MGmapper: Reference based mapping and taxonomy annotation of metagenomics sequence reads.
An increasing amount of species and gene identification studies rely on the use of next generation sequence analysis of either single isolate or metagenomics samples. Several methods are available to perform taxonomic annotations and a previous metagenomics benchmark study has shown that a vast number of false positive species annotations are a problem unless thresholds or post-processing are applied to differentiate between correct and false annotations. MGmapper is a package to process raw next generation sequence data and perform reference based sequence assignment, followed by a post-processing analysis to produce reliable taxonomy annotation at species and strain level resolution. An in-vitro bacterial mock community sample comprised of 8 genuses, 11 species and 12 strains was previously used to benchmark metagenomics classification methods. After applying a post-processing filter, we obtained 100% correct taxonomy assignments at species and genus level. A sensitivity and precision at 75% was obtained for strain level annotations. A comparison between MGmapper and Kraken at species level, shows MGmapper assigns taxonomy at species level using 84.8% of the sequence reads, compared to 70.5% for Kraken and both methods identified all species with no false positives. Extensive read count statistics are provided in plain text and excel sheets for both rejected and accepted taxonomy annotations. The use of custom databases is possible for the command-line version of MGmapper, and the complete pipeline is freely available as a bitbucked package (https://bitbucket.org/genomicepidemiology/mgmapper). A web-version (https://cge.cbs.dtu.dk/services/MGmapper) provides the basic functionality for analysis of small fastq datasets.


Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation.
Considerable evidence indicates that the general blockade of protein synthesis prevents both the initial consolidation and the postretrieval reconsolidation of long-term memories. These findings come largely from studies of drugs that block ribosomal function, so as to globally interfere with both cap-dependent and -independent forms of translation. Here we show that intra-amygdala microinfusions of 4EGI-1, a small molecule inhibitor of cap-dependent translation that selectively disrupts the interaction between eukaryotic initiation factors (eIF) 4E and 4G, attenuates fear memory consolidation but not reconsolidation. Using a combination of behavioral and biochemical techniques, we provide both in vitro and in vivo evidence that the eIF4E-eIF4G complex is more stringently required for plasticity induced by initial learning than for that triggered by reactivation of an existing memory.


Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial.
Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723). 110 hospitals in 22 countries. 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80 mm Hg or greater; before and for 2 days after surgery, renin-angiotensin-aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130 mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60 mm Hg or greater; all antihypertensive medications were continued before and after surgery. The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P = 0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications. Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and Research Grant Council of Hong Kong.


Closed-Loop Active Compensation for Needle Deflection and Target Shift During Cooperatively Controlled Robotic Needle Insertion.
Intra-operative imaging is sometimes available to assist needle biopsy, but typical open-loop insertion does not account for unmodeled needle deflection or target shift. Closed-loop image-guided compensation for deviation from an initial straight-line trajectory through rotational control of an asymmetric tip can reduce targeting error. Incorporating robotic closed-loop control often reduces physician interaction with the patient, but by pairing closed-loop trajectory compensation with hands-on cooperatively controlled insertion, a physician's control of the procedure can be maintained while incorporating benefits of robotic accuracy. A series of needle insertions were performed with a typical 18G needle using closed-loop active compensation under both fully autonomous and user-directed cooperative control. We demonstrated equivalent improvement in accuracy while maintaining physician-in-the-loop control with no statistically significant difference (p > 0.05) in the targeting accuracy between any pair of autonomous or individual cooperative sets, with average targeting accuracy of 3.56 mmrms. With cooperatively controlled insertions and target shift between 1 and 10 mm introduced upon needle contact, the system was able to effectively compensate up to the point where error approached a maximum curvature governed by bending mechanics. These results show closed-loop active compensation can enhance targeting accuracy, and that the improvement can be maintained under user directed cooperative insertion.


Booming far: the long-range vocal strategy of a lekking bird.
The pressures of selection acting on transmission of information by acoustic signals are particularly high in long-distance communication networks. Males of the North African houbara bustard (Chlamydotis undulata undulata) produce extremely low-frequency vocalizations called 'booms' as a component of their courtship displays. These displays are performed on sites separated by a distance of on average 550 m, constituting exploded leks. Here, we investigate the acoustic features of booms involved in species-specific identity. We first assessed the modifications of acoustic parameters during boom transmission at long range within the natural habitat of the species, finding that the frequency content of booms was reliably transmitted up to 600 m. Additionally, by testing males' behavioural responses to playbacks of modified signals, we found that the presence of the second harmonic and the frequency modulation are the key parameters for species identification, and also that a sequence of booms elicited stronger responses than a single boom. Thus, the coding-decoding process relies on redundant and propagation-resistant features, making the booms particularly well adapted for the long-range transmission of information between males. Moreover, by experimentally disentangling the presentation of visual and acoustic signals, we showed that during the booming phase of courtship, the two sensory modalities act in synergy. The acoustic component is dominant in the context of intra-sexual competition. While the visual component is not necessary to induce agonistic response, it acts as an amplifier and reduces the time of detection of the signaller. The utilization of these adaptive strategies allows houbara males to maximize the active space of vocalizations emitted in exploded leks.


Biocompatibility and microstructural analysis of osteopromotive property of allogenic demineralized dentin matrix.
Bone grafting materials and methods have been used to compensate anatomical limitations and improve ridge and sinus structure for implant placement. The objective of this study was to evaluate the osteopromotive property of allogenic demineralized dentin matrix (DDM) as a bone grafting material using micro-computed tomography and blood biomarkers. Two surgical bone defects were created on the skull of 30 female New Zealand White rabbits. Experimental defects in 24 rabbits were filled with allogenic DDM applying guided bone regeneration technique, while the control defects were covered by membrane without receiving the graft. In the remaining six rabbits, both defects were left empty and these rabbits served as control for blood biomarkers. The 24 experimental rabbits were sacrificed after 15, 30, 60, and 90 days (n = 6 at each time point). Blood samples were collected from all rabbits at the baseline, 48 hours postsurgery, and at each time point. Bone thickness was significantly higher in the experimental group at all time points. Micro-computed tomography results showed increased bone mass and superior bone quality in the experimental group. At all time points except for 48 hours postsurgery, the white blood cell count was numerically higher in control rabbits compared to experimental rabbits, suggesting a lack of inflammation or infection due to allogenic DDM. Bone-specific alkaline phosphatase activities were lower in both experimental and control groups at all time points in comparison to baseline values, which is indicative of either a lower rate of bone formation or bone turnover. Within the limitations of this study, allogenic demineralized dentin matrix significantly increased bone mass and improved bone quality without causing an inflammatory reaction or infection.


Adaptive exposure estimation for high dynamic range imaging applied to natural scenes and daylight skies.
Digital imaging of natural scenes and optical phenomena present on them (such as shadows, twilights, and crepuscular rays) can be a very challenging task because of the range spanned by the radiances impinging on the capture system. We propose a novel method for estimating the set of exposure times (bracketing set) needed to capture the full dynamic range of a scene with high dynamic range (HDR) content. The proposed method is adaptive to scene content and to any camera response and configuration, and it works on-line since the exposure times are estimated as the capturing process is ongoing. Besides, it requires no a priori information about scene content or radiance values. The resulting bracketing sets are minimal in the default method settings, but the user can set a tolerance for the maximum percentage of pixel population that is underexposed or saturated, which allows for a higher number of shots if a better signal-to-noise ratio (SNR) in the HDR scene is desired. This method is based on the use of the camera response function that is needed for building the HDR radiance map by stitching together several differently exposed low dynamic range images of the scene. The use of HDR imaging techniques converts our digital camera into a tool for measuring the relative radiance outgoing from each point of the scene, and for each color channel. This is important for accurate characterization of optical phenomena present in the atmosphere while not suffering any loss of information due to its HDR. We have compared our method with the most similar one developed so far [IEEE Trans. Image Process.17, 1864 (2008)]. Results of the experiments carried out for 30 natural scenes show that our proposed method equals or outperforms the previously developed best approach, with less shots and shorter exposure times, thereby asserting the advantage of being adaptive to scene content for exposure time estimation. As we can also tune the balance between capturing time and the SNR in our method, we have compared its SNR performance against that of Barakat's method as well as against a ground-truth HDR image of maximum SNR. Results confirm the success of the proposed method in exploiting its tunability to achieve the desired balance of total Δt and SNR.


Bacteraemia in homozygous sickle cell disease in Africa: is pneumococcal prophylaxis justified?
The high frequency of Streptococcus pneumoniae as a cause of bacteraemia in homozygous sickle cell (SS) disease and its effective prevention has led to the routine use of pneumococcal prophylaxis in developed countries. The reported infrequency of this organism as a cause of bacteraemia in SS disease in Africa raises questions on the epidemiology of bacterial infection and on the need for pneumococcal prophylaxis in that continent. A study of blood cultures in 155 Ugandan children (165 episodes) with SS disease and axillary temperatures of > or =38 degrees C, attending the University Teaching Hospital in Kampala (Uganda, East Africa). Positive blood cultures, obtained in 47/165 episodes, showed Staphylococcus aureus in 28 (60%) samples, Haemophilus influenzae in 9 (19%), Staphylococcus epidermidis in 4 (9%), and single cases of Streptococcus viridans, Escherichia coli and an unidentified Gram negative rod. Streptococcus pneumoniae was identified in only 3 (6%) episode. The infrequent isolation of Streptococcus pneumoniae from febrile children with SS disease in this study and in four other studies from Nigeria raises questions on a different spectrum of bacterial causes for bacteraemia in malarial areas. There are several possible explanations for this finding, but the data cast sufficient doubt on the case for pneumococcal prophylaxis for a controlled trial on its effectiveness in that environment to seem justified. These data are necessary to determine its role in African children and to provide the evidence base for healthcare authorities in equatorial Africa.


Measuring executive function skills in young children in Kenya.
Interest in measuring executive function skills in young children in low- and middle-income country contexts has been stymied by the lack of assessments that are both easy to deploy and scalable. This study reports on an initial effort to develop a tablet-based battery of executive function tasks, which were designed and extensively studied in the United States, for use in Kenya. Participants were 193 children, aged 3-6 years old, who attended early childhood development and education centers. The rates of individual task completion were high (65-100%), and 85% of children completed three or more tasks. Assessors indicated that 90% of all task administrations were of acceptable quality. An executive function composite score was approximately normally distributed, despite higher-than-expected floor and ceiling effects on inhibitory control tasks. Children's simple reaction time (β = -0.20, p = .004), attention-related behaviors during testing (β = 0.24, p = .0005), and age (β = -0.24, p = .0009) were all uniquely related to performance on the executive function composite. Results are discussed as they inform efforts to develop valid and reliable measures of executive function skills among young children in developing country contexts.


ALOX12 gene is associated with the onset of natural menopause in white women.
Natural menopause is a key physiological event in a woman's life. Timing of menopause affects risk for many postmenopausal systemic disorders and may thus influence life expectancy. Age at natural menopause (ANM) is largely determined genetically, but a list of candidate genes is far from complete. This study investigated the ALOX12 gene for its possible association with ANM. Six single-nucleotide polymorphisms (SNPs) of the gene (rs9904779, rs2073438, rs11571340, rs434473, rs2307214, and rs312462) were genotyped in a random sample of 210 unrelated white women. The SNPs and common haplotypes were then analyzed for their association with ANM. Smoking, alcohol consumption, and duration of breast-feeding were used as covariates. Two SNPs, rs9904779 and rs434473 (encodes a replacement of asparagine by serine in the protein), were significantly associated with ANM (P = 0.022 and 0.033, respectively). The minor alleles of both SNPs seem to promote about 1.3- to 1.5-year earlier menopause and confer a 1.6 to 1.8 times higher risk for early menopause. All SNPs indicated significant or nearly significant interactions with alcohol use and duration of breast-feeding. Five common haplotypes were also associated with ANM. The ALOX12 gene seems to be associated with the timing of natural menopause in white women.


Cytomegalovirus-specific CD4 and CD8 T cell responses in infants and children.
Congenital cytomegalovirus (CMV) infection is the most common congenital infection causing childhood morbidity. The pathogenetic mechanisms behind long-term sequelae are unclear, but long-standing viremia as a consequence of the inability to convert the virus to a latent state has been suggested to be involved. Whereas primary CMV infection in adults is typically rapidly controlled by the immune system, children have been shown to excrete virus for years. Here, we compare T cell responses in children with congenital CMV infection, children with postnatal CMV infection and adults with symptomatic primary CMV infection. The study groups included 24 children with congenital CMV infection, 19 children with postnatal CMV infection and eight adults with primary CMV infection. Among the infants with congenital CMV infection, 13 were symptomatic. T cell responses were determined by analysis of interferon gamma production after stimulation with CMV antigen. Our results show that whereas adults display high CMV-specific CD4 T cell responses in the initial phase of the infection, children younger than 2 years have low or undetectable responses that appear to increase with time. There were no differences between groups with regard to CD8 T cell function. In conclusion, inadequate CD 4 T cell function seems to be involved in the failure to get immune control of the CMV infection in children younger than 2 years of age with congenital as well as postnatal CMV infection.


IR, NIR, and UV Absorption Spectroscopy of C60(2+) and C60(3+) in Neon Matrixes.
C60(2+) and C60(3+) were produced by electron-impact ionization of sublimed C60 and charge-state-selectively codeposited onto a gold mirror substrate held at 5 K together with neon matrix gas containing a few percent of the electron scavengers CO2 or CCl4. This procedure limits charge-changing of the incident fullerene projectiles during matrix isolation. IR, NIR, and UV-vis spectra were then measured. Ten IR absorptions of C60(2+) were identified. C60(3+) was observed to absorb in the NIR region close to the known vibronic bands of C60(+). UV spectra of C60, C60(+), and C60(2+) were almost indistinguishable, consistent with a plasmon-like nature of their UV absorptions. The measurements were supported by DFT and TDDFT calculations, revealing that C60(2+) has a singlet D5d ground state whereas C60(3+) forms a doublet of Ci symmetry. The new results may be of interest regarding the presence of C60(2+) and C60(3+) in space.


Spatially resolved metabolic phenotyping of breast cancer by desorption electrospray ionization mass spectrometry.
Breast cancer is a heterogeneous disease characterized by varying responses to therapeutic agents and significant differences in long-term survival. Thus, there remains an unmet need for early diagnostic and prognostic tools and improved histologic characterization for more accurate disease stratification and personalized therapeutic intervention. This study evaluated a comprehensive metabolic phenotyping method in breast cancer tissue that uses desorption electrospray ionization mass spectrometry imaging (DESI MSI), both as a novel diagnostic tool and as a method to further characterize metabolic changes in breast cancer tissue and the tumor microenvironment. In this prospective single-center study, 126 intraoperative tissue biopsies from tumor and tumor bed from 50 patients undergoing surgical resections were subject to DESI MSI. Global DESI MSI models were able to distinguish adipose, stromal, and glandular tissue based on their metabolomic fingerprint. Tumor tissue and tumor-associated stroma showed evident changes in their fatty acid and phospholipid composition compared with normal glandular and stromal tissue. Diagnosis of breast cancer was achieved with an accuracy of 98.2% based on DESI MSI data (PPV 0.96, NVP 1, specificity 0.96, sensitivity 1). In the tumor group, correlation between metabolomic profile and tumor grade/hormone receptor status was found. Overall classification accuracy was 87.7% (PPV 0.92, NPV 0.9, specificity 0.9, sensitivity 0.92). These results demonstrate that DESI MSI may be a valuable tool in the improved diagnosis of breast cancer in the future. The identified tumor-associated metabolic changes support theories of de novo lipogenesis in tumor tissue and the role of stroma tissue in tumor growth and development and overall disease prognosis.


Ultrafast Method for the Analysis of Fluorescence Lifetime Imaging Microscopy Data Based on the Laguerre Expansion Technique.
We report a new deconvolution method for fluorescence lifetime imaging microscopy (FLIM) based on the Laguerre expansion technique. The performance of this method was tested on synthetic and real FLIM images. The following interesting properties of this technique were demonstrated. 1) The fluorescence intensity decay can be estimated simultaneously for all pixels, without a priori assumption of the decay functional form. 2) The computation speed is extremely fast, performing at least two orders of magnitude faster than current algorithms. 3) The estimated maps of Laguerre expansion coefficients provide a new domain for representing FLIM information. 4) The number of images required for the analysis is relatively small, allowing reduction of the acquisition time. These findings indicate that the developed Laguerre expansion technique for FLIM analysis represents a robust and extremely fast deconvolution method that enables practical applications of FLIM in medicine, biology, biochemistry, and chemistry.


Assortative mixing in close-packed spatial networks.
In recent years, there is aroused interest in expressing complex systems as networks of interacting nodes. Using descriptors from graph theory, it has been possible to classify many diverse systems derived from social and physical sciences alike. In particular, folded proteins as examples of self-assembled complex molecules have also been investigated intensely using these tools. However, we need to develop additional measures to classify different systems, in order to dissect the underlying hierarchy. In this study, a general analytical relation for the dependence of nearest neighbor degree correlations on degree is derived. Dependence of local clustering on degree is shown to be the sole determining factor of assortative versus disassortative mixing in networks. The characteristics of networks constructed from spatial atomic/molecular systems exemplified by self-organized residue networks built from folded protein structures and block copolymers, atomic clusters and well-compressed polymeric melts are studied. Distributions of statistical properties of the networks are presented. For these densely-packed systems, assortative mixing in the network construction is found to apply, and conditions are derived for a simple linear dependence. Our analyses (i) reveal patterns that are common to close-packed clusters of atoms/molecules, (ii) identify the type of surface effects prominent in different close-packed systems, and (iii) associate fingerprints that may be used to classify networks with varying types of correlations.


Synthetic lethality of rpn11-1 rpn10Δ is linked to altered proteasome assembly and activity.
An rpn11-1 temperature-sensitive mutant shows defect in proteolysis, mitochondrial function and proteasome assembly. The Rpn11 protein is a proteasome subunit that deubiquitinates proteolytic substrates. Multiubiquitinated proteins interact with proteasome receptors, such as Rpn10, which intriguingly is also required for promoting proteasome stability. We report here that Rpn10 binds Rpn11, and genetic studies revealed synthetic lethality of an rpn11-1 rpn10Δ double mutant. The carboxy-terminus of Rpn11 is critical for function, as deletion of 7 C-terminal residues prevented suppression of rpn11-1 rpn10Δ. Native gel electrophoresis showed increased levels of the proteasome 20S catalytic particle in rpn11-1 rpn10Δ, and altered assembly. The inviability of rpn11-1 rpn10Δ was suppressed by rpn10(uim), a mutant that can bind the proteasome, but not multiubiquitin chains. rpn10(uim) reduced the levels of free 20S, and increased formation of intact proteasomes. In contrast, rpn10(vwa), which binds multiubiquitin chains but not the proteasome, failed to suppress rpn11-1 rpn10Δ. Moreover, high levels of multiubiquitinated proteins were bound to rpn10(vwa), but were not delivered to the proteasome. Based on these findings, we propose that the lethality of rpn11-1 rpn10Δ results primarily from altered proteasome integrity. It is conceivable that Rpn10/Rpn11 interaction couples proteasome assembly to substrate binding.


T cells in tumor microenvironment.
Tumors progress in a specific area, which supports its development, spreading or shrinking in time with the presence of different factors that effect the fate of the cancer cells. This specialized site is called "tumor microenvironment" and has a composition of heterogenous materials. The immune cells are also residents of this stromal, cancerous, and inflammatory environment, and their types, densities, or functional differences are one of the key factors that mediate the fate of a tumor. T cells as a vital part of the immune system also are a component of tumor microenvironment, and their roles have been elucidated in many studies. In this review, we focused on the immune system components by focusing on T cells and detailed T helper cell subsets in tumor microenvironment and how their behaviors affect either the tumor or the patient's outcome.


Biomarkers for early detection of Alzheimer disease.
The existence of an effective biomarker for early detection of Alzheimer disease would facilitate improved diagnosis and stimulate therapeutic trials. Multidisciplinary clinical diagnosis of Alzheimer disease is time consuming and expensive and relies on experts who are rarely available outside of specialty clinics. Thus, many patients do not receive proper diagnosis until the disease has progressed beyond stages in which treatments are maximally effective. In the clinical trial setting, rapid, cost-effective screening of patients for Alzheimer disease is of paramount importance for the development of new treatments. Neuroimaging of cortical amyloid burden and volumetric changes in the brain and assessment of protein concentrations (eg, β-amyloid 1-42, total tau, phosphorylated tau) in cerebrospinal fluid are diagnostic tools that are not widely available. Known genetic markers do not provide sufficient discriminatory power between different forms of dementia to be useful in isolation. Recent studies using panels of biomarkers for diagnosis of Alzheimer disease or mild cognitive impairment have been promising, though no such studies have been cross-validated in independent samples of subjects. The ideal biomarker enabling early detection of Alzheimer disease has not yet been identified.


Novel Therapeutic Approaches for the Treatment of Retinal Degenerative Diseases: Focus on CRISPR/Cas-Based Gene Editing.
Inherited retinal diseases encompass a highly heterogenous group of disorders caused by a wide range of genetic variants and with diverse clinical symptoms that converge in the common trait of retinal degeneration. Indeed, mutations in over 270 genes have been associated with some form of retinal degenerative phenotype. Given the immune privileged status of the eye, cell replacement and gene augmentation therapies have been envisioned. While some of these approaches, such as delivery of genes through recombinant adeno-associated viral vectors, have been successfully tested in clinical trials, not all patients will benefit from current advancements due to their underlying genotype or phenotypic traits. Gene editing arises as an alternative therapeutic strategy seeking to correct mutations at the endogenous locus and rescue normal gene expression. Hence, gene editing technologies can in principle be tailored for treating retinal degeneration. Here we provide an overview of the different gene editing strategies that are being developed to overcome the challenges imposed by the post-mitotic nature of retinal cell types. We further discuss their advantages and drawbacks as well as the hurdles for their implementation in treating retinal diseases, which include the broad range of mutations and, in some instances, the size of the affected genes. Although therapeutic gene editing is at an early stage of development, it has the potential of enriching the portfolio of personalized molecular medicines directed at treating genetic diseases.


Clinical placements in mental health: a literature review.
Gaining experience in clinical mental health settings is central to the education of health practitioners. To facilitate the ongoing development of knowledge and practice in this area, we performed a review of the literature on clinical placements in mental health settings. Searches in Academic Search Complete, CINAHL, Medline and PsycINFO databases returned 244 records, of which 36 met the selection criteria for this review. Five additional papers were obtained through scanning the reference lists of those papers included from the initial search. The evidence suggests that clinical placements may have multiple benefits (e.g. improving students' skills, knowledge, attitudes towards people with mental health issues and confidence, as well as reducing their fears and anxieties about working in mental health). The location and structure of placements may affect outcomes, with mental health placements in non-mental health settings appearing to have minimal impact on key outcomes. The availability of clinical placements in mental health settings varies considerably among education providers, with some students completing their training without undertaking such structured clinical experiences. Students have generally reported that their placements in mental health settings have been positive and valuable experiences, but have raised concerns about the amount of support they received from education providers and healthcare staff. Several strategies have been shown to enhance clinical placement experiences (e.g. providing students with adequate preparation in the classroom, implementing learning contracts and providing clinical supervision). Educators and healthcare staff need to work together for the betterment of student learning and the healthcare professions.


Severe T2-high asthma in the biologics era: European experts' opinion.
The European Respiratory Biologics Forum gathered participants from 21 countries in Madrid, Spain, to discuss the management and treatment of severe asthma in the era of biologics. The current insights on the pathophysiology of severe asthma were discussed, as well as the role of respiratory biologics in clinical practice and strategies for eliminating chronic use of oral corticosteroids. The participants also highlighted the key challenges in identifying patients with severe asthma based on phenotypes, biomarkers and treatable traits, and the existing problems in patient referral to specialist care. The monitoring of treatment was debated and the need for a change towards precision medicine and personalised care was emphasised throughout the meeting. This review provides a summary of the discussions and highlights important concerns identified by the participants regarding the current management of severe asthma.


Empirical correlation between protein backbone 15N and 13C secondary chemical shifts and its application to nitrogen chemical shift re-referencing.
The linear analysis of chemical shifts (LACS) has provided a robust method for identifying and correcting 13C chemical shift referencing problems in data from protein NMR spectroscopy. Unlike other approaches, LACS does not require prior knowledge of the three-dimensional structure or inference of the secondary structure of the protein. It also does not require extensive assignment of the NMR data. We report here a way of extending the LACS approach to 15N NMR data from proteins, so as to enable the detection and correction of inconsistencies in chemical shift referencing for this nucleus. The approach is based on our finding that the secondary 15N chemical shift of the backbone nitrogen atom of residue i is strongly correlated with the secondary chemical shift difference (experimental minus random coil) between the alpha and beta carbons of residue i-1. Thus once alpha and beta 13C chemical shifts are available (their difference is referencing error-free), the 15N referencing can be validated, and an appropriate offset correction can be derived. This approach can be implemented prior to a structure determination and can be used to analyze potential referencing problems in database data not associated with three-dimensional structure. Application of the LACS algorithm to the current BMRB protein chemical shift database, revealed that nearly 35% of the BMRB entries have delta 15N values mis-referenced by over 0.7 ppm and over 25% of them have delta 1HN values mis-referenced by over 0.12 ppm. One implication of the findings reported here is that a backbone 15N chemical shift provides a better indicator of the conformation of the preceding residue than of the residue itself.


The effects of retiree health insurance plan characteristics on retirees' choice and employers' costs.
To moderate the rate of growth of retiree health insurance costs, employers can modify plans and move retirees into less expensive plans. We examine policy modifications implemented by the North Carolina State Health Plan. We investigate whether incentives produce the desired plan elections and whether these changes, along with cost shifting, produce the expected reductions in cost growth. Using individual-level administrative data, along with aggregated data on expenditures for retirees, we estimate the effects of the introduction and subsequent repeal of a Comprehensive Wellness Initiative for non-Medicare eligible retirees, as well as increases in coinsurance and copayments and the introduction of a premium for all retirees. Over a third of non-Medicare retirees shifted into the least generous plan between June 2009 and December 2012. The level effects on annual costs and unfunded accrued liabilities were relatively modest, but growth rates were diminished. Increases in the retiree premiums reduced the state's projected costs.


Seagrass Posidonia oceanica diel pH fluctuations reduce the mortality of epiphytic forams under experimental ocean acidification.
It is hypothesized that pH fluctuations produced by seagrasses metabolism may confer marine calcifiers resistance to ocean acidification. Here, we tested this thesis by comparing the net population growth rate (NPGR) of a foraminifer species (Rosalina sp.) epiphytic of Mediterranean seagrass (Posidonia oceanica) to average current and projected pH scenarios under either stable conditions or diel fluctuations in pH of 0.3 units; variations similar to that experienced in their habitat. No significant differences were found in NPGRs between the fluctuating and stable pH treatments at current pH levels. NPGRs in treatments where pH fluctuated did not present significant differences to the treatment with high and stable pH conditions. In contrast, foraminifers exposed to stable low pH regimes experienced a steep decline in NPGR. These results suggest that diel pH fluctuations generated by P. oceanica photosynthetic activity could confer resistance to ocean acidification to Rosalina sp.


Intrarenal arteries in rats with early two-kidney, one clip hypertension.
Structural arterial adaptation and decompensation were studied in the contralateral untouched kidneys of two-kidney, one clip hypertensive rats 1 to 64 days after constricting one renal artery. Focal necroses of intrarenal arteries were observed as early as 24 hours after starting the experiment. The necroses reached their maximum on Day 8 and thereafter decreased significantly in spite of still increasing blood pressure values. After 8 days the media thickness of the interlobular arteries was significantly increased by more than 30% and remained so until the end of the experiment. Blood pressure levels as measured by tail plethysmography were nearly normal within the first 4 days. The continuous 24-hour blood pressure recording in the conscious rats, however, showed shortlasting intermittent hypertensive spikes as early as 6 hours after renal artery constriction. In spite of these acute hypertensive peaks, which frequently exceeded 200 mm Hg, intimal lesions, potentially leading to malignant nephrosclerosis, began to appear after only 2 weeks. Thus, the development of nonobliterating, acute focal necroses of intrarenal arteries in the earliest stage of two-kidney, one clip hypertension may be explained by intermittent hypertensive episodes accompanied by a segmental overstretching of the nonadapted vascular bed. On the other hand, the occurrence of obliterating malignant nephrosclerosis in the presence of severe hypertension may also depend on the previously changed composition of the vessel walls.


Relation between small intestinal motor activity and transit in secretory diarrhea.
Our objective in this study was to correlate small intestinal motor activity with transit time in the fed state under normal conditions and in the secretory state induced by cholera toxin. In the control state, transit time was strongly and inversely correlated with the mean distance of propagation and to a lesser degree with frequency and total duration of all contractions. By contrast, transit time was not correlated with total amplitude and area of all contractions. When contractions were separated into propagating and nonpropagating contractions, there was a highly significant inverse correlation between transit time and all parameters of propagating contractions but no relation with any parameter of nonpropagating contractions. Similar results were obtained during the secretory state induced by cholera toxin. The control data were used to develop a mathematical model to predict transit time from contractile parameters and was validated using the data obtained in the secretory state. Our findings demonstrate that transit through the small intestine in the normal and secretory states is strongly related to the parameters of propagating contractions but not to parameters of nonpropagating contractions.


Overcoming Organizational Challenges of Integrating Patient-Reported Outcomes in Oncology Clinical Trials.
Patients with cancer frequently experience multiple symptoms that may cause significant distress and may impair physical, emotional, and social functioning and health-related quality of life. Drug development in oncology is characterized by a high attrition rate of new compounds, faster development times encouraged by the regulatory process, studies that are often open and single-arm, and emphasis on survival-related endpoints, creating unique challenges for the inclusion of patient reported outcomes (PROs). These challenges to include PRO-related endpoints in oncology research are further exacerbated by downward pressure on budget and resources and also an overly rigorous application of the US Food and Drug Administration's PRO guidance, which can in turn prevent study teams from optimally including PROs in oncology clinical trials. With increasing calls for demonstration of value of new cancer drugs from payers, patients, and their caregivers, study teams should consider the utility of PROs beyond regulatory needs. Optimal implementation of a PRO strategy in oncology research can be achieved by applying the PRO guidance to the greatest extent possible, making use of off-the-shelf PRO measures to capture concepts of interest, discussing plans with the regulatory bodies early in the process, and treating PRO-related endpoints with the same level of rigor as other endpoints.


Method development for PPB culture screening, pigment analysis with UPLC-UV-HRMS vs. spectrophotometric methods, and spectral decomposition-based analysis.
PPB carotenoids are usually measured through spectrophotometric analysis, measuring total carotenoids (TCs) which has low accuracy and cannot identify individual carotenoids or isomers. Here, we developed an ultra-performance liquid chromatography method with ultraviolet and high-resolution mass spectrometry detection (UPLC-UV-HRMS) to quantify neurosporene, lycopene, and bacteriochlorophyll a contents in PPB cultures. The method exhibited satisfactory recoveries for individual pigments (between 82.1% and 99.5%) and was applied to a range of mixed PPB cultures. The use of a C30 column also enabled the detection of three different isomers of lycopene. In addition, a method for anaerobic photoheterotrophic PPB cultivation to acquire live-cell spectrophotometric information was developed and tested by modifying a standard microbial culture microplate system. A rapid, and relatively low effort principal component analysis (PCA) based decomposition of the whole-cell spectra for pigment analysis in the microplates was also developed. Analysing whole-cell spectra via PCA allowed more accurate prediction of individual pigments compared to absorption methods, and can be done non-destructively, during live-cell growth, but requires calibration for new media and microbial matrices.


Prostaglandins and leukotrienes: advances in eicosanoid biology.
Prostaglandins and leukotrienes are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and actions are blocked by clinically relevant nonsteroidal anti-inflammatory drugs, the newer generation coxibs (selective inhibitors of cyclooxygenase-2), and leukotriene modifiers. The prime mode of prostaglandin and leukotriene action is through specific G protein-coupled receptors, many of which have been cloned recently, thus enabling specific receptor agonist and antagonist development. Important insights into the mechanisms of inflammatory responses, pain, and fever have been gleaned from our current understanding of eicosanoid biology.


Prognostic significance of interleukin-8 and CD163-positive cell-infiltration in tumor tissues in patients with oral squamous cell carcinoma.
We investigated whether serum interleukin (IL)-8 reflects the tumor microenvironment and has prognostic value in patients with oral squamous cell carcinoma (OSCC). Fifty OSCC patients who received radical resection of their tumor(s) were enrolled. Preoperative sera were measured for IL-8 by ELISA. Expression of IL-8 and the infiltration of immune cells in tumor tissues were analyzed by an immunohistochemical staining of surgical specimens. We found that disease-free survival (DFS) was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p = 0.001). The tumor expression of IL-8, i.e., IL-8(T) and the density of CD163-positive cells in the tumor invasive front, i.e., CD163(IF) were correlated with the serum IL-8 level (p = 0.033 and p = 0.038, respectively), and they were associated with poor clinical outcome (p = 0.007 and p = 0.002, respectively, in DFS) in all patients. A multivariate analysis revealed that N status, IL-8(T) and CD163(IF) significantly affected the DFS of the patients. Further analysis suggested that combination of N status with serum IL-8, IL-8(T) or CD163(IF) may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Interestingly, the in vitro experiments demonstrated that IL-8 enhanced generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10. These findings indicate that IL-8 may be involved in poor clinical outcomes via generation of CD163-positive M2 macrophages, and that these factors in addition to N status may have prognostic value in patients with resectable OSCSS.


Cardiovascular effects of antihypertensive polar and neutral renomedullary lipids.
Two antihypertensive lipids can be extracted from fresh renal medulla. One is polar (the antihypertensive polar renomedullary lipid, or APRL) and the other is nonpolar (the antihypertensive neutral renomedullary lipid, or ANRL). APRL and ANRL differ in their biologic activities: APRL in bolus intravenous injections causes a very rapid decline in the arterial pressure (AP) while ANRL, after a lag of 2 minutes, causes a slower decline in AP. APRL increases heart rate and sympathetic activity. ANRL decreases heart rate and sympathetic activity. ANRL appears to convert to APRL, under certain in vitro circumstances, suggesting that the structure of the two molecules is related. ANRL and APRL appear in the renal venous effluent after unclipping; biologically, ANRL seems dominant. The renal venous effluent of the unclipped isolated kidney lowers the HR and sympathetic activity of the normal rat. Unclipping degranulates the renomedullary interstitial cells (RIC). The antihypertensive effect of unclipping appears due to the secretion of ANRL and APRL by the kidney. It is concluded that ANRL seems to be the antihypertensive hormone of the RIC.


Structural diversity and spectral and thermal properties of the first alkaline earth metal tetracyanidoborates: [Mg(H₂O)₆][B(CN)₄]₂, [Mg(H₂O)₂][B(CN)₄]₂, [Mg(DMF)₆][B(CN)₄]₂, [Ca(H₂O)₃][B(CN)₄]₂, and [Ca(H₂O)₂(CH₃CN)][B(CN)₄]₂.
The first members of tetracyanidoborate salts with alkaline earth cations, [Mg(H2O)6][B(CN)4]2 (1), [Mg(H2O)2][B(CN)4]2 (2), [Mg(DMF)6][B(CN)4]2 (3), [Ca(H2O)3][B(CN)4]2 (4), and [Ca(H2O)2(CH3CN)][B(CN)4]2 (5), were synthesized. Their structures, obtained by single crystal X-ray diffraction, IR- and Raman spectra, as well as their thermal properties were determined. Whereas 1 and 3 consist of isolated ions, the other three compounds comprise coordination polymers. IR and Raman spectra give information about the coordination modes of the respective tetracyanidoborate anions. Calorimetric measurements show that the coordinated solvent molecules can be removed at elevated temperatures and anhydrous/solvent free compounds form. The anhydrous compounds are thermally very stable. They do not start to decompose below 500 °C. No melting is observed below decomposition.


Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin.
The fate of double-stranded RNA (dsRNA) in the cell depends on both its length and location . The expression of dsRNA in the nucleus leads to several distinct consequences. First, the promiscuous deamination of adenosines to inosines by dsRNA-specific adenosine deaminase (ADAR) can lead to the nuclear retention of edited transcripts . Second, dsRNAs might induce heterochromatic gene silencing through an RNAi-related mechanism . Is RNA editing also connected to heterochromatin? We report that members of the conserved Vigilin class of proteins have a high affinity for inosine-containing RNAs. In agreement with other work , we find that these proteins localize to heterochromatin and that mutation or depletion of the Drosophila Vigilin, DDP1, leads to altered nuclear morphology and defects in heterochromatin and chromosome segregation. Furthermore, nuclear Vigilin is found in complexes containing not only the editing enzyme ADAR1 but also RNA helicase A and Ku86/70. In the presence of RNA, the Vigilin complex recruits the DNA-PKcs enzyme, which appears to phosphorylate a discrete set of targets, some or all of which are known to participate in chromatin silencing. These results are consistent with a mechanistic link between components of the DNA-repair machinery and RNA-mediated gene silencing.


Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition.
The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and CO-primed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-α secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile- and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO- or CO-RM-mediated toxicities in AP and a wide range of diseases.


Evidence-based medicine, part 4. An introduction to critical appraisal of articles on harm.
This article provides an introductory step-by-step process to appraise an article on harm. The authors introduce these principles using a systematic approach and case-based format. The process of assessing the validity of an article on harm, determining its importance, and applying it to an individual patient is reviewed. The concepts of study population homogeneity, equal treatment, sufficient follow-up periods, and completeness are discussed to help physicians determine an article's validity. Instruction on calculating odds ratios, relative risk, absolute risk increase, and the number needed to harm is provided and applied to the clinical scenario. Finally, information that is learned from the previous two steps is applied to patient care. Study generalizability and the role of patient values, patient expectations, and patient concerns are also addressed. The skills learned from appraising an article on harm in the manner outlined provides a solid basis for lifelong learning and improved patient care.


Who Is Serving Us? Food Safety Rules Compliance Among Brazilian Food Truck Vendors.
The rise of food trucks as an eating out option requires knowledge of this sector. Balancing the reality of the food truck sector with access to safe food should guide actions and public policies to cater to its peculiarities. Therefore, this study aimed to characterize the Brazilian food truck vendors' profile regarding their socioeconomic status and compliance with food safety rules. From the 118 food truck vendors registered in the Brazilian Federal District, 30% (n = 35) participated in the study. We conducted structured interviews from December 2017 to April 2018. We ranked compliance levels according to a five-point Likert scale based on calculated compliance scores. The interviews revealed that food truck vendors were mostly married males, who had completed at least a tertiary education level, and wanted to start up their own businesses. The compliance levels depict good compliance with food safety rules (overall compliance (OC)-score = 0.69, on a 0 to 1 scale). The food trucks assessed in this study distinguished themselves from the street food and food retail sectors due to their operational structure and the complexity of food production processes. Those particular features should be considered to ensure adequate and effective sanitary control and inspections, as well as to reduce the probability of microbial growth and food contamination and the consequent risk of foodborne illnesses.


Beneficial effects of hydrogen gas inhalation on a murine model of allergic rhinitis.
Allergic rhinitis (AR) is a common chronic inflammatory condition. It has been previously indicated that oxidative stress may contribute to allergic inflammation, including AR. Although molecular hydrogen (H2), an antioxidative agent, has been effective in treatment of numerous oxidative stress-associated diseases, the effect of inhalation of a high concentration of H2 on AR remains unknown. In the current study, female BALB/c mice were sensitized with ovalbumin (OVA) followed by intranasal OVA challenge to establish an animal model of AR. Mice were subjected to exposure to H2 and the inert gas helium at different frequencies and durations. The frequencies of sneezing/scratching and the body weights of mice were recorded. Histological analysis and multiplex cytokine assays were performed to evaluate the effects of H2 on AR. Challenge with OVA induced significant nasal mucosa inflammation. H2 inhalation reduced the infiltration of inflammatory cells into mucosa and lowered the levels of interleukin (IL)-5, IL-13 and monocyte chemoattractant protein-1 in serum. H2 inhalation slightly increased the level of interferon-γ, however the difference was not statistically significant. Treatment with H2 limited the weight increase in healthy mice and reversed the weight loss in mice with AR. Furthermore, H2 inhalation induced a therapeutic effect on AR in a dose-dependent manner. The current results demonstrate that H2 may demonstrate a therapeutic value for allergic diseases.


Computer task performance by subjects with Duchenne muscular dystrophy.
Two specific objectives were established to quantify computer task performance among people with Duchenne muscular dystrophy (DMD). First, we compared simple computational task performance between subjects with DMD and age-matched typically developing (TD) subjects. Second, we examined correlations between the ability of subjects with DMD to learn the computational task and their motor functionality, age, and initial task performance. The study included 84 individuals (42 with DMD, mean age of 18±5.5 years, and 42 age-matched controls). They executed a computer maze task; all participants performed the acquisition (20 attempts) and retention (five attempts) phases, repeating the same maze. A different maze was used to verify transfer performance (five attempts). The Motor Function Measure Scale was applied, and the results were compared with maze task performance. In the acquisition phase, a significant decrease was found in movement time (MT) between the first and last acquisition block, but only for the DMD group. For the DMD group, MT during transfer was shorter than during the first acquisition block, indicating improvement from the first acquisition block to transfer. In addition, the TD group showed shorter MT than the DMD group across the study. DMD participants improved their performance after practicing a computational task; however, the difference in MT was present in all attempts among DMD and control subjects. Computational task improvement was positively influenced by the initial performance of individuals with DMD. In turn, the initial performance was influenced by their distal functionality but not their age or overall functionality.


Population Pharmacokinetics of Doxycycline in Children.
Doxycycline is a tetracycline-class antimicrobial labeled by the United States (U.S.) Food and Drug Administration for children >8 years of age for many common childhood infections. Doxycycline is not labeled for children ≤8 years of age, due to the association between tetracycline class antibiotics and tooth staining, although doxycycline may be used off-label in severe conditions. Accordingly, there is a paucity of pharmacokinetic (PK) data to guide dosing in children 8 years and younger. We leveraged opportunistically-collected plasma samples after intravenous (IV) and oral doxycycline doses received per standard of care to characterize the PK of doxycycline in children of different ages, and evaluated the effect of obesity and fasting status on PK parameters.We developed a population PK model of doxycycline using data collected from 47 patients 0-18 years of age, including 14 participants ≤8 years. We developed a 1 compartment PK model and found doxycycline clearance to be 3.32 L/h/70 kg and volume to be 96.8 L/70kg for all patients; comparable to values reported in adults. We estimated a bioavailability of 89.6%, also consistent with adult data. Allometrically scaled clearance and volume of distribution did not differ between children 2 to ≤8 years of age and children >8 to ≤18 years of age, suggesting that younger children may be given the same per kg dosing. Obese and fasting status were not selected for inclusion in the final model. Additional doxycycline PK samples collected in future studies may be used to improve model performance and maximize its clinical value.


Inheritance of abnormal erythrocyte cation transport in essential hypertension.
Net fluxes of sodium and potassium ions were determined in sodium-loaded, potassium-depleted erythrocytes from 370 white subjects, 194 of whom had essential hypertension or had been born to parents with essential hypertension. Findings were compared with those in 86 controls who were normotensive and did not have a family history of hypertension. Compared with controls all patients with essential hypertension had a low sodium to potassium ratio secondary to a deficit in the sodium-potassium cotransport system. A similar abnormality was found in subjects born to parents with essential hypertension, the prevalences of a deficient cotransport system in such subjects being 53.6% (52 out of 97) among those with one hypertensive parent and 73.7% (14 out of 19) among those with two hypertensive parents. Both sexes were equally affected. Studies in 14 families over two or three generations showed the erythrocyte cation abnormality in one or more members of each consecutive generation. No close association was evident between the deficient erythrocyte sodium-potassium cotransport system and either blood groups ABO, Rh, Kidd, Duffy, P, and MNS or the major histocompatibility HLA antigens. Out of 90 consecutive unrelated and normotensive white blood donors, 36 showed a low erythrocyte sodium-potassium net flux ratio. It is concluded that in white people abnormal erythrocyte cation transport is a biochemical disorder characteristic of essential hypertension and transmitted by a dominant and autosomal mode expressing a single abnormal gene.


Interaction of internal anions with potassium channels of the squid giant axon.
The interaction of internal anions with the delayed rectifier potassium channel was studied in perfused squid axons. Changing the internal potassium salt from K+ glutamate- to KF produced a reversible decline of outward K currents and a marked slowing of the activation of K channels at all voltages. Fluoride ions exert a differential effect upon K channel gating kinetics whereby activation of IK during depolarizing steps is slowed dramatically, but the rate of closing after the step is not much altered. These effects develop with a slow time course (30-60 min) and are specific for K channels over Na channels. Both the amplitude and activation rate of IK were restored within seconds upon return to internal glutamate solutions. The fluoride effect is independent of the external K+ concentration and test membrane potential, and does not recover with repetitive application of depolarizing voltage steps. Of 11 different anions tested, all inorganic species induced similar decreases and slowing of IK, while K currents were maintained during extended perfusion with several organic anions. Anions do not alter the reversal potential or shape of the instantaneous current-voltage relation of open K channels. The effect of prolonged exposure to internal fluoride could be partially reversed by the addition of cationic K channel blocking agents such as TEA+, 4-AP+, and Cs+. The competitive antagonism between inorganic anions and internal cationic K channel blockers suggests that they may interact at a related site(s). These results indicate that inorganic anions modify part of the K channel gating mechanism (activation) at a locus near the inner channel surface.


Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis.
The WHO elimination strategy for hepatitis C virus advocates scaling up screening and treatment to reduce global hepatitis C incidence by 80% by 2030, but little is known about how this reduction could be achieved and the costs of doing so. We aimed to evaluate the effects and cost of different strategies to scale up screening and treatment of hepatitis C in Pakistan and determine what is required to meet WHO elimination targets for incidence. We adapted a previous model of hepatitis C virus transmission, treatment, and disease progression for Pakistan, calibrating using available data to incorporate a detailed cascade of care for hepatitis C with cost data on diagnostics and hepatitis C treatment. We modelled the effect on various outcomes and costs of alternative scenarios for scaling up screening and hepatitis C treatment in 2018-30. We calibrated the model to country-level demographic data for 1960-2015 (including population growth) and to hepatitis C seroprevalence data from a national survey in 2007-08, surveys among people who inject drugs (PWID), and hepatitis C seroprevalence trends among blood donors. The cascade of care in our model begins with diagnosis of hepatitis C infection through antibody screening and RNA confirmation. Diagnosed individuals are then referred to care and started on treatment, which can result in a sustained virological response (effective cure). We report the median and 95% uncertainty interval (UI) from 1151 modelled runs. One-time screening of 90% of the 2018 population by 2030, with 80% referral to treatment, was projected to lead to 13·8 million (95% UI 13·4-14·1) individuals being screened and 350 000 (315 000-385 000) treatments started annually, decreasing hepatitis C incidence by 26·5% (22·5-30·7) over 2018-30. Prioritised screening of high prevalence groups (PWID and adults aged ≥30 years) and rescreening (annually for PWID, otherwise every 10 years) are likely to increase the number screened and treated by 46·8% and decrease incidence by 50·8% (95% UI 46·1-55·0). Decreasing hepatitis C incidence by 80% is estimated to require a doubling of the primary screening rate, increasing referral to 90%, rescreening the general population every 5 years, and re-engaging those lost to follow-up every 5 years. This approach could cost US$8·1 billion, reducing to $3·9 billion with lowest costs for diagnostic tests and drugs, including health-care savings, and implementing a simplified treatment algorithm. Pakistan will need to invest about 9·0% of its yearly health expenditure to enable sufficient scale up in screening and treatment to achieve the WHO hepatitis C elimination target of an 80% reduction in incidence by 2030. UNITAID.


Occurrence, Bioavailability, Anti-inflammatory, and Anticancer Effects of Pterostilbene.
Supplementation with natural compounds found in fruits and vegetables has long been associated with a reduced risk of several types of cancer. Pterostilbene is a natural stilbenoid and a dimethylated analogue of resveratrol which is found primarily in blueberries. Pterostilbene exhibits a range of pharmacological properties, particularly anti-inflammatory and anticancer effects. Due to two methoxy groups in its skeleton, pterostilbene is more lipophilic than resveratrol and thus possesses higher intestinal permeability and cellular uptake and enhanced stability. Moreover, pterostilbene exhibits less toxicity and fewer adverse effects, providing it with superior potential in cancer chemoprevention and chemotherapy applications. Numerous research studies have demonstrated that pterostilbene possesses detoxification activities, mediating the anti-inflammation response, regulating the cell cycle, augmenting apoptosis, enhancing autophagy, and inhibiting tumor angiogenesis, invasion, and metastasis by modulating signal transduction pathways which block multiple stages of carcinogenesis. In this review, we illustrate that pterostilbene is a natural compound having bioavailability. The extensive metabolism of pterostilbene will be discussed. We also summarize recent research on pterostilbene's anti-inflammatory and anticancer properties in the multistage carcinogenesis process and related molecular mechanism and conclude that it should contribute to improved cancer management.


Sniffing out Parkinson disease: can olfactory testing differentiate parkinsonian disorders?
: Akinetic-rigid syndromes are a heterogeneous group of diseases with overlapping clinical manifestations. A recent American Academy of Neurology practice parameter indicated that olfactory testing was "probably useful" for differentiating idiopathic Parkinson disease (IPD) from other diseases with features of parkinsonism. : To determine the diagnostic accuracy of olfactory testing for differentiating IPD from other parkinsonian disorders. : The objective was addressed using a structured, evidence-based, critically appraised topic format. This format includes development of a clinical scenario, focused and answerable clinical question, search strategy, evidence appraisal, reporting and interpretation of results, commentary, and bottom line conclusions. Participants included neurology consultants and residents, clinical epidemiologists, a medical librarian, and neurologists with expertise in movement disorders. : Two studies evaluated the diagnostic accuracy of olfactory testing within a broad spectrum of parkinsonian syndromes. Each study examined different test methods [University of Pennsylvania Smell Identification Test; "Sniffin' Sticks"] and both were compromised by several potential biases in sampling and outcome evaluation. The University of Pennsylvania Smell Identification Test is moderately sensitive (77%; likelihood ratio 0.27) and specific (85%; likelihood ratio 4.9) for differentiation of IPD from non-IPD syndromes, but less specific (62%; likelihood ratio 2.0) for distinguishing IPD from multiple system atrophy. : The diagnostic accuracy of olfactory testing for differentiating IPD from other disorders is insufficient to justify its routine clinical use but available evidence is derived from small samples and studies of questionable validity. Recommendations for future research of olfactory testing for diagnosis and disease predication are discussed.


Sex and Gender Differences in Migraine-Evaluating Knowledge Gaps.
Migraine is a common chronic neurological disease that disproportionately affects women. Migraine has significant negative effects on physical, emotional, and social aspects of health, and can be costly for patients, employers, and society as a whole. Growing evidence supports the roles of sex and gender in migraine risk, pathophysiology, presentation, diagnosis, treatment, and management. However, sex and gender differences in migraine have received limited attention, which can impede advancements in migraine detection, treatment, care, and education. The Society for Women's Health Research convened an interdisciplinary expert panel of researchers, clinicians, and advocates for a roundtable meeting to review the current research on sex and gender differences in migraine. This review summarizes discussions from the roundtable and prioritizes areas of need that warrant further attention in migraine research, care, and education. Examining sex and gender differences in migraine and addressing knowledge gaps will decrease the health and economic burden of migraine for both women and men.


Recent trends in robot-assisted therapy environments to improve real-life functional performance after stroke.
Upper and lower limb robotic tools for neuro-rehabilitation are effective in reducing motor impairment but they are limited in their ability to improve real world function. There is a need to improve functional outcomes after robot-assisted therapy. Improvements in the effectiveness of these environments may be achieved by incorporating into their design and control strategies important elements key to inducing motor learning and cerebral plasticity such as mass-practice, feedback, task-engagement, and complex problem solving. This special issue presents nine articles. Novel strategies covered in this issue encourage more natural movements through the use of virtual reality and real objects and faster motor learning through the use of error feedback to guide acquisition of natural movements that are salient to real activities. In addition, several articles describe novel systems and techniques that use of custom and commercial games combined with new low-cost robot systems and a humanoid robot to embody the " supervisory presence" of the therapy as possible solutions to exercise compliance in under-supervised environments such as the home.


Lymphomas associated with chronic hepatitis C virus infection: A prospective multicenter cohort study from the Rete Ematologica Lombarda (REL) clinical network.
Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease.


Hans Asperger, National Socialism, and "race hygiene" in Nazi-era Vienna.
Hans Asperger (1906-1980) first designated a group of children with distinct psychological characteristics as 'autistic psychopaths' in 1938, several years before Leo Kanner's famous 1943 paper on autism. In 1944, Asperger published a comprehensive study on the topic (submitted to Vienna University in 1942 as his postdoctoral thesis), which would only find international acknowledgement in the 1980s. From then on, the eponym 'Asperger's syndrome' increasingly gained currency in recognition of his outstanding contribution to the conceptualization of the condition. At the time, the fact that Asperger had spent pivotal years of his career in Nazi Vienna caused some controversy regarding his potential ties to National Socialism and its race hygiene policies. Documentary evidence was scarce, however, and over time a narrative of Asperger as an active opponent of National Socialism took hold. The main goal of this paper is to re-evaluate this narrative, which is based to a large extent on statements made by Asperger himself and on a small segment of his published work. Drawing on a vast array of contemporary publications and previously unexplored archival documents (including Asperger's personnel files and the clinical assessments he wrote on his patients), this paper offers a critical examination of Asperger's life, politics, and career before and during the Nazi period in Austria. Asperger managed to accommodate himself to the Nazi regime and was rewarded for his affirmations of loyalty with career opportunities. He joined several organizations affiliated with the NSDAP (although not the Nazi party itself), publicly legitimized race hygiene policies including forced sterilizations and, on several occasions, actively cooperated with the child 'euthanasia' program. The language he employed to diagnose his patients was often remarkably harsh (even in comparison with assessments written by the staff at Vienna's notorious Spiegelgrund 'euthanasia' institution), belying the notion that he tried to protect the children under his care by embellishing their diagnoses. The narrative of Asperger as a principled opponent of National Socialism and a courageous defender of his patients against Nazi 'euthanasia' and other race hygiene measures does not hold up in the face of the historical evidence. What emerges is a much more problematic role played by this pioneer of autism research. Future use of the eponym should reflect the troubling context of its origins in Nazi-era Vienna.


Identity, relationship quality, and subjective burden in caregivers of persons with dementia.
The aim of the current study was to examine the associations between informal caregivers' perception of identity change in their care-partner, the quality of the caregiver/care-recipient relationship, and caregiver burden in a sample of 56 informal caregivers of persons with dementia. Most (96.4%) of the caregivers of persons who received a dementia diagnosis reported a perceived change in the identity of their care-partner. Caregivers' perception of relationship satisfaction was measured with the Burns Relationship Satisfaction Scale for premorbid relationship and current relationship quality, and caregiver burden was measured with the Zarit Burden scale. After controlling for variance due to dementia severity, premorbid relationship satisfaction, and current relationship satisfaction, caregivers' perceived change in the identity of the person with dementia accounted for significant variance in caregiver burden. Using a mediational model, we found support for a direct effect between perceived change in identity and caregiver burden, but we also found support for an indirect effect of relationship quality on the relation between perceived identity change and caregiver burden. The demonstrated model provides an empirically supported theoretical framework for guiding potential research and development of future interventions, which we suggest should emphasize dyads.


Current threats to osteopathic graduate medical education.
The Balanced Budget Act of 1997 and continuing changes put into place by the Educational Commission on Foreign Medical Graduates (ECFMG) are altering the environment for graduate medical education (GME) in ways that threaten osteopathic graduate medical education in particular. Hospital revenue is decreasing due to declines in Medicare GME and patient-care reimbursements. The new 3-year rolling average methodology for counting "house staff" makes it likely that unfilled positions will be eliminated. With osteopathic GME positions unfilled and financial resources decreasing, osteopathic medical programs may shrink further. Additionally, the ECFMG has put into place policies that may restrict the number of international medical graduates entering the United States. Approximately 25% of all allopathic GME positions in the United States are filled by international medical graduates. If this applicant pool decreases, allopathic medical programs may turn to osteopathic medical graduates as the only other available pool of individuals to fill program positions. At a time when allopathic internship positions are already unfilled and 30% of osteopathic medical graduates enter allopathic first-year programs, further inroads by allopathic programs could severely impact osteopathic GME efforts.


Current management of ALS: comparison of the ALS CARE Database and the AAN Practice Parameter. The American Academy of Neurology.
The American Academy of Neurology (AAN) ALS Practice Parameter was published in April 1999. The ALS CARE Database has been collecting data on the management of patients with ALS in North America since 1996. To compare the management of patients with ALS in North America as recorded in the ALS CARE Database with the recommendations of the AAN ALS Practice Parameter. Data were analyzed from 2018 patients at enrollment and from 373 of these patients who died between enrollment and May 1999. Eighty-two percent of the enrolled patients reported that they had been given enough information about ALS. Only 54% of patients with drooling were receiving medication for this problem. Only 41% of those who reported being depressed most of the time were receiving antidepressant medications. Only 28% of those with dyspnea and only 9.2% of those with a forced vital capacity <40% predicted were receiving noninvasive positive pressure ventilator support. Only 30% of those with moderate to severe dysphagia had a gastrostomy tube. Half of the patients who died did so at home, but only 47% of them received residential hospice services. Although 89% of patients who died were recorded as having done so peacefully, 17% were reported to have had breathing difficulties (i.e., respiratory distress), 8% anxiety, 3.3% pain, and 2.5% choking. Advance directives were in place for 90% of the patients who died, and in 97% of cases these directives were followed. These findings indicate that in the 3-year period prior to the publication of the AAN Practice Parameter, many but not all patients received the care that is recommended in that parameter; there were deficiencies, particularly in the key areas of gastrostomy and noninvasive positive pressure ventilation.


A hepatitis A, B, C and HIV prevalence and risk factor study in ever injecting and non-injecting drug users in Luxembourg associated with HAV and HBV immunisations.
In Luxembourg, viral hepatitis and HIV infection data in problem drug users (PDUs) are primarily based on self-reporting. Our study aimed to determine the prevalence of HAV, HBV, HCV and HIV infections in ever injecting (IDUs) and non-injecting drug users (nIDUs) including inherent risk factors analysis for IDUs. Secondary objectives were immunisation against HAV and HBV, referral to care and treatment facilities as well as reduction in risk behaviour. A nationwide, cross-sectional multi-site survey, involving 5 in-, 8 out-treatment and 2 prison centres, included both an assisted questionnaire (n = 368) and serological detection of HIV and Hepatitis A, B, C (n = 334). A response rate of 31% resulted in the participation of 310 IDUs and 58 nIDUs. Risk factors such as drug use, sexual behaviour, imprisonment, protection and health knowledge (HAV, HBV status and immunisations, HCV, HIV), piercing/tattoo and use of social and medical services were studied by means of chi2 and logistic models. Seroprevalence results for IDUs were 81.3% (218/268, 95%CI=[76.6; 86.0]) for HCV, 29.1% (74/254, 95%CI=[25.5;34.7 ]) for HBV (acute/chronic infection or past cured infection), 2.5% (5/202, 95%CI=[0.3; 4.6]) for HIV-1 and 57.1% (108/189, 95%CI=[50.0; 64.1]) for HAV (cured infections or past vaccinations). Seroprevalence results for nIDUs were 19.1% (9/47, 95%CI=[7.9;30.3]) for HCV, 8.9% (4/45, 95%CI=[0.6;17.2]) for HBV (acute/chronic infection or past cured infection), 4.8% (2/42, 95%CI=[-1.7;11.3]) for HIV-1 and 65.9% (27/41, 95%CI=[51.4;80.4]) for HAV. Prisoners showed the highest rates for all infections. Age, imprisonment and setting of recruitment were statistically associated with HCV seropositivity. Age, speedball career and nationality were significantly associated with HBV seropositivity. Only 56% of the participants in outpatient centres collected their serology results and 43 doses of vaccine against HAV and/or HBV were administered. Despite the existing national risk-reduction strategies implemented since 1993, high prevalence of HCV and HBV infections in injecting drug users is observed. Our study showed that implementing risk-prevention strategies, including immunisation remains difficult with PDUs. Improvement should be looked for by the provision of field healthcare structures providing tests with immediate results, advice, immunisation or treatment if appropriate.


Comparison of benzoate- and dodecaborate-based linkers for attachment of radioiodine to HER2-targeting Affibody ligand.
The use of radionuclide molecular imaging enables the selection of patients for treatment using molecular medicine. Preclinical studies have demonstrated that a novel low-molecular-weight affinity ligand, Affibody molecule Z(HER2:342) can image the expression of HER2 with high sensitivity and specificity in tumour xenografts and has a potential for the selection of patients for treatment using Herceptin or other anti-HER2 medicine. In this study, we performed a comparative evaluation of two possible linkers for radioiodination of the Affibody molecule Z(HER2:342), 4-iodobenzoate (PIB) and [4-isothiocyanatobenzyl)-amino]-undecahydro-closo-dodecaborate (DABI). It was shown that the use of DABI makes it possible to obtain radioiodinated Z(HER2:342) with preserved capacity for selective binding to HER2-expressing cells. There was no difference between 125I-PIB-Z(HER2:342) and 125I-DABI-Z(HER2:342) in cellular retention of radioactivity after interrupted incubation with radiolabelled Affibody ligands. In vivo, the biodistribution of 125I-PIB-Z(HER2:342) was characterized by a high tumour uptake at 4 h pi (12.7+/-4.6% IA/g) and a quick clearance from blood and normal organs. The tumour uptake of 125I-DABI-Z(HER2:342) was appreciably lower (2.7+/-1.2% IA/g), and a high uptake of this conjugate in the liver was observed. A gamma-camera experiment (at 6 h pi) demonstrated that the use of 125I-PIB-Z(HER2:342) provided a much better contrast of imaging HER2-expressing xenografts than the use of 125I-DABI-Z(HER2:342). In conclusion, 125I-PIB-Z(HER2:342) is superior to 125I-DABI-Z(HER2:342) as an agent for imaging HER2 expression in vivo.


Outcome measures in immune-mediated neuropathies: the need to standardize their use and to understand the clinimetric essentials.
Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy-related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.


A nuclear factor Y (NFY) site positively regulates the human CD34 stem cell gene.
Proper regulation of the human CD34 gene requires a combinatorial action of multiple proximal and long-range, cis elements. This report shows that, like the murine CD34 5' untranslated region (UTR), the corresponding region of the human CD34 gene is necessary for optimal promoter activity. We localized the most critical element of this region to base pairs +48/+75. Through oligonucleotide competition and antibody supershift experiments in electrophoretic mobility shift assays, we found that this sequence contains a binding site (CCAAT box) for the transcription factor NFY (nuclear factor Y), a factor mediating cell type-specific and cell-cycle regulated expression of genes. Mutating this site led to a 5-fold decrease in CD34 promoter activity in transient transfection experiments. Interestingly, NFY binds adjacently to the earlier identified c-myb binding site. Here we show that both binding sites are important for CD34 promoter function: mutating either site alone decreased CD34 promoter-driven reporter gene activity 4-fold. We also show that the integrity of the c-myb binding site is necessary for stabilization of NFY binding to its site. Such cooperation between c-myb, which is expressed in early hematopoietic cells, and NFY, which is expressed in many cell types, might contribute to specific activation of CD34 in stem cells. The CCAAT box motif was also noted in the 5' UTR of the murine CD34 gene, however, NFY did not bind to this region. Thus, our results indicate that the functional similarities between the human and murine CD34 5' UTRs are achieved through different molecular mechanism(s).


Immunogenicity of Danish-SSI 1331 BCG vaccine in the UK: comparison with Glaxo-Evans 1077 BCG vaccine.
The immunogenicity and reactogenicity, in British schoolchildren, of the newly introduced Danish-SSI 1331 BCG vaccine was compared with that of the previously used Glaxo-Evans 1077 BCG vaccine. Interferon-gamma (IFN-gamma) response to M. tuberculosis purified protein derivative (M.tb PPD) in a 6-day whole blood assay and delayed type hypersensitivity (DTH) to tuberculin PPD were determined before and 1 year after receiving BCG or no vaccination. Scar size was measured 1 year after vaccination. There was no evidence of a difference in immunogenicity (IFN-gamma and DTH conversion rates) but evidence of lower reactogenicity (scar size) with Danish-SSI 1331 compared to Glaxo-Evans 1077 vaccines.


Mediastinal mass diagnosed as a benign schwannoma.
Neurogenic tumours of the mediastinum are most commonly present in the posterior mediastinal compartment. Schwannomas, being the most frequently encountered type, can be either benign or malignant, although the former is more common. They typically appear as an asymptomatic mass on radiographic imaging. These tumours with spindle-shaped cells are often asymptomatic, and are routinely detected on standard pulmonary radiography. However, computed tomography and magnetic resonance imaging, especially for posterior mediastinal tumours, provide additional information and help to determine its possible extension to adjacent structures. Therefore, radiographic and histopathological examinations are vital diagnostic tools in the detection of these silent tumours. Complete surgical resection using video-assisted thoracic surgical technique is the mainstay of treatment, and offers an excellent prognosis.


A large comparison of integrated SAR/QSAR models of the Ames test for mutagenicity$.
Results from the Ames test are the first outcome considered to assess the possible mutagenicity of substances. Many QSAR models and structural alerts are available to predict this endpoint. From a regulatory point of view, the recommendation from international authorities is to consider the predictions of more than one model and to combine results in order to develop conclusions about the mutagenicity risk posed by chemicals. However, the results of those models are often conflicting, and the existing inconsistency in the predictions requires intelligent strategies to integrate them. In our study, we evaluated different strategies for combining results of models for Ames mutagenicity, starting from a set of 10 diverse individual models, each built on a dataset of around 6000 compounds. The novelty of our study is that we collected a much larger set of about 18,000 compounds and used the new data to build a family of integrated models. These integrations used probabilistic approaches, decision theory, machine learning, and voting strategies in the integration scheme. Results are discussed considering balanced or conservative perspectives, regarding the possible uses for different purposes, including screening of large collection of substances for prioritization.


Relations between response trajectories on the continuous performance test and teacher-rated problem behaviors in preschoolers.
Although both the continuous performance test (CPT) and behavior rating scales are used in both practice and research to assess inattentive and hyperactive/impulsive behaviors, the correlations between performance on the CPT and teachers' ratings are typically only small-to-moderate. This study examined trajectories of performance on a low target-frequency visual CPT in a sample of preschool children and how these trajectories were associated with teacher-ratings of problem behaviors (i.e., inattention, hyperactivity/impulsivity [H/I], and oppositional/defiant behavior). Participants included 399 preschool children (mean age = 56 months; 49.4% female; 73.7% White/Caucasian). An attention deficit/hyperactivity disorder (ADHD) rating scale was completed by teachers, and the CPT was completed by the preschoolers. Results showed that children's performance across 4 temporal blocks on the CPT was not stable across the duration of the task, with error rates generally increasing from initial to later blocks. The predictive relations of teacher-rated problem behaviors to performance trajectories on the CPT were examined using growth curve models. Higher rates of teacher-reported inattention and H/I were uniquely associated with higher rates of initial omission errors and initial commission errors, respectively. Higher rates of teacher-reported overall problem behaviors were associated with increasing rates of omission but not commission errors during the CPT; however, the relation was not specific to 1 type of problem behavior. The results of this study indicate that the pattern of errors on the CPT in preschool samples is complex and may be determined by multiple behavioral factors. These findings have implications for the interpretation of CPT performance in young children.


Effect of B-type natriuretic peptides on long-term outcomes after transcatheter aortic valve implantation.
B-type natriuretic peptide (BNP) levels are elevated in patients with aortic stenosis (AS) and decrease acutely after replacement of the stenotic valve. The long-term prognostic value of BNP after transcatheter aortic valve implantation (TAVI) and the relative prognostic utility of single versus serial peri-interventional measurements of BNP and N-terminal prohormone BNP (NT-pro-BNP) are unknown. This study sought to determine the impact of BNP levels on long-term outcomes after TAVI and to compare the utility of BNP versus NT-pro-BNP measured before and after intervention. We analyzed 340 patients with severe AS and baseline pre-TAVI assessment of BNP. In 219 patients, BNP and NT-pro-BNP were measured serially before and after intervention. Clinical outcomes over 2 years were recorded. Patients with high baseline BNP (higher tertile ≥591 pg/ml) had increased risk of all-cause mortality (adjusted hazard ratio 3.16, 95% confidence interval 1.84 to 5.42; p <0.001) and cardiovascular death at 2 years (adjusted hazard ratio 3.37, 95% confidence interval 1.78 to 6.39; p <0.001). Outcomes were most unfavorable in patients with persistently high BNP before and after intervention. Comparing the 2 biomarkers, NT-pro-BNP levels measured after TAVI showed the highest prognostic discrimination for 2-year mortality (area under the curve 0.75; p <0.01). Baseline-to-discharge reduction, but not baseline levels of BNP, was related to New York Heart Association functional improvement. In conclusion, high preintervention BNP independently predicts 2-year outcomes after TAVI, particularly when elevated levels persist after the intervention. BNP and NT-pro-BNP and their serial periprocedural changes provide complementary prognostic information for symptomatic improvement and survival.


The Kinetics of Circulating Monocyte Subsets and Monocyte-Platelet Aggregates in the Acute Phase of ST-Elevation Myocardial Infarction: Associations with 2-Year Cardiovascular Events.
In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; P = 0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; P = 0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; P = 0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; P = 0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.


Dealing with feeling: a meta-analysis of the effectiveness of strategies derived from the process model of emotion regulation.
The present meta-analysis investigated the effectiveness of strategies derived from the process model of emotion regulation in modifying emotional outcomes as indexed by experiential, behavioral, and physiological measures. A systematic search of the literature identified 306 experimental comparisons of different emotion regulation (ER) strategies. ER instructions were coded according to a new taxonomy, and meta-analysis was used to evaluate the effectiveness of each strategy across studies. The findings revealed differences in effectiveness between ER processes: Attentional deployment had no effect on emotional outcomes (d(+) = 0.00), response modulation had a small effect (d(+) = 0.16), and cognitive change had a small-to-medium effect (d(+) = 0.36). There were also important within-process differences. We identified 7 types of attentional deployment, 4 types of cognitive change, and 4 types of response modulation, and these distinctions had a substantial influence on effectiveness. Whereas distraction was an effective way to regulate emotions (d(+) = 0.27), concentration was not (d(+) = -0.26). Similarly, suppressing the expression of emotion proved effective (d(+) = 0.32), but suppressing the experience of emotion or suppressing thoughts of the emotion-eliciting event did not (d(+) = -0.04 and -0.12, respectively). Finally, reappraising the emotional response proved less effective (d(+) = 0.23) than reappraising the emotional stimulus (d(+) = 0.36) or using perspective taking (d(+) = 0.45). The review also identified several moderators of strategy effectiveness including factors related to the (a) to-be-regulated emotion, (b) frequency of use and intended purpose of the ER strategy, (c) study design, and (d) study characteristics.