Knowledge of nutritional and health needs of children among rural residents of Enugu north senatorial zone in Enugu State, Nigeria.
The article assessed knowledge of the nutritional and health needs of children among rural dwellers in Nigeria. Focus group discussions were conducted with all male and female groups in four purposively chosen rural communities in Nsukka Senatorial zone of Enugu State. These generated data on participants' knowledge on the nutritional and health needs of the children as well as their socio-demographic characteristics. All the participants were married with mean age of 41 and 36 years for males and females, respectively. The participants had six and four children on the average for male and female participants, respectively. Findings show that participants demonstrate knowledge of basic dietary needs of children; however, actual practice is lacking. Men believe women have the sole responsibility for children's nutrition. Exclusive breastfeeding is not adhered to by participants. Some reservation still exists about immunization. Sustained health education on exclusive breastfeeding and child immunization targeting both sexes is still needed.


Excess protons in mesoscopic water-acetone nanoclusters.
We carried out molecular dynamics simulation experiments to examine equilibrium and dynamical characteristics of the solvation of excess protons in mesoscopic, [m:n] binary polar clusters comprising m = 50 water molecules and n = 6, 25, and 100 acetone molecules. Contrasting from what is found in conventional macroscopic phases, the characteristics of the proton solvation are dictated, to a large extent, by the nature of the concentration fluctuations prevailing within the clusters. At low acetone contents, the overall cluster morphology corresponds to a segregated aqueous nucleus coated by an external aprotic phase. Under these circumstances, the proton remains localized at the surface of the water core, in a region locally deprived from acetone molecules. At higher acetone concentrations, we found clear evidence of the onset of the mixing process. The cluster structures present aqueous domains with irregular shape, fully embedded within the acetone phase. Still, the proton remains coordinated to the aqueous phase, with its closest solvation shell composed exclusively by three water molecules. As the relative concentration of acetone increases, the time scales characterizing proton transfer events between neighboring water molecules show considerable retardations, stretching into the nanosecond time domain already for n ~ 25. In water-rich aggregates, and similarly to what is found in the bulk, proton transfers are controlled by acetone/water exchange processes taking place at the second solvation shell of the proton. As a distinctive feature of the transfer mechanism, translocation pathways also include diffusive motions of the proton from the surface down into inner regions of the underlying water domain.


Influence of femoral stem surface finish on the apparent static shear strength at the stem-cement interface.
The stem-cement interface has long been implicated in failure of cemented total hip replacement. Much research has been performed to study the factors affecting the bond strength between the femoral stem and the bone cement. The present study aims to further investigate the influence of femoral stem surface finish on the apparent static shear strength at the stem-cement interface through a series of pull out tests, where stainless steel rods are employed to represent the femoral stem. The results demonstrated that there was a general tendency for the apparent static shear strength to be increased with the rise of surface roughness. The polished and glass bead-blasted rods illustrated a slip-stick-slip failure whereas the shot-blasted and grit-blasted rods displayed gross interface failure. Following pull out test, cement transfer films were detected on the polished rods, and there was cement debris adhered to the surface of the grit-blasted rods. Micropores, typically 120 mum in diameter, were prevalent in the cement surface interfaced with the polished rods, and the cement surfaces in contact with the shot-blasted and grit-blasted rods were greatly damaged. There was also evidence of metal debris embedding within the cement mantle originating from the tests of the grit-blasted rods, indicating an extremely strong mechanical interlocking at the interface. In summary, this present research demonstrated that the grit-blasted rods with the highest surface roughness were the best in terms of apparent static shear strength. However, it seemed to be most applicable only to the stem designs in which mechanical interlocking of the stem in the initial fixed position was essential.


Adrenergic and metabolic effects of electrical weapons: review and meta-analysis of human data.
Electronic control with the CEW (conducted electrical weapon) has gained widespread acceptance as the preferred force option due to its significant injury reduction. However, a CEW application does stress the human body. In the case of the CEW, the human body response is similar to the challenge of physical exercise combined with emotional stress over a very short time interval. There has been concern whether the tension of the skeletal-muscle system together with the emotional stress of being exposed to the effects of a CEW, can lead to severe metabolic dysfunction. A systematic and careful search of the MedLine database was performed to find publications describing pathophysiological effects of CEWs. Additional publications were collected through a manual search of reference lists in retrieved articles. After preliminary exclusions, we carefully reviewed the remaining publications and found 24 papers reporting prospective human clinical research data on adrenergic, ventilation, or metabolic effects. Where there were multiple studies on the same endpoints, we performed meta-analyses. A CEW exposure provides a clinically insignificant increase in heart rate (7.5 BPM) and a drop in both systolic and diastolic blood pressure. Alpha-amylase goes down but cortisol levels increase-both epinephrine and norepinephrine levels are increased by levels similar to mild exercise. A CEW exposure increases ventilation but does not appear to interfere with gas exchange. Lactate is increased slightly while the pH is decreased slightly with changes equivalent to mild exercise. The lactate and pH changes appear quickly and do not appear to be affected by increasing the exposure duration from 5 to 30 s. Thorough review and meta-analyses show that electrical weapon exposures have mixed and mild adrenergic effects. Ventilation is increased and there are metabolic changes similar to mild exercise.


Burden of Clostridium difficile infection in the United States.
The magnitude and scope of Clostridium difficile infection in the United States continue to evolve. In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents ≥ 1 year of age). Cases were classified as community-associated or health care-associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection. A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8% were health care-associated, but only 24.2% had onset during hospitalization. After adjustment for predictors of disease incidence, the estimated number of incident C. difficile infections in the United States was 453,000 (95% confidence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95% CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16 to 9.31). The estimated number of first recurrences of C. difficile infection was 83,000 (95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95% CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1 (NAP1) strain was more prevalent among health care-associated infections than among community-associated infections (30.7% vs. 18.8%, P<0.001). C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011. (Funded by the Centers for Disease Control and Prevention.).


Domain-Based Analysis of Colon Polyp in CT Colonography Using Image-Processing Techniques
Background: The purpose of the research was to improve the polyp detection accuracy in CT Colonography (CTC) through effective colon segmentation, removal of tagged fecal matter through Electronic Cleansing (EC), and measuring the smaller polyps. Methods: An improved method of boundary-based semi-automatic colon segmentation with the knowledge of colon distension, an adaptive multistep method for the virtual cleansing of segmented colon based on the knowledge of Hounsfield Units, and an automated method of smaller polyp measurement using skeletonization technique have been implemented. Results: The techniques were evaluated on 40 CTC dataset. The segmentation method was able to delineate the colon wall accurately. The submerged colonic structures were preserved without soft tissue erosion, pseudo enhanced voxels were corrected, and the air-contrast layer was removed without losing the adjacent tissues. The smaller polyp of size less than <10mm was detected correctly. The results were statistically validated qualitatively and quantitatively. Segmented colons were validated through volumetric overlap computation, and accuracy of 95.826±0.6854% was achieved. In polyp measurement, the paired t-test method was applied to compare the difference with ground truth and at α=5%, t=0.9937 and p=0.098 was achieved. The statistical values of TPR=90%, TNR=82.3% and accuracy=88.31% were achieved. Conclusion: An automated system of polyp measurement has been developed starting from colon segmentation to improve the existing CTC solutions. The analysis of domain-based approach of polyp has given good results. A prototype software, which can be used as a low-cost polyp diagnosis tool, has been developed.


SMA1, a homolog of the splicing factor Prp28, has a multifaceted role in miRNA biogenesis in Arabidopsis.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that repress gene expression. In plants, the RNase III enzyme Dicer-like (DCL1) processes primary miRNAs (pri-miRNAs) into miRNAs. Here, we show that SMALL1 (SMA1), a homolog of the DEAD-box pre-mRNA splicing factor Prp28, plays essential roles in miRNA biogenesis in Arabidopsis. A hypomorphic sma1-1 mutation causes growth defects and reduces miRNA accumulation correlated with increased target transcript levels. SMA1 interacts with the DCL1 complex and positively influences pri-miRNA processing. Moreover, SMA1 binds the promoter region of genes encoding pri-miRNAs (MIRs) and is required for MIR transcription. Furthermore, SMA1 also enhances the abundance of the DCL1 protein levels through promoting the splicing of the DCL1 pre-mRNAs. Collectively, our data provide new insights into the function of SMA1/Prp28 in regulating miRNA abundance in plants.


Deep learning models for electrocardiograms are susceptible to adversarial attack.
Electrocardiogram (ECG) acquisition is increasingly widespread in medical and commercial devices, necessitating the development of automated interpretation strategies. Recently, deep neural networks have been used to automatically analyze ECG tracings and outperform physicians in detecting certain rhythm irregularities1. However, deep learning classifiers are susceptible to adversarial examples, which are created from raw data to fool the classifier such that it assigns the example to the wrong class, but which are undetectable to the human eye2,3. Adversarial examples have also been created for medical-related tasks4,5. However, traditional attack methods to create adversarial examples do not extend directly to ECG signals, as such methods introduce square-wave artefacts that are not physiologically plausible. Here we develop a method to construct smoothed adversarial examples for ECG tracings that are invisible to human expert evaluation and show that a deep learning model for arrhythmia detection from single-lead ECG6 is vulnerable to this type of attack. Moreover, we provide a general technique for collating and perturbing known adversarial examples to create multiple new ones. The susceptibility of deep learning ECG algorithms to adversarial misclassification implies that care should be taken when evaluating these models on ECGs that may have been altered, particularly when incentives for causing misclassification exist.


Zeolitic imidazolate framework-71 nanocrystals and a novel SOD-type polymorph: solution mediated phase transformations, phase selection via coordination modulation and a density functional theory derived energy landscape.
We report a rapid additive-free synthesis of nanocrystals (NCs) of RHO-type ZIF-71 () of composition [Zn(dcim)2] (dcim = 4,5-dichloroimidazolate) in 1-propanol as solvent at room temperature. NC- has a size of 30-60 nm and exhibits permanent microporosity with a surface area (SBET = 970 m(2) g(-1)) comparable to that of microcrystalline material. When kept under the mother solution NC- undergoes transformation into a novel SOD-type polymorph (), which in turn converts into known ZIF-72 () with lcs topology. It is shown that microcrystals (MCs) of can be favourably synthesised using 1-methylimidazole as a coordination modulator. NC- with size <200 nm was prepared using NC-ZIF-8 as a template with SOD topology in a solvent assisted ligand exchange-related process. DFT-assisted Rietveld analysis of powder XRD data revealed that novel polymorph possesses an unusual SOD framework conformation. was further characterised with regard to microporosity (SBET = 597 m(2) g(-1)) and thermal as well as chemical stability. DFT calculations were performed to search for further potentially existing but not-yet synthesised polymorphs in the [Zn(dcim)2] system.


The potential stickiness of pandemic-induced behavior changes in the United States.
Human behavior is notoriously difficult to change, but a disruption of the magnitude of the COVID-19 pandemic has the potential to bring about long-term behavioral changes. During the pandemic, people have been forced to experience new ways of interacting, working, learning, shopping, traveling, and eating meals. A critical question going forward is how these experiences have actually changed preferences and habits in ways that might persist after the pandemic ends. Many observers have suggested theories about what the future will bring, but concrete evidence has been lacking. We present evidence on how much US adults expect their own postpandemic choices to differ from their prepandemic lifestyles in the areas of telecommuting, restaurant patronage, air travel, online shopping, transit use, car commuting, uptake of walking and biking, and home location. The analysis is based on a nationally representative survey dataset collected between July and October 2020. Key findings include that the "new normal" will feature a doubling of telecommuting, reduced air travel, and improved quality of life for some.


Comparison of electrode reduction activities of Geobacter sulfurreducens and an enriched consortium in an air-cathode microbial fuel cell.
An electricity-generating bacterium, Geobacter sulfurreducens PCA, was inoculated into a single-chamber, air-cathode microbial fuel cell (MFC) in order to determine the maximum electron transfer rate from bacteria to the anode. To create anodic reaction-limiting conditions, where electron transfer from bacteria to the anode is the rate-limiting step, anodes with electrogenic biofilms were reduced in size and tests were conducted using anodes of six different sizes. The smallest anode (7 cm(2), or 1.5 times larger than the cathode) achieved an anodic reaction-limiting condition as a result of a limited mass of bacteria on the electrode. Under these conditions, the limiting current density reached a maximum of 1,530 mA/m(2), and power density reached a maximum of 461 mW/m(2). Per-biomass efficiency of the electron transfer rate was constant at 32 fmol cell(-1) day(-1) (178 micromol g of protein(-1) min(-1)), a rate comparable to that with solid iron as the electron acceptor but lower than rates achieved with fumarate or soluble iron. In comparison, an enriched electricity-generating consortium reached 374 micromol g of protein(-1) min(-1) under the same conditions, suggesting that the consortium had a much greater capacity for electrode reduction. These results demonstrate that per-biomass electrode reduction rates (calculated by current density and biomass density on the anode) can be used to help make better comparisons of electrogenic activity in MFCs.


Genes Unite Executive Functions in Childhood.
Individual differences in children's executive functions (EFs) are relevant for a wide range of normal and atypical psychological outcomes across the life span, but the origins of variation in children's EFs are not well understood. We used data from a racially and socioeconomically diverse sample of 505 third- through eighth-grade twins and triplets from the Texas Twin Project to estimate genetic and environmental influences on a Common EF factor and on variance unique to four core EF domains: inhibition, switching, working memory, and updating. As has been previously demonstrated in young adults, the Common EF factor was 100% heritable, which indicates that correlations among the four EF domains are entirely attributable to shared genetic etiology. Nonshared environmental influences were evident for variance unique to individual domains. General EF may thus serve as an early life marker of genetic propensity for a range of functions and pathologies later in life.


SARS-CoV-2 infection of the nervous system: A review of the literature on neurological involvement in novel coronavirus disease-(COVID-19).
The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is believed to have emerged from an animal source and has been spreading rapidly among humans. Recent evidence shows that SARS-CoV-2 exhibits neurotropic properties and causes neurological diseases. Here, we review the literature on neurological involvement in SARS-CoV-2 infections and the possible mechanisms of invasion of the nervous system by this virus, to provide a summary and critical analysis of the early reporting of neurological involvement in COVID-19. An exhaustive search of scientific articles on neurological involvement in COVID-19 was performed in the Web of Science, Scopus, Medline/PubMed, and several other databases. Nineteen relevant articles that had been published or were in preprint were carefully selected according to the inclusion and exclusion criteria. Based on our research, we found that patients with COVID-19 can present with neurological symptoms that can be broadly divided into central nervous system involvement, such as headache, dizziness, altered mental state, and disorientation, and peripheral nervous system involvement, such as anosmia and hypogeusia. Most of these patients are in the older age group and exhibit comorbidities, especially hypertension, and severe infection. In extreme presentations of COVID-19, some patients exhibit seizures, stroke, flaccid paraparesis, corticospinal weakness, and even coma. Moreover, the neurological man-ifestations can occur independently of the respiratory system. In conclusion, SARS-CoV-2 infection can cause multiple neurological syndromes in a more complex presentation. Therefore, this review elucidated the involvement of the nervous system in SARS-CoV-2 infection and will hopefully help improve the management of COVID-19.


In Vivo Cellular Imaging for Translational Medical Research.
Personalized treatment using stem, modified or genetically engineered, cells is becoming a reality in the field of medicine, in which allogenic or autologous cells can be used for treatment and possibly for early diagnosis of diseases. Hematopoietic, stromal and organ specific stem cells are under evaluation for cell-based therapies for cardiac, neurological, autoimmune and other disorders. Cytotoxic or genetically altered T-cells are under clinical trial for the treatment of hematopoietic or other malignant diseases. Before using stem cells in clinical trials, translational research in experimental animal models are essential, with a critical emphasis on developing noninvasive methods for tracking the temporal and spatial homing of these cells to target tissues. Moreover, it is necessary to determine the transplanted cell's engraftment efficiency and functional capability. Various in vivo imaging modalities are in use to track the movement and incorporation of administered cells. Tagging cells with reporter genes, fluorescent dyes or different contrast agents transforms them into cellular probes or imaging agents. Recent reports have shown that magnetically labeled cells can be used as cellular magnetic resonance imaging (MRI) probes, demonstrating the cell trafficking to target tissues. In this review, we will discuss the methods to transform cells into probes for in vivo imaging, along with their advantages and disadvantages as well as the future clinical applicability of cellular imaging method and corresponding imaging modality.


Access to substance use treatment among young adults who use prescription opioids non-medically.
Non-medical prescription opioid (NMPO) use is a substantial public health problem in the United States, with 1.5 million new initiates annually. Only 746,000 people received treatment for NMPO use in 2013, demonstrating substantial disparities in access to treatment. This study aimed to assess correlates of accessing substance use treatment among young adult NMPO users in Rhode Island, a state heavily impacted by NMPO use and opioid overdose. This analysis uses data from a study of 200 Rhode Island residents aged 18 to 29 who reported NMPO use in the past 30 days. We compared individuals who had ever successfully enrolled in a substance use treatment program without ever facing barriers, individuals who had ever attempted to enroll but were unable, and individuals who never attempted to enroll. We used multinomial logistic regression to determine the independent correlates of never attempting and unsuccessfully attempting to access substance use treatment. Among 200 participants, the mean age was 24.5, 65.5% were male, and 61.5% were white. Nearly half (45.5%) had never attempted to enroll in substance use treatment, while 35.0% had successfully enrolled without ever facing barriers and 19.5% were unsuccessful in at least one attempt to enroll. In multivariable models, non-white participants were more likely to never have attempted to enroll compared to white participants. Previous incarceration, experiencing drug-related discrimination by the medical community, and a monthly income of $501 - $1500 were associated with a decreased likelihood of never attempting to enroll. A history of overdose and a monthly income of $501 - $1500 were associated with an increased likelihood of unsuccessfully accessing treatment. The most commonly reported barriers to accessing treatment were waiting lists (n = 23), health insurance not approving enrollment (n = 20), and inability to pay (n = 16). This study demonstrates significant disparities in access to treatment among young adults who report NMPO use. A history of overdose was shown to correlate with experiencing barriers to substance use treatment utilization. Interventions are needed to reduce drug-related discrimination in clinical settings and to provide mechanisms that link young adults (particularly with a history of overdose) to evidence-based treatment.


Association of symptoms of attention-deficit/hyperactivity disorder with physical activity, media time, and food intake in children and adolescents.
The aim of the study was to assess the association between attention deficit/hyperactivity disorder (ADHD) symptoms and potentially obesogenic behaviors. Data of 11,676 German children and adolescents (6-17 years) were analyzed. Television/video exposure, physical activity, food frequency and portion size were assessed using questionnaires. A dietary quality index, energy density and volumes of consumed food, and total energy intake were calculated. The parent-rated hyperactivity/inattention subscale of the Strengths and Difficulties Questionnaire (SDQ-HI) was used as a continuous measure of ADHD symptoms. Associations were analyzed with general linear models adjusting for sex, age, socioeconomic status, migrant status, parental BMI, and parental smoking. SDQ-HI scores correlated positively with physical activity, average energy density of food, volume of beverages, total energy intake, and television exposure and negatively with the nutritional quality score (HuSKY) even after adjustment for parental variables (BMI, smoking, socioeconomic status, migrant status), age, sex, as well as the other SDQ subscales. The adjusted association of the SDQ-HI scores with the nutritional quality score was stronger in girls and the associations with food volume, food energy, and total energy intake was significant only in girls. Poor nutritional quality, high energy intake and television exposure appear to be independently associated with ADHD symptoms. The relationship between food energy intake and ADHD symptoms was especially pronounced in girls and this may help to explain the reported association of ADHD symptoms with overweight in adolescent girls.


Understanding, testimony and interpretation in psychiatric diagnosis.
Psychiatric diagnosis depends, centrally, on the transmission of patients' knowledge of their experiences and symptoms to clinicians by testimony. In the case of non-native speakers, the need for linguistic interpretation raises significant practical problems. But determining the best practical approach depends on determining the best underlying model of both testimony and knowledge itself. Internalist models of knowledge have been influential since Descartes. But they cannot account for testimony. Since knowledge by testimony is possible, and forms the basis of psychiatric diagnosis, its very existence is a factor in support of an externalist model of knowledge in general. Internalist and externalist models of knowledge also suggest different ways of responding to the practical challenges of basing psychiatric diagnosis on testimony. Thus the argument in favour of externalism also supports a potentially empirically testable hypothesis about interpretation of non-native speakers for accurate psychiatric diagnosis: interpretation of non-English speakers should be as transparent and unhindered by specialised medical knowledge as possible.


Effect of sugars on artemisinin production in Artemisia annua L.: transcription and metabolite measurements.
The biosynthesis of the valuable sesquiterpene anti-malarial, artemisinin, is known to respond to exogenous sugar concentrations. Here young Artemisia annua L. seedlings (strain YU) were used to measure the transcripts of six key genes in artemisinin biosynthesis in response to growth on sucrose, glucose, or fructose. The measured genes are: from the cytosolic arm of terpene biosynthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), farnesyl disphosphate (FPS); from the plastid arm of terpene biosynthesis, 1-deoxyxylulose-5-phosphate synthase (DXS), 1-deoxyxylulouse 5-phosphate reductoisomerase (DXR); from the dedicated artemisinin pathway amorpha-4,11-diene synthase (ADS), and the P450, CYP71AV1 (CYP). Changes in intracellular concentrations of artemisinin (AN) and its precursors, dihydroartemisinic acid (DHAA), artemisinic acid (AA), and arteannuin B (AB) were also measured in response to these three sugars. FPS, DXS, DXR, ADS and CYP transcript levels increased after growth in glucose, but not fructose. However, the kinetics of these transcripts over 14 days was very different. AN levels were significantly increased in glucose-fed seedlings, while levels in fructose-fed seedlings were inhibited; in both conditions this response was only observed for 2 days after which AN was undetectable until day 14. In contrast to AN, on day 1 AB levels doubled in seedlings grown in fructose compared to those grown in glucose. Results showed that transcript level was often negatively correlated with the observed metabolite concentrations. When seedlings were gown in increasing levels of AN, some evidence of a feedback mechanism emerged, but mainly in the inhibition of AA production. Together these results show the complex interplay of exogenous sugars on the biosynthesis of artemisinin in young A. annua seedlings.


On-road driving impairments and associated cognitive deficits after stroke.
Little is known about the critical on-road driving skills that get affected after a stroke. The purpose of this study was to investigate the key on-road driving impairments and their associated cognitive deficits after a stroke. A second aim was to investigate if lateralization of stroke impacts results of the cognitive and on-road driving tests. In this cross-sectional study, 99 participants with a first-ever stroke who were actively driving prior to stroke underwent a cognitive battery and a standardized road test that evaluated 13 specific on-road driving skills. These on-road driving skills were mapped onto an existing, theoretical framework that categorized the on-road items into hierarchic clusters of operational, tactical, visuo-integrative, and mixed driving skills. The total score on the road test and the on-road decision, made by a certified fitness-to-drive expert, decided the main outcome. The critical on-road driving skills predicting the on-road decision were identified using logistic regression analysis. Linear regression analysis was employed to determine the cognitive impairments leading to poor total on-road scores. Analyses were repeated for right- and left-sided strokes. In all, 37 persons scored poorly on the road test. These participants performed worse in all hierarchic clusters of on-road driving. Performances on the operational cluster and the visuo-integrative cluster best predicted on-road decisions (R(2) = 0.60). 'Lane changing' and 'understanding, insight, and quality of traffic participation' were the critical skill deficits leading to poor performance on the road test (R(2) = 0.65). Divided attention was the main determinant of on-road scores in the total group (R(2) = 0.06). Participants with right-sided stroke performed worse on visual field, visual neglect, visual scanning, visuo-constructive skills, and divided attention compared with those with left-sided stroke. Divided attention was the main determinant of total on-road scores in the right-sided stroke group (R(2) = 0.10). A combination of visual scanning, speed of processing, and executive dysfunction yielded the best model to predict on-road scores in left-sided strokes (R(2) = 0.46). Poor performance in the road test after stroke is determined by critical operational and visuo-integrative driving impairments. Specific and different driving evaluation and training programs are needed for right- and left-sided strokes.


Radiological Image Traits Predictive of Cancer Status in Pulmonary Nodules.
Purpose: We propose a systematic methodology to quantify incidentally identified pulmonary nodules based on observed radiological traits (semantics) quantified on a point scale and a machine-learning method using these data to predict cancer status.Experimental Design: We investigated 172 patients who had low-dose CT images, with 102 and 70 patients grouped into training and validation cohorts, respectively. On the images, 24 radiological traits were systematically scored and a linear classifier was built to relate the traits to malignant status. The model was formed both with and without size descriptors to remove bias due to nodule size. The multivariate pairs formed on the training set were tested on an independent validation data set to evaluate their performance.Results: The best 4-feature set that included a size measurement (set 1), was short axis, contour, concavity, and texture, which had an area under the receiver operator characteristic curve (AUROC) of 0.88 (accuracy = 81%, sensitivity = 76.2%, specificity = 91.7%). If size measures were excluded, the four best features (set 2) were location, fissure attachment, lobulation, and spiculation, which had an AUROC of 0.83 (accuracy = 73.2%, sensitivity = 73.8%, specificity = 81.7%) in predicting malignancy in primary nodules. The validation test AUROC was 0.8 (accuracy = 74.3%, sensitivity = 66.7%, specificity = 75.6%) and 0.74 (accuracy = 71.4%, sensitivity = 61.9%, specificity = 75.5%) for sets 1 and 2, respectively.Conclusions: Radiological image traits are useful in predicting malignancy in lung nodules. These semantic traits can be used in combination with size-based measures to enhance prediction accuracy and reduce false-positives. Clin Cancer Res; 23(6); 1442-9. ©2016 AACR.


Sensitivity enhancement by population transfer in Gd(III) spin labels.
In order to enhance echo signals observed with selective pulses, equilibrium populations of the energy levels of S = 7/2 Gd(III) spin labels are rearranged with frequency-swept passage pulses. To transfer population from as many energy levels as possible, the 2 μs long passage pulses range over more than 1 GHz. Application of this technique at Q-band frequencies to three different Gd(III) complexes and spin dynamics simulations reveal large signal enhancements beyond 100% for Gd(III) complexes with zero-field splitting parameters below 1 GHz. For complexes with larger splittings, experimental enhancements are on the order of 90%. Moreover, population transfer is combined with distance measurements on a model system with a pair of Gd(III) ions. As a result, a signal enhancement of 85% is achieved without inducing changes in the obtained distance information. Besides this enhancement by population transfer, a dipolar modulation depth of 9% is demonstrated, which results in a total enhancement of 3.3 with respect to data obtained with monochromatic rectangular pulses. The limitations of the population transfer technique are discussed. In particular, the extraordinary broad pulse bandwidths caused heating effects and pulse distortions, which constrain the pulse length and thus the achievable signal enhancement.


Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice.
The realization that the microbiota-gut-brain axis plays a critical role in health and disease, including neuropsychiatric disorders, is rapidly advancing. Nurturing a beneficial gut microbiome with prebiotics, such as fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS), is an appealing but underinvestigated microbiota manipulation. Here we tested whether chronic prebiotic treatment modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior. C57BL/6J male mice were administered FOS, GOS, or a combination of FOS+GOS for 3 weeks prior to testing. Plasma corticosterone, microbiota composition, and cecal short-chain fatty acids were measured. In addition, FOS+GOS- or water-treated mice were also exposed to chronic psychosocial stress, and behavior, immune, and microbiota parameters were assessed. Chronic prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic effects. Moreover, the administration of GOS and the FOS+GOS combination reduced stress-induced corticosterone release. Prebiotics modified specific gene expression in the hippocampus and hypothalamus. Regarding short-chain fatty acid concentrations, prebiotic administration increased cecal acetate and propionate and reduced isobutyrate concentrations, changes that correlated significantly with the positive effects seen on behavior. Moreover, FOS+GOS reduced chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels and depression-like and anxiety-like behavior in addition to normalizing the effects of stress on the microbiota. Taken together, these data strongly suggest a beneficial role of prebiotic treatment for stress-related behaviors. These findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology.


The isolation of ecdysterone inducible genes by hybridization subtraction chromatography.
We have developed a procedure for selectively enriching a mRNA population for inducible sequences. Other than the induced mRNA species, the population of mRNA in control cells is approximately the same as the mRNA population in induced cells. Cytoplasmic mRNA from control cells is bound to oligo (dT)-cellulose and used as a template for reverse transcriptase, the oligo (dT) serving as a primer. After removing the template mRNAs, the cDNA-cellulose column is used to hybridize a population of mRNAs from induced cells. The non-hybridized poly A+ RNAs are greatly enriched in the inducible sequences. We have used this technique of hybridization subtraction chromatography to select a mRNA population enriched for the mRNAs inducible by ecdysterone in Schneider's Line 2 Drosophila cells. This population of RNAs was used to screen a recombinant library. Preliminary results indicate that approximately 10% of the RNA in the probe population represents ecdysterone inducible sequences. Methods are described for optimizing the cDNA synthesis reaction (we obtain greater than or equal to 30% efficiency) and hybridizing RNA to the cDNA-cellulose resin. This method can be used to select induced mRNAs regardless of the way in which the induction is brought about.


A single-cell molecular map of mouse gastrulation and early organogenesis.
Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1-/- chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.


Association genetics of the loblolly pine (Pinus taeda, Pinaceae) metabolome.
The metabolome of a plant comprises all small molecule metabolites, which are produced during cellular processes. The genetic basis for metabolites in nonmodel plants is unknown, despite frequently observed correlations between metabolite concentrations and stress responses. A quantitative genetic analysis of metabolites in a nonmodel plant species is thus warranted. Here, we use standard association genetic methods to correlate 3563 single nucleotide polymorphisms (SNPs) to concentrations of 292 metabolites measured in a single loblolly pine (Pinus taeda) association population. A total of 28 single locus associations were detected, representing 24 and 20 unique SNPs and metabolites, respectively. Multilocus Bayesian mixed linear models identified 2998 additional associations for a total of 1617 unique SNPs associated to 255 metabolites. These SNPs explained sizeable fractions of metabolite heritabilities when considered jointly (56.6% on average) and had lower minor allele frequencies and magnitudes of population structure as compared with random SNPs. Modest sets of SNPs (n = 1-23) explained sizeable portions of genetic effects for many metabolites, thus highlighting the importance of multi-SNP models to association mapping, and exhibited patterns of polymorphism consistent with being linked to targets of natural selection. The implications for association mapping in forest trees are discussed.


Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor.
Erythropoietin (EPO) is the principal growth factor regulating the production of circulating erythrocytes. We introduced null mutations into both Epo and the EPO receptor (EpoR) gene. Both heterozygotes appeared normal. Homozygous animals exhibited reduced primitive erythropoiesis and died around embryonic day 13, owing to failure of definitive fetal liver erythropoiesis. Both types of mutations exhibited identical phenotypes, indicating that EPO and the EPOR are crucial for definitive erythropoiesis in vivo and that no other ligands or receptors can replace them. Committed erythroid BFU-E and CFU-E progenitors were present in both homozygous fetal livers. Thus, neither EPO nor the EPOR is required for erythroid lineage commitment or for the proliferation and differentiation of BFU-E to CFU-E progenitors. EPO and the EPOR are crucial in vivo for the proliferation and survival of CFU-E progenitors and their irreversible terminal differentiation.


An axon scaffold induced by retinal axons directs glia to destinations in the Drosophila optic lobe.
In the developing Drosophila visual system, glia migrate into stereotyped positions within the photoreceptor axon target fields and provide positional information for photoreceptor axon guidance. Glial migration conversely depends on photoreceptor axons, as glia precursors stall in their progenitor zones when retinal innervation is eliminated. Our results support the view that this requirement for retinal innervation reflects a role of photoreceptor axons in the establishment of an axonal scaffold that guides glial cell migration. Optic lobe cortical axons extend from dorsal and ventral positions towards incoming photoreceptor axons and establish at least four separate pathways that direct glia to proper destinations in the optic lobe neuropiles. Photoreceptor axons induce the outgrowth of these scaffold axons. Most glia do not migrate when the scaffold axons are missing. Moreover, glia follow the aberrant pathways of scaffold axons that project aberrantly, as occurs in the mutant dachsous. The local absence of glia is accompanied by extensive apoptosis of optic lobe cortical neurons. These observations reveal a mechanism for coordinating photoreceptor axon arrival in the brain with the distribution of glia to multiple target destinations, where they are required for axon guidance and neuronal survival.


Monoclonal antibody to intercellular adhesion molecule 1 protects skin flaps against ischemia-reperfusion injury: an experimental study in rats.
The purpose of this study was to evaluate the blockage of polymorphonuclear neutrophil endothelial adhesion by using a monoclonal antibody to the intercellular adhesion molecule 1 (ICAM-1) ligand to prevent ischemia-reperfusion injury in rat skin flaps. A skin and subcutaneous tissue flap (3.0 cm x 4.5 cm) supplied by the superficial epigastric artery and vein including the femoral vessels was isolated unilaterally in 45 male Sprague-Dawley rats and clamped for 9 hours (groups II and III) or 12 hours (groups IV and V) of ischemia. Five animals in group I were sham-operated only with 5 minutes of ischemia. Animals in groups II (n = 10) and IV (n = 10) received 0.05 mg of monoclonal antibody to ICAM-1 (0.20 mg/kg) in 0.5 ml of 0.9% normal saline intravenously 15 minutes before reperfusion; those in groups III (n = 10) and V (n = 10) received 0.5 ml of normal saline. The flaps were assessed histologically, by measuring viable and nonviable areas, and by diffuse reflectance spectroscopy to determine the ratio of oxyhemoglobin to deoxyhemoglobin. Flap measurements revealed that the average area of flap survival was 90.6 +/- 12.8 percent in group II and 18.3 +/- 19.6 percent in the control group (III) (p < 0.002). In the animals subjected to 12 hours of ischemia, those treated with monoclonal antibody to ICAM-1 (group IV) were 57.1 +/- 23.1 percent viable, which was significantly greater than the control animals (group V), in which only 0.3 +/- 1.0 percent of the flap was viable. Analysis of the diffuse reflectance spectra showed a hyperemic response during the first 10 minutes after reperfusion in animals treated with monoclonal antibody to ICAM-1. In group III, however, the spectra demonstrated a decreased amount of oxyhemoglobin, indicating decreased reperfusion of the flap after ischemia when compared with group II. Histopathologically, few inflammatory changes could be observed in groups I, II, and the viable areas of group IV. Marked damage was observed in groups III and V. We concluded that treating ischemic skin flaps with monoclonal antibody to ICAM-1 was effective for alleviating reperfusion injury after 9 or 12 hours of warm ischemia. The reactive hyperemic response determined by diffuse reflectance spectroscopy in groups II and IV correlated with areas of flap survival. Antibodies to particular adhesion molecules, such as ICAM-1, have potential clinical utility in that they could be administered, individually or together, to patients immediately before reestablishing perfusion after free-tissue transfer or replantation to block the adverse effects attributed to reperfusion injury.


Characterization of Fusarium oxysporum Isolates Obtained from Cucumber in China by Pathogenicity, VCG, and RAPD.
Thirty-four isolates of Fusarium oxysporum, obtained in China from cucumber plants showing either Fusarium wilt (F. oxysporum f. sp. cucumerinum) or root and stem rot (F. oxysporum f. sp. radicis-cucumerinum) symptoms, were characterized by pathogenicity, vegetative compatibility, and random amplified polymorphic DNA (RAPD). Of these, 23 isolates were identified by pathogenicity as F. oxysporum f. sp. cucumerinum, and one as F. oxysporum f. sp. radicis-cucumerinum, while 10 isolates were avirulent on cucumber, melon, sponge gourd, and pumpkin. The Chinese isolates of F. oxysporum f. sp. cucumerinum were assigned to RAPD groups III and XXI and to vegetative compatibility group (VCG) 0183, four new VCGs, 0184 to 0187, and a single-member VCG included in the artificial VCG 018-. The Chinese isolate of F. oxysporum f. sp. radicis-cucumerinum was assigned to RAPD group I and bridging VCG 0260/0261. The occurrence of F. oxysporum f. sp. radicis-cucumerinum on cucumber is reported for the first time in China.


Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial.
Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions. To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up. Adult psychiatric services, treating people with schizophrenia. Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity. Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study. The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich's Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale. No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference -1.3, 95% confidence interval -2.5 to -0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation. The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies. Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge. European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2009-009235-30 and Current Controlled Trials ISRCTN42305247. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 29. See the NIHR Journals Library website for further project information.


Pain after spinal cord injury: an evidence-based review for clinical practice and research. Report of the National Institute on Disability and Rehabilitation Research Spinal Cord Injury Measures meeting.
To examine the reliability, validity, sensitivity, and practicality of various outcome measures for pain after spinal cord injury (SCI), and to provide recommendations for specific measures for use in clinical trials. Relevant articles were obtained through a search of MEDLINE, EMBASE, CINAHL, and PubMed databases from inception through 2006. The authors performed literature searches to find articles containing data relevant to the reliability and validity of each pain outcome measure in SCI and selected non-SCI populations. After reviewing the articles, an investigator extracted information utilizing a standard template. A second investigator reviewed the chosen articles and the extracted pertinent information to confirm the findings of the first investigator. Taking into consideration both the quantity and quality of the studies analyzed, judgments on reliability and validity of the measures were made by the two investigators. Based upon these judgments, recommendations were formulated for use of specific measures in future clinical trials. In addition, for a subset of measures a voting process by a larger group of SCI experts allowed formulation of recommendations including determining which measures should be incorporated into a minimal dataset of measures for clinical trials and which ones need revision and further validity and reliability testing before use. A 0-10 Point Numerical Rating Scale (NRS) is recommended as the outcome measure for pain intensity after SCI, while the 7-Point Guy/Farrar Patient Global Impression of Change (PGIC) scale is recommended as the outcome measure for global improvement in pain. The SF-36 single pain interference question and the Multidimensional Pain Inventory (MPI) or Brief Pain Inventory (BPI) pain interference items are recommended as the outcome measures for pain interference after SCI. Brush or cotton wool and at least one high-threshold von Frey filament are recommended to test mechanical allodynia/hyperalgesia while a Peltier-type thermotester is recommended to test thermal allodynia/hyperalgesia. The International Association for the Study of Pain (IASP) or Bryce-Ragnarsson pain taxonomies are recommended for classification of pain after SCI, while the Neuropathic Pain Scale (NPS) is recommended for measuring change in neuropathic pain and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) for quantitating neuropathic and nociceptive pain discrimination.


Genotype is a stronger determinant than sex of the mouse gut microbiota.
The mammalian gut microbiota is considered to be determined mostly by diet, while the effect of genotype is still controversial. Here, we examined the effect of genotype on the gut microbiota in normal populations, exhibiting only natural polymorphisms, and evaluated this effect in comparison to the effect of sex. DNA fingerprinting approaches were used to profile the gut microbiota of eight different recombinant inbred mouse lines of the collaborative cross consortium, whose level of genetic diversity mimics that of a natural human population. Analyses based on automated ribosomal internal transcribed spacer analysis demonstrated significant higher similarity of the gut microbiota composition within mouse lines than between them or within same-gender groups. Thus, genetic background significantly impacts the microbiota composition and is a stronger determinant than gender. These findings imply that genetic polymorphisms help shape the intestinal microbiota of mammals and consequently could affect host susceptibility to diseases.


Human and murine anti-DNA antibodies induce the production of anti-idiotypic antibodies with autoantigen-binding properties (epibodies) through immune-network interactions.
To examine the potential role of immune-network interactions in the production of lupus autoantibodies, normal NZW rabbit antibody responses were analyzed after immunization with one of the following Ig preparations: human lupus serum anti-dsDNA antibodies, human lupus serum anti-ssDNA antibodies, a mixture of human lupus serum anti-dsDNA and anti-ssDNA antibodies, the MRL-lpr/lpr anti-dsDNA mAb H241, and the MRL-lpr/lpr anti-ssDNA mAb H130. Four of five rabbits produced Ig typical of lupus autoantibodies: individual rabbit Ig cross-reacted with multiple autoantigens including nucleic acids, cardiolipin, SmRNP, glomerular extract, laminin, and exogenous Ag. Rabbit anti-Id against human anti-dsDNA antibodies were highly specific for dsDNA. Notably, in each serum the autoantibody activity was confined to the anti-Id Ig fraction. A similar spontaneously occurring Id-anti-Id interaction was also found between anti-ssDNA and anti-dsDNA antibodies isolated from an individual lupus patient. These results indicate that lupus autoantibodies which share Ag binding properties with pathogenic Ig, including both cross-reactive and anti-dsDNA antibodies, can induce the production of Ig with similar autoantigen binding properties through immune-network interactions. This phenomenon, if unregulated, could lead to the amplification of pathogenic autoantibody production in individuals with systemic lupus.


Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study.
Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy. Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = -0.48, p<0.0001) and eGFR (rho = -0.33, p = 0.005). These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets.


The stories bones tell. Collaboration between forensic teams and victims' relatives in the interpretation and ritual accompaniment of human remains in Guatemala.
This article focuses on the collaborative practices between forensic experts and victims' relatives through the exhumation process in Guatemala. In a context where there is still no real recognition of the victims by the state, and no national common narrative about the violence of the armed conflict, exhumations have been developed in the framework of transitional justice, as a tool for victim recognition as well as historical clarification. In a post-political violence context, the exhumation process produces knowledge and narratives about the past, through the scientific analysis of human remains as material evidence, the collection of testimony, and shared stories. Based on extensive ethnographic work conducted with civil society actors involved in exhumations, this article focuses on the dynamics of production and coexistence of scientific and subjective forms of interpretation of the remains, as well as scientific and ceremonial practices of treatment of the remains. We will question how different regimes of truth coexist around the interpretation of the bones, and how forensics scientists and victims' relatives collaborate to produce them.


Prognostic Implications of Tumor-Infiltrating Lymphocytes in Association With Programmed Death Ligand 1 Expression in Early-Stage Breast Cancer.
The immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes. We investigated the relationship between TIL profiles for CD8+ and forkhead box P3-positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS). The median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P < .001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P < .001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P < .001), and PD-L1 expression was more frequent in HR-positive BC (P < .001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations. Higher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC.


Impact of transforming mental health services for young people in England on patient access, resource use and health: a quasi-experimental study.
To evaluate the impact of child and adolescent mental health services (CAMHS) transformation in South East England on patient access, resource utilisation and health outcomes. In an observational study, we use difference-in-differences analysis with propensity score matching to analyse routinely collected patient level data. Three CAMHS services in South East England. All patients attending CAMHS between April 2012 and December 2018, with more than 57 000 spells of care included. The rate and volume of people accessing CAMHS; waiting times to the first contact and waiting times between the first and second contact; and health outcomes, including the Strengths and Difficulties Questionnaire (SDQ) and the Revised Child Anxiety and Depression Scale (RCADS). The intervention led to 20% (incidence rate ratio: 1.20; 95% CI: 1.15 to 1.24) more new patients starting per month. There was mixed evidence on waiting times for the first contact. The intervention led to 10% (incidence rate ratio: 1.10; 95% CI: 1.02 to 1.18) higher waiting time for the second contact. The number of contacts per spell (OR: 1.08; 95% CI: 0.94 to 1.25) and the rereferral rate (OR: 1.06; 95% CI: 0.96 to 1.17) were not significantly different. During the post intervention period, patients in the intervention group scored on average 3.3 (95% CI: -5.0 to -1.6) points lower on the RCADS and 1.0 (95% CI: -1.8 to -0.3) points lower on the SDQ compared with the control group after adjusting for the baseline score. Overall, there are signs that transformation can help CAMHS achieve the objectives of greater access and improved health outcomes, but trade-offs exist among different performance metrics, particularly between access and waiting times. Commissioners and providers should be conscious of any trade-offs when undertaking service redesign and transformation.


Election Forensics: Quantitative methods for electoral fraud detection.
The last decade has witnessed an explosion on the computational power and a parallel increase of the access to large sets of data - the so called Big Data paradigm - which is enabling to develop brand new quantitative strategies underpinning description, understanding and control of complex scenarios. One interesting area of application concerns fraud detection from online data, and more particularly extracting meaningful information from massive digital fingerprints of electoral activity to detect, a posteriori, evidence of fraudulent behavior. In this short article we discuss a few quantitative methodologies that have emerged in recent years on this respect, which altogether form the nascent interdisciplinary field of election forensics. Aiming to foster discussion and raise awareness on this interdisciplinary area, we hereby enumerate a few of the most relevant approaches and methods.


Small room for compromise between oil palm cultivation and primate conservation in Africa.
Despite growing awareness about its detrimental effects on tropical biodiversity, land conversion to oil palm continues to increase rapidly as a consequence of global demand, profitability, and the income opportunity it offers to producing countries. Although most industrial oil palm plantations are located in Southeast Asia, it is argued that much of their future expansion will occur in Africa. We assessed how this could affect the continent's primates by combining information on oil palm suitability and current land use with primate distribution, diversity, and vulnerability. We also quantified the potential impact of large-scale oil palm cultivation on primates in terms of range loss under different expansion scenarios taking into account future demand, oil palm suitability, human accessibility, carbon stock, and primate vulnerability. We found a high overlap between areas of high oil palm suitability and areas of high conservation priority for primates. Overall, we found only a few small areas where oil palm could be cultivated in Africa with a low impact on primates (3.3 Mha, including all areas suitable for oil palm). These results warn that, consistent with the dramatic effects of palm oil cultivation on biodiversity in Southeast Asia, reconciling a large-scale development of oil palm in Africa with primate conservation will be a great challenge.


Patient-Provider Communication and Health Outcomes Among Individuals With Atherosclerotic Cardiovascular Disease in the United States: Medical Expenditure Panel Survey 2010 to 2013.
Consumer-reported patient-provider communication (PPC) assessed by Consumer Assessment of Health Plans Survey in ambulatory settings is incorporated as a complementary value metric for patient-centered care of chronic conditions in pay-for-performance programs. In this study, we examine the relationship of PPC with select indicators of patient-centered care in a nationally representative US adult population with established atherosclerotic cardiovascular disease. The study population consisted of a nationally representative sample of 6810 individuals (aged ≥18 years), representing 18.3 million adults with established atherosclerotic cardiovascular disease (self-reported or International Classification of Diseases, Ninth Edition diagnosis) reporting a usual source of care in the 2010 to 2013 pooled Medical Expenditure Panel Survey cohort. Participants responded to questions from Consumer Assessment of Health Plans Survey that assessed PPC, and we developed a weighted PPC composite score using their responses, categorized as 1 (poor), 2 (average), and 3 (optimal). Outcomes of interest were (1) patient-reported outcomes: 12-item Short Form physical/mental health status, (2) quality of care measures: statin and ASA use, (3) healthcare resource utilization: emergency room visits and hospital stays, and (4) total annual and out-of-pocket healthcare expenditures. Atherosclerotic cardiovascular disease patients reporting poor versus optimal were over 2-fold more likely to report poor outcomes; 52% and 26% more likely to report that they are not on statin and aspirin, respectively, had a significantly greater utilization of health resources (odds ratio≥2 emergency room visit, 1.41 [95% confidence interval, 1.09-1.81]; odds ratio≥2 hospitalization, 1.36 [95% confidence interval, 1.04-1.79]), as well as an estimated $1243 ($127-$2359) higher annual healthcare expenditure. This study reveals a strong relationship between PPC and patient-reported outcomes, utilization of evidence-based therapies, healthcare resource utilization, and expenditures among those with established atherosclerotic cardiovascular disease.


Force distribution on multiple bonds controls the kinetics of adhesion in stretched cells.
We show herein how mechanical forces at macro or micro scales may affect the biological response at the nanoscale. The reason resides in the intimate link between chemistry and mechanics at the molecular level. These interactions occur under dynamic conditions such as the shear stress induced by flowing blood or the intracellular tension. Thus, resisting removal by mechanical forces, e.g., shear stresses, is a general property of cells provided by cellular adhesion. Using classical models issued from theoretical physics, we review the force regulation phenomena of the single bond. However, to understand the force regulation of cellular adhesion sites, we need to consider the collective behavior of receptor-ligand bonds. We discuss the applicability of single bond theories to describe collective bond behavior. Depending on bond configuration, e.g., presently "parallel" and "zipper", the number of bonds and dissociation forces variably affect the kinetics of multiple bonds. We reveal a marked efficiency of the collective organization to stabilize multiple bonds by sharply increasing bond lifetime compared to single bond. These theoretical predictions are then compared to experimental results of the literature concerning the kinetic parameters of bonds measured by atomic force microscopy and by shear flow. These comparisons reveal that the force-control of bonds strongly depends on whether the force distribution on multiple bonds is homogeneous, e.g., in AFM experiments, or heterogeneous, e.g., in shear flow experiments. This reinforces the need of calculating the stress/strain fields exerted on living tissues or cells at various scales and certainly down to the molecular scale.


T-Cell recovery in adults and children following umbilical cord blood transplantation.
T-cell reconstitution following allogeneic stem cell transplantation may involve thymic education of donor-derived precursors or peripheral expansion of mature T cells transferred in the graft. T cell-receptor excision circles (sjTRECs) are generated within the thymus and identify new thymic emigrants and those that have not divided. We measured quantitative and qualitative immunologic reconstitution and sjTREC levels in adult and pediatric recipients of umbilical cord blood transplants (UCBTs). sjTRECs were detected at normal levels in all children, starting 12 months after transplantation. sjTRECs were not detected until 18 months after transplantation in adults, and then only at a 3-fold lower level than expected for age. We used complementarity-determining region 3 (CDR3) spectratyping to measure changes in T cell-receptor diversity occurring with restoration of thymic function. T-cell repertoires were skewed in adults and children at 12 to 18 months after transplantation but recovered to near-normal diversity at 2 to 3 years post-UCBT. T-cell repertoires appeared more diverse earlier in children (at 1 to 2 years post-UCBT) than in adults (at 3 to 4 years post-UCBT). We conclude that early T-cell recovery after UCBT occurs primarily through peripheral expansion of adoptively transferred donor T cells and results in skewing of the T-cell repertoire. The reappearance of sjTREC-containing cells after UCBT is associated with increasing numbers of phenotypicaly naive T cells, improved mitogen and recall antigen responses, and diversification of the T-cell repertoire. The delay in central T-cell recovery in adults relative to children may be due to differences in thymic function resulting from age-related atrophy, graft-versus-host disease, or the pharmacologic effects of prophylaxis and treatment of graft-versus-host disease.


Gram-negative bacteria-binding protein, a pattern recognition receptor for lipopolysaccharide and beta-1,3-glucan that mediates the signaling for the induction of innate immune genes in Drosophila melanogaster cells.
Pattern recognition receptors, non-clonal immune proteins recognizing common microbial components, are critical for non-self recognition and the subsequent induction of Rel/NF-kappaB-controlled innate immune genes. However, the molecular identities of such receptors are still obscure. Here, we present data showing that Drosophila possesses at least three cDNAs encoding members of the Gram-negative bacteria-binding protein (DGNBP) family, one of which, DGNBP-1, has been characterized. Western blot, flow cytometric, and confocal laser microscopic analyses demonstrate that DGNBP-1 exists in both a soluble and a glycosylphosphatidylinositol-anchored membrane form in culture medium supernatant and on Drosophila immunocompetent cells, respectively. DGNBP-1 has a high affinity to microbial immune elicitors such as lipopolysaccharide (LPS) and beta-1,3-glucan whereas no binding affinity is detected with peptidoglycan, beta-1,4-glucan, or chitin. Importantly, the overexpression of DGNBP-1 in Drosophila immunocompetent cells enhances LPS- and beta-1,3-glucan-induced innate immune gene (NF-kappaB-dependent antimicrobial peptide gene) expression, which can be specifically blocked by pretreatment with anti-DGNBP-1 antibody. These results suggest that DGNBP-1 functions as a pattern recognition receptor for LPS from Gram-negative bacteria and beta-1, 3-glucan from fungi and plays an important role in non-self recognition and the subsequent immune signal transmission for the induction of antimicrobial peptide genes in the Drosophila innate immune system.


Predicting tumor location by modeling the deformation of the breast.
Breast cancer is one of the biggest killers in the western world, and early diagnosis is essential for improved prognosis. The shape of the breast varies hugely between the scenarios of magnetic resonance (MR) imaging (patient lies prone, breast hanging down under gravity), X-ray mammography (breast strongly compressed) and ultrasound or biopsy/surgery (patient lies supine), rendering image fusion an extremely difficult task. This paper is concerned with the use of the finite-element method and nonlinear elasticity to build a 3-D, patient-specific, anatomically accurate model of the breast. The model is constructed from MR images and can be deformed to simulate breast shape and predict tumor location during mammography or biopsy/surgery. Two extensions of the standard elasticity problem need to be solved: an inverse elasticity problem (arising from the fact that only a deformed, stressed, state is known initially), and the contact problem of modeling compression. The model is used for craniocaudal mediolateral oblique mammographic image matching, and a number of numerical experiments are performed.


Effect of wet vs. dry testing on the mechanical properties of hydrophilic self-etching primer polymers.
Self-etching primers and adhesives contain very hydrophilic methacrylate monomers that result in high water sorptions by their polymers. Water sorption plasticizes the polymers and lowers their mechanical properties. The purpose of this work was to rank the hydrophilicity of a series of acidic primers by their Hoy's solubility parameters (delta) to determine if there was a significant relationship between the delta of polymers and their mechanical properties. A series of six acidic primer blends containing a fixed concentration of phenyl-P but variable amounts of 2-hydroxyethyl methacrylate (HEMA), 2,2 bi[4-(2-hydroxy-3-methacryloyloxy)propane (BisGMA), and triethylene-glycol dimethacrylate (TEGDMA) was formulated and their Hoy's solubility parameters calculated. The polymers were cast into small 'I' beams and light-cured. The modulus of elasticity (E) and ultimate tensile strength (UTS) were measured in dry polymers and after immersion in water for 24 h. The results showed significant correlations between E and UTS under dry or wet conditions. Both E and UTS fell significantly when the specimens were immersed in water. After water immersion, the E and UTS showed significant correlations with Hoy's delta(p) values. Both E and UTS correlated significantly with the BisGMA concentration of the polymers, either wet or dry. The percentage changes in E or UTS were significantly correlated with the water sorption of the polymers.


Foundation literacy acquisition in European orthographies.
Several previous studies have suggested that basic decoding skills may develop less effectively in English than in some other European orthographies. The origins of this effect in the early (foundation) phase of reading acquisition are investigated through assessments of letter knowledge, familiar word reading, and simple nonword reading in English and 12 other orthographies. The results confirm that children from a majority of European countries become accurate and fluent in foundation level reading before the end of the first school year. There are some exceptions, notably in French, Portuguese, Danish, and, particularly, in English. The effects appear not to be attributable to differences in age of starting or letter knowledge. It is argued that fundamental linguistic differences in syllabic complexity and orthographic depth are responsible. Syllabic complexity selectively affects decoding, whereas orthographic depth affects both word reading and nonword reading. The rate of development in English is more than twice as slow as in the shallow orthographies. It is hypothesized that the deeper orthographies induce the implementation of a dual (logographic + alphabetic) foundation which takes more than twice as long to establish as the single foundation required for the learning of a shallow orthography.


The electron depolarization during dynamic nuclear polarization: measurements and simulations.
Dynamic nuclear polarization is typically explained either using microscopic systems, such as in the solid effect and cross effect mechanisms, or using the macroscopic formalism of spin temperature which assumes that the state of the electrons can be described using temperature coefficients, giving rise to the thermal mixing mechanism. The distinction between these mechanisms is typically made by measuring the DNP spectrum - i.e. the nuclear enhancement profile as a function of irradiation frequency. In particular, we have previously used the solid effect and cross effect mechanisms to explain temperature dependent DNP spectra. Our past analysis has however neglected the effect of depolarization of the electrons resulting from the microwave (MW) irradiation. In this work we concentrate on this electron depolarization process and perform electron-electron double resonance (ELDOR) experiments on TEMPOL and trityl frozen solutions, using a 3.34 Tesla magnet and at 2.7-30 K, in order to measure the state of the electron polarization during DNP. The experiments indicate that a significant part of the EPR line is affected by the irradiation due to spectral diffusion. Using a theoretical framework based on rate equations for the polarizations of the different electron spin packets and for those of the nuclei we simulated the various ELDOR line-shapes and reproduced the MW frequency and irradiation time dependence. The obtained electron polarization distribution cannot be described using temperature coefficients as required by the classical thermal mixing mechanism, and therefore the DNP mechanism cannot be described by thermal mixing. Instead, the theoretical framework presented here for the analysis of the ELDOR data forms a basis for future interpretation of DNP spectra in combination with EPR measurements.


Computed tomography using broadband Bessel THz beams and phase contrast.
We present new results demonstrating the capability of performing computed tomography (CT) using broadband Bessel terahertz (THz) beams. Nondiffractive beams such as these exhibit propagation-invariant lines of focus with an extended depth-of-field compared to conventional Gaussian beams. Using this property, we demonstrate a considerable improvement in the 3D reconstruction image of a synthetic sample through the backprojection algorithm. Only when THz Bessel beams are used, a full reconstruction of the object structure is made. Moreover, we use phase-contrast mechanism which improves the spatial resolution and reconstructed images. Our results highlight the potential in using nondiffractive Bessel beams to significantly improve 3D-image reconstruction of THz CT.


Safeguardsing our military space systems.
The vulnerability military space systems depends on their orbits, functions, and other characteristics. The high-altitude satellites needed for warning and communications in particular could be vulnerable to prompt destruction by certain space-based systems and, in the future, possibly by ground-based high power lasers. A combination of passive countermeasures and arms control agreements could give these satellites some protection against such attack. Deployment of strategic defensive systems with the capability to reach far into space would invalidate this approach.


[Osteosynthesis using a buttress plate--a new principle for stabilizing scaphoid pseudarthroses].
Deformity with palmar bone resorption can be observed in 20-50% of scaphoid pseudarthroses. A palmar wedge-shaped defect develops after repositioning and debridement of the pseudarthrosis. In the present paper 16 cases in which operations with cancellous bone grafting and palmar buttress plate osteosynthesis in addition were performed are presented. In all but 1, the pseudarthrosis united. All patients were pain-free at follow-up examination a minimum of 9 months (mean 28 months) only slightly reduced. Grip strength and mobility were after operation. The persisting pseudarthrosis necessitated wrist arthrodesis because of radiocarpal arthrosis. Metal slackening with erosion and rupture of the flexor pollicis longus tendon occurred in 1 patient. Palmar buttress plating is a biomechanically consistent form of osteosynthesis. It neutralizes all relevant forces. This means that cancellous bone grafts are sufficient, whereas lag screw or tension band osteosyntheses need cortico-cancellous grafts to resist compression forces. Stability and better chances of healing of pure cancellous bone grafts are the main advantages of palmar buttress plating in scaphoid pseudarthroses.


Recent developments in research into the Cyathostominae and Anoplocephala perfoliata.
Intestinal helminths are an important cause of equine disease. Of these parasites, the Cyathostominae are the commonest group that infect horses. These nematodes consist of a complex tribe of 51 species, although individual horses tend to harbour 10 or so common species, in addition to a few rarer species. The Cyathostominae can be extremely pathogenic, and high levels of infection result in clinical symptoms ranging from chronic weight loss to colic, diarrhoea and death. As part of their life cycle, immature cyathostomins penetrate the large intestinal wall, where they can enter a state of inhibited larval development. These larvae can exist in this state for months to years, after which they subsequently re-emerge. If larvae re-emerge in large numbers (i.e. several million), severe pathological consequences ensue. The inhibited larvae are also relatively refractory to several of the currently available anthelmintics, so that horses treated previously with anthelmintics can still carry life-threatening burdens of these parasitic stages. Little is known about the cyathostomin larvae during their mucosal phase, and current research efforts are focused on investigating the biology of these stages. Much of the research described here highlights this area of research and details studies aimed at investigating the host immune responses that the mucosal larvae invoke. As part of this research effort, molecular tools have been developed to facilitate the identification of larval and egg stages of cyathostomins. These molecular tools are now proving very useful in the investigation of the relative contributions that individual, common cyathostomin species make to the pathology and epidemiology of mixed helminth infections. At the more applied level, research is also in progress to develop an immunodiagnostic test that will allow numbers of mucosal larvae to be estimated. This test utilises antigen-specific IgG(T) serum antibody responses as markers of infection. As anthelmintic resistance will be the major constraint on the future control of the Cyathostominae, researchers are now actively investigating this area and studies aimed at elucidating the molecular mechanisms of drug resistance are described. Another parasite which has assumed a clinically important role in horses is the tapeworm, Anoplocephala perfoliata. This parasite is prevalent world-wide and has been shown to be a significant cause of equine colic. Because previous methods of estimating the infection intensity of tapeworm were inaccurate, recent research has been directed at developing an immunodiagnostic ELISA for these cestodes. Specific IgG(T) responses to antigens secreted by adult tapeworms have been shown to provide a reasonable indication of infection intensity. An ELISA based on these responses is now commercially available. The steps involved in the development of this ELISA are described here. In addition to these recent advances in research, this review also outlines the principle areas for future research into these important equine parasites.


Variant ionotropic receptors are expressed in olfactory sensory neurons of coeloconic sensilla on the antenna of the desert locust (Schistocerca gregaria).
The behaviour of the desert locust, Schistocera gregaria, is largely directed by volatile olfactory cues. The relevant odorants are detected by specialized antennal sensory neurons which project their sensory dendrites into hair-like structures, the sensilla. Generally, the responsiveness of the antennal chemosensory cells is determined by specific receptors which may be either odorant receptors (ORs) or variant ionotropic receptors (IRs). Previously, we demonstrated that in locust the co-receptor for ORs (ORco) is only expressed in cells of sensilla basiconica and sensilla trichodea, suggesting that cells in sensilla coeloconica may express different types of chemosensory receptors. In this study, we have identified the genes of S. gregaria which encode homologues of co-receptors for the variant ionotropic receptors, the subtypes IR8a and IR25a. It was found that both subtypes, SgreIR8a and SgreIR25a, are expressed in the antennae of all five nymphal stages and in adults. Attempts to assign the relevant cell types by means of in situ hybridization revealed that SgreIR8a and SgreIR25a are expressed in cells of sensilla coeloconica. Double fluorescence in situ hybridization experiments disclosed that the two IR-subtypes are co-expressed in some cells of this sensillum type. Expression of SgreIR25a was also found in some of the sensilla chaetica, however, neither SgreIR25a nor SgreIR8a was found to be expressed in sensilla basiconica and sensilla trichodea. This observation was substantiated by the results of double FISH experiments demonstrating that cells expressing SgreIR8a or SgreIR25a do not express ORco. These results support the notion that the antenna of the desert locust employs two different populations of OSNs to sense odors; cells which express IRs in sensilla coeloconica and cells which express ORs in sensilla basiconica and sensilla trichodea.


Modeling low impact development potential with hydrological response units.
Evaluations of benefits of implementing low impact development (LID) stormwater management techniques can extend up to a watershed scale. This presents a challenge for representing them in watershed models, since they are typically orders of magnitude smaller in size. This paper presents an approach that is focused on trying to evaluate the benefits of implementing LIDs on a lot level. The methodology uses the concept of urban hydrological response Unit and results in developing and applying performance curves that are a function of lot properties to estimate the potential benefit of large-scale LID implementation. Lot properties are determined using a municipal geographic information system database and processed to determine groups of lots with similar properties. A representative lot from each group is modeled over a typical rainfall year using USEPA Stormwater Management Model to develop performance functions that relate the lot properties and the change in annual runoff volume and corresponding phosphorus loading with different LIDs implemented. The results of applying performance functions on all urban areas provide the potential locations, benefit and cost of implementation of all LID techniques, guiding future decisions for LID implementation by watershed area municipalities.


Peripheral doses in patients undergoing Cyberknife treatment for intracranial lesions. A single centre experience.
Stereotactic radiosurgery/radiotherapy procedures are known to deliver a very high dose per fraction, and thus, the corresponding peripheral dose could be a limiting factor for the long term surviving patients. The aim of this clinical study was to measure the peripheral dose delivered to patients undergoing intracranial Cyberknife treatment, using the MOSFET dosimeters. The influence of the supplemental shielding, the number of monitor units and the collimator size to the peripheral dose were investigated. MOSFET dosimeters were placed in preselected anatomical regions of the patient undergoing Cyberknife treatment, namely the thyroid gland, the nipple, the umbilicus and the pubic symphysis. The mean peripheral doses before the supplemental shielding was added to the Cyberknife unit were 51.79 cGy, 13.31 cGy and 10.07 cGy while after the shielding upgrade they were 38.40 cGy, 10.94 cGy, and 8.69 cGy, in the thyroid gland, the umbilicus and the pubic symphysis, respectively. The increase of the collimator size corresponds to an increase of the PD and becomes less significant at larger distances, indicating that at these distances the PD is predominate due to the head leakage and collimator scatter. Weighting the effect of the number of monitor units and the collimator size can be effectively used during the optimization procedure in order to choose the most suitable treatment plan that will deliver the maximum dose to the tumor, while being compatible with the dose constraints for the surrounding organs at risk. Attention is required in defining the thyroid gland as a structure of avoidance in the treatment plan especially in patients with benign diseases.


Accurate, practical and cost-effective assessment of carotid stenosis in the UK.
To determine whether less invasive imaging tests [ultrasound (US), magnetic resonance angiography (MRA), computed tomographic angiography (CTA) and contrast-enhanced MRA (CEMRA)], alone or combined, could replace intra-arterial angiography (IAA), what effect this would have on strokes and deaths, endarterectomies performed and costs, and whether less invasive tests were cost-effective. Electronic databases covering the years 1980-2003 inclusive, updated to April 2004. Key journals from 1990 to the end of 2002. The authors constituted a panel of experts in stroke, imaging, vascular surgery, statistics and health economic modelling. The accuracy of less invasive carotid imaging was systematically reviewed using Standards for Reporting of Diagnostic Accuracy (STARD) methodology, supplemented by individual patient data from UK primary research and audit studies. A systematic review of the costs of less invasive tests, outpatient clinics, endarterectomy and stroke was performed, along with a microcosting exercise. A model of the process of care following a transient ischaemic attack (TIA)/minor stroke was developed, populated with data from stroke epidemiology studies in the UK, effects of medical and surgical interventions, outcomes, quality of life and costs. A survey of UK stroke prevention clinics provided typical timings. Twenty-two different carotid imaging strategies were evaluated for short- and long-term outcomes, quality-adjusted life-years (QALYs) and net benefit. In 41 included studies (2404 patients, median age 60-65 years), most data were available on 70-99% stenosis. CEMRA was the most accurate [sensitivity 0.94, 95% confidence interval (CI) 0.88 to 0.97; specificity 0.93, 95% CI 0.89 to 0.96], compared with US, MRA and CTA, which were all similar (e.g. for US: sensitivity 0.89, 95% CI 0.85 to 0.92; specificity 0.84, 95% CI 0.77 to 0.89). Data for 50-69% stenoses and on combinations of tests were too sparse to be reliable. There was heterogeneity between studies for all imaging modalities except for CTA. The individual patient data (2416 patients) showed that the literature overestimated test accuracy in routine practice and that, in general, tests perform with higher sensitivity and specificity in asymptomatic than in symptomatic arteries. In the cost-effectiveness model, on current UK timings, strategies allowed more patients to reach endarterectomy very quickly, and where those with 50-69% stenosis would be offered surgery in addition to those with 70-99%, prevented most strokes and produced greatest net benefit. This included most strategies with US as first or repeat test, and not those with IAA. However, the model was sensitive to less invasive test accuracy, cost and timing of endarterectomy. In patients investigated late after TIA, test accuracy is crucial and CEMRA should be used before surgery. In the UK, less invasive tests can be used in place of IAA if radiologists trained in carotid imaging are available. Imaging should be carefully audited. Stroke prevention clinics should reduce waiting times at all stages to improve speed of access to endarterectomy. In patients presenting late after TIA, test accuracy is very important and US results should be confirmed by CEMRA, as patients with 50-69% stenosis are less likely to benefit. More data are required to define the accuracy of the less invasive tests, with improvements made in the data collection methods used and how data are presented. Consideration should also be given to the use of new technologies and randomised trials.


Genetic, histochemical and biochemical studies on goat TSE cases from Cyprus.
Scrapie and bovine spongiform encephalopathy (BSE) are transmissible spongiform encephalopathies (TSE's) affecting sheep and goats. Susceptibility of goats to scrapie is influenced by polymorphisms of the prion protein gene (PRNP) of the host. Five polymorphisms are associated with reduced susceptibility to TSE's. In the study presented here caprine samples from a scrapie eradication program on Cyprus were genotyped and further characterized using BioRad TeSeE rapid test, histological, immunohistochemical and biochemical methods. In total 42 goats from 20 flocks were necropsied from which 25 goats showed a positive result in the rapid test, a spongiform encephalopathy and an accumulation of pathological prion protein (PrPSc) in the obex. PrPSc deposits were demonstrated in the placenta, peripheral nervous and lymphoreticular system. Two animals showed PrPSc-accumulations in peripheral tissues only. By discriminatory immunoblots a scrapie infection could be confirmed for all cases. Nevertheless, slight deviations in the glycosylation pattern might indicate the presence of different scrapie strains. Furthermore scrapie samples from goats in the current study demonstrated less long term resistance to proteinase K than ovine or caprine BSE control samples. Reduced scrapie susceptibility according to the PRNP genotype was demonstrated (Fishers Exact test, p < 0.05) for the goats with at least one polymorphism (p = 0.023) at the six codons examined and in particular for those with polymorphisms at codon 146 (p = 0.016). This work characterizes scrapie in goats having implications for breeding and surveillance strategies.


Soluble CD14 and CD14 polymorphisms in rheumatoid arthritis.
Soluble CD14 (sCD14) is involved in innate immune responses and has been implicated to play a pathogenic role in inflammatory diseases including rheumatoid arthritis (RA). No studies have identified the specific factors that influence sCD14 expression in RA. We used cross-sectional data to evaluate the relationship of sCD14 concentrations in RA with measures of disease activity and severity. We hypothesized that sCD14 concentrations would be elevated in subjects with greater RA disease severity and markers of disease activity, compared to subjects with lower disease activity. We also examined whether well-defined polymorphisms in CD14 are associated with sCD14 expression in RA. Soluble CD14 concentrations were measured using banked serum from patients with RA (n = 1270) and controls (n = 186). Associations of patient factors including demographics, measures of RA disease activity/severity, and select CD14 single-nucleotide polymorphisms (SNP) with sCD14 concentration were examined in patients with RA using ordinal logistic regression. Circulating concentrations of sCD14 were higher in patients with RA compared to controls (p < 0.0001). Factors significantly and independently associated with higher sCD14 levels in patients with RA included older age, being white (vs African American), lower body mass index, elevated high sensitivity C-reactive protein, and higher levels of disease activity based on the Disease Activity Score (DAS28). There were no significant associations of CD14 tagging SNP with sCD14 level in either univariate or multivariable analyses. Circulating levels of sCD14 are increased in RA and are highest in patients with increased levels of RA disease activity. In the context of RA, sCD14 concentrations also appear to be strongly influenced by specific patient factors including older age and race but not by genetic variation in CD14.