Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents.
Depressive disorders are common in children and adolescents and, if left untreated, are likely to recur in adulthood. Depression is highly debilitating, affecting psychosocial, family and academic functioning. To evaluate the effectiveness of psychological therapies and antidepressant medication, alone and in combination, for the treatment of depressive disorder in children and adolescents. We have examined clinical outcomes including remission, clinician and self reported depression measures, and suicide-related outcomes. We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to 11 November 2011. This register contains reports of relevant randomised controlled trials (RCTs) from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). RCTs were eligible for inclusion if they compared i) any psychological therapy with any antidepressant medication, or ii) a combination of psychological therapy and antidepressant medication with a psychological therapy alone, or an antidepressant medication alone, or iii) a combination of psychological therapy and antidepressant medication with a placebo or 'treatment as usual', or (iv) a combination of psychological therapy and antidepressant medication with a psychological therapy or antidepressant medication plus a placebo.We included studies if they involved participants aged between 6 and 18 years, diagnosed by a clinician as having Major Depressive Disorder (MDD) based on Diagnostic and Statistical Manual (DSM) or International Classification of Diseases (ICD) criteria. Two review authors independently selected studies, extracted data and assessed the quality of the studies. We applied a random-effects meta-analysis, using the odds ratio (OR) to describe dichotomous outcomes, mean difference (MD) to describe continuous outcomes when the same measures were used, and standard mean difference (SMD) when outcomes were measured on different scales. We included ten studies, involving 1235 participants in this review. Studies recruited participants with different severities of disorder and with a variety of comorbid disorders, including anxiety and substance use disorder, therefore limiting the comparability of the results. Regarding the risk of bias in studies, half the studies had adequate allocation concealment (there was insufficient information to determine allocation concealment in the remainder), outcome assessors were blind to the participants' intervention in six studies, and in general, studies reported on incomplete data analysis methods, mainly using intention-to-treat (ITT) analyses. For the majority of outcomes there were no statistically significant differences between the interventions compared. There was limited evidence (based on two studies involving 220 participants) that antidepressant medication was more effective than psychotherapy on measures of clinician defined remission immediately post-intervention (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.27 to 0.98), with 67.8% of participants in the medication group and 53.7% in the psychotherapy group rated as being in remission. There was limited evidence (based on three studies involving 378 participants) that combination therapy was more effective than antidepressant medication alone in achieving higher remission from a depressive episode immediately post-intervention (OR 1.56, 95% CI 0.98 to 2.47), with 65.9% of participants treated with combination therapy and 57.8% of participants treated with medication, rated as being in remission. There was no evidence to suggest that combination therapy was more effective than psychological therapy alone, based on clinician rated remission immediately post-intervention (OR 1.82, 95% CI 0.38 to 8.68).Suicide-related Serious Adverse Events (SAEs) were reported in various ways across studies and could not be combined in meta-analyses. However suicidal ideation specifically was generally measured and reported using standardised assessment tools suitable for meta-analysis. In one study involving 188 participants, rates of suicidal ideation were significantly higher in the antidepressant medication group (18.6%) compared with the psychological therapy group (5.4%) (OR 0.26, 95% CI 0.09 to 0.72) and this effect appeared to remain at six to nine months (OR 1.27, 95% CI 0.68 to 2.36), with 13.6% of participants in the medication group and 3.9% of participants in the psychological therapy group reporting suicidal ideation. It was unclear what the effect of combination therapy was compared with either antidepressant medication alone or psychological therapy alone on rates of suicidal ideation. The impact of any of the assigned treatment packages on drop out was also mostly unclear across the various comparisons in the review.Limited data and conflicting results based on other outcome measures make it difficult to draw conclusions regarding the effectiveness of any specific intervention based on these outcomes. There is very limited evidence upon which to base conclusions about the relative effectiveness of psychological interventions, antidepressant medication and a combination of these interventions. On the basis of the available evidence, the effectiveness of these interventions for treating depressive disorders in children and adolescents cannot be established. Further appropriately powered RCTs are required.


Interpretation of genomic variants using a unified biological network approach.
The decreasing cost of sequencing is leading to a growing repertoire of personal genomes. However, we are lagging behind in understanding the functional consequences of the millions of variants obtained from sequencing. Global system-wide effects of variants in coding genes are particularly poorly understood. It is known that while variants in some genes can lead to diseases, complete disruption of other genes, called 'loss-of-function tolerant', is possible with no obvious effect. Here, we build a systems-based classifier to quantitatively estimate the global perturbation caused by deleterious mutations in each gene. We first survey the degree to which gene centrality in various individual networks and a unified 'Multinet' correlates with the tolerance to loss-of-function mutations and evolutionary conservation. We find that functionally significant and highly conserved genes tend to be more central in physical protein-protein and regulatory networks. However, this is not the case for metabolic pathways, where the highly central genes have more duplicated copies and are more tolerant to loss-of-function mutations. Integration of three-dimensional protein structures reveals that the correlation with centrality in the protein-protein interaction network is also seen in terms of the number of interaction interfaces used. Finally, combining all the network and evolutionary properties allows us to build a classifier distinguishing functionally essential and loss-of-function tolerant genes with higher accuracy (AUC = 0.91) than any individual property. Application of the classifier to the whole genome shows its strong potential for interpretation of variants involved in mendelian diseases and in complex disorders probed by genome-wide association studies.


Lack of significant difference between internal spermatic vein and brachial vein ischemia modified albumin levels in patients with varicocele.
Varicocele is the most common and surgically correctible cause of male infertility in men attending to infertility clinics. Infertility affects 15% of all couples and male factor is the primary or contributing cause in 40% to 60% of cases. Varicocele has been shown to cause male infertility in about 15% of infertile couples. Molecular mechanisms responsible from varicocele induced testicular dysfunction and male infertility have not been completely unknown. Recent years have witnessed a huge amount of scientific works devoted to the mechanism of varicocele associated male infertility and rapid progress in research on its cellular and molecular mechanisms, including apoptosis and oxidative stress of germ cells. Here we evaluated internal spermatic vein and brachal vein ischemia modified albumin (IMA) level in 40 adult male patients with varicocele. IMA level was analyzed using albumin cobalt-binding test. Spermatic vein and brachial vein IMA levels were 0.381 ± 0.135 ABSU (absorbance units) and 0.385 ± 0.131 ABSU, respectively. There was no statistically significant difference between the two areas. IMA levels in the internal spermatic vein of patients with varicocele should not be used as a marker of hypoxia.


Procalcitonin predicts response to beta-lactam treatment in hospitalized children with community-acquired pneumonia.
Antibiotic treatment of community-acquired pneumonia (CAP) in children remains mostly empirical because clinical and paraclinical findings poorly discriminate the principal causes of CAP. Fast response to beta-lactam treatment can be considered a proxy of pneumococcal aetiology. We aimed to identify the best biological predictor of response to beta-lactam therapy in children hospitalized for CAP. A retrospective, single-centre cohort study included all consecutive patients 1 month to 16 years old hospitalized in a teaching hospital in Paris, France, because of CAP empirically treated with a beta-lactam alone from 2003 to 2010. Uni- and multivariate analyses were used to study the ability of routine biological parameters available in the Emergency Department to predict a favourable response to beta-lactam (defined as apyrexia within 48 hours of treatment onset). Among the 125 included patients, 85% (106) showed a favourable response to beta-lactam. In multivariate logistic regression, we found procalcitonin (PCT) the only independent predictor of apyrexia (p = 0.008). The adjusted odds ratio for the decadic logarithm of PCT was 4.3 (95% CI 1.5-12.7). At ≥ 3 ng/mL, PCT had 55.7% sensitivity (45.7-65.3), 78.9% specificity (54.4-93.9), 93.7% positive predictive value (84.5-98.2), 24.2% negative predictive value (14.2-36.7), 2.64 positive likelihood ratio (1.09-6.42) and 0.56 negative likelihood ratio (0.41-0.77). In the 4 children with a PCT level ≥ 3 ng/mL and who showed no response to beta-lactam treatment, secondary pleural effusion had developed in 3, and viral co-infection was documented in 1. PCT is the best independent biologic predictor of favourable response to beta-lactam therapy in children hospitalized for CAP. Thus, a high PCT level is highly suggestive of pneumococcal aetiology. However, a 3-ng/mL cut-off does not seem compatible with daily medical practice, and additional research is needed to further define the role of PCT in managing CAP in children.


Visual processing and the bodily self.
The 'body schema' has traditionally been defined as a passively updated, proprioceptive representation of the body. However, recent work has suggested that body representations are more complex and flexible than previously thought. They may integrate current perceptual information from all sensory modalities, and can be extended to incorporate indirect representations of the body and functional portions of tools. In the present study, we investigate the source of a facilitatory effect of viewing the body on speeded visual discrimination reaction times. Participants responded to identical visual stimuli that varied only in their context: being presented on the participant's own body, on the experimenter's body, or in a neutral context. The stimuli were filmed and viewed in real-time on a projector screen. Careful controls for attention, biological saliency, and attribution confirmed that the facilitatory effect depends critically on participants attributing the context to a real body. An intermediate effect was observed when the stimuli were presented on another person's body, suggesting that the effect of viewing one's own body might represent a conjunction of an interpersonal body effect and an egocentric effect.


Improvements in Irritability with Open-Label Methylphenidate Treatment in Youth with Comorbid Attention Deficit/Hyperactivity Disorder and Disruptive Mood Dysregulation Disorder.
The purpose of this open-label study was to examine the effects of long-acting methylphenidate (MPH) treatment on irritability and related emotional symptoms associated with disruptive mood dysregulation disorder (DMDD) in youth with comorbid attention-deficit/hyperactivity disorder (ADHD). The sample included 22 medication-free male and female subjects (ages 9-15) who met criteria for both DMDD and ADHD. Participants underwent a 4-week trial of long-acting MPH treatment (Concerta®), with weekly dosing increases until a therapeutic dose was reached. Repeated measures t-tests were used to compare pre- and posttreatment ratings of primary and secondary measures. The primary outcome was self-report irritability. Secondary outcomes included parent and child ratings of emotional frequency, emotional lability, and negative affect (NA). Multiple regression was used to examine the impact baseline hyperactivity, age, gender, race, socioeconomic status, or comorbid diagnosis had on treatment outcomes. Significant improvements (medium to large effect sizes) in child-rated irritability as well as parent and child ratings of emotional lability, NA, and anger were found. As anticipated, ADHD symptoms also improved. While a majority of the sample saw improvement in child-rated irritability (71%), symptoms worsened a small proportion (19%), and an even smaller portion experienced no change (10%). No demographics, psychiatric comorbidities, or severity of ADHD symptoms influenced treatment outcomes. Study findings suggest that MPH treatment significantly improved mood and emotional symptoms associated with DMDD comorbid with ADHD. These findings, coupled with good tolerability in this open-label pilot study supports further research into the use of MPH as a first-line treatment for DMDD. Future work examining MPH treatment of youth with DMDD with and without comorbid ADHD is needed.


Evaluation of three commercial detection systems for Mycobacterium tuberculosis where clinical diagnosis is difficult.
To assess the performance of three commercially available Mycobacterium tuberculosis detection systems employing nucleic acid amplification, when applied directly to respiratory and non-respiratory specimens from patients where the diagnosis of tuberculosis is difficult using clinical and traditional bacteriological methods. 42 respiratory and 21 non-respiratory specimens were concentrated, examined with auramine staining, and cultured on Lowenstein-Jensen slopes. These specimens were also assayed using the Amplicor Mycobacterium tuberculosis test (AM) (Roche Diagnostic Systems), the Amplified Mycobacterium tuberculosis direct test (AMD) (Gen-Probe), and the LCx Mycobacterium tuberculosis assay (LMA) (Abbott Laboratories). All three amplification systems used in this study gave specificities of 100% when used on respiratory specimens. When used on non-respiratory specimens, AM and LMA gave specificities of 100% and AMD 75%. With respiratory specimens the AM, AMD, and LMA systems gave sensitivities of 75%, 65.2%, and 79.2%, respectively. With non-respiratory specimens the sensitivities were 50%, 66.7%, and 60%, while with smear negative, culture positive specimens they were 33.3%, 66.7%, and 55.6%. Positive predictive values of 100% were seen with all specimens except non-respiratory specimens assayed using AMD where the value was 66.7%. The manufacturers of these systems recommend that they should only be used for the direct analysis of respiratory specimens, and the US Food and Drug Administration has approved them for use only with smear positive specimens. This study confirms that sensitivities are lower for non-respiratory and smear negative specimens, but positive predictive values are high. Provided they are interpreted with caution, positive results with these tests in respiratory and non-respiratory specimens are useful in tuberculous patients who are otherwise difficult to diagnose. Each amplification has advantages and disadvantages compared with the others.


Electronic Diabetes Management System Replaces Paper Insulin Chart: Improved Quality in Diabetes Inpatient Care Processes Due to Digitalization.
GlucoTab, an electronic diabetes management system (eDMS), supports healthcare professionals (HCPs) in inpatient blood glucose (BG) management at point-of-care and was implemented for the first time under routine conditions in a regional hospital to replace the paper insulin chart. To investigate quality of the eDMS for inpatients with type 2 diabetes mellitus a monocentric retrospective before-after evaluation was conducted. We compared documentation possibilities by assessing a blank paper chart vs the eDMS user interface. Further quality aspects were compared by assessing filled-in paper charts (n = 106) vs filled-in eDMS documentation (n = 241). HCPs (n = 59) were interviewed regarding eDMS satisfaction. The eDMS represented an improvement of documentation possibilities by offering a more structured and comprehensive user interface compared to the blank paper chart. The number of good diabetes days averaged to a median value of four days in both groups (paper chart: 4.38 [0-7] vs eDMS: 4.38 [0-7] days). Median daily BG was 170 (117-297) mg/dL vs 168 (86-286) mg/dL and median fasting BG was 152 (95-285) mg/dL vs 145 (69-333) mg/dL, and 0.1% vs 0.4% BG values <54 mg/dL were documented. Diabetes documentation quality improved when using eDMS, for example, documentation of ordered BG measurement frequency (1% vs 100%) and ordered BG targets (0% vs 100%). HCPs stated that by using eDMS errors could be prevented (74%), and digital support of work processes was completed (77%). Time saving was noted by 8 out of 11 HCPs and estimated at 10-15 minutes per patient day by two HCPs. The eDMS completely replaced the paper chart, showed comparable glycemic control, was positively accepted by HCPs, and is suitable for inpatient diabetes management.


Plasmonic enhancement of molecular hydrogen dissociation on metallic magnesium nanoclusters.
Light-driven plasmonic enhancement of chemical reactions on metal catalysts is a promising strategy to achieve highly selective and efficient chemical transformations. The study of plasmonic catalyst materials has traditionally focused on late transition metals such as Au, Ag, and Cu. In recent years, there has been increasing interest in the plasmonic properties of a set of earth-abundant elements such as Mg, which exhibit interesting hydrogenation chemistry with potential applications in hydrogen storage. This work explores the optical, electronic, and catalytic properties of a set of metallic Mg nanoclusters with up to 2057 atoms using time-dependent density functional tight-binding and density functional theory calculations. Our results show that Mg nanoclusters are able to produce highly energetic hot electrons with energies of up to 4 eV. By electronic structure analysis, we find that these hot electrons energetically align with electronic states of physisorbed molecular hydrogen, occupation of which by hot electrons can promote the hydrogen dissociation reaction. We also find that the reverse reaction, hydrogen evolution on metallic Mg, can potentially be promoted by hot electrons, but following a different mechanism. Thus, from a theoretical perspective, Mg nanoclusters display very promising behaviour for their use in light promoted storage and release of hydrogen.


The role of contrast sensitivity in global motion processing deficits in the elderly.
This study compared the effects of age on the perception of translational, radial, and rotational global motion patterns. Motion coherence thresholds were measured for judging the direction of each motion type as a function of contrast (visibility) and temporal sampling rate in young and elderly participants. Coherence thresholds decreased as dot contrast increased asymptoting at high dot contrasts but were higher in elderly compared to young participants. This equated to global motion impairment in the elderly of a factor of around 2, characterized by a shift of the threshold vs. contrast function along the horizontal axes (dot contrast). The effect of contrast interacted with the temporal sampling rate. Old participants were deleteriously affected by reduced temporal sampling particularly at low contrasts. The findings suggest that age-related changes in global motion perception may be driven principally by deficits in contrast encoding, rather than by deficits in motion integration and suggest a role for increased internal noise in the older visual system.


Age-specific diastolic dysfunction improves prediction of symptomatic heart failure by Stage B heart failure.
We investigated whether addition of diastolic dysfunction (DD) and longitudinal strain (LS) to Stage B heart failure (SBHF) criteria (structural or systolic abnormality) improves prediction of symptomatic HF in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. Both American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) criteria and age-specific Atherosclerosis Risk in Communities (ARIC) study criteria, for SBHF and DD, and ARIC criteria for abnormal LS, were examined. Inclusion criteria were age ≥60 years with one or more of self-reported ischaemic or other heart disease, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment, or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known HF, or ejection fraction <50% or >mild valve abnormality detected on previous echocardiography or other imaging. Echocardiography was performed in 3190 participants who were followed for a median of 3.9 (interquartile range: 3.4, 4.5) years after echocardiography. Symptomatic HF was diagnosed in 139 participants at a median of 3.1 (interquartile range: 2.1, 3.9) years after echocardiography. ARIC structural, systolic, and diastolic abnormalities predicted HF in univariate and multivariable proportional hazards analyses, whereas ASE/EACVI structural and systolic, but not diastolic, abnormalities predicted HF. ARIC and ASE/EACVI SBHF criteria predicted HF with sensitivities of 81% and 55%, specificities of 39% and 76%, and C statistics of 0.60 (95% confidence interval: 0.57, 0.64) and 0.66 (0.61, 0.71), respectively. Adding ARIC DD to SBHF increased sensitivity to 94% with specificity of 24% and C statistic of 0.59 (0.57, 0.61), whereas addition of ASE/EACVI DD to SBHF increased sensitivity to 97% but reduced specificity to 9% and the C statistic to 0.52 (0.50, 0.54, P < 0.0001). Addition of LS to ARIC or ASE/EACVI SBHF criteria had minimal impact on prediction of HF. Age-specific ARIC DD criteria, but not ASE/EACVI DD criteria, predicted symptomatic HF, and addition of age-specific ARIC DD criteria to ARIC SBHF criteria improved prediction of symptomatic HF in asymptomatic individuals with cardiovascular disease risk factors. Addition of LS to ASE/EACVI or ARIC SBHF criteria did not improve prediction of symptomatic HF.


Light scattering by a coated sphere illuminated with a Gaussian beam.

The intensity of light scattered by a coated sphere illuminated with an off-axis Gaussian beam is calculated. Results are shown for different beam positions with respect to the sphere. As the beam is shifted further away from the surface of the sphere, the higher-Q morphology-dependent resonances become increasingly important in the backscatter spectra, and the angular scattering intensity becomes smoother.

The scattered intensity depends on the beam position, the refractive indices of the core and coat, the radius of the core, and the thickness of the coat. As the beam is moved further away from the sphere, the effect of the core on the scattering intensity decreases. When the incident Gaussian beam is focused outside of a particle with a relatively small core, the scattering spectra and angular scattering patterns become similar to those of a homogeneous sphere having the refractive index of the coat. These calculated results suggest that measurements of spectral scattering and angular scattering patterns for several Gaussian beam positions could be useful for the characterization of coated spheres.


The comparative effectiveness of a multimodal program versus exercise alone for the secondary prevention of chronic low back pain and disability.
The objective of this study was to examine whether a multimodal, secondary prevention program (MP) is superior to a general physical exercise program (EP) in influencing the process leading to chronic low back pain (LBP) in nurses with a history of back pain. The study was conducted as a randomized controlled parallel-group trial. The interventions were performed in a single center at the Department of Physical and Rehabilitation Medicine at the University of Munich in Germany. A total of 235 nurses from 14 nearby hospitals and nursing homes who experienced at least one episode of back pain during the previous 2 years were invited into the study. Of these, 183 nurses were enrolled and 169 (83 in the MP and 86 in the EP) qualified for the intent-to-treat analysis. The EP consisted of 11 group sessions, each lasting 1 hour. After introductory sessions, subsequent sessions included general physical strengthening and stretching exercises as well as instructions for a home-training program. The MP consisted of 17 group sessions of 1.75 hours and one individual session of 45 minutes. In addition to the full EP, the MP included 5 psychological units, 7 segmental stabilization exercises units, and 8 ergonomic and workplace-specific units. The primary study end-point variable was pain interference, and the secondary study end-point variables were pain intensity and functioning as measured with the West Haven-Yale Multidimensional Pain Inventory and the Short Form-36, respectively. These study end-point variables were defined a priori. There was no statistically significant difference between the 2 groups. Small-to-moderate effects were observed in both intervention programs across all study end-point variables. For pain interference, the effect size at 12 months after intervention was 0.58 in the MP and 0.47 in the EP. A multimodal program is not superior to a general exercise program in influencing the process leading to chronic LBP in a population of nurses with a history of pain. The most likely explanation is a common psychological mechanism leading to improved pain interference that is irrespective of the program used. Considering the lower resources of the general exercise program, the expense for a multimodal program is not justified for the secondary prevention of LBP and disability.


The immediate effects of abrupt diet composition changes in young pigs.
Forty pigs (twenty males and twenty females) were weaned at 4 weeks of age into individual cages, and their weights and feed intakes measured daily. From weaning to 16 kg live weight they were given free access to a feed with either 134 (L) or 278 (H) g crude protein (nitrogen x 6.25)/kg fresh weight. During this period pigs on feed L grew at a slower rate and converted feed less efficiently than pigs on feed H. At 16 kg live weight they were introduced to a 6 d period of feeding when, on successive days, they were given feeds L, H, L, H, L and H (if previously fed on L) or feeds H, L, H, L, H and L (if previously fed on H). For pigs previously given access to feed L the live-weight gain was 1061 v. 575 g/d on the days when H or L was given; the feed intake was 1078 v. 1027 g/d respectively. For pigs previously given access to feed H, the live-weight gain was 655 v. 610 g/d and the feed intake 844 v. 1071 g/d on the days when H or L were given. The interactions between the feed given previously and the feed given for the 3 d of the subsequent 6 d period were highly significant for both live-weight and feed intake. These rapid changes in feed intake and growth rate suggest that the metabolism of young pigs is extremely flexible, with a rapid rate of response to a change in the protein content of their feed.


Curcumin modified silver nanoparticles for highly efficient inhibition of respiratory syncytial virus infection.
Interactions between nanoparticles and viruses have attracted increasing attention due to the antiviral activity of nanoparticles and the resulting possibility to be employed as biomedical interventions. In this contribution, we developed a very simple route to prepare uniform and stable silver nanoparticles (AgNPs) with antiviral properties by using curcumin, which is a member of the ginger family isolated from rhizomes of the perennial herb Curcuma longa and has a wide range of biological activities like antioxidant, antifungal, antibacterial and anti-inflammatory effects, and acts as reducing and capping agents in this synthetic route. The tissue culture infectious dose (TCID50) assay showed that the curcumin modified silver nanoparticles (cAgNPs) have a highly efficient inhibition effect against respiratory syncytial virus (RSV) infection, giving a decrease of viral titers about two orders of magnitude at the concentration of cAgNPs under which no toxicity was found to the host cells. Mechanism investigations showed that cAgNPs could prevent RSV from infecting the host cells by inactivating the virus directly, indicating that cAgNPs are a novel promising efficient virucide for RSV.


BoLA-6*01301 and BoLA-6*01302, two allelic variants of the A18 haplotype, present the same epitope from the Tp1 antigen of Theileria parva.
We have recently shown that the BoLA-A18 variant haplotype (BoLA-6*01302) is more prevalent than the BoLA-A18 haplotype (BoLA-6*01301) in a sample of Holstein/Friesian cattle in Kenya. These MHC class I allelic variants differ by a single amino acid polymorphism (Glu97 to Leu97) in the peptide-binding groove. We have previously mapped an 11-mer peptide epitope from the Theileria parva antigen Tp1 (Tp1214-224) that is presented by BoLA-6*01301. Crystal structure data indicates that Glu97 in the MHC molecule plays a role in epitope binding through electro-static interaction with a lysine residue in position 5 of the epitope, which also functions as an additional anchor residue. In contrast to expectations, we demonstrate that the amino acid substitution in BoLA-6*01302 does not divert the CTL response away from Tp1214-224. The two MHC molecules exhibit similar affinity for the Tp1 epitope and can present the epitope to parasite-specific CTLs derived from either BoLA allelic variants. These data confirm that this BoLA polymorphism does not alter Tp1 epitope specificity and that both allelic variants can be used for Tp1 vaccine studies.


Patterns of metabolite changes identified from large-scale gene perturbations in Arabidopsis using a genome-scale metabolic network.
Metabolomics enables quantitative evaluation of metabolic changes caused by genetic or environmental perturbations. However, little is known about how perturbing a single gene changes the metabolic system as a whole and which network and functional properties are involved in this response. To answer this question, we investigated the metabolite profiles from 136 mutants with single gene perturbations of functionally diverse Arabidopsis (Arabidopsis thaliana) genes. Fewer than 10 metabolites were changed significantly relative to the wild type in most of the mutants, indicating that the metabolic network was robust to perturbations of single metabolic genes. These changed metabolites were closer to each other in a genome-scale metabolic network than expected by chance, supporting the notion that the genetic perturbations changed the network more locally than globally. Surprisingly, the changed metabolites were close to the perturbed reactions in only 30% of the mutants of the well-characterized genes. To determine the factors that contributed to the distance between the observed metabolic changes and the perturbation site in the network, we examined nine network and functional properties of the perturbed genes. Only the isozyme number affected the distance between the perturbed reactions and changed metabolites. This study revealed patterns of metabolic changes from large-scale gene perturbations and relationships between characteristics of the perturbed genes and metabolic changes.


Use of entomopathogenic nematodes to suppress Meloidogyne incognita on greenhouse tomatoes.
Tomato seedlings in a growth chamber were inoculated with 150 Meloidogyne incognita eggs and 25 infective juveniles (IJ)/cm² of Steinernema feltiae, S. riobrave, or Heterorhabditis bacteriophora. With the exception of seedling roots treated with H. bacteriophora, all seedlings treated with entomopathogenic nematodes had fewer M. incognita juveniles inside roots and produced fewer eggs than the control seedlings. Tomato plants in the greenhouse were infested with 4,000 M. incognita eggs and treated 2 weeks before, 1 week before, at the same time, 1 week after, or 2 weeks after with 25 or 125 IJ/cm² of S. feltiae, S. riobrave, or H. bacteriophora. Plants with pre- and post-infestation applications of S. feltiae or S. riobrave suppressed M. incognita. Plants treated with H. bacteriophora 1 week before and at the time of infestation suppressed M. incognita. Increasing the rate of H. bacteriophora and S. feltiae from 25 to 125 IJ/cm² improved M. incognita suppression.


In vivo vascular engineering: directed migration of smooth muscle cells to limit neointima.
Pathologic neointima formation requires directional smooth muscle cell (SMC) migration from media to intima. The very direction of SMC migration thus becomes a potential therapeutic target. Here, we hypothesize that proliferating SMC after injury can be redirected using engineered chemotactic gradients of elastin degradation to limit late pathologic neointima formation. Buffered bioerodible polymeric microspheres (MS) were constructed to provide 4-week sustained release of elastase, heat-killed elastase, or polymer only. In vitro elastase function and timecourse of release at 37 degrees C, physiologic pH, and shear was determined. Curves revealed an initial bolus followed by sustained linear release for elastase MS, while controls exhibited baseline hydrolysis of substrate. We then employ controlled perivascular release of elastase after angioplasty to engineer modified in vivo gradients of elastin degradation in rabbit femoral arteries. NZW rabbits (n = 8 each) underwent balloon angioplasty of the common femoral artery followed by perivascular distribution of MS. Significant early perivascular elastin degradation resulted. Concurrently, proliferating SMC were guided peripherally (further from lumen) with treatment without significant changes in total proliferation or inflammation. At 28 days, treatment significantly reduces neointima by 42% relative to controls. These results confirm that directionally guiding SMC responses after injury achieves favorable arterial remodeling and limits development of pathologic neointima. Thus, a potential class of therapeutics and the paradigm of in vivo vascular engineering emerge from this work.


Feeding goals sought by mothers of 3-5-year-old children.
One means through which children learn eating behaviours is the feeding strategies used by parents. Although research has studied the effects of parental feeding strategies on consumption, choice, and liking, little is known about the goals parents themselves seek. The study aimed to explore the feeding goals sought by parents of preschool children. An exploratory qualitative study using in-depth, semi-structured interviews was undertaken. Data were analysed using thematic and interpretative techniques. A snowballing sample of 12 mothers of children aged 3-5 years was used. Mothers were asked to recall and talk through their feeding experiences with this child. Probe questions were used to explore the reasoning behind the actions described. Data were transcribed and subjected to concurrent coding and interpretation. Mothers spontaneously classified their child as a 'good' or a 'bad' eater. Consumption emerged as the dominant feeding goal. For 'bad' eaters, a short-term goal of consuming any food, rather than no food, was adopted. For 'good' eaters, a long-term goal of consuming a varied, well-balanced diet was favoured. Liking as a feeding goal was not mentioned. Although the literature suggests that liking is the most appropriate feeding goal for the establishment of long-term healthy eating behaviours, parents do not knowingly, repeatedly and consistently target food likes as a direct outcome of their feeding strategies. Interventions that focus on 'how' parents feed their children, as well as 'what', are recommended.


Psychiatric emergency services and the system of care.
Admissions to psychiatric emergency services have frequently been cited as a gauge of how well a mental health system manages behavioral disorders. However, few measurements of the longitudinal association between psychiatric emergencies and characteristics of a mental health system have been described. The purpose of this study was to assess whether weekly admissions to psychiatric emergency services would increase when outpatient services were reduced, whether weekly admissions would increase when greater effort was made to identify and treat persons with acute mental illness, and whether weekly admissions would decrease when emergency services were enhanced to include postrelease case management. Time-series methods were applied to approximately 29,010 admissions to three psychiatric emergency services of the San Francisco Department of Public Health over a 180-week period. Reduced outpatient services, efforts to identify acutely ill persons, and changes in emergency services themselves were found to affect admissions to emergency services. However, community events such as extreme weather, holidays, job loss, and the scheduling of receipt of income also affected the workload of the emergency service. The causes and course of mental illness inextricably tie a psychiatric emergency service to the overall mental health system and to events in the community it serves. These connections make it possible for managers to anticipate the use of emergency services and to detect disruptions in the remainder of the mental health services systems.


Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma: evaluation of potential chemopreventive activity.
Reduced melanoma risk has been reported with regular use of nonsteroidal anti-inflammatory drugs (NSAIDs). However, the ability of NSAIDs to reach melanocytes in vivo and modulate key biomarkers in preneoplastic lesions such as atypical nevi has not been evaluated. This randomized, double-blind, placebo-controlled trial of sulindac was conducted in individuals with atypical nevi (AN) to determine bioavailability of sulindac and metabolites in nevi and effect on apoptosis and vascular endothelial growth factor A (VEGFA) expression in AN. Fifty subjects with AN ≥ 4 mm in size and 1 benign nevus (BN) were randomized to sulindac (150 mg twice a day) or placebo for 8 weeks. Two AN were randomized for baseline excision, and 2 AN and BN were excised after intervention. Postintervention sulindac, sulindac sulfone, and sulindac sulfide concentrations were 0.31 ± 0.36, 1.56 ± 1.35, and 2.25 ± 2.24 μg/mL in plasma, and 0.51 ± 1.05, 1.38 ± 2.86, and 0.12 ± 0.12 μg/g in BN, respectively. Sulindac intervention did not significantly change VEGFA expression but did increase expression of the apoptotic marker cleaved caspase-3 in AN (increase of 3 ± 33 in sulindac vs decrease of 25 ± 45 in the placebo arm, P = .0056), although significance was attenuated (P = .1103) after adjusting for baseline expression. Eight weeks of sulindac intervention resulted in high concentrations of sulindac sulfone, a proapoptotic metabolite, in BN but did not effectively modulate VEGFA and cleaved caspase-3 expression. Study limitations included limited exposure time to sulindac and the need to optimize a panel of biomarkers for NSAID intervention studies.


Biological and antigenic characterization of Netivot virus, an unusual new Orbivirus recovered from mosquitoes in Israel.
The antigenic and biological characteristics of a new Orbivirus, designated Netivot virus, are described. This agent was originally recovered in cultures of the C6/36 clone of Aedes albopictus cells from a pool of Culex pipiens captured in Israel. Netivot virus is not pathogenic for newborn mice, nor did it initially produce detectable cytopathic effect (CPE) in Vero cells. It is closely related antigenically to Umatilla and Llano Seco viruses; these 3 agents appear to constitute a new serogroup within the genus Orbivirus. Netivot virus is also more distantly related to a number of other orbiviruses in the blue-tongue, epizootic hemorrhagic disease of deer, and Eubenangee serogroups. Netivot virus replicated to high titer and produced CPE in a variety of mosquito cell cultures, but it did not grow in 2 sand fly cell lines. Inoculation of Ae. aegypti and Ae. albopictus with Netivot virus resulted in almost 100% mortality in both species within 15 days after infection. The recovery of this and a number of other yet unidentified viral agents from field-collected mosquitoes in cultures of C6/36 cells, but not in the conventional vertebrate assay systems, suggests the existence in nature of many yet unrecognized mosquito-associated viruses. It also demonstrates the value of using new isolation methods in arbovirus studies.


MDMA Is Not Ecstasy: The Production of Pharmaceutical Safety through Documents in Clinical Trials.
Nonprofit efforts to develop ±3,4-methylenedioxymethamphetamine (MDMA)-better known as the street drug Ecstasy-as a prescription pharmaceutical provide the opportunity to examine recent theorizations of pharmaceuticals as fluid objects transformed in new informational and material environments. Drawing from ethnographic research, this article interrogates MDMA researchers' own distinction between MDMA and the street drug Ecstasy. While researchers maintain that pure MDMA is distinct from Ecstasy, this article argues that the difference between the two hangs not on a distinction in substance, but on a distinction in safety that must be produced through the trial. This article tracks the production of safety through the inter-connected work of clinical documents, which manage both which bodies are allowed to absorb the drug and which bodily events count as effects. MDMA's safety emerges from the careful management of relations through these documentary practices.


Waist-to-hip ratio versus body mass index as predictors of fitness in women.
The claim that men prefer women with low waist-to-hip ratios (WHR) has been vigorously disputed. We examine self-report data from 359 primiparous Polish women (with normal singleton births and healthy infants) and show that WHR correlates with at least one component of a woman's biological fitness (her first child's birth weight, a variable that significantly affects infant survival rates). However, a woman's Body Mass Index (BMI) is a better predictor of her child's neonatal weight in small-bodied women (<54 kg). The failure to find a preference for low WHR in some traditional populations may thus be a consequence of the fact that, even in western populations, body mass is a better predictor of fitness in those cases characterized by low maternal body weight.


Albumin is taken up by hippocampal NG2 cells and astrocytes and decreases gap junction coupling.
Dysfunction of the blood-brain barrier (BBB) and albumin extravasation have been suggested to play a role in the etiology of human epilepsy. In this context, dysfunction of glial cells attracts increasing attention. Our study was aimed to analyze in the hippocampus (1) which cell types internalize albumin injected into the lateral ventricle in vivo, (2) whether internalization into astrocytes impacts their coupling and expression of connexin 43 (Cx43), and (3) whether expression of Kir4.1, the predominating astrocytic K(+) channel subunit, is altered by albumin. The patch-clamp method was combined with single cell tracer filling to investigate electrophysiologic properties and gap junction coupling (GJC). For cell identification, mice with cell type-specific expression of a fluorescent protein (NG2kiEYFP mice) and immunohistochemistry were employed. Semiquantitative real time polymerase chain reaction (RT-PCR) allowed analysis of Kir4.1 and Cx43 transcript levels. We show that fluorescently labeled albumin is taken up by astrocytes, NG2 cells, and neurons, with NG2 cells standing out in terms of the quantity of uptake. Within 5 days postinjection (dpi), intracellular albumin accumulation was largely reduced suggesting rapid degradation. Electrophysiologic analysis of astrocytes and NG2 cells revealed no changes in their membrane properties at either time point. However, astrocytic GJC was significantly decreased at 1 dpi but returned to control levels within 5 dpi. We found no changes in hippocampal Cx43 transcript expression, suggesting that other mechanisms account for the observed changes in coupling. Kir4.1 mRNA was regulated oppositely in the CA1 stratum radiatum, with a strong increase at 1 dpi followed by a decrease at 5 dpi. The present study demonstrates that extravasal albumin in the hippocampus induces rapid changes of astrocyte function, which can be expected to impair ion and transmitter homeostasis and contribute to hyperactivity and epileptogenesis. Therefore, astrocytes may represent alternative targets for antiepileptic therapeutic approaches.


Effect of separating layer thickness on W/Si multilayer replication.
The direct replication of W/Si multilayers and the effect of separating layer thickness on the performance of the multilayer before and after replication are investigated systematically. Platinum separating layers with different layer thicknesses were first deposited onto different supersmooth mandrels and then W/Si multilayers with the similar structure were deposited onto these Pt-coated mandrels by using a high vacuum DC magnetron sputtering system. After the deposition, these multilayers were replicated onto the commercially available float glass substrates by epoxy replication technique. These multilayers before and after replication are characterized by grazing-incident X-ray reflectance measurement and atomic force microscope. The measured results show that before and after replication, the reflectivity curves are much similar to those calculated and the surface roughness of each sample is close to that of the mandrel, when the separating layer thickness is larger than 1.5 nm. These results reveal that the W/Si multilayer with the separating layer thickness larger than 1.5 nm can be successfully replicated onto a substrate without modification of the structure, significant increase of surface roughness or apparent change of reflectivity.


Reassembly of functional nucleoli following in situ unraveling by low-ionic-strength treatment of cultured mammalian cells.
In order to determine the most persistent components of the nucleolus that might serve as "core" nucleolar elements, we studied the reactivity of nucleoli in living mammalian cells subjected to hypotonic buffer saline followed by the incubation of the cells in an isotonic medium. To document as precisely as possible the fine structural changes which occurred, the cells were examined by video-enhanced optical microscopy, fluorescence confocal laser scanning microscopy, and electron microscopy combined with cytochemistry. Light microscopic autoradiography was used to demonstrate the transcriptional characteristics of the reassembled nucleoli. It was shown that all the major compartments of the intact nucleolus could be substantially affected by reduction of the osmolarity of the environmental media. The dynamic events of the nucleolar unraveling in low-salt buffers occurred in the following order: dispersion of the nucleolar pars granulosa, disassociation of the fibrillar complexes into discrete fibrillar centers (FCs) and the dense fibrillar component (DFC), and the almost complete unraveling of the DFC and FCs. At the terminal stages of nucleolar dispersion, the nuclear interior was mainly composed of a loose filamentous meshwork, and none of the typically discerned nucleolar constituents was recognized. Nevertheless, when hypotonically treated cells were returned to isotonic conditions, the nucleolar bodies rapidly began to reassemble. Within 1-2 h of cell incubation under isotonicity, the nucleoli not only became clearly visible, but also reconstituted to their initial size, shape, and position within the nucleus. The ultrastructure and functional activity of the reassembled nucleoli were also found to be fully comparable to those of the untreated controls. These data indicate that the architectural composition of the interphase nucleolus is strictly controlled by the cell. As far as could be determined, none of the usual substructures of the intact nucleolus that could be substituted by complete reassembly of the nucleolar bodies in normotonic conditions, including FCs and the DFC, remained clearly preserved in the terminal stage of nucleolar unraveling. We concluded that the integrity of the nucleolus was mainly preserved by the nuclear or nucleolar matrix system rather than by any other nucleolar structural domains.


Oral contraceptive pill use and fractures in women: a prospective study.
It has been suggested that use of the oral contraceptive pill by women confers protection against osteoporosis later in life. However, cross-sectional studies of bone density among pill users have yielded discrepant results. We therefore investigated the relationship between pill use and subsequent occurrence of fracture in a cohort of 46,000 women enrolled in the Royal College of General Practitioners Oral Contraception Study during 482,083 person-years of follow-up. Fracture risk was lower among multiparous women, non-smokers, and those of lower socio-economic class. The risk of subsequent fractures among the women who had ever used the oral contraceptive pill was significantly greater than that among women who had never used it (relative risk 1.20, 95% confidence intervals 1.08-1.34) after adjustment for these variables. When the analysis was confined to forearm fractures, no significant effect of pill use on fracture risk was detected. Although the study only includes limited observation of older women to date, these data do not support the hypothesis that pill use protects women against the occurrence of osteoporotic fractures in later life.


Optimal Sampling of Dynamical Large Deviations in Two Dimensions via Tensor Networks.
We use projected entangled-pair states (PEPS) to calculate the large deviation statistics of the dynamical activity of the two-dimensional East model, and the two-dimensional symmetric simple exclusion process (SSEP) with open boundaries, in lattices of up to 40×40 sites. We show that at long times both models have phase transitions between active and inactive dynamical phases. For the 2D East model we find that this trajectory transition is of the first order, while for the SSEP we find indications of a second order transition. We then show how the PEPS can be used to implement a trajectory sampling scheme capable of directly accessing rare trajectories. We also discuss how the methods described here can be extended to study rare events at finite times.


Mechanisms underlying rapid aldosterone effects in the kidney.
The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.


Inferring the effectiveness of government interventions against COVID-19.
Governments are attempting to control the COVID-19 pandemic with nonpharmaceutical interventions (NPIs). However, the effectiveness of different NPIs at reducing transmission is poorly understood. We gathered chronological data on the implementation of NPIs for several European and non-European countries between January and the end of May 2020. We estimated the effectiveness of these NPIs, which range from limiting gathering sizes and closing businesses or educational institutions to stay-at-home orders. To do so, we used a Bayesian hierarchical model that links NPI implementation dates to national case and death counts and supported the results with extensive empirical validation. Closing all educational institutions, limiting gatherings to 10 people or less, and closing face-to-face businesses each reduced transmission considerably. The additional effect of stay-at-home orders was comparatively small.


Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells.
The macrophage mannose receptor is an integral membrane protein expressed on the surface of tissue macrophages. After ligation of mannose-rich glycoconjugates or pathogens, the receptor mediates endocytosis and phagocytosis of the bound ligands by macrophages. The cDNA-derived primary structure of the mannose receptor predicts a cysteine-rich NH2-terminal domain, followed by a fibronectin type II region. The remainder of the ectodomain is comprised of eight carbohydrate recognition-like domains, followed by a transmembrane region, and a cytoplasmic tail. Transfection of the mannose receptor cDNA into Cos-I cells is necessary for receptor-mediated endocytosis of mannose-rich glycoconjugate as well as phagocytosis of yeasts. Deletion of the cytoplasmic tail results in a mutant receptor that is able to bind but not ingest the ligated pathogens, suggesting that the signal for phagocytosis is contained in the cytoplasmic tail.


Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data.
Immunohistochemistry is frequently employed to aid the distinction between mesothelioma and pulmonary adenocarcinoma metastatic to the pleura, but there is uncertainty as to which antibodies are most useful. We analysed published data in order to establish sensitivity and specificity of antibodies used to distinguish between these tumours with a view to defining the most appropriate immunohistochemical panel to use when faced with this diagnostic problem. A systematic analysis of the results of 88 published papers comparing immunohistochemical staining of a panel of antibodies in mesothelioma with epithelioid areas, and pulmonary adenocarcinoma metastatic to the pleura. Results for a total of 15 antibodies were analysed and expressed in terms of sensitivity and specificity. The most sensitive antibodies for identifying pulmonary adenocarcinoma were MOC-31 and BG8 (both 93%), whilst the most specific were monoclonal CEA (97%) and TTF-1 (100%). The most sensitive antibodies to identify epithelioid mesothelioma were CK5/6 (83%) and HBME-1 (85%). The most specific antibodies were CK5/6 (85%) and WT1 (96%). No single antibody is able to differentiate reliably between these two tumours. The use of a small panel of antibodies with a high combined sensitivity and specificity is recommended.


Volume reduction in meningiomas after gamma knife surgery.
The purpose of this study was to evaluate the volume-reducing effects of gamma knife surgery (GKS) of meningiomas with and without previous surgical treatment. A group of 127 patients with a mean age of 57.1 years (range 9-81 years) with 142 meningiomas (128 World Health Organization Grade I and 14 Grade II) were included in this study. The management strategy reduces tumor volume with surgery when necessary (81 patients). Stereotactic GKS with a Gamma Knife model C was performed in all tumors of suitable size. Magnetic resonance imaging follow-up examinations with volumetric tumor analysis was performed 6 months after treatment and annually thereafter. The mean tumor volume was 5.9 cm3 (range < 5 to > 40 cm3). The mean follow-up time after GKS was 29.3 months (range 11-61 months). The mean prescription dose was 13.8 Gy (range 10-18 Gy). A reduction in volume occurred in 117 (82.4%) of all tumors, and in 20 tumors (14.1%) growth ceased. The overall tumor control rate of 96.4%. The mean volume reduction achieved with GKS was more than 46.1%. Only five tumors (3.5%) stowed a volume increase. Gamma knife surgery was effective in reducing meningioma volume at short-term follow up. Further studies are needed to examine the development of these findings over a longer period.


Exercise duration and mood state: how much is enough to feel better?
The effects of exercise duration on mood state were examined. In a repeated-measures design, the Profile of Mood States inventory (D. M. McNair, M. Lorr, & L. F. Droppleman, 1971) was administered before and after 1 quiet resting trial and 3 exercise trials of 10, 20, and 30 min on a bicycle ergometer. Heart rate levels were controlled at 60% of the participant's estimated VO2max level. An overall analysis of variance found improved levels of vigor with reduced levels of confusion, fatigue, and total negative mood. Planned analyses revealed that the improvements in vigor, fatigue, and total mood occurred after 10 min of exercise, with progressive improvements in confusion over 20 min and with no additional improvement over longer periods. These results complement current recommendations, which suggest that to experience positive fitness and health benefits, healthy adults should participate in a total of 30 min of moderate physical exercise daily, accumulated in short bouts throughout the day.


Novel open-framework europium silicates prepared under high-temperature and high-pressure conditions.
Two new europium silicates, Na15Eu3Si12O36 (denoted as 1) and K2EuSi4O10F (denoted as 2), were successfully synthesized under high-temperature and high-pressure conditions, and structurally characterized by single-crystal and powder X-ray diffraction (XRD). The single-crystal XRD analysis of 1 reveals that its structure is based on [Si6O18]n(12n-) cyclosilicate anions that are built from six SiO4 tetrahedra sharing two of their four O corners with each other. Such [Si6O18]n(12n-) cyclosilicate anions are linked via EuO6 octahedra to form a three-dimensional (3D) framework containing 6-membered ring channels delimited by the SiO4 tetrahedra and EuO6 octahedra along the [010] direction. The structure of 2 consists of infinite tubular chains of corner-sharing SiO4 tetrahedra, which are further linked together via corner sharing O atoms by infinite chains of EuO4F2 octahedra forming a 3-D framework that contains 8-ring and 6-ring channels along the [010] direction. The photoluminescence properties of 1 and 2 were also investigated.


Relationship between funding source and conclusion among nutrition-related scientific articles.
Industrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions. Medline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding. Industry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health.


Reducing radiation-induced gastrointestinal toxicity - the role of the PHD/HIF axis.
Radiotherapy is an effective treatment strategy for cancer, but a significant proportion of patients experience radiation-induced toxicity due to damage to normal tissue in the irradiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiotherapy is a long-held goal. Hypoxia-inducible factors (HIFs) regulate the production of factors that may protect several cellular compartments affected by radiation-induced toxicity. Pharmacological inhibitors of prolyl hydroxylase domain-containing enzymes (PHDs), which result in stabilization of HIFs, have recently been proposed as a new class of radioprotectors. In this review, radiation-induced toxicity in the gastrointestinal (GI) tract and the main cellular compartments studied in this context will be discussed. The effects of PHD inhibition on GI radioprotection will be described in detail.


Cochrane corner: hypothermia for neuroprotection in adults after cardiopulmonary resuscitation.
Good neurologic outcome after cardiac arrest is hard to achieve. Interventions during the resuscitation phase and treatment within the first hours after the event are critical. Experimental evidence suggests that therapeutic hypothermia is beneficial, and a number of clinical studies on this subject have been published. We performed a systematic review and meta-analysis to assess the effectiveness of therapeutic hypothermia in patients after cardiac arrest. Neurologic outcome, survival and adverse events were our main outcome parameters. We aimed to perform individual patient data analysis if data were available, and to from subgroups according to the cardiac arrest situation. We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2007 Issue 1); MEDLINE (1971 to January 2007); EMBASE (1987 to January 2007); CINAHL (1988 to January 2007); PASCAL (2000 to January 2007); and BIOSIS (1989 to January 2007). We included all randomized controlled trials assessing the effectiveness of the therapeutic hypothermia in patients after cardiac arrest without language restrictions. Studies were restricted to adult populations cooled with any cooling method applied within six hours of cardiac arrest. Validity measures, the intervention, outcome parameters and additional baseline variables were entered into the database. Meta-analysis was only done for a subset of comparable studies with negligible heterogeneity. For these studies individual patient data were available. Four trials and one abstract reporting on 481 patients were included in the systematic review. Quality of the included studies was good in three out of five included studies. For the three comparable studies on conventional cooling methods all authors provided individual patient data. With conventional cooling methods patients in the hypothermia group were more likely to reach a best cerebral performance categories score of one or two (CPC, five point scale; 1=good cerebral performance, to 5=brain death) during hospital stay (individual patient data; RR, 1.55; 95% CI 1.22 to 1.96) and were more likely to survive to hospital discharge (individual patient data; RR, 1.35; 95% CI 1.10 to 1.65) compared to standard post-resuscitation care. Across all studies there was no significant difference in reported adverse events between hypothermia and control. Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after cardiac arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines.


The role of multisensory interplay in enabling temporal expectations.
Temporal regularities can guide our attention to focus on a particular moment in time and to be especially vigilant just then. Previous research provided evidence for the influence of temporal expectation on perceptual processing in unisensory auditory, visual, and tactile contexts. However, in real life we are often exposed to a complex and continuous stream of multisensory events. Here we tested - in a series of experiments - whether temporal expectations can enhance perception in multisensory contexts and whether this enhancement differs from enhancements in unisensory contexts. Our discrimination paradigm contained near-threshold targets (subject-specific 75% discrimination accuracy) embedded in a sequence of distractors. The likelihood of target occurrence (early or late) was manipulated block-wise. Furthermore, we tested whether spatial and modality-specific target uncertainty (i.e. predictable vs. unpredictable target position or modality) would affect temporal expectation (TE) measured with perceptual sensitivity (d') and response times (RT). In all our experiments, hidden temporal regularities improved performance for expected multisensory targets. Moreover, multisensory performance was unaffected by spatial and modality-specific uncertainty, whereas unisensory TE effects on d' but not RT were modulated by spatial and modality-specific uncertainty. Additionally, the size of the temporal expectation effect, i.e. the increase in perceptual sensitivity and decrease of RT, scaled linearly with the likelihood of expected targets. Finally, temporal expectation effects were unaffected by varying target position within the stream. Together, our results strongly suggest that participants quickly adapt to novel temporal contexts, that they benefit from multisensory (relative to unisensory) stimulation and that multisensory benefits are maximal if the stimulus-driven uncertainty is highest. We propose that enhanced informational content (i.e. multisensory stimulation) enables the robust extraction of temporal regularities which in turn boost (uni-)sensory representations.


Correlation between 18F-fluorodeoxyglucose Positron Emission Tomography/computed Tomography and Clinicopathological Features in Invasive Ductal Carcinoma of the Breast.
We evaluated the usefulness of preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) examinations to predict the pathological features in primary breast cancer. In particular, we evaluated the correlation between the maximum standardized uptake values (SUVmax) obtained by 18F-FDG PET/CT and the Ki67 expression in estrogen receptor (ER)-positive invasive ductal carcinoma (IDC). Primary IDC patients operated between March 2009 and July 2013 at Okayama University Hospital were enrolled. We evaluated the correlations between the SUVmax and age, postoperative pT, histological grade, lymph vascular invasion, status of hormone receptor, human epidermal growth factor receptor 2 (HER2), Ki67 expression and node status. The Ki67 expression was classified as high (> 14%) versus low (< 14%). We enrolled 138 patients with IDC. Their median SUVmax was 3.85 (range:0-52.57). In a univariate analysis, the SUVmax was significantly related to age, pT, histological grade, lymphovascular invasion, hormone receptor status, HER2 status, node status and Ki67. In the 113 patients with ER-positive IDC, there was a significant correlation between Ki67 and SUVmax (p = 0.0030). The preoperative 18F-FDG PET/CT results of IDC patients had significant relationships with pathological status parameters. The determination of the preoperative SUVmax might help classify Luminal A and Luminal B patients among luminal-type breast cancer patients.


Use of polymerase chain reaction for detection of toxigenic Vibrio cholerae O1 strains from the Latin American cholera epidemic.
In January 1991, an outbreak of cholera started in Peru and spread throughout most of Latin America within 8 months. As of March 1992, over 450,000 cases and approximately 4,000 deaths have been reported to the Pan American Health Organization. The causative organism is toxigenic Vibrio cholerae O1 of the El Tor biotype and is distinct from the U.S. Gulf Coast strains. A polymerase chain reaction (PCR) that amplifies a 564-bp fragment of the cholera toxin A subunit gene (ctxA) was used to identify toxigenic V. cholerae O1 strains. A total of 150 V. cholerae O1 isolates were tested. They were of unknown toxin status, were associated with recent outbreaks, and were isolated from patients, food, and water. One hundred forty isolates were found to be toxigenic both by PCR and the routine diagnostic enzyme-linked immunosorbent assay. Thirty-eight known toxigenic strains isolated worldwide from 1921 to 1991 were also positive in the PCR. A collection of 18 nontoxigenic V. cholerae O1 strains, 35 Escherichia coli heat-labile-enterotoxin-I-producing strains, 26 Campylobacter strains, and 8 strains of Aeromonas hydrophila, previously reported to produce cholera toxin-like toxin, were all negative in the ctxA PCR. We conclude that this PCR is a diagnostic method that specifically detects toxin genes in V. cholerae O1 strains in a reference laboratory. It is more rapid and less cumbersome than other diagnostic methods for detection of toxicity in these strains.


Young children's understanding of markedness in non-verbal communication.
Speakers often anticipate how recipients will interpret their utterances. If they wish some other, less obvious interpretation, they may 'mark' their utterance (e.g. with special intonations or facial expressions). We investigated whether two- and three-year-olds recognize when adults mark a non-verbal communicative act--in this case a pointing gesture--as special, and so search for a not-so-obvious referent. We set up the context of cleaning up and then pointed to an object. Three-year-olds inferred that the adult intended the pointing gesture to indicate that object, and so cleaned it up. However, when the adult marked her pointing gesture (with exaggerated facial expression) they took the object's hidden contents or a hidden aspect of it as the intended referent. Two-year-olds' appreciation of such marking was less clear-cut. These results demonstrate that markedness is not just a linguistic phenomenon, but rather something concerning the pragmatics of intentional communication more generally.


Closed-form analytical solutions for ray tracing in optically anisotropic inhomogeneous media.
Closed-form analytical solutions are obtained for ray tracing in several types of optically anisotropic inhomogeneous media whose optical properties are characterized by a matrix form of the inhomogeneous dielectric tensor in principal coordinates. The first solution is for anisotropic axial media, the second solution is for meridional rays in epsilon-negative metamaterial, and the third solution is an approximate one for rectangular lenses fabricated by molding procedures. The validation of numerical ray-tracing procedures for optically anisotropic inhomogeneous media was widely ignored since the solution was not available, and thus the present solutions are also useful for the validation. Furthermore, as examples of validation, ray trajectories are calculated by the closed-form solutions, and their results are compared with those obtained by a numerical solution of the geodesic equation which can be interpreted as a generalized ray equation.


Preparation of tuberculin antigen L.
The preparation of antigen L using culture filtrates of live BCG is described. The procedure consisted essentially of precipitating this filtrate with 10% trichloroacetic acid in the presence of N-butyl alcohol 4% final concentration. The precipitate was chromatographed on carboxy-methyl-trisacryl-M and then on DEAE-trisacryl-M; in both cases, maximal biological activity (delayed-type hypersensitivity) was found in the void volume. The product thus obtained was chromatographed on a molecular sieve so as to eliminate poorly active fractions. The final product was 30-fold more active on guinea-pigs sensitized with live BCG than on those sensitized with inactivated BCG.


Microbial community composition explains soil respiration responses to changing carbon inputs along an Andes-to-Amazon elevation gradient.
1. The Andes are predicted to warm by 3-5 °C this century with the potential to alter the processes regulating carbon (C) cycling in these tropical forest soils. This rapid warming is expected to stimulate soil microbial respiration and change plant species distributions, thereby affecting the quantity and quality of C inputs to the soil and influencing the quantity of soil-derived CO2 released to the atmosphere. 2. We studied tropical lowland, premontane and montane forest soils taken from along a 3200-m elevation gradient located in south-east Andean Peru. We determined how soil microbial communities and abiotic soil properties differed with elevation. We then examined how these differences in microbial composition and soil abiotic properties affected soil C-cycling processes, by amending soils with C substrates varying in complexity and measuring soil heterotrophic respiration (RH). 3. Our results show that there were consistent patterns of change in soil biotic and abiotic properties with elevation. Microbial biomass and the abundance of fungi relative to bacteria increased significantly with elevation, and these differences in microbial community composition were strongly correlated with greater soil C content and C:N (nitrogen) ratios. We also found that RH increased with added C substrate quality and quantity and was positively related to microbial biomass and fungal abundance. 4. Statistical modelling revealed that RH responses to changing C inputs were best predicted by soil pH and microbial community composition, with the abundance of fungi relative to bacteria, and abundance of gram-positive relative to gram-negative bacteria explaining much of the model variance. 5. Synthesis. Our results show that the relative abundance of microbial functional groups is an important determinant of RH responses to changing C inputs along an extensive tropical elevation gradient in Andean Peru. Although we do not make an experimental test of the effects of climate change on soil, these results challenge the assumption that different soil microbial communities will be 'functionally equivalent' as climate change progresses, and they emphasize the need for better ecological metrics of soil microbial communities to help predict C cycle responses to climate change in tropical biomes.


A structure-based approach for mapping adverse drug reactions to the perturbation of underlying biological pathways.
Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug's ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature.


Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood.
alpha Thalassemia modifies the hematologic expression of homozygous sickle cell (SS) disease, resulting in increased total hemoglobin and HbA2 and decreased HbF, mean cell volume, reticulocytes, irreversibly sickled cells, and bilirubin levels. The age at which these changes develop in children with SS disease is unknown. Ascertainment of globin gene status in a large representative sample of children with SS disease has afforded an opportunity to study the hematologic indices in nine children homozygous for alpha thalassemia 2 (two-gene group), 90 children heterozygous for alpha thalassemia 2 (three-gene group), and 167 children with a normal alpha globin gene complement (four-gene group). The two-gene group had significantly lower mean cell volumes from birth, higher red cell counts from one month, lower reticulocytes from three months, and higher HbA2 levels from one year, as compared with the four-gene group. Children with three genes had intermediate indices but resembled more closely the four-gene group. Differences in total hemoglobin or in fetal hemoglobin between the groups were not apparent by eight years of age. The most characteristic differences of the two-gene group were the raised proportional HbA2 level and low mean cell volume, the latter having some predictive value for alpha thalassemia status at birth.


Non-ventilatory treatment of acute hypoxic respiratory failure.
Severe acute hypoxic respiratory failure is uncommon but often fatal. Standard treatment involves high inspired oxygen concentrations, mechanical ventilation and positive end-expiratory pressure. Many other interventions have been used in parallel with conventional treatment or as rescue therapy when it fails, including extracorporeal gas exchange, prone positioning, inhaled vasodilators, exogenous surfactants and drugs which modify the inflammatory process. Nearly all these treatments improve arterial oxygenation or markers of lung injury. However, the relationship between oxygenation and survival in acute hypoxaemic respiratory failure is not established, so improved oxygenation cannot be used as a surrogate for survival. Randomised controlled trials are, therefore, needed to assess the effects of these treatments on mortality. In such trials, extracorporeal oxygenation and extracorporeal carbon dioxide elimination, surfactant, early methylprednisolone, and prostaglandin E1 offer no survival advantage over conventional therapy. Prophylactic ketoconazole and pentoxifylline appear to improve mortality in small studies in surgical and oncology patients respectively, and methylprednisolone improves mortality and morbidity in unresolving disease.


Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia.
Although immune checkpoint molecules regulate the progression of certain cancers, their significance in malignant development of Waldenstrom macroglobulinemia (WM), an incurable low-grade B-cell lymphoma, remains unknown. Recently, cytokines in the bone marrow (BM) microenvironment are shown to contribute to the pathobiology of WM. Here, we investigated the impact of cytokines, including interleukin-6 (IL-6) and IL-21, on immune regulation and particularly on the programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2. We showed that IL-21, interferon γ, and IL-6 significantly induced PD-L1 and PD-L2 gene expression in WM cell lines. Increased PD-L1 and PD-L2 messenger RNA was also detected in patients' BM cells. Patients' nonmalignant BM cells, including T cells and monocytes, showed increased PD-L1, but minimal or undetectable PD-L2 surface expression. There was also very modest PD-L1 and PD-L2 surface expression by malignant WM cells, suggesting that ligands are cleaved from the cell surface. Levels of soluble ligands were higher in patients' BM plasma and blood serum than controls. Furthermore, IL-21 and IL-6 increased secreted PD-L1 in the culture media of WM cell lines, implying that elevated levels of soluble PD-1 ligands are cytokine mediated. Soluble PD-1 ligands reduced T-cell proliferation, phosphorylated extracellular signal-regulated kinase and cyclin A levels, mitochondrial adenosine triphosphate production, and spare respiratory capacity. In conclusion, we identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM BM, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM.


AAV-mediated gene augmentation therapy of CRB1 patient-derived retinal organoids restores the histological and transcriptional retinal phenotype.
Retinitis pigmentosa and Leber congenital amaurosis are inherited retinal dystrophies that can be caused by mutations in the Crumbs homolog 1 (CRB1) gene. CRB1 is required for organizing apical-basal polarity and adhesion between photoreceptors and Müller glial cells. CRB1 patient-derived induced pluripotent stem cells were differentiated into CRB1 retinal organoids that showed diminished expression of variant CRB1 protein observed by immunohistochemical analysis. Single-cell RNA sequencing revealed impact on, among others, the endosomal pathway and cell adhesion and migration in CRB1 patient-derived retinal organoids compared with isogenic controls. Adeno-associated viral (AAV) vector-mediated hCRB2 or hCRB1 gene augmentation in Müller glial and photoreceptor cells partially restored the histological phenotype and transcriptomic profile of CRB1 patient-derived retinal organoids. Altogether, we show proof-of-concept that AAV.hCRB1 or AAV.hCRB2 treatment improved the phenotype of CRB1 patient-derived retinal organoids, providing essential information for future gene therapy approaches for patients with mutations in the CRB1 gene.


Microarray analysis of hepatic gene expression in gallstone-susceptible and gallstone-resistant mice.
Cholesterol gallstone disease affects 40 million Americans, and evidence indicates that there is a genetic component to human gallstone disease. In a mouse model of gallstone formation, where mice are fed a lithogenic diet, QTL analysis has been employed to identify the Lith 1 locus on Chromosome (Chr) 2. In order to identify genes in which the difference in expression is independent of factors other than strain-specific genotype, we employed microarray analysis of hepatic gene expression in gallstone-susceptible (C57L/J) and gallstone-resistant (AKR/J) mice. We observed 57 genes with consistent differential expression between C57L/J and AKR/J mice, including many cytochrome, antioxidant, and lipid peroxidation genes. Analysis of differentially expressed genes identified numerous genes involved in fatty acid metabolism. Northern analysis of selected lipid metabolic genes further confirmed the strain-specific differential expression. Literature searches of common regulatory elements within antioxidant systems identified the nuclear transcription factor Nrf2, which maps to the Lith 1 loci. Hepatic Nrf2 gene and protein expression is also increased in strain AKR/J, compared with C57L/J mice, identifying Nrf2 as a putative Lith 1 gallstone gene. These data indicate that microarray analysis may complement QTL analysis to identify systems of regulation and genotypic differences responsible for polygenic diseases.


MicroRNA-142 is mutated in about 20% of diffuse large B-cell lymphoma.
MicroRNAs (miRNAs) are short 18-23 nucleotide long noncoding RNAs that posttranscriptionally regulate gene expression by binding to mRNA. Our previous miRNA profiling of diffuse large B-cell lymphoma (DLBCL) revealed a mutation in the seed sequence of miR-142-3p. Further analysis now showed that miR-142 was mutated in 11 (19.64%) of the 56 DLBCL cases. Of these, one case had a mutation in both alleles, with the remainder being heterozygous. Four mutations were found in the mature miR-142-5p, four in the mature miR-142-3p, and three mutations affected the miR-142 precursor. Two mutations in the seed sequence redirected miR-142-3p to the mRNA of the transcriptional repressor ZEB2 and one of them also targeted the ZEB1 mRNA. However, the other mutations in the mature miR-142-3p did not influence either the ZEB1 or ZEB2 3' untranslated region (3' UTR). On the other hand, the mutations affecting the seed sequence of miR-142-3p resulted in a loss of responsiveness in the 3' UTR of the known miR-142-3p targets RAC1 and ADCY9. In contrast to the mouse p300 gene, the human p300 gene was not found to be a target for miR-142-5p. In one case with a mutation of the precursor, we observed aberrant processing of the miR-142-5p. Our data suggest that the mutations in miR-142 probably lead to a loss rather than a gain of function. This is the first report describing mutations of a miRNA gene in a large percentage of a distinct lymphoma subtype.


Five-Factor Model personality profiles of drug users.
Personality traits are considered risk factors for drug use, and, in turn, the psychoactive substances impact individuals' traits. Furthermore, there is increasing interest in developing treatment approaches that match an individual's personality profile. To advance our knowledge of the role of individual differences in drug use, the present study compares the personality profile of tobacco, marijuana, cocaine, and heroin users and non-users using the wide spectrum Five-Factor Model (FFM) of personality in a diverse community sample. Participants (N = 1,102; mean age = 57) were part of the Epidemiologic Catchment Area (ECA) program in Baltimore, MD, USA. The sample was drawn from a community with a wide range of socio-economic conditions. Personality traits were assessed with the Revised NEO Personality Inventory (NEO-PI-R), and psychoactive substance use was assessed with systematic interview. Compared to never smokers, current cigarette smokers score lower on Conscientiousness and higher on Neuroticism. Similar, but more extreme, is the profile of cocaine/heroin users, which score very high on Neuroticism, especially Vulnerability, and very low on Conscientiousness, particularly Competence, Achievement-Striving, and Deliberation. By contrast, marijuana users score high on Openness to Experience, average on Neuroticism, but low on Agreeableness and Conscientiousness. In addition to confirming high levels of negative affect and impulsive traits, this study highlights the links between drug use and low Conscientiousness. These links provide insight into the etiology of drug use and have implications for public health interventions.


The impact of health insurance on health.
How does health insurance affect health? After reviewing the evidence on this question, we reach three conclusions. First, many of the studies claiming to show a causal effect of health insurance on health do not do so convincingly because the observed correlation between insurance and good health may be driven by other, unobservable factors. Second, convincing evidence demonstrates that health insurance can improve health measures of some population subgroups, some of which, although not all, are the same subgroups that would be the likely targets of coverage expansion policies. Third, for policy purposes we need to know whether the results of these studies generalize. Solid answers to the multitude of important questions about how specific health insurance policy options may affect health seem likely to be forthcoming only with investment of substantial resources in social experiments.


Correlation between white matter microstructure and executive functions suggests early developmental influence on long fibre tracts in preterm born adolescents.
Executive functions are frequently a weakness in children born preterm. We examined associations of executive functions and general cognitive abilities with brain structure in preterm born adolescents who were born with appropriate weight for gestational age and who have no radiological signs of preterm brain injury on neuroimaging. The Stockholm Neonatal Project (SNP) is a longitudinal, population-based study of children born preterm (<36 weeks of gestation) with very low birth weight (<1501g) between 1988-1993. At age 18 years (mean 18 years, SD 2 weeks) 134 preterm born and 94 full term participants underwent psychological assessment (general intelligence, executive function measures). Of these, 71 preterm and 63 full term participants underwent Magnetic Resonance Imaging (MRI) at mean 15.2 years (range 12-18 years), including 3D T1-weighted images for volumetric analyses and Diffusion Tensor Imaging (DTI) for assessment of white matter microstructure. Group comparisons of regional grey and white matter volumes and fractional anisotropy (FA, as a measure of white matter microstructure) and, within each group, correlation analyses of cognitive measures with MRI metrics were carried out. Significant differences in grey and white matter regional volumes and widespread differences in FA were seen between the two groups. No significant correlations were found between cognitive measures and brain volumes in any group after correction for multiple comparisons. However, there were significant correlations between FA in projection fibres and long association fibres, linking frontal, temporal, parietal, and occipital lobes, and measures of executive function and general cognitive abilities in the preterm born adolescents, but not in the term born adolescents. In persons born preterm, in the absence of perinatal brain injury on visual inspection of MRI, widespread alterations in regional brain tissue volumes and microstructure are present in adolescence/young adulthood. Importantly, these alterations in WM tracts are correlated with measures of executive function and general cognitive abilities. Our findings suggest that disturbance of neural pathways, rather than changes in regional brain volumes, are involved in the impaired cognitive functions.


Meaningful Use of Electronic Health Records and Medicare Expenditures: Evidence from a Panel Data Analysis of U.S. Health Care Markets, 2010-2013.
To determine if recent growth in hospital and physician electronic health record (EHR) adoption and use is correlated with decreases in expenditures for elderly Medicare beneficiaries. American Hospital Association (AHA) General Survey and Information Technology Supplement, Health Information Management Systems Society (HIMSS) Analytics survey, SK&A Information Services, and the Centers for Medicare & Medicaid Services (CMS) Chronic Conditions Data Warehouse Geographic Variation Database for 2010 through 2013. Fixed effects model comparing associations between hospital referral region (HRR) level measures of hospital and physician EHR penetration and annual Medicare expenditures for beneficiaries with one of four chronic conditions. Calculated hospital penetration rates as the percentage of Medicare discharges from hospitals that satisfied criteria analogous to Meaningful Use (MU) Stage 1 requirements and physician rates as the percentage of physicians using ambulatory care EHRs. An increase in the hospital penetration rate was associated with a small but statistically significant decrease in total Medicare and Medicare Part A acute care expenditures per beneficiary. An increase in physician EHR penetration was also associated with a significant decrease in total Medicare and Medicare Part A acute care expenditures per beneficiary as well as a decrease in Medicare Part B expenditures per beneficiary. For the study population, we estimate approximately $3.8 billion in savings related to hospital and physician EHR adoption during 2010-2013. We also found that an increase in physician EHR penetration was associated with an increase in lab test expenses. Health care markets that had steeper increases in EHR penetration during 2010-2013 also had steeper decreases in total Medicare and acute care expenditures per beneficiary. Markets with greater increases in physician EHR had greater declines in Medicare Part B expenditures per beneficiary.


Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age.
The increasing incidence of diffuse large B-cell lymphoma (DLBCL) in ageing populations places a significant burden on healthcare systems. Co-morbidity, frailty, and reduced organ and physiological reserve contribute to treatment-related complications. The optimal dose intensity of R-CHOP to optimize outcome across different ages with variable frailty and comorbidity burden is unclear. We examined the influence of intended (IDI) and relative (RDI) dose intensity of the combination of cyclophosphamide and doxorubicin, age and comorbidity on outcomes for DLBCL patients ≥70 years in a representative, consecutive cohort across eight UK centres (2009-2018). We determined predictors of survival using multivariable Cox regression, and predictors of recurrence before death using competing risks regression. Porgression-free survival (PFS) and overall survival (OS) were significantly inferior in patients ≥80 vs. 70-79 years (P < 0.001). In contrast, 2-year cumulative relapse incidence, when accounting for non-relapse mortality as a competing risk, was no different between 70-79 vs. ≥80 years (P = 0.27) or comorbidity status (CIRS-G: 0-6 vs. >6) (P = 0.27). In 70-79 years, patients with an IDI ≥80% had a significantly improved PFS and OS (P < 0.001) compared to IDI < 80%. Conversely, in patients ≥80 years, there was no difference in PFS (P = 0.88) or OS (P = 0.75) according to IDI <80% vs. ≥80%. On multivariable analysis, when comparing by age, there was a significantly higher cumulative relapse rate for patients aged 70-79 years with an IDI <80% (vs. >80%) (P = 0.04) but not for patients ≥80 years comparing IDI (P = 0.32). 'R-mini-CHOP' provides adequate lymphoma-specific disease control and represents a reasonable treatment option in elderly patients ≥80 years aiming for cure.


Growth rate consequences of coloniality in a harmful phytoplankter.
Allometric studies have shown that individual growth rate is inversely related to body size across a broad spectrum of organisms that vary greatly in size. Fewer studies have documented such patterns within species. No data exist directly documenting the influence of colony size on growth rate for microscopic, colonial organisms. To determine if similar negative relationships between growth rate and size hold for colonial organisms, we developed a technique for measuring the growth of individual colonies of a bloom-forming, toxic cyanobacterium, Microcystis aeruginosa using microscopy and digital image analysis. For five out of six genotypes of M. aeruginosa isolated from lakes in Michigan and Alabama, we found significant negative relationships between colony size and growth rate. We found large intraspecific variation in both the slope of these relationships and in the growth rate of colonies at a standard size. In addition, growth rate estimates for individual colonies were generally consistent with population growth rates measured using standard batch culture. Given that colony size varies widely within populations, our results imply that natural populations of colonial phytoplankton exist as a mosaic of individuals with widely varying ecological attributes (since size strongly affects growth rate, grazing mortality, and migration speed). Quantifying the influence of colony size on growth rate will permit development of more accurate, predictive models of ecological interactions (e.g., competition, herbivory) and their role in the proliferation of harmful algal blooms, in addition to increasing our understanding about why these interactions vary in strength within and across environments.