 years or younger, OR of 1.16 (95% CI 1.00-1.34), whereas no SNP was replicated when all ages were included. In line with this, one F11 haplotype was associated with overall ischemic stroke in the discovery sample and in the replication sample ≤70 years. We found significant associations between F11 variation and overall ischemic stroke up to 70 years of age. These findings motivate further studies on the role of F11 in ischemic stroke, especially in younger individuals.


Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation.
Ianthelliformisamines A-C are a novel class of bromotyrosine-derived antibacterial agents isolated recently from the marine sponge Suberea ianthelliformis. We have synthesized ianthelliformisamines A-C straightforwardly by the condensation of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic acid and the corresponding Boc-protected polyamine followed by Boc-deprotection with TFA. Further, using this reaction protocol, a library of their analogues (39 analogues) has been synthesized by employing 3-phenylacrylic acid derivatives and Boc-protected polyamine chains through various combinations of these two fragments differing in phenyl ring substitution, double bond geometry or chain length of the central spacer of the polyamine chain (shown in red color). All the synthesized compounds (ianthelliformisamines A-C and their analogues) were screened for antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains. All synthetic analogues of ianthelliformisamine A showed bacterial growth inhibition against both strains (Escherichia coli and Staphylococcus aureus), having MIC values in the range of 117.8-0.10 μM, while none of the synthetic analogues of ianthelliformisamine C as well as the parent compound showed any detectable antibacterial activity. Interestingly, some of the synthetic analogues of ianthelliformisamines A and B exerted a bactericidal effect against both E. coli and S. aureus strains, decreasing viable bacterial count by 99% at concentrations as low as 2 × MIC.


The relationship between greenspace and the mental wellbeing of adults: A systematic review.
The view that interacting with nature enhances mental wellbeing is commonplace, despite a dearth of evidence or even agreed definitions of 'nature'. The aim of this review was to systematically appraise the evidence for associations between greenspace and mental wellbeing, stratified by the different ways in which greenspace has been conceptualised in quantitative research. We undertook a comprehensive database search and thorough screening of articles which included a measure of greenspace and validated mental wellbeing tool, to capture aspects of hedonic and/or eudaimonic wellbeing. Quality and risk of bias in research were assessed to create grades of evidence. We undertook detailed narrative synthesis of the 50 studies which met the review inclusion criteria, as methodological heterogeneity precluded meta-analysis. Results of a quality assessment and narrative synthesis suggest associations between different greenspace characteristics and mental wellbeing. We identified six ways in which greenspace was conceptualised and measured: (i) amount of local-area greenspace; (ii) greenspace type; (iii) visits to greenspace; (iv) views of greenspace; (v) greenspace accessibility; and (vi) self-reported connection to nature. There was adequate evidence for associations between the amount of local-area greenspace and life satisfaction (hedonic wellbeing), but not personal flourishing (eudaimonic wellbeing). Evidence for associations between mental wellbeing and visits to greenspace, accessibility, and types of greenspace was limited. There was inadequate evidence for associations with views of greenspace and connectedness to nature. Several studies reported variation in associations between greenspace and wellbeing by life course stage, gender, levels of physically activity or attitudes to nature. Greenspace has positive associations with mental wellbeing (particularly hedonic wellbeing), but the evidence is not currently sufficient or specific enough to guide planning decisions. Further studies are needed, based on dynamic measures of greenspace, reflecting access and uses of greenspace, and measures of both eudaimonic and hedonic mental wellbeing.


Concomitant activation and antigen uptake via human dectin-1 results in potent antigen-specific CD8+ T cell responses.
Dectin-1, a C-type lectin recognizing fungal and mycobacterial pathogens, can deliver intracellular signals that activate dendritic cells (DCs), resulting in initiation of immune responses and expansion of Th17 CD4(+) T cell responses. In this paper, we studied the roles of human Dectin-1 (hDectin-1) expressed on DCs in the induction and activation of Ag-specific CD8(+) T cell responses. We first generated an agonistic anti-hDectin-1 mAb, which recognizes the hDectin-1 Glu(143)-Ile(162) region. It bound to in vitro monocyte-derived DCs and to in vivo CD1c(+)CD1a(+) dermal DCs but not to epidermal Langerhans cells. Anti-hDectin-1-mediated DC activation resulted in upregulation of costimulatory molecules and secretion of multiple cytokines and chemokines in a Syk-dependent manner. DCs activated with the anti-hDectin-1 mAb could significantly enhance both neo and foreign Ag-specific CD8(+) T cell responses by promoting both the expansion of CD8(+) T cells and their functional activities. We further demonstrated that delivering Ags to DCs via hDectin-1 using anti-hDectin-1-Ag conjugates resulted in potent Ag-specific CD8(+) T cell responses. Thus, hDectin-1 expressed on DCs can contribute to the induction and activation of cellular immunity against intracellular pathogens, such as mycobacteria, that are recognized by DCs via Dectin-1. Vaccines based on delivering Ags to DCs with an agonistic anti-hDectin-1 mAb could elicit CD8(+) T cell-mediated immunity.


National Working Group Meeting on ALK diagnostics in lung cancer.
The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors.


Effect of surface wettability properties on the electrical properties of printed carbon nanotube thin-film transistors on SiO2/Si substrates.
The precise placement and efficient deposition of semiconducting single-walled carbon nanotubes (sc-SWCNTs) on substrates are challenges for achieving printed high-performance SWCNT thin-film transistors (TFTs) with independent gates. It was found that the wettability of the substrate played a key role in the electrical properties of TFTs for sc-SWCNTs sorted by poly[(9,9-dioctylfluorene-2,7-diyl)-co-(1,4-benzo-2,1,3-thiadiazole)] (PFO-BT). In the present work we report a simple and scalable method which can rapidly and selectively deposit a high concentration of sc-SWCNTs in TFT channels by aerosol-jet-printing. The method is based on oxygen plasma treatment of substrates, which tunes the surface wettability. TFTs printed on the treated substrates demonstrated a low operation voltage, small hysteresis, high mobility up to 32.3 cm(2) V(-1) s(-1), and high on/off ratio up to 10(6) after only two printings. Their mobilities were 10 and 30 times higher than those of TFTs fabricated on untreated and low-wettability substrates. The uniformity of printed TFTs was also greatly improved. Inverters were constructed by printed top-gate TFTs, and a maximum voltage gain of 17 at Vdd = 5 V was achieved. The mechanism of such improvements is that the PFO-BT-functionalized sc-SWCNTs are preferably immobilized on the oxygen plasma treated substrates due to the strong hydrogen bonds between sc-SWCNTs and hydroxyl groups on the substrates.


Presence of a central vein within white matter lesions on susceptibility weighted imaging: a specific finding for multiple sclerosis?
Susceptibility weighted imaging depicts the perivenous extent of multiple sclerosis white matter lesions (MS-WML) in vivo by directly visualizing their centrally running vein. The aim of this study was to investigate the specificity of this finding for MS. Fifteen patients with MS and 15 patients with microangiopathic white matter lesions (mWML) underwent 3T MRI, including a fluid-attenuated inversion recovery sequence (FLAIR) and a susceptibility weighted angiography (SWAN). All WMLs were identified on FLAIR and assigned to one of the following localizations: supratentorial peripheral, supratentorial periventricular, or infratentorial. Subsequently, the presence of a central vein within these lesions was assessed on SWAN. A total of 711 MS-WMLs and 1,119 m-WMLs were identified on FLAIR, all of which could also be visualized on SWAN. A central vein was detectable in 80% of the MS-WMLs and in 78% of the m-WMLs (in 73% and 76% of the peripheral, in 92% and 94% of the periventricular, and in 71% and 75% of the infratentorial MS-WMLs and m-WMLs, respectively). With regard to the supratentorial peripheral lesions, significantly more m-WMLs showed a central vein compared to the MS-WMLs. For the other localizations, there was no significant difference between the groups with regard to the percentage of lesions with central vein. Our results indicate that the detection of a central vein within a WML should not be considered a specific finding for MS; it is also found in WMLs of other etiologies.