Development of a novel poly bisphosphonate conjugate for treatment of skeletal metastasis and osteoporosis.
Advanced stage prostate and breast cancer frequently metastasize to the skeleton (approximately 75%). An additional complication in these patients, that further affects the bones, is that their hormonal treatment, induces osteoporosis. Bisphosphonates (bpns) are standard drugs against osteoporosis and have been shown to have clinically significant anti-tumor effects. This study describes the development of a new polybisphosphonate conjugate (ODX) with enhanced dual efficacy i.e. with anti-bone resorption and anti-tumor properties. Zoledronic acid (Zometa) was used as a positive control (at equimolar concentrations). Alendronic acid and aminoguanidine were conjugated to oxidized dextran with subsequent reductive amination (on average approximately 8 alendronate and approximately 50 guanidine moieties per conjugate). ODX was tested in a bone resorption assay for its capacity to inhibit bone resorbing osteoclasts (bone organ culture from neonatal mice, 45Ca labelled bone mineral). Tumor cell toxicity was studied on prostate (PC3) and breast cancer (MDA231, MDA453) cell cultures. Two methods were employed, a fluorescent cytotoxicity assay (FMCA) and an apoptosis assay (Annexin V assay). In the bone resorption assay, Zometa and ODX showed very similar potency with 50% osteoclast inhibition at approximately 20 nM and 100% at 0.2 microM. In the FMCA, IC50 for ODX was at approximately 2 microM and 25 microM for Zometa (PC3). In the apoptosis assay, ODX induced approximately 85-97% apoptosis at 10 microM in both cell lines, while Zometa failed to induce any significant apoptosis in any of the cell lines at the tested concentration range (10 nM-10 microM). ODX appears to be a promising drug candidate with high dual efficacy for the treatment of bone metastasis and osteoporosis. It has both potent osteoclast inhibiting properties and enhanced anti-tumor efficacy.


Removal of Canvas Patterns in Digital Acquisitions of Paintings.
We address the removal of canvas artifacts from high-resolution digital photographs and X-ray images of paintings on canvas. Both imaging modalities are common investigative tools in art history and art conservation. Canvas artifacts manifest themselves very differently according to the acquisition modality; they can hamper the visual reading of the painting by art experts, for instance, in preparing a restoration campaign. Computer-aided canvas removal is desirable for restorers when the painting on canvas they are preparing to restore has acquired over the years a much more salient texture. We propose a new algorithm that combines a cartoon-texture decomposition method with adaptive multiscale thresholding in the frequency domain to isolate and suppress the canvas components. To illustrate the strength of the proposed method, we provide various examples, for acquisitions in both imaging modalities, for paintings with different types of canvas and from different periods. The proposed algorithm outperforms previous methods proposed for visual photographs such as morphological component analysis and Wiener filtering and it also works for the digital removal of canvas artifacts in X-ray images.


Trends in incidence and susceptibility among methicillin-resistant Staphylococcus aureus isolated from intranasal cultures associated with rhinosinusitis.
Reports regarding the incidence and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) in rhinosinusitis (RS) are limited. This study was designed to identify epidemiology and trends of MRSA incidence and antimicrobial resistance in the sinonasal cavities. This is a retrospective case series. All intranasal/sinus cultures obtained by otolaryngologists at Stanford over a 20-year period (1990-2010) were retrospectively reviewed by mining the microbiology database. Nested searches were then made for all S. aureus and MRSA cultures. Patterns of incidence and changes in antibiotic susceptibilities were tabulated and statistical analysis was performed. Our search retrieved 10,387 positive intranasal culture samples, with S. aureus found in 800 (7.7%), and MRSA comprising 110 (1.06%) of this subset. Between the years of 1990 and 1999, only 2/112 (1.7%) of S. aureus-positive nasal cultures were positive for MRSA, with a sharp rise in incidence to 86/606 (14.2%) from 2000 to 2005, and to 22/82, 26.8% from 2006 to 2010. On a percent basis, using logistic regression modeling, this represents a statistically significant increasing trend (p < 0.0001) for MRSA sinusitis. However, over the 20-year interval studied, the patterns of antibiotic resistance among MRSA remained unaltered, especially with regard to trimethoprim-sulfamethoxazole and vancomycin. S. aureus and MRSA isolates from intranasal cultures, which were essentially absent before the year 2000, became significantly more common earlier this decade. These data show the increased role of MRSA in sinusitis. MRSA antibiotic susceptibilities have remained, however, largely stable during this time period.


Public health nurses in rural/frontier one-nurse offices.
Public health nursing is the foundation of the United States' (US) public health system, particularly in rural and remote areas. Recent increasing interest in public health in the USA has highlighted that there is limited information available about public health nursing in the most isolated areas, particularly in the US. The purposes of this study were to: (1) describe the characteristics, competency levels, and practice patterns of public health nurses (PHNs) working in remote one-nurse offices; and (2) compare PHNs working in one-nurse offices with nurses working in multi-nurse offices in Idaho, in relation to their demographic characteristics, practice patterns and competency levels. Using a cross-sectional descriptive design, a statewide sample of 124 PHNs in Idaho, including 15 working in one-nurse satellite offices, were assessed in relation to their demographic characteristics, experience, educational background, job satisfaction, practice characteristics, and competency levels in March to May 2007. The solo (nurses working in one-nurse offices) PHNs were based in 15 different counties, 10 frontier (population density of less than 7 persons/1.6 km(2); 7 persons/mile(2)) and 5 rural. The counties ranged in population from 2781 to 28 114 (mean = 11 013), with population densities ranging from 0.9 to 29.4 persons/1.6 km(2) (mean = 8.6; 0.9 to 29.4 persons/mile(2)). The distance from their offices to the district main office ranged from 25.8 to 241.4 km (mean = 104 km; 16 to 150 miles, mean = 64.6 miles). All the solo PHNs were Caucasian females, with a mean age of 46.9 years and a mean of 22.5 years' nursing experience. Educationally, 7 (47%) held a bachelor degree in nursing, 6 (40%) had associates degrees, 1 (7%) had a diploma in nursing, and 1 (7%) was a licensed practical nurse (LPN). These solo PHNs provided a wide array of services with support from other nurses in the district, including epidemiology, family planning/sexually transmitted disease clinics, immunization clinics, communicable disease surveillance, and school nursing. They expressed strong job satisfaction, citing the benefits of autonomy, variety, and close community ties, but also voiced some frustrations related to isolation. Their self-rated levels of competency were highest in the areas of communication, cultural competency, community dimensions of care, and leadership/systems thinking skills; and lowest in the areas of financial management, analytical assessment, policy development/program planning, and basic public health sciences skills. When the solo PHNs were compared with PHNs based in multi-nurse offices, there were no statistically significant differences between the solo and non-solo PHNs in demographics or competency levels, except in the competency area of community dimensions of practice skills. The mean self-rating for solo PHNs in relation to community dimensions of practice skills was significantly higher (3.9) than non-solo PHNs (3.2) (t = 3.547, p = .002). These findings suggest that US PHNs practicing in isolated one-nurse offices in rural and remote communities are comparable to PHNs working in less isolated settings; however, solo nurses may have stronger community dimensions of practice skills. Their practice is more generalized than other PHNs and they express high levels of job satisfaction. The study was limited in that it was conducted in only one state and data were collected only by self-report. Further research is indicated to describe this unique subset of PHNs, particularly in terms of factors promoting recruitment and retention. Additional study into the conceptual aspect of isolation is also indicated in relation to public health practice in rural and remote areas.


Multiple imputation of missing covariates with non-linear effects and interactions: an evaluation of statistical methods.
Multiple imputation is often used for missing data. When a model contains as covariates more than one function of a variable, it is not obvious how best to impute missing values in these covariates. Consider a regression with outcome Y and covariates X and X2. In 'passive imputation' a value X* is imputed for X and then X2 is imputed as (X*)2. A recent proposal is to treat X2 as 'just another variable' (JAV) and impute X and X2 under multivariate normality. We use simulation to investigate the performance of three methods that can easily be implemented in standard software: 1) linear regression of X on Y to impute X then passive imputation of X2; 2) the same regression but with predictive mean matching (PMM); and 3) JAV. We also investigate the performance of analogous methods when the analysis involves an interaction, and study the theoretical properties of JAV. The application of the methods when complete or incomplete confounders are also present is illustrated using data from the EPIC Study. JAV gives consistent estimation when the analysis is linear regression with a quadratic or interaction term and X is missing completely at random. When X is missing at random, JAV may be biased, but this bias is generally less than for passive imputation and PMM. Coverage for JAV was usually good when bias was small. However, in some scenarios with a more pronounced quadratic effect, bias was large and coverage poor. When the analysis was logistic regression, JAV's performance was sometimes very poor. PMM generally improved on passive imputation, in terms of bias and coverage, but did not eliminate the bias. Given the current state of available software, JAV is the best of a set of imperfect imputation methods for linear regression with a quadratic or interaction effect, but should not be used for logistic regression.


CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma.
The cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens and estrogen. We hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for endometrial hyperplasia (EH) and endometrial carcinoma (ECa). We therefore evaluated this hypothesis in patients with EH and ECa and control subjects using allele-specific polymerase chain reaction-based method in a Turkish population. The patients with CYP1A1 Ile/Val genotype had a fivefold higher risk of having EH than those with Ile/Ile. In contrast, a higher frequency of any Val genotype (Ile/Val and Val/Val) was found in patients with EH, indicating that persons carrying any Val allele are at increased risk for developing EH. In the ECa group, patients were also more likely to have CYP1A1 Ile/Val allele, with an adjusted odds ratio of 3.0. Moreover, there was a statistically significant increase in relative risk association with any Val genotype between patients and controls, suggesting that individuals carrying any Val genotype are at increased risk for developing ECa. We concluded that variant alleles of the CYP1A1 gene might be associated with EH and ECa susceptibility. Further studies with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.


Effect of long-term antibiotic use on weight in adolescents with acne.
Antibiotics increase weight in farm animals and may cause weight gain in humans. We used electronic health records from a large primary care organization to determine the effect of antibiotics on weight and BMI in healthy adolescents with acne. We performed a retrospective cohort study of adolescents with acne prescribed ≥4 weeks of oral antibiotics with weight measurements within 18 months pre-antibiotics and 12 months post-antibiotics. We compared within-individual changes in weight-for-age Z-scores (WAZs) and BMI-for-age Z-scores (BMIZs). We used: (i) paired t-tests to analyse changes between the last pre-antibiotics versus the first post-antibiotic measurements; (ii) piecewise-constant-mixed models to capture changes between mean measurements pre- versus post-antibiotics; (iii) piecewise-linear-mixed models to capture changes in trajectory slopes pre- versus post-antibiotics; and (iv) χ(2) tests to compare proportions of adolescents with ≥0.2 Z-scores WAZ or BMIZ increase or decrease. Our cohort included 1012 adolescents with WAZs; 542 also had BMIZs. WAZs decreased post-antibiotics in all analyses [change between last WAZ pre-antibiotics versus first WAZ post-antibiotics = -0.041 Z-scores (P < 0.001); change between mean WAZ pre- versus post-antibiotics = -0.050 Z-scores (P < 0.001); change in WAZ trajectory slopes pre- versus post-antibiotics = -0.025 Z-scores/6 months (P = 0.002)]. More adolescents had a WAZ decrease post-antibiotics ≥0.2 Z-scores than an increase (26% versus 18%; P < 0.001). Trends were similar, though not statistically significant, for BMIZ changes. Contrary to original expectations, long-term antibiotic use in healthy adolescents with acne was not associated with weight gain. This finding, which was consistent across all analyses, does not support a weight-promoting effect of antibiotics in adolescents.


Effects of adenosine agonists on ventilation during hypercapnia, hypoxia and hyperoxia in rhesus monkeys.
This study characterized in rhesus monkeys the effects of selected adenosine agonists on ventilation during normal atmospheric conditions and during conditions of hypercapnia, hypoxia and hyperoxia. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to air, CO2 (3, 4 and 5%) mixed in air (hypercapnia), 10% O2 mixed in N2 (hypoxia) and 100% O2 (hyperoxia) was measured during cumulative dosing with each drug. The nonselective (A1/A2) agonist, 5'-N-ethylcarboxamidadenosine (NECA), the peripherally active, A2-selective agonist, CGS 21680 [2-(carboxyethylphenylamino)adenosine-5'-carboxamide], and the A1-selective agonists, N6-cyclohexyladenosine and N6-cyclopentyladenosine, increased respiratory frequency (f), but had no significant effect on minute volume (VE) during exposure to air. The relative potencies for increasing f corresponded closely with their potencies for binding at A2 receptors. NECA and CGS 21680 increased f in a dose-dependent manner during exposure to 3% CO2, but proportional increases in f were less pronounced as the concentration of CO2 increased. NECA and CGS 21680 also increased f during hypoxia, but neither had a significant effect on f during subsequent hyperoxia. The highest dose of CHA and CPA decreased f below control values during exposure to 5% CO2 and decreased f and VE during hyperoxia. In contrast, the adenosine antagonist, caffeine, and the selective phosphodiesterase inhibitor, rolipram, increased f and VE under all conditions. During hypercapnia, the magnitude of the increases in f was similar at each concentration of CO2 studied. Caffeine and rolipram increased f and VE during hypoxia, and f and VE remained elevated during hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)


Wideband acoustic immittance normative data: ethnicity, gender, aging, and instrumentation.
This article describes the effect of ethnicity, gender, aging, and instrumentation on wideband acoustic immittance (WAI). This is an important topic to investigate as the goal of any audiological test is optimize the test's sensitivity and specificity. One way to improve the test's sensitivity and specificity is to reduce the variability of the normative data. The impact of the aforementioned demographic characteristics on WAI norms has been reviewed, and where applicable its potential impact on clinical outcome has been discussed. Overall, differences observed between Caucasian and Chinese ethnic groups in adults population may warrant the use of ethnicity-specific norms especially for detection of otosclerosis; however, these differences in the school-aged children are not large enough to warrant the use of ethnicity-specific norms. It is important to explore whether the observed differences between Caucasian and Chinese ethnic groups is due to body-size indices and whether these differences can be replicated in other East Asian ethnic groups that share similar body-size indices. The differences observed between school-aged children and adults could also potentially impact clinical decision analysis. Therefore, use of age-specific norm is recommended. The differences in WAI between different systems are not clinically significant, and the use of instrument-specific norms does not result in improved test performance at least for the detection of otosclerosis. However, measuring WAI at ambient pressure (static) or at pressure corresponding to the peak (dynamic mode) could potentially impact the normative data and may prove to be clinically useful in cases of negative and positive middle ear pressure.


Making sense of genomic islands of differentiation in light of speciation.
As populations diverge, genetic differences accumulate across the genome. Spurred by rapid developments in sequencing technology, genome-wide population surveys of natural populations promise insights into the evolutionary processes and the genetic basis underlying speciation. Although genomic regions of elevated differentiation are the focus of searches for 'speciation genes', there is an increasing realization that such genomic signatures can also arise by alternative processes that are not related to population divergence, such as linked selection. In this Review, we explore methodological trends in speciation genomic studies, highlight the difficulty in separating processes related to speciation from those emerging from genome-wide properties that are not related to reproductive isolation, and provide a set of suggestions for future work in this area.


Protected areas facilitate species' range expansions.
The benefits of protected areas (PAs) for biodiversity have been questioned in the context of climate change because PAs are static, whereas the distributions of species are dynamic. Current PAs may, however, continue to be important if they provide suitable locations for species to colonize at their leading-edge range boundaries, thereby enabling spread into new regions. Here, we present an empirical assessment of the role of PAs as targets for colonization during recent range expansions. Records from intensive surveys revealed that seven bird and butterfly species have colonized PAs 4.2 (median) times more frequently than expected from the availability of PAs in the landscapes colonized. Records of an additional 256 invertebrate species with less-intensive surveys supported these findings and showed that 98% of species are disproportionately associated with PAs in newly colonized parts of their ranges. Although colonizing species favor PAs in general, species vary greatly in their reliance on PAs, reflecting differences in the dependence of individual species on particular habitats and other conditions that are available only in PAs. These findings highlight the importance of current PAs for facilitating range expansions and show that a small subset of the landscape receives a high proportion of colonizations by range-expanding species.


Greening of Daycare Yards with Biodiverse Materials Affords Well-Being, Play and Environmental Relationships.
Nature contacts are recognized as positively contributing to humans' health and well-being. Although there have been projects to green daycare or schoolyards, yard greening and microbial biodiversity have never been studied simultaneously. We asked whether simultaneously increasing biodiversity exposure and greening urban daycare yards affects 3-5 years-old children's physical activity and play, their environmental relationships, and their perceived well-being. For transforming six daycare yards in Finland, we used a forest floor with high biodiversity, sod, peat blocks, and planters for vegetable and flower growing. We used qualitative interview and survey-based data collected from the daycare personnel and parents to analyze how green yards encourage children's engagement with their everyday life-worlds. We identified the functional possibilities provided by the yards and the dynamic aspects related to the greening. Green, biodiverse yards were considered safe, and inspired children's play, diversified their activities, and increased physical activity. The greenery offered embodied experiences of nature and provided the children with multi-sensory exploration and diverse learning situations. The dynamic and emotional ways of engaging with the natural environment increased their well-being. The activities related to caring for the yards and exploring them promoted the development of environmental relationships. The results can be used for designing health-enhancing yards.


CONTRASTING HABITAT ASSOCIATIONS OF SAGEBRUSH-STEPPE SONGBIRDS IN THE INTERMOUNTAIN WEST.
Sagebrush (Artemisia spp.) steppe is one of North America's most imperiled ecosystems, as the result of many factors including grazing, development, fire, and invasion of exotic plants. Threats to sagebrush steppe are expected to increase because of climate change and further human development. Many songbirds use sagebrush steppe opportunistically, but a few obligate species are dependent on it. To quantify the habitat associations of three sagebrush obligates, the Sage Thrasher (Oreoscoptes montanus), Sagebrush Sparrow (Artemisiospiza nevadensis), and Brewer's Sparrow (Spizella breweri), and nine other songbird species that use this habitat, we surveyed across a broad region of Idaho. At each of 104 sites, we selected three plots, one each in relatively poor, moderate, and good condition, defined qualitatively by the cover of native shrubs. We quantified bird abundance by point counts, described the habitat at these points by a line-intercept method, and at each plot calculated the fraction of a circle (radius 1 km) covered in shrubs or grassland. We compared two-scale occupancy models based on these data by the information-theoretic approach. According to the models, our qualitative assessment of habitat condition within a site distinguished birds' use of relatively good habitat from their use of poor habitats only, not from those in moderate condition. Thus the sagebrush-obligate species may tolerate some local habitat degradation, at least up to some unidentified threshold. Occurrence of all three sagebrush obligates correlated well with one or more characteristics of sagebrush such as its cover, height, or heterogeneity in height. They differed in the Sage Thrasher being most sensitive to sagebrush cover, the Sagebrush Sparrow being found more often at lower elevations, and the Brewer's Sparrow being less sensitive to ground cover. The nine other species evaluated were less or negatively associated with attributes of sagebrush. On the basis of these results, we suggest that the three sagebrush obligates are best conserved by promoting shrublands over a broad range of elevations, containing both sagebrush and other shrubs in patches of mixed height, and minimizing invasive annual grasses.


Statins for acute coronary syndrome.
The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear. To assess the benefits and harms of early administered statins in patients with ACS from randomized controlled trials (RCTs). We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (to 1 February 2010). No language restrictions were applied. We supplemented the search by contacting experts in the field, by reviewing reference lists of reviews and editorials on the topic, and by searching trial registries. RCTs comparing statins with placebo or usual care, initiation of statin therapy within 14 days following the onset of ACS, and follow-up of at least 30 days reporting at least one clinical outcome. Two authors independently assessed study quality and extracted data. We pooled treatment effects and calculated risk ratios (RRs) for all outcomes in the treatment and control groups using a random effects model. Eighteen studies (14,303 patients) compared early statin treatment versus placebo or usual care in patients with ACS. Compared to placebo or usual care, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction (MI), and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) and four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month and at four months, although there were favorable trends related to statin use for each of these endpoints. The incidence of episodes of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels > 10 times the upper limit of normal) in statin treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. Based on available evidence, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS.


Anthropometric and physiological profiling of youth soccer goalkeepers.
Studies focused on position-related characteristics of young soccer players often ignore the goalkeepers. The aim of this study was to examine the effect of playing position on anthropometry, physiological attributes, soccer skills, and goal orientation across adolescence. One hundred forty-five soccer players age 11-19 y were assessed in training experience, body size, maturation, physiological parameters, soccer skills, and goal orientation. Factorial ANOVA was used to test the effect of age group, playing position, and respective interaction terms, while analysis of variance was used to compare goalkeepers vs outfielders in middle (under 13 [U-13] and U-15) and late (U-17 and U-19) adolescence. Discriminant analysis was used to identify the variables that contributed to explaining playing positions. Age group was a consistent source of variation for all variables except task and ego orientations. Fat mass, agility, endurance, dribbling speed, shooting accuracy, and passing were affected by the gradient derived from the classification between goalkeepers and outfielders. It was possible to correctly classify the playing position based on fat-free mass and 3 manipulative skills in younger players and on 4 skills in U-17 and U-19 soccer players. Future research should include longitudinal information to improve our understanding of the factors that contribute to distinguish goalkeepers from outfielders.


Characteristics and co-occurrence of adolescent non-suicidal self-injury and suicidal behaviours in pediatric emergency crisis services.
During the potentially tumultuous adolescent period, non-suicidal self-injury (NSSI) and suicide attempts are relatively common, particularly amongst youth who present to mental health services. These phenomena frequently co-occur but their relationship is unclear. This study evaluated clinical data from 468 youth between the ages of 12 and 17 years (63.5% female) to determine the incidence of NSSI 24 h prior to presentation at emergency crisis services, evaluated the overlap between NSSI and suicide attempt, and examined the characteristics of different types of self-harm. Half of the adolescents presenting to emergency crisis services had self-harmed within the previous 24 h, with most of these (91%) classified as NSSI only. The percentage of youth with a suicide attempt was 5% and the co-occurrence of these two behaviours was 4%. Group differences in depressive symptoms, suicidal ideation and impulsivity were identified, with the co-occurring NSSI and suicide attempt group presenting with the highest level of psychopathology. This study underscores the necessity of assessing suicidal ideation and NSSI in all youth presenting to mental health services.


Minimum complexity echo state network.
Reservoir computing (RC) refers to a new class of state-space models with a fixed state transition structure (the reservoir) and an adaptable readout form the state space. The reservoir is supposed to be sufficiently complex so as to capture a large number of features of the input stream that can be exploited by the reservoir-to-output readout mapping. The field of RC has been growing rapidly with many successful applications. However, RC has been criticized for not being principled enough. Reservoir construction is largely driven by a series of randomized model-building stages, with both researchers and practitioners having to rely on a series of trials and errors. To initialize a systematic study of the field, we concentrate on one of the most popular classes of RC methods, namely echo state network, and ask: What is the minimal complexity of reservoir construction for obtaining competitive models and what is the memory capacity (MC) of such simplified reservoirs? On a number of widely used time series benchmarks of different origin and characteristics, as well as by conducting a theoretical analysis we show that a simple deterministically constructed cycle reservoir is comparable to the standard echo state network methodology. The (short-term) MC of linear cyclic reservoirs can be made arbitrarily close to the proved optimal value.


A randomized, placebo-controlled trial of prednisone in early Henoch Schönlein Purpura [ISRCTN85109383].
Henoch Schönlein Purpura (HSP) is the most common systemic vasculitis of childhood. There is considerable controversy over whether children with HSP should be treated with corticosteroids. The goal of this study was to investigate whether early corticosteroid administration could reduce the rate of renal or gastrointestinal complications in children with HSP. Forty children with HSP, seen in the emergency room of a tertiary-care, paediatric centre, entered a randomized, double-blind, placebo controlled study. The treatment group (n = 21) received oral prednisone, 2 mg/kg/day for one week, with weaning over a second week, while the placebo group (n = 19) received an identical appearing placebo. Co-primary outcomes were the rate of renal involvement at one year and the rate of acute gastrointestinal complications. Co-primary outcomes were analysed using Fisher's Exact test. At one year, there was no difference in the rate of renal involvement (3/21 prednisone group vs. 2/19 placebo group, P = 1.0). There was also no statistically significant difference in the rate of acute gastrointestinal complications (2/21 prednisone group vs. 3/19 placebo group, P = 0.7). Two children in the placebo group did experience intussusceptions compared with none in the prednisone group (P = 0.2). Early prednisone therapy in HSP does not appear to reduce the risk of renal involvement at one year, or the risk of acute gastrointestinal complications. There may be a reduced risk of intussusception. The routine, early use of prednisone in uncomplicated HSP cannot be recommended at this time.


Jones matrices of a quarter-wave plate for Gaussian beams.
The Jones matrix of a quarter-wave plate is studied theoretically and experimentally, taking into account internal reflections, the ellipsoid of the indices, geometric defects, the tilt angle, and the characteristics of the incident Gaussian beam. The influence of the different parameters is isolated, and large discrepancies are observed with respect to results obtained from the Jones matrix that are usually given in textbooks. It is shown that the effective Jones matrix of the plate does not depend on the longitudinal position of the plate on the Gaussian beam but only on the beam-waist size. This leads to a method of characterization of the defects of a quarter-wave plate that is more precise than the usual methods. Different procedures to optimize the efficiency of a given plate are discussed, taking the plate defects into account. In all cases, a good agreement between experiments and theory is obtained.


Craniofacial Secular Change in Recent Mexican Migrants.
Research by economists suggests that recent Mexican migrants are better educated and have higher socioeconomic status (SES) than previous migrants. Because factors associated with higher SES and improved education can lead to positive secular changes in overall body form, secular changes in the craniofacial complex were analyzed within a recent migrant group from Mexico. The Mexican group represents individuals in the act of migration, not yet influenced by the American environment, and thus can serve as a starting point for future studies of secular change in this population group. The excavation of a historic Hispanic cemetery in Tucson, Arizona, also allows for a comparison between historic Hispanics and recent migrants to explore craniofacial trends over a broad time period, as both groups originate from Mexico. The present research addresses two main questions: (1) Are cranial secular changes evident in recent Mexican migrants? (2) Are historic Hispanics and recent Mexican migrants similar? By studying secular changes within a migrant population group, secular trends may be detected, which will be important for understanding the biological variation of the migrants themselves and will serve as a preliminary investigation of secular change within Mexican migrants. The comparison of a sample of recent Mexican migrants with a historic Hispanic sample, predominantly of Mexican origin, allows us to explore morphological similarities and differences between early and recent Mexicans within the United States. Vault and face size and a total of 82 craniofacial interlandmark distances were used to explore secular changes within the recent Mexican migrants (females, n = 38; males, n = 178) and to explore the morphological similarities between historic Hispanics (females, n = 54; males, n = 58) and recent migrants. Sexes were separated, and multivariate adaptive regression splines and basis splines (quadratic with one knot) were used to assess the direction and magnitude of secular trends for the recent Mexican migrants. Because dates of birth were unavailable for the historic sample, partial least squares discriminant analysis (PLS-DA) was used to evaluate morphological differences between historic and recent Mexican migrant samples. The data were separated into a training data set and a testing data set to ensure realistic results. Males had eight variables (four positive and four negative) and females had six variables (two positive and four negative) that demonstrated significant differences over time. In the PLS-DA, three components were identified as important in model creation and resulted in a classification accuracy of 87% when applied to a testing sample. The high classification accuracy demonstrates significant morphological differences between the two groups, with the historic Hispanic sample displaying overall larger craniofacial dimensions. While differences in cranial morphology are evident between historic Hispanics and recent Mexican migrants, relatively few positive and negative secular trends were detected within the recent migrant sample.


Magnesium deficiency in patients on long-term diuretic therapy for heart failure.
Magnesium levels in serum, erythrocytes, skeletal muscle, and bone were measured in 10 patients with valvular heart disease who had received diuretic therapy for heart failure for an average of 3.3 years. Five patients were found to have diminished values for skeletal muscle, indicating significant magnesium deficit. Values for erythrocytes were low in only two of the five patients, and none had low values for serum ultrafiltrate and bone: Magnesium replacement therapy restored skeletal muscle values to normal. Clinical features consistent with the presence of magnesium deficiency were found in all five magnesium-deficient patients. These features were, with few exceptions, corrected by magnesium replacement. The latter also corrected low skeletal muscle potassium values present in all five patients with low skeletal muscle magnesium, four of whom showed clinical features of digoxin poisoning before magnesium therapy was given. Concomitant secondary aldosteronism, inadequate dietary intake, and digoxin therapy had probably augmented the magnesium loss due to diuretic therapy.


Validity of 5-year-old children's oral hygiene pattern referred by mothers.
To determine the validity of oral hygiene questions for children, as commonly used in epidemiological studies, and assess their validity by family income and mother's education. A subsample of 1122 children from the 2004 Pelotas Birth Cohort, Southern Brazil (who had participated in a 2009 oral health study) was analyzed. The children received dental examinations, and their mothers were interviewed at home. The gold standard for oral hygiene was the Simplified Oral Hygiene Index; from its total score, the outcome was dichotomized into the absence (total score = 0) or presence (total score ≥ 1) of dental plaque. The mothers answered questions related to their child's oral hygiene, including daily toothbrushing, toothbrushing before sleeping and the combination of the two (oral hygiene). These responses were dichotomized into regular and irregular. The validity was determined by calculating the percentages and respective 95% confidence intervals for sensitivity, specificity, positive predictive value and negative predictive value. The overall prevalence of dental plaque was 37.0%. The following sensitivities, specificities, positive predictive values and negative predictive values were observed: 29.6%, 82.5%, 49.8% and 66.6%, respectively, for irregular daily toothbrushing; 41.8%, 64.6%, 40.9% and 65.5%, respectively, for irregular toothbrushing before sleeping; and 48.8%, 60.8%, 42.2% and 67.0%, respectively, for irregular oral hygiene. The validity of the oral hygiene reporting varied across different levels of family income and mother's education. The sensitivity and positive predictive values were higher among children with lower incomes and less educated mothers, while opposite associations were observed for specificity and negative predictive value. Oral hygiene questions answered by mothers of five year-old children are not an appropriate substitute for direct oral hygiene assessment by the clinical examination of dental plaque.


Zero-gain slow & fast light propagation in an optical fiber.
Slow & fast light with null amplification or loss of a light signal is experimentally demonstrated. This novel method for producing zero-gain slow & fast light takes advantage of the great flexibility of stimulated Brillouin scattering in optical fibers to generate synthesized gain spectra. Generation of optical delays and advancements with minor amplitude change is realized through the superposition of gain and loss profiles showing very different spectral widths, resulting in a synthesized spectral profile identical to an ideal electromagnetically-induced transparency.


Call to action on use and reimbursement for home blood pressure monitoring: Executive Summary. A joint scientific statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association.
Home blood pressure monitoring (HBPM) overcomes many of the limitations of traditional office blood pressure (BP) measurement and is both cheaper and easier to perform than ambulatory BP monitoring. Monitors that use the oscillometric method are currently available that are accurate, reliable, easy to use, and relatively inexpensive. An increasing number of patients are using them regularly to check their BP at home, but although this has been endorsed by national and international guidelines, detailed recommendations for their use have been lacking. There is a rapidly growing literature showing that measurements taken by patients at home are often lower than readings taken in the office and closer to the average BP recorded by 24-hour ambulatory monitors, which is the BP that best predicts cardiovascular risk. Because of the larger numbers of readings that can be taken by HBPM than in the office and the elimination of the white-coat effect (the increase of BP during an office visit), home readings are more reproducible than office readings and show better correlations with measures of target organ damage. In addition, prospective studies that have used multiple home readings to express the true BP have found that home BP predicts risk better than office BP (class IIa; level of evidence A). This call-to-action article makes the following recommendations: (1) It is recommended that HBPM should become a routine component of BP measurement in the majority of patients with known or suspected hypertension; (2) Patients should be advised to purchase oscillometric monitors that measure BP on the upper arm with an appropriate cuff size and that have been shown to be accurate according to standard international protocols. They should be shown how to use them by their healthcare providers; (3) Two to 3 readings should be taken while the subject is resting in the seated position, both in the morning and at night, over a period of 1 week. A total of > or =12 readings are recommended for making clinical decisions; (4) HBPM is indicated in patients with newly diagnosed or suspected hypertension, in whom it may distinguish between white-coat and sustained hypertension. If the results are equivocal, ambulatory BP monitoring may help to establish the diagnosis; (5) In patients with prehypertension, HBPM may be useful for detecting masked hypertension; (6) HBPM is recommended for evaluating the response to any type of antihypertensive treatment and may improve adherence; (7) The target HBPM goal for treatment is <135/85 mm Hg or <130/80 mm Hg in high-risk patients; (8) HBPM is useful in the elderly, in whom both BP variability and the white-coat effect are increased; (9) HBPM is of value in patients with diabetes, in whom tight BP control is of paramount importance; (10) Other populations in whom HBPM may be beneficial include pregnant women, children, and patients with kidney disease; and (11) HBPM has the potential to improve the quality of care while reducing costs and should be reimbursed.


Age-preserved semantic memory and the CRUNCH effect manifested as differential semantic control networks: An fMRI study.
Semantic memory representations are overall well-maintained in aging whereas semantic control is thought to be more affected. To explain this phenomenon, this study aims to test the predictions of the Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) focusing on task demands in aging as a possible framework. The CRUNCH effect would manifest itself in semantic tasks through a compensatory increase in neural activation in semantic control network regions but only up to a certain threshold of task demands. This study will compare 40 young (20-35 years old) with 40 older participants (60-75 years old) in a triad-based semantic judgment task performed in an fMRI scanner while manipulating levels of task demands (low vs. high) through semantic distance. In line with the CRUNCH predictions, differences in neurofunctional activation and behavioral performance (accuracy and response times) are expected in young vs. old participants in the low- vs. high-demand conditions manifested in semantic control Regions of Interest.


Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy.
Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but stratification of risk and final outcomes remain suboptimal. In view of the fact that glutamine metabolism is usually altered in cancer, we profiled and validated the significance of genes involved in this pathway in rectal cancers treated with CCRT. From a published transcriptome of rectal cancers (GSE35452), we focused on glutamine metabolic process-related genes (GO:0006541) and found upregulation of carbamoyl phosphate synthetase 1 (CPS1) gene most significantly predicted poor response to CCRT. We evaluated the expression levels of CPS1 using immunohistochemistry to analyze tumor specimens obtained during colonoscopy from 172 rectal cancer patients. Expression levels of CPS1 were further correlated with major clinicopathological features and survivals in this validation cohort. To further confirm CPS1 expression levels, Western blotting was performed for human colon epithelial primary cell (HCoEpiC) and four human colon cancer cells, including HT29, SW480, LoVo, and SW620. CPS1 overexpression was significantly related to advanced posttreatment tumor (T3, T4; P = 0.006) and nodal status (N1, N2; P < 0.001), and inferior tumor regression grade (P = 0.004). In survival analyses, CPS1 overexpression was significantly associated with shorter disease-specific survival (DSS) and metastasis-free survival (MeFS). Furthermore, using multivariate analysis, it was also independently predictive of worse DSS (P = 0.021, hazard ratio = 2.762) and MeFS (P = 0.004, hazard ratio = 3.897). CPS1 protein expression, as detected by Western blotting, is more abundant in colon cancer cells than nonneoplastic HCoEpiC. Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS1 for such patients.


Use of continuous and grab sample data for calculating total maximum daily load (TMDL) in agricultural watersheds.
Measuring the discharge of diffuse pollution from agricultural watersheds presents unique challenges. Flows in agricultural watersheds, particularly in Mediterranean climates, can be predominately irrigation runoff and exhibit large diurnal fluctuation in both volume and concentration. Flow and pollutant concentrations in these smaller watersheds dominated by human activity do not conform to a normal distribution and it is not clear if parametric methods are appropriate or accurate for load calculations. The objective of this study was to compare the accuracy of five load estimation methods to calculate pollutant loads from agricultural watersheds. Calculation of loads using results from discrete (grab) samples was compared with the true-load computed using in situ continuous monitoring measurements. A new method is introduced that uses a non-parametric measure of central tendency (the median) to calculate loads (median-load). The median-load method was compared to more commonly used parametric estimation methods which rely on using the mean as a measure of central tendency (mean-load and daily-load), a method that utilizes the total flow volume (volume-load), and a method that uses measure of flow at the time of sampling (instantaneous-load). Using measurements from ten watersheds in the San Joaquin Valley of California, the average percent error compared to the true-load for total dissolved solids (TDS) was 7.3% for the median-load, 6.9% for the mean-load, 6.9% for the volume-load, 16.9% for the instantaneous-load, and 18.7% for the daily-load methods of calculation. The results of this study show that parametric methods are surprisingly accurate, even for data that have starkly non-normal distributions and are highly skewed.


Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.
Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.


Process, Mechanism, and Modeling in Macroecology.
Macroecology has traditionally relied on descriptive characterization of large-scale ecological patterns to offer narrative explanations for the origin and maintenance of those patterns. Only recently have macroecologists begun to employ models termed 'process-based' and 'mechanistic', in contrast to other areas of ecology, where such models have a longer history. Here, we define and differentiate between process-based and mechanistic features of models, and we identify and discuss important advantages of working with models possessing such features. We describe some of the risks associated with process-based and mechanistic model-centered research programs, and we propose ways to mitigate these risks. Giving process-based and mechanistic models a more central role in research programs can reinvigorate macroecology by strengthening the link between theory and data.


Oncology professionals' views on the use of antidepressants in cancer patients: a qualitative interview study.
Emotional distress, including depression, is an important issue for cancer patients and their families. Guidelines recommend the use of antidepressant drugs (ADs) for the management of depression in cancer. This study explores the views of oncology professionals about the inclusion of ADs in treatment plans. Semi-structured interview study. Data were analysed using framework analysis. A specialist cancer centre and six district general hospitals across the Yorkshire Cancer Network. 18 randomly selected professionals from lung, breast, urology and colorectal cancer teams: oncologists (n=8), surgeons (n=3), clinical nurse specialists (n=2) and ward nurses (n=5). Three main themes emerged relating to professionals' attitudes, knowledge and behaviour. Positive attitudes were primarily expressed by nurses. However, negative views were expressed about the potential for over-reliance on ADs, and their use constituting 'giving in'. Doctors reported a lack of confidence in the use of and knowledge about ADs with an associated reluctance to prescribe. The general practitioner (GP) was regarded as the most appropriate professional to prescribe ADs. Cancer professionals highlighted a need for training in the appropriate use of ADs. Further, this research suggests that negative attitudes towards antidepressants may be a factor in their exclusion from treatment plans. The GP is seen to have a key prescribing role for AD therapy; however, it is unclear whether the GPs is asked to do this. This research raises questions about the adequacy of ADs in cancer care and to what extent the GP is able to meet this need.


Association between Kawasaki disease and autism: a population-based study in Taiwan.
The association between Kawasaki disease and autism has rarely been studied in Asian populations. By using a nationwide Taiwanese population-based claims database, we tested the hypothesis that Kawasaki disease may increase the risk of autism in Taiwan. Our study cohort consisted of patients who had received the diagnosis of Kawasaki disease (ICD-9-CM: 446.1) between 1997 and 2005 (N = 563). For a comparison cohort, five age- and gender-matched control patients for every patient in the study cohort were selected using random sampling (N = 2,815). All subjects were tracked for 5 years from the date of cohort entry to identify whether they had developed autism (ICD-9-CM code 299.0) or not. Cox proportional hazard regressions were then performed to evaluate 5-year autism-free survival rates. The main finding of this study was that patients with Kawasaki disease seem to not be at increased risk of developing autism. Of the total patients, four patients developed autism during the 5-year follow-up period, among whom two were Kawasaki disease patients and two were in the comparison cohort. Further, the adjusted hazard ratios (AHR) (AHR: 4.81; 95% confidence interval: 0.68-34.35; P = 0.117) did not show any statistical significance between the Kawasaki disease group and the control group during the 5-year follow-up. Our study indicated that patients with Kawasaki disease are not at increased risk of autism.


High-bandwidth detection of short DNA in nanopipettes.
Glass or quartz nanopipettes have found increasing use as tools for studying the biophysical properties of DNA and proteins, and as sensor devices. The ease of fabrication, favourable wetting properties and low capacitance are some of the inherent advantages, for example compared to more conventional, silicon-based nanopore chips. Recently, we have demonstrated high-bandwidth detection of double-stranded (ds) DNA with microsecond time resolution in nanopipettes, using custom-designed electronics. The electronics design has now been refined to include more sophisticated control features, such as integrated bias reversal and other features. Here, we exploit these capabilities and probe the translocation of short dsDNA in the 100 bp range, in different electrolytes. Single-stranded (ss) DNA of similar length are in use as capture probes, so label-free detection of their ds counterparts could therefore be of relevance in disease diagnostics.


Setting development goals using stochastic dynamical system models.
The Millennium Development Goals (MDG) programme was an ambitious attempt to encourage a globalised solution to important but often-overlooked development problems. The programme led to wide-ranging development but it has also been criticised for unrealistic and arbitrary targets. In this paper, we show how country-specific development targets can be set using stochastic, dynamical system models built from historical data. In particular, we show that the MDG target of two-thirds reduction of child mortality from 1990 levels was infeasible for most countries, especially in sub-Saharan Africa. At the same time, the MDG targets were not ambitious enough for fast-developing countries such as Brazil and China. We suggest that model-based setting of country-specific targets is essential for the success of global development programmes such as the Sustainable Development Goals (SDG). This approach should provide clear, quantifiable targets for policymakers.


Shp2 activates Fyn and Ras to regulate RBL-2H3 mast cell activation following FcεRI aggregation.
The protein-tyrosine phosphatase (PTP) Shp2 has been implicated in many immunoreceptor signaling pathways, but its role in immunoreceptor FcεRI signaling, which leads to the activation of mast cells and blood basophils, is still largely undefined. Using Shp2 knockdown RBL-2H3 (RBL) mast cells, we here reported that Shp2 is required for the activation of RBL cells induced by FcεRI. FcεRΙ-evoked degranulation, calcium mobilization, and synthesis of cytokine transcripts (IL-1β, IL-10, and monocyte chemoattractant protein 1 (MCP-1)) were reduced in Shp2 knockdown RBL cells. Signaling regulatory mechanism investigation using immunoblotting, immunoprecipitation, and GST pull-down assay reveals that the down-regulation of Shp2 expression in RBL cells leads to decreased activities of Fyn, PLCγ, JNK, p38MAPK, and Ras/Erk1/2 after FcεRΙ aggregation. Further studies suggest that Paxillin phosphoryaltion was also impaired, but PAG phosphorylation was normal after FcεRΙ stimulation as a consequence of the inhibition of Shp2 expression in RBL cells. Collectively, our data strongly indicate that Shp2 is essential for the activation of RBL cells in response to FcεRΙ aggregation. Shp2 regulates this process through Fyn and Ras with no involvement of PAG. In addition, we identify Paxillin as an indirect substrate of Shp2 in FcεRΙ-initiated signaling of RBL cells.


Non-invasive ventilation for preoxygenation before general anesthesia: a systematic review and meta-analysis of randomized controlled trials.
Preoxygenation is crucial for providing sufficient oxygen reservoir to a patient before intubation and enables the extension of the period between breathing termination and critical desaturation (safe apnoea time). Conventionally, face mask ventilation is used for preoxygenation. Non-invasive ventilation is a new preoxygenation method. The study objective was to compare the outcomes of non-invasive ventilation and face mask ventilation for preoxygenation. PubMed, Embase, Cochrane Library, and the ClinicalTrials.gov registry were searched for eligible studies published from database inception to September 2021. Individual effect sizes were standardized, and a meta-analysis was conducted using random effects models to calculate the pooled effect size. Inclusion criteria were randomised controlled trials of comparing the outcomes of non-invasive ventilation or face mask ventilation for preoxygenation in patients scheduled for surgeries. The primary outcome was safe apnea time, and the secondary outcomes were post-operative complications, number of patients who achieved the expired O2 fraction (FeO2) after 3 min of preoxygenation, minimal SpO2 during tracheal intubation, partial pressure of oxygen in the arterial blood (PaO2) and partial pressure of carbon dioxide (PaCO2) after preoxygenation, and PaO2 and PaCO2 after tracheal intubation. 13 trials were eligible for inclusion in this study. Significant differences were observed in safe apnoea time, number of patients who achieved FeO2 90% after preoxygenation for 3 min, and PaO2 and PaCO2 after preoxygenation and tracheal intubation. Only in the non-obese subgroup, no significant difference was observed in safe apnoea time (mean difference: 125.38, 95% confidence interval: - 12.26 to 263.03). Non-invasive ventilation appeared to be more effective than conventional methods for preoxygenation. We recommend non-invasive ventilation based on our results.


Dynamic changes of Chest CT follow-up in Coronavirus Disease-19 (COVID-19) pneumonia: relationship to clinical typing.
To investigate the CT changes of different clinical types of COVID-19 pneumonia. This retrospective study included 50 patients with COVID-19 from 16 January 2020 to 25 February 2020. We analyzed the clinical characteristics, CT characteristics and the pneumonia involvement of the patients between the moderate group and the severe and critical group, and the dynamic changes of severity with the CT follow-up time. There were differences in the CT severity score of the right lung in the initial CT, and total CT severity score in the initial and follow-up CT between the moderate group and the severe and critical group (all p < 0.05). There was a quadratic relationship between total CT severity score and CT follow-up time in the severe and critical group (r2 = 0.137, p = 0.008), the total CT severity score peaked at the second follow-up CT. There was no correlation between total CT severity score and CT follow-up time in the moderate group (p > 0.05). There were no differences in the occurrence rate of CT characteristics in the initial CT between the two groups (all p > 0.05). There were differences in the occurrence rate of ground-glass opacity and crazy-paving pattern in the second follow-up CT, and pleural thickening or adhesion in the third follow-up CT between the two groups (all p < 0.05). The CT changes of COVID-19 pneumonia with different severity were different, and the extent of pneumonia involvement by CT can help to assess the severity of COVID-19 pneumonia rather than the initial CT characteristics.


Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice.
The IL-6 cytokine family, which signals via the shared gp130 coreceptor, is linked with the pathogenesis of emphysema. However, the definitive mechanisms by which these cytokines cause emphysema remain ill-defined. We took an in vivo genetic complementation approach to identify the specific IL-6 cytokine family members and gp130-regulated cellular processes that cause emphysema. We used gp130(F/F) mice homozygous for a subtle knock-in mutation in gp130 that deregulates intracellular signaling by the IL-6 cytokine family. The gp130(F/F) mice spontaneously develop emphysema by age 6 months. Within the IL-6 cytokine family, only IL-6 was significantly up-regulated in the lungs of gp130(F/F) mice, and the genetic targeting of IL-6 in gp130(F/F) mice (gp130(F/F):IL-6(-/-)) prevented emphysema. By contrast, the genetic ablation of receptor signaling via IL-11, which like IL-6 signals via a gp130 homodimer and uses the same signaling machinery, failed to ameliorate emphysema in gp130(F/F) mice. Among the disease-associated processes examined, emphysema strongly correlated with elevated alveolar cell apoptosis. Acute (4-day) exposure to cigarette smoke (CS) further augmented the expression of IL-6 in lungs of gp130(F/F) mice, and subchronic (6-week) exposure to CS exacerbated emphysematous and apoptotic changes in the lungs of gp130(F/F) but not gp130(F/F): IL-6(-/-) mice. IL-6 is the main causative agent of IL-6 cytokine family-induced emphysema, and operates to induce apoptosis in the lung. We propose that the discrete targeting of IL-6 signaling may provide an effective therapeutic strategy against human lung disease.


A Zernike mode decomposition decoupling control algorithm for dual deformable mirrors adaptive optics system.
A simple but effective decoupling control algorithm based on Zernike mode decomposition for adaptive optics systems with dual deformable mirrors is proposed. One of the two deformable mirrors is characterized with a large stroke (woofer) and the other with high spatial resolutions (tweeter). The algorithm works as follows: wavefront gradient vector is decoupled using the Zernike modes at first, and then the control vector for the woofer is generated with low order Zernike coefficients to eliminate high order modes. At the same time the control vector for the tweeter is reset by a constraint matrix in order to avoid coupling error accumulation. Simulation indicates the algorithm could get better performance compared with traditional Zernike mode decomposition control algorithms. Experiments demonstrate that this algorithm can effectively compensate for phase distortions and significantly suppress the coupling between the woofer and tweeter.


The new world of health care quality and measurement.
This column is designed to provide a nursing perspective on the new hospital quality measurements. Future articles will cover the various quality indicators hospitals face and the role of the nurse in meeting mandated benchmarks. Reader responses to this column are welcome and will help to make it more useful to nurses in meeting the challenges posed by health care reform and changing Medicare reimbursement programs.


Evaluation of 5-ethynyl-2'-deoxyuridine staining as a sensitive and reliable method for studying cell proliferation in the adult nervous system.
Recently, a novel method for detection of DNA synthesis has been developed based on the incorporation of 5-ethynyl-2'-deoxyuridine (EdU), a thymidine analogue, into cellular DNA and the subsequent reaction of EdU with a fluorescent azide in a copper-catalyzed [3+2] cycloaddition ("Click" reaction). In the present study, we evaluated this method for studying cell proliferation in the adult central nervous system in comparison with the "gold standard" method of 5-bromo-2'-deoxyuridine (BrdU) staining using two behavioral paradigms, voluntary exercise and restraint stress. Our data demonstrate that the number of EdU-positive cells in the dentate gyrus of the hippocampus (DG) slightly increased in an EdU dose-dependent manner in both the control and voluntary exercise (running) mouse groups. The number of EdU-labeled cells was comparable to the number of BrdU-labeled cells in both the control and running mice. Furthermore, EdU and BrdU co-localized to the same cells within the DG. Voluntary exercise significantly increased the number of EdU- and BrdU-positive cells in the DG. In contrast, restraint stress significantly decreased the number of EdU-positive cells. The EdU-positive cells differentiated into mature neurons. EdU staining is compatible with immunohistochemical staining of other antigens. Moreover, our data demonstrated EdU staining can be combined with BrdU staining, providing a valuable tool of double labeling DNA synthesis, e.g., for tracking the two populations of neurons generated at different time points. In conclusion, our results suggest that EdU staining is a fast, sensitive and reproducible method to study cell proliferation in the central nervous system.


Evolutionary discrimination of mammalian conserved non-genic sequences (CNGs).
Analysis of the human and mouse genomes identified an abundance of conserved non-genic sequences (CNGs). The significance and evolutionary depth of their conservation remain unanswered. We have quantified levels and patterns of conservation of 191 CNGs of human chromosome 21 in 14 mammalian species. We found that CNGs are significantly more conserved than protein-coding genes and noncoding RNAS (ncRNAs) within the mammalian class from primates to monotremes to marsupials. The pattern of substitutions in CNGs differed from that seen in protein-coding and ncRNA genes and resembled that of protein-binding regions. About 0.3% to 1% of the human genome corresponds to a previously unknown class of extremely constrained CNGs shared among mammals.


Quantitative analysis of ginger components in commercial products using liquid chromatography with electrochemical array detection.
For the first time, a sensitive reversed-phase HPLC electrochemical array method has been developed for the quantitative analysis of 8 major ginger components ([6]-, [8]-, and [10]-gingerol, [6]-, [8]-, and [10]-shogaol, [6]-paradol, and [1]-dehydrogingerdione) in 11 ginger-containing commercial products. This method was valid with unrivaled sensitivity as low as 7.3-20.2 pg of limit of detection and a range of 14.5-40.4 pg for the limit of quantification. The levels of 8 ginger components in 11 different commercial products were quantified by use of this method. The results found that both levels and ratios among the 8 compounds vary greatly in commercial products.


To accept a pilot? Addressing men's ambivalence and altering their expectancies about therapy.
When considering the challenges therapists encounter with their male clients, perhaps the most daunting tasks occur at the very beginning. Getting boys and men to avail themselves of psychological services is the first challenge. But when men do present, the second challenge is to get them to trust therapists sufficiently enough to share their issues and to form an effective working alliance. This article describes these gender-related challenges from male clients' point of view, and then elaborates upon effective techniques to help them engage in and benefit from psychotherapy. We suggest that good therapists for men, like good ship pilots, are informed and prepared. They learn the major cognitive and emotional issues they are likely to encounter with their male clients, and develop a variety of ways to help their male clients navigate the tricky psychological issues of their lives.


Cytoprotection of human endothelial cells against oxidative stress by 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im): application of systems biology to understand the mechanism of action.
Cellular damage from oxidative stress, in particular following ischemic injury, occurs during heart attack, stroke, or traumatic injury, and is potentially reducible with appropriate drug treatment. We previously reported that caffeic acid phenethyl ester (CAPE), a plant-derived polyphenolic compound, protected human umbilical vein endothelial cells (HUVEC) from menadione-induced oxidative stress and that this cytoprotective effect was correlated with the capacity to induce heme oxygenase-1 (HMOX1) and its protein product, a phase II cytoprotective enzyme. To further improve this cytoprotective effect, we studied a synthetic triterpenoid, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), which is known as a potent phase II enzyme inducer with antitumor and anti-inflammatory activities, and compared it to CAPE. CDDO-Im at 200nM provided more protection to HUVEC against oxidative stress than 20μM CAPE. We explored the mechanism of CDDO-Im cytoprotection with gene expression profiling and pathway analysis and compared to that of CAPE. In addition to potent up-regulation of HMOX1, heat shock proteins (HSP) were also found to be highly induced by CDDO-Im in HUVEC. Pathway analysis results showed that transcription factor Nrf2-mediated oxidative stress response was among the top canonical pathways commonly activated by both CDDO-Im and CAPE. Compared to CAPE, CDDO-Im up-regulated more HSP and some of them to a much higher extent. In addition, CDDO-Im treatment affected Nrf2 pathway more significantly. These findings may provide an explanation why CDDO-Im is a more potent cytoprotectant than CAPE against oxidative stress in HUVEC.


Minor and unsystematic cortical topographic changes of attention correlates between modalities.
In this study we analyzed the topography of induced cortical oscillations in 20 healthy individuals performing simple attention tasks. We were interested in qualitatively replicating our recent findings on the localization of attention-induced beta bands during a visual task [1], and verifying whether significant topographic changes would follow the change of attention to the auditory modality. We computed corrected latency averaging of each induced frequency bands, and modeled their generators by current density reconstruction with Lp-norm minimization. We quantified topographic similarity between conditions by an analysis of correlations, whereas the inter-modality significant differences in attention correlates were illustrated in each individual case. We replicated the qualitative result of highly idiosyncratic topography of attention-related activity to individuals, manifested both in the beta bands, and previously studied slow potential distributions [2]. Visual inspection of both scalp potentials and distribution of cortical currents showed minor changes in attention-related bands with respect to modality, as compared to the theta and delta bands, known to be major contributors to the sensory-related potentials. Quantitative results agreed with visual inspection, supporting to the conclusion that attention-related activity does not change much between modalities, and whatever individual changes do occur, they are not systematic in cortical localization across subjects. We discuss our results, combined with results from other studies that present individual data, with respect to the function of cortical association areas.


Mosquito vitellogenin genes: Comparative sequence analysis, gene duplication, and the role of rare synonymous codon usage in regulating expression.
Comparative sequence analysis of mosquito vitellogenin (Vg) genes was carried out to gain a better understanding of their evolution. The genomic clones of vitellogenin genes were isolated and sequenced from all three subfamilies of the family Culicidae including Culicinae (Aedes aegypti, Ochlerotatus atropalpus, Ae. polynesiensis, Ae. albopictus, Ochlerotatus triseriatus and Culex quinquefasciatus), Toxorhynchitinae (Toxorhynchites amboinensis), and Anophelinae (Anopheles albimanus). Genomic clones of vitellogenin genes Vg-B and Vg-C were isolated from Ae. aegypti and sequenced. A comparison of Vg-B and Vg-C, with the previously characterized vitellogenin gene, Vg-A1, suggests that Vg-A1 and Vg-B probably arose by a recent gene duplication, and Vg-C apparently diverged from the two other members of the gene family in an earlier gene duplication event. Two vitellogenin genes orthologous to Vg-C were cloned from a Cx. quinquefasciatus DNA library, one of which is truncated at the N-terminal end. Single vitellogenin genes, orthologous to Vg-C, were cloned from the An. albimanus and Tx. amboinensis libraries. Incomplete sequences orthologous to Vg-B and Vg-C were isolated from the Oc. atropalpus library. Only partial sequences were isolated from Ae. polynesiensis, Ae. albopictus and Oc. triseriatus. Inferred phylogenetic relationships based on analysis of these sequences suggest that Vg-C was the ancestral gene and that a recent gene duplication gave rise to Vg-A1 and Vg-B after the separation of the genus Aedes. The deduced amino acid composition of mosquito vitellogenin proteins exhibits higher tyrosine and phenylalanine composition than other mosquito proteins except for the hexamerin storage proteins. Analysis of vitellogenin coding sequences showed that a majority of amino acid substitutions were due to conserved and moderately conserved changes suggesting that the vitellogenins are under moderately selective constrains to maintain tertiary structure. The vitellogenin genes of the three anautogenous mosquitoes, that require a blood meal to develop eggs, had very high synonymous codon usage biases similar to highly expressed genes of other organisms. On the other hand, the vitellogenin genes of autogenous mosquitoes, that develop at least one batch of eggs without a blood meal, exhibited low synonymous codon usage bias. An unusual pattern of synonymous codon usage was observed in the first 15 amino acid residues encoding the signal peptide in the vitellogenin genes, where a high number of rarely used synonymous codons are present. It is hypothesized that rare synonymous codons have selectively accumulated in the signal peptide region to down-regulate the rate of translation initiation in the absence of a blood meal. Real-time PCR gene expression experiments showed that all three Ae. aegypti vitellogenin genes were highly expressed after a blood meal, and expressed in non-blood-fed females, males, larvae and pupae at trace levels. Sequences were deposited in GenBank (accession numbers: Ae. aegypti Vg-B, AY380797, Vg-C, AY373377; Oc. atropalpus Vg-B, AY691321, Vg-C, AY691322; Ae. polynesiensis Vg-A1, AY691318, Vg-B, AY691319, Vg-C, AY691320; Ae. albopictus Vg-A1, AY691316, Vg-C, AY691317; Oc. triseriatus Vg-C, AY691323; Cx. quinquefasciatus Vg-C1, AY691324, Vg-C2, AY691325; Tx. amboinensis Vg-C, AY691326; An. albimanus Vg-C, AY691327).


(CuxZn1-x)0.456In1.084Ge0.46O3 (0 ≤ x ≤ 1): A Complex, Ordered, Anion-Deficient Fluorite with Unusual Site-Specific Cation Mixing.
The anion-deficient fluorite-related family of materials exhibits a number of commercially useful properties arising from the specific arrangement of anion vacancies in each structure. One recently reported member, Zn0.456In1.084Ge0.46O3, is the only known example with its particular complex structure in which cation coordinations span one 4-coordinate (4b), two 6-coordinate (8e and 16f), and one 8-coordinate (4a) site. A new, complete, solid solution (CuxZn1-x)0.456In1.084Ge0.46O3, (0 ≤ x ≤ 1) has been discovered via the isovalent substitution of Cu2+ for Zn2+, significantly expanding the known phase space of this structure. Synchrotron X-ray data confirm the ZIGO structure over the entire composition range. Inclusion of Cu in the structure is found to occur exclusively at the 16f site, increasing the number of cations mixed on that site from three to four, while all others remain singly occupied, including the other 6-coordinate (8e) position. Furthermore, transmission electron microscopy investigations show no evidence of long-range cation ordering. Thus, disorder on the 16f site appears remarkably favorable in this otherwise highly ordered structure. Nonideal trends in the lattice parameters and diffuse reflectance spectra as a function of Cu content are examined. Further implications of the mixed order and disorder in the solid solution for materials discovery and possible properties of interest are briefly discussed.


Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases.
Connective tissue growth factor (CTGF) is known to be a potent angiogenic factor. Here we investigated how CTGF and matrix metalloproteinases (MMPs) are involved in the early stage of hypoxia-induced angiogenesis using human breast cancer cell line, MDA231, and vascular endothelial cells. Hypoxic stimulation (5% O(2)) of MDA231 cells increased their steady-state level of ctgf mRNA by approximately 2-fold within 1.5 h, and the levels remained at a plateau up to 6 h, and then decreased by 12 h as compared with the cells cultured under the normoxic condition. Membrane-type 1 MMP (MT1-MMP) mRNA levels was also increased within a few hours of the exposure to hypoxia. Indeed, ELISA revealed that the CTGF protein/cell in medium conditioned by MDA231 cells exposed to hypoxia was maximally greater at 24 h than in the medium from normoxic cultures and that the secretion rate (supernatant CTGF/cell layer CTGF) increased in a time-dependent manner from 24 to 72 h of hypoxic exposure. Hypoxic induction of CTGF was also confirmed by immunohistochemical analyses. Furthermore, zymogram analysis revealed that the production of active MMP-9 was also induced in MDA231 cells incubated under hypoxic conditions. Finally, we found that recombinant CTGF also increased the expression of a number of metalloproteinases that play a role in the vascular invasive processes and decreased the expression of tissue inhibitors of metalloproteinases by vascular endothelial cells. These findings suggest that hypoxia stimulates MDA231 cells to release CTGF as an angiogenic modulator, which initiates the invasive angiogenesis cascade by modulating the balance of extracellular matrix synthesis and degradation via MMPs secreted by endothelial cells in response to CTGF. This cascade may play critical roles in the hypoxia-induced neovascularization that accompanies tumor invasion in vivo.


The pancreas cancer microenvironment.
Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.


Broadband waveguide intersections with low cross talk in photonic crystal circuits.
We propose a new mechanism for constructing waveguide intersections with broad bandwidth and low cross talk in photonic crystal (PC) circuits. The intersections are created by combination of coupled-cavity wave-guides (CCWs) with conventional line-defect waveguides. This mechanism utilizes the strong dependence of the defect coupling on the field pattern in the defects and the alignment of the defects (i.e., the coupling angle) in CCWs. By properly designing the defect mode, we demonstrate through numerical simulation the establishment of such a waveguide intersection in one of the most useful PCs, which is based on a two-dimensional triangular lattice of air holes made in a dielectric material. The transmission of a 500-fs pulse at ~1.3 microm is simulated by use of the finite-difference time-domain method, showing negligible distortion and low cross talk.


Characterization of invasive Neisseria meningitidis strains isolated at the Children's Hospital of Tunis, Tunisia.
Neisseria meningitidis, a leading cause of bacterial meningitis and other serious infections, is responsible for approximately one-third of cases of bacterial meningitis in the Children's Hospital of Tunis. The serogroup distribution, antibiotic susceptibility and antigenic and molecular characteristics of N. meningitidis isolates were determined in patients aged 3 days-13 years between February 1998 and June 2013. In all 107 invasive strains of N. meningitidis were isolated. Reduced susceptibility to penicillin G was seen in 55.7% of isolates, with a low level of resistance in all cases; 28.4% showed a low level of resistance to amoxicillin. Serogroup B isolates were the most frequent (80.4%), followed by serogroups C (12.2%) and A (5.6%). Isolates of serogroup A had the same antigenic formula (A:4:P1.9), the same variable regions VR1, VR2 and VR3, and belonged to the same clonal complex (CC5). Isolates of serogroups B and C were more heterogeneous with several antigenic formulae. The most frequent clonal complex in these isolates was CC35. Serogroup B accounted for a large percentage of our isolates with marked diversity.


Multi-frame super-resolution algorithm for complex motion patterns.
Multi-frame super-resolution algorithms offer resolution enhancement for sequences of images with sampling limited resolution. However, classical approaches have been constrained by the accuracy of motion estimation while nonlocal approaches that use implicit motion estimation have attained only modest resolution improvement. In this paper, we propose a new multi-frame optical flow based super-resolution algorithm, which provides significant resolution enhancement for image sequences containing complex motion. The algorithm uses the standard camera image formation model and a variational super-resolution formulation with an anisotropic smoothness term adapting to local image structures. The key elements enabling super-resolution of complex motion patterns are the computation of two-way optical flow between the images and use of two corresponding uncertainty measures that approximate the optical flow interpolation error. Using the developed algorithm, we are able to demonstrate super-resolution of images for which optical flow estimation experiences near breakdown, due to the complexity of the motion patterns and the large magnitudes of the displacements. In comparison, we show that for these images some conventional super-resolution approaches fail, while others including nonlocal super-resolution technique produce distortions and provide lower (1-1.8 dB) image quality enhancement compared to the proposed algorithm.


The effect of pupil size and peripheral brightness on detection and discrimination performance.
It is easier to read dark text on a bright background (positive polarity) than to read bright text on a dark background (negative polarity). This positive-polarity advantage is often linked to pupil size: A bright background induces small pupils, which in turn increases visual acuity. Here we report that pupil size, when manipulated through peripheral brightness, has qualitatively different effects on discrimination of fine stimuli in central vision and detection of faint stimuli in peripheral vision. Small pupils are associated with improved discrimination performance, consistent with the positive-polarity advantage, but only for very small stimuli that are at the threshold of visual acuity. In contrast, large pupils are associated with improved detection performance. These results are likely due to two pupil-size related factors: Small pupils increase visual acuity, which improves discrimination of fine stimuli; and large pupils increase light influx, which improves detection of faint stimuli. Light scatter is likely also a contributing factor: When a display is bright, light scatter creates a diffuse veil of retinal illumination that reduces perceived image contrast, thus impairing detection performance. We further found that pupil size was larger during the detection task than during the discrimination task, even though both tasks were equally difficult and similar in visual input; this suggests that the pupil may automatically assume an optimal size for the current task. Our results may explain why pupils dilate in response to arousal: This may reflect an increased emphasis on detection of unpredictable danger, which is crucially important in many situations that are characterized by high levels of arousal. Finally, we discuss the implications of our results for the ergonomics of display design.


Knowledge discovery for Deep Phenotyping serious mental illness from Electronic Mental Health records.
Background: Deep Phenotyping is the precise and comprehensive analysis of phenotypic features in which the individual components of the phenotype are observed and described. In UK mental health clinical practice, most clinically relevant information is recorded as free text in the Electronic Health Record, and offers a granularity of information beyond what is expressed in most medical knowledge bases. The SNOMED CT nomenclature potentially offers the means to model such information at scale, yet given a sufficiently large body of clinical text collected over many years, it is difficult to identify the language that clinicians favour to express concepts. Methods: By utilising a large corpus of healthcare data, we sought to make use of semantic modelling and clustering techniques to represent the relationship between the clinical vocabulary of internationally recognised SMI symptoms and the preferred language used by clinicians within a care setting. We explore how such models can be used for discovering novel vocabulary relevant to the task of phenotyping Serious Mental Illness (SMI) with only a small amount of prior knowledge. Results: 20 403 terms were derived and curated via a two stage methodology. The list was reduced to 557 putative concepts based on eliminating redundant information content. These were then organised into 9 distinct categories pertaining to different aspects of psychiatric assessment. 235 concepts were found to be expressions of putative clinical significance. Of these, 53 were identified having novel synonymy with existing SNOMED CT concepts. 106 had no mapping to SNOMED CT. Conclusions: We demonstrate a scalable approach to discovering new concepts of SMI symptomatology based on real-world clinical observation. Such approaches may offer the opportunity to consider broader manifestations of SMI symptomatology than is typically assessed via current diagnostic frameworks, and create the potential for enhancing nomenclatures such as SNOMED CT based on real-world expressions.


A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms.
This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the "right particles" are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience. This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (email@example.com); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.


A global core outcome measurement set for snakebite clinical trials.
Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Five universal core outcome measures should be included in all future snakebite clinical trials-mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.


Development of Threat Expression Following Infant Maltreatment: Infant and Adult Enhancement but Adolescent Attenuation.
Early life maltreatment by the caregiver constitutes a major risk factor for the development of later-life psychopathologies, including fear-related pathologies. Here, we used an animal model of early life maltreatment induced by the Scarcity-Adversity Model of low bedding (LB) where the mother is given insufficient bedding for nest building while rat pups were postnatal days (PN) 8-12. To assess effects of maltreatment on the expression of threat-elicited defensive behaviors, animals underwent odor-shock threat conditioning at three developmental stages: late infancy (PN18), adolescence (PN45) or adulthood (>PN75) and tested the next day with odor only presentations (cue test). Results showed that in typically developing rats, the response to threat increases with maturation, although experience with maltreatment in early infancy produced enhanced responding to threat in infancy and adulthood, but a decrease in maltreated adolescents. To better understand the unique features of this decreased threat responding in adolescence, c-Fos expression was assessed within the amygdala and ventromedial prefrontal cortex (vmPFC) associated with the cued expression of threat learning. Fos counts across amygdala subregions were lower in LB rats compared to controls, while enhanced c-Fos expression was observed in the vmPFC prelimbic cortex (PL). Correlational analysis between freezing behavior and Fos revealed freezing levels were correlated with CeA in controls, although more global correlations were detected in LB-reared rats, including the BA, LA, and CeA. Functional connectivity analysis between brain regions showed that LB reared rats exhibited more diffuse interconnectivity across amygdala subnuclei, compared the more heterogeneous patterns observed in controls. In addition, functional connectivity between the IL and LA switched from positive to negative in abused adolescents. Overall, these results suggest that in adolescence, the unique developmental decrease in fear expression following trauma is associated with distinct changes in regional function and long-range connectivity, reminiscent of pathological brain function. These results suggest that early life maltreatment from the caregiver perturbs the developmental trajectory of threat-elicited behavior. Indeed, it is possible that this form of trauma, where the infant's safety signal or "safe haven" (the caregiver) is actually the source of the threat, produces distinct outcomes across development.


Reconstruction-free sensitive wavefront sensor based on continuous position sensitive detectors.
We propose a new device that is able to perform highly sensitive wavefront measurements based on the use of continuous position sensitive detectors and without resorting to any reconstruction process. We demonstrate experimentally its ability to measure small wavefront distortions through the characterization of pump-induced refractive index changes in laser material. In addition, it is shown using computer-generated holograms that this device can detect phase discontinuities as well as improve the quality of sharp phase variations measurements. Results are compared to reference Shack-Hartmann measurements, and dramatic enhancements are obtained.


Long-lived complexes between peptide and class II major histocompatibility complex are formed at low pH with no requirement for pH neutralization.
The binding of peptide antigens to class II histocompatibility glycoproteins can be markedly enhanced at pH values approximating those found in acidic endosomal compartments in antigen-presenting cells (APC). It has been proposed by others that low pH may increase the conformational flexibility of class II, facilitating both the association and dissociation of peptides. Neutralization of pH, as class II is expressed on the plasma membrane of APC, could then serve to trap peptide in a stable complex. If this were the only mechanism accounting for enhanced peptide binding at low pH, one would predict that there should be a concordance between the pH conditions required for enhanced binding and those associated with increased peptide dissociation. Furthermore, long-lived complexes of class II and peptide should not be observed at low pH without neutralization. In the present communization, I provide the data that support the generality of my previous conclusion that both affinity and maximal binding are regulated by pH in experiments using purified class II and biotin-labeled peptides. The pH profile for binding and dissociation using three different class II glycoproteins was analyzed, and the results demonstrated that enhanced binding is not coupled to enhanced dissociation. Peptide complexes were observed to be quite stable at pH 4.5 and above. This result was further substantiated in experiments where biotin-peptide/class II complexes were extensively dialyzed at low pH followed by analysis on Western blots probed with avidin. Finally, a low pH assay system was devised to analyze the formation of stable peptide/class II complexes without pH neutralization. Our results indicate that stable complexes can be formed at low pH without the requirement for a shift to neutral pH.