Resurgence of HIV infection among men who have sex with men in Switzerland: mathematical modelling study.
New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995-1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions.


Systematic correlation of environmental exposure and physiological and self-reported behaviour factors with leukocyte telomere length.
It is hypothesized that environmental exposures and behaviour influence telomere length, an indicator of cellular ageing. We systematically associated 461 indicators of environmental exposures, physiology and self-reported behaviour with telomere length in data from the US National Health and Nutrition Examination Survey (NHANES) in 1999-2002. Further, we tested whether factors identified in the NHANES participants are also correlated with gene expression of telomere length modifying genes. We correlated 461 environmental exposures, behaviours and clinical variables with telomere length, using survey-weighted linear regression, adjusting for sex, age, age squared, race/ethnicity, poverty level, education and born outside the USA, and estimated the false discovery rate to adjust for multiple hypotheses. We conducted a secondary analysis to investigate the correlation between identified environmental variables and gene expression levels of telomere-associated genes in publicly available gene expression samples. After correlating 461 variables with telomere length, we found 22 variables significantly associated with telomere length after adjustment for multiple hypotheses. Of these varaibales, 14 were associated with longer telomeres, including biomarkers of polychlorinated biphenyls([PCBs; 0.1 to 0.2 standard deviation (SD) increase for 1 SD increase in PCB level, P < 0.002] and a form of vitamin A, retinyl stearate. Eight variables associated with shorter telomeres, including biomarkers of cadmium, C-reactive protein and lack of physical activity. We could not conclude that PCBs are correlated with gene expression of telomere-associated genes. Both environmental exposures and chronic disease-related risk factors may play a role in telomere length. Our secondary analysis found no evidence of association between PCBs/smoking and gene expression of telomere-associated genes. All correlations between exposures, behaviours and clinical factors and changes in telomere length will require further investigation regarding biological influence of exposure.


Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.
Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.


Veno-occlusive disease in hematopoietic stem cell transplantation recipients.
Veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation that affects the liver, as well as other organs. Although mild cases resolve on their own, severe cases of VOD carry a high mortality rate. The diagnosis usually is clinically based, with nonspecific signs such as weight gain, ascites, hepatomegaly, right upper quadrant abdominal pain, and elevated serum bilirubin. Although studies are ongoing, no U.S. Food and Drug Administration-approved treatments for VOD exist to date. Therefore, supportive care is a critical part of the treatment plan. Oncology nurses should be familiar with the risk factors and clinical signs of VOD so that patients can be monitored closely for its occurrence. Accurate and timely recognition of VOD is crucial for appropriate treatment.


The steroid hormone 20-hydroxyecdysone enhances neurite growth of Drosophila mushroom body neurons isolated during metamorphosis.
Mushroom bodies (MBs) are symmetrically paired neuropils in the insect brain that are of critical importance for associative olfactory learning and memory. In Drosophila melanogaster, the MB intrinsic neurons (Kenyon cells) undergo extensive reorganization at the onset of metamorphosis. A phase of rapid axonal degeneration without cell death is followed by axonal regeneration. This re-elaboration occurs as levels of the steroid hormone 20-hydroxyecdysone (20E) are rising during the pupal stage. Based on the known role of 20E in directing many features of CNS remodeling during insect metamorphosis, we hypothesized that the outgrowth of MB axonal processes is promoted by 20E. Using a GAL4 enhancer trap line (201Y) that drives MB-restricted reporter gene expression, we identified Kenyon cells in primary cultures dissociated from early pupal CNS. Paired cultures derived from single brains isolated before the 20E pupal peak were incubated in medium with or without 20E for 2-4 d. Morphometric analysis demonstrated that MB neurons exposed to 20E had significantly greater total neurite length and branch number compared with that of MB neurons grown without hormone. The relationship between branch number and total neurite length remained constant regardless of hormone treatment in vitro, suggesting that 20E enhances the rate of outgrowth from pupal MB neurons in a proportionate manner and does not selectively increase neuritic branching. These results implicate 20E in enhancing axonal outgrowth of Kenyon cells to support MB remodeling during metamorphosis.


Health effects of indebtedness: a systematic review.
In the aftermath of the global financial crisis, millions of households have been left with debts that they are unable to manage. Indebtedness may impair the wellbeing of those affected by it for years to come. This systematic review focuses on the long-term consequences of indebtedness on health. The method used in the paper is a systematic review. First, bibliographic databases were searched for peer-reviewed articles. Second, the references and citations of the included articles were searched for additional articles. The results from our sample of 33 peer-reviewed studies demonstrate serious health effects related to indebtedness. Individuals with unmet loan payments had suicidal ideation and suffered from depression more often than those without such financial problems. Unpaid financial obligations were also related to poorer subjective health and health-related behaviour. Debt counselling and other programmes to mitigate debt-related stress are needed to alleviate the adverse effects of indebtedness on health. The results demonstrate that indebtedness has serious effects on health.


Lysine residues at positions 234 and 236 in yeast porin are involved in its assembly into the mitochondrial outer membrane.
Various point mutations of lysyl residues in yeast mitochondrial porin (283 residues) were tested for their ability to assemble in vitro into the outer membranes of intact yeast mitochondria. Assembly was evaluated by protection from proteinases. The extent of assembly of two of the mutants, K234E and K236E porins, was much less than for wild-type in either post-translational or co-translational assembly assays. Lysine to glutamate mutants at other positions and K234R porin assembled as well as wild-type, but K234Q porin was poorly inserted. When both Lys-234 and Lys-236 were mutated, K234R/K236R porin was inserted better than K234Q/K236Q porin, which was inserted better than K234E/K236E; however, none of these mutants assembled as well as wild-type porin. It was concluded that optimal assembly of yeast porin depended on the presence of positively charged residues at both positions 234 and 236 and a lysine at one of these positions. After undergoing the assembly reaction, mutants that were vulnerable to proteinase K (i.e. K234E, K234Q, and K236E porins) seemed to be incompletely digested and were, to varying degrees, resistant to extraction by Na2CO3 (pH 11.5). These experiments suggested that these mutants were incompletely inserted into the outer membrane. Both Lys-234 and Lys-236 are included in an internal pentapeptide, VKAKV, that is conserved in porins from protists, plants, and animals, and it is possible that, at least, the lysines in this tract are one of the signals for the membrane assembly of these proteins.


Chronic hypertension produced by infusion of endothelin in rats.
Endothelin, a potent vasoconstrictor peptide synthesized by the vascular smooth muscle endothelium, was chronically infused into male Sprague-Dawley rats to determine whether a long-term increase in circulating endothelin levels would cause a sustained elevation in mean arterial pressure. Rats were catheterized, housed in metabolic cages, and maintained on a fixed 6 meq/day sodium intake throughout the experiment with daily measurements including mean arterial pressure, heart rate, water intake, urine output, urinary sodium excretion, urinary potassium excretion, cardiac output, total peripheral resistance, and stroke volume. Infusion of endothelin-1 (ET-1) at rates of 3, 5, or 7.5 pmol/kg/min for 7 days was associated with significant, sustained, and dose-dependent increases in mean arterial pressure and smaller less consistent elevations in total peripheral resistance. Other parameters were unaffected. Similar results were observed in rats receiving endothelin-3 (ET-3), except that a higher dose of ET-3 was required. These results indicate that elevated blood levels of endothelin could produce a maintained hypertension without sodium or water retention and that the hemodynamic basis for the increased mean arterial pressure is similar to that seen in most other forms of experimental and clinical hypertension.


Glycolate oxidase isozymes are coordinately controlled by GLO1 and GLO4 in rice.
Glycolate oxidase (GLO) is a key enzyme in photorespiratory metabolism. Four putative GLO genes were identified in the rice genome, but how each gene member contributes to GLO activities, particularly to its isozyme profile, is not well understood. In this study, we analyzed how each gene plays a role in isozyme formation and enzymatic activities in both yeast cells and rice tissues. Five GLO isozymes were detected in rice leaves. GLO1 and GLO4 are predominately expressed in rice leaves, while GLO3 and GLO5 are mainly expressed in the root. Enzymatic assays showed that all yeast-expressed GLO members except GLO5 have enzymatic activities. Further analyses suggested that GLO1, GLO3 and GLO4 interacted with each other, but no interactions were observed for GLO5. GLO1/GLO4 co-expressed in yeast exhibited the same isozyme pattern as that from rice leaves. When either GLO1 or GLO4 was silenced, expressions of both genes were simultaneously suppressed and most of the GLO activities were lost, and consistent with this observation, little GLO isozyme protein was detected in the silenced plants. In contrast, no observable effect was detected when GLO3 was suppressed. Comparative analyses between the GLO isoforms expressed in yeast and the isozymes from rice leaves indicated that two of the five isozymes are homo-oligomers composed of either GLO1 or GLO4, and the other three are hetero-oligomers composed of both GLO1 and GLO4. Our current data suggest that GLO isozymes are coordinately controlled by GLO1 and GLO4 in rice, and the existence of GLO isozymes and GLO molecular and compositional complexities implicate potential novel roles for GLO in plants.


Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture.
The fungal kingdom includes at least 6 million eukaryotic species and is remarkable with respect to its profound impact on global health, biodiversity, ecology, agriculture, manufacturing, and biomedical research. Approximately 625 fungal species have been reported to infect vertebrates, 200 of which can be human associated, either as commensals and members of our microbiome or as pathogens that cause infectious diseases. These organisms pose a growing threat to human health with the global increase in the incidence of invasive fungal infections, prevalence of fungal allergy, and the evolution of fungal pathogens resistant to some or all current classes of antifungals. More broadly, there has been an unprecedented and worldwide emergence of fungal pathogens affecting animal and plant biodiversity. Approximately 8,000 species of fungi and Oomycetes are associated with plant disease. Indeed, across agriculture, such fungal diseases of plants include new devastating epidemics of trees and jeopardize food security worldwide by causing epidemics in staple and commodity crops that feed billions. Further, ingestion of mycotoxins contributes to ill health and causes cancer. Coordinated international research efforts, enhanced technology translation, and greater policy outreach by scientists are needed to more fully understand the biology and drivers that underlie the emergence of fungal diseases and to mitigate against their impacts. Here, we focus on poignant examples of emerging fungal threats in each of three areas: human health, wildlife biodiversity, and food security.


Organization of early frog embryos by chemical waves emanating from centrosomes.
The large cells in early vertebrate development face an extreme physical challenge in organizing their cytoplasm. For example, amphibian embryos have to divide cytoplasm that spans hundreds of micrometres every 30 min according to a precise geometry, a remarkable accomplishment given the extreme difference between molecular and cellular scales in this system. How do the biochemical reactions occurring at the molecular scale lead to this emergent behaviour of the cell as a whole? Based on recent findings, we propose that the centrosome plays a crucial role by initiating two autocatalytic reactions that travel across the large cytoplasm as chemical waves. Waves of mitotic entry and exit propagate out from centrosomes using the Cdk1 oscillator to coordinate the timing of cell division. Waves of microtubule-stimulated microtubule nucleation propagate out to assemble large asters that position spindles for the following mitosis and establish cleavage plane geometry. By initiating these chemical waves, the centrosome rapidly organizes the large cytoplasm during the short embryonic cell cycle, which would be impossible using more conventional mechanisms such as diffusion or nucleation by structural templating. Large embryo cells provide valuable insights to how cells control chemical waves, which may be a general principle for cytoplasmic organization.


Expression of reelin, the gene responsible for the reeler mutation, in embryonic development and adulthood in the mouse.
reelin has recently been isolated as a candidate gene, the mutation of which gives rise to the reeler phenotype in mice. In this study, we analyzed the expression of reelin during embryonic development in the mouse and in adult mouse tissues, by in situ hybridization. reelin transcripts were present on embryonic day (E) 8.5 in the somite, foregut, yolk sac, and unclosed neural plate. reelin was expressed in the brain, spinal cord, liver, and kidney throughout embryonic development, and transiently in many developing organs such as the optic cup, blood vessels, precartilage, stomach, pituitary, vibrissae, tooth germ, and in cells along growing nerve fibers. These observations indicate a role for reelin in development of organs in addition to that in neuronal migration. Furthermore, we demonstrated the existence of reelin mRNA and its cellular distribution in the adult brain, spinal cord, liver, kidney, testis, and ovary, suggesting additional roles for reelin in stabilizing the cyto-architecture and in remolding in adult organs. However, we detected no obvious phenotype of the reelin-expressing organs except for the brain in the reeler mouse, indicating the functional redundancy of this gene during the development of these organs.


Soda consumption and overweight status of 2-year-old mexican-american children in california.
The prevalence of overweight in United States children, 2 to 5 years old, has increased 2-fold since 1975, with the highest prevalence in Mexican Americans. The objective of this study was to determine the association between current soda consumption and overweight in 2-year-old Mexican-American children. The Center for the Health Assessment of Mothers and Children of Salinas study is a longitudinal study of the health of low-income Latino pregnant women and their children living in the Salinas Valley, CA. Six hundred pregnant women were enrolled (October 1999 to October 2000), and their children were followed until 2 years of age. This cross-sectional analysis includes the 354 children who completed the 2-year follow-up interview. Standing height (centimeters) and weight (grams) were measured at 2 years. Overweight was defined as > or =95th percentile of the sex-specific BMI for each child's age. Fifty-five (15.5%) children were overweight. Over half (56%) reported consuming any soda in the last week. After covariate adjustment, compared with no soda consumption, <1 soda/d was not related to overweight (adjusted odds ratio, 0.97; 95% confidence interval, 0.47, 1.99), but > or =1 soda/d was significantly associated with overweight (adjusted odds ratio, 3.39; 95% confidence interval, 1.43, 8.07), and the test for trend was significant (p = 0.02). At 2 years of age, the prevalence of overweight among the Center for the Health Assessment of Mothers and Children of Salinas cohort is higher than the national prevalence estimate for Mexican-American 2- to 5-year-old children and is significantly associated with current soda consumption. Interventions to reduce consumption of soda in young Mexican-American children should be considered.


Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation.
Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h(flox) mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27(Kip1) (Cdkn1b) and p57(Kip2) (Cdkn1c) gene expression. The abnormal Snf2h(-/-) fiber cells also retain their nuclei. RNA profiling of Snf2h(-/) (-) and Brg1(-/-) eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIβ, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation.


Secure management of biomedical data with cryptographic hardware.
The biomedical community is increasingly migrating toward research endeavors that are dependent on large quantities of genomic and clinical data. At the same time, various regulations require that such data be shared beyond the initial collecting organization (e.g., an academic medical center). It is of critical importance to ensure that when such data are shared, as well as managed, it is done so in a manner that upholds the privacy of the corresponding individuals and the overall security of the system. In general, organizations have attempted to achieve these goals through deidentification methods that remove explicitly, and potentially, identifying features (e.g., names, dates, and geocodes). However, a growing number of studies demonstrate that deidentified data can be reidentified to named individuals using simple automated methods. As an alternative, it was shown that biomedical data could be shared, managed, and analyzed through practical cryptographic protocols without revealing the contents of any particular record. Yet, such protocols required the inclusion of multiple third parties, which may not always be feasible in the context of trust or bandwidth constraints. Thus, in this paper, we introduce a framework that removes the need for multiple third parties by collocating services to store and to process sensitive biomedical data through the integration of cryptographic hardware. Within this framework, we define a secure protocol to process genomic data and perform a series of experiments to demonstrate that such an approach can be run in an efficient manner for typical biomedical investigations.


Integration and impact of pharmacists in general practice internationally: A rapid review.
English general practices have been facing ongoing pressures, arising from complicated health care needs and the recent pandemic. To overcome these pressures and reduce the workload of general practitioners, there have been extensive attempts to integrate pharmacists into general practices. A number of literature reviews, often systematic, have partially explored the topic of general practice-based pharmacists (GPBPs) internationally. Our aim was to further explore the employment/integration models of GPBPs and their actual activities and impact, concepts that have not been thoroughly investigated by previous reviews. Two databases were searched from inception to June 2021 for studies published in the English language. Results were independently screened by two reviewers to establish eligibility for inclusion. Original research studies, or protocols where results had not been released at the time of search, that reported on services provided by pharmacists with some sort of integration into general practices were included. The studies were analysed using narrative synthesis. Searches identified 3206 studies in total, of which 75 met the inclusion criteria. The included studies were highly heterogeneous in terms of participants involved and methodologies employed. Integration of pharmacists into general practices has occurred in several countries, with funds originating from multiple sources. Several employment models for GPBPs were described - for example, part-time and full-time work and/or coverage of multiple or single practices. GPBP activities, with some exceptions, were comparable between different countries, with medication reviews being the most common task globally. GPBP impact was identified through both observational and/or interventional research methods, by pursuing a large variety of measures (e.g. activity volume, contact with patients, perceptions/experiences, and patient outcomes). Independent, quantifiable outcomes from GPBP activities were all positive but were of varying statistical significance. Our findings suggest that GPBP services can lead to positive, quantifiable outcomes, mainly in relation to medication use. This shows the usefulness of GPBP services. The findings of this review can help policy makers decide how best to implement and fund GPBP services, and how to identify and measure GPBP impact.


Differential effect of a selective cyclooxygenase-2 inhibitor versus indomethacin on renal blood flow in conscious volume-depleted dogs.
Renal effects of a selective cyclooxygenase-2 (COX-2) inhibitor [MF-Tricyclic; 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone] were studied in control and volume-depleted conscious dogs. MF-Tricyclic was compared with the nonselective COX-1/COX-2 inhibitor indomethacin. Six instrumented male dogs were randomly selected to receive MF-Tricyclic or indomethacin at 10 mg/kg. Volume depletion was effected by a sodium-restricted diet (14 days) with administration of furosemide (7.5 mg/kg, i.v.) the day before the experiment. Indomethacin ablated systemic COX-1 activity (p < 0.05), whereas MF-Tricyclic did not affect this activity. Each compound achieved plasma concentrations in excess of their respective median inhibitory concentrations (IC50 values) against canine COX-2. In controls, neither compound affected mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF), fractional excretion (FE) Na+, or FE K+. In volume-depleted dogs, indomethacin reduced RBF (p < 0.05), whereas MF-Tricyclic did not affect this parameter. Indices of renal function in volume-depleted dogs were not affected. These data are consistent with the view that the effects of indomethacin on RBF are a consequence of inhibition of COX-1 activity. Furthermore, in these studies, short-term administration of a selective COX-2 inhibitor was without deleterious effects on renal function.


Deciphering regulatory DNA sequences and noncoding genetic variants using neural network models of massively parallel reporter assays.
The relationship between noncoding DNA sequence and gene expression is not well-understood. Massively parallel reporter assays (MPRAs), which quantify the regulatory activity of large libraries of DNA sequences in parallel, are a powerful approach to characterize this relationship. We present MPRA-DragoNN, a convolutional neural network (CNN)-based framework to predict and interpret the regulatory activity of DNA sequences as measured by MPRAs. While our method is generally applicable to a variety of MPRA designs, here we trained our model on the Sharpr-MPRA dataset that measures the activity of ∼500,000 constructs tiling 15,720 regulatory regions in human K562 and HepG2 cell lines. MPRA-DragoNN predictions were moderately correlated (Spearman ρ = 0.28) with measured activity and were within range of replicate concordance of the assay. State-of-the-art model interpretation methods revealed high-resolution predictive regulatory sequence features that overlapped transcription factor (TF) binding motifs. We used the model to investigate the cell type and chromatin state preferences of predictive TF motifs. We explored the ability of our model to predict the allelic effects of regulatory variants in an independent MPRA experiment and fine map putative functional SNPs in loci associated with lipid traits. Our results suggest that interpretable deep learning models trained on MPRA data have the potential to reveal meaningful patterns in regulatory DNA sequences and prioritize regulatory genetic variants, especially as larger, higher-quality datasets are produced.


US news media coverage of tobacco control issues.
To characterise the relative amount and type of daily newspaper, local and national TV newscast, and national news magazine coverage of tobacco control issues in the United States in 2002 and 2003. Content analysis of daily newspapers, news magazines, and TV newscasts. Items about tobacco in daily newspapers, local and national TV newscasts, and three national news magazines in a nationally representative sample of 56 days of news stratified by day of week and season of the year, from 2002 and 2003. Story theme, tobacco topics, sources, story prominence, story valence (orientation), and story type. Tobacco coverage was modest over the two-year period as estimated in our sample. Only 21 TV stories, 17 news magazine stories, and 335 daily newspaper stories were found during the two-year sampling period. Noteworthy results for the newspaper data set include the following: (1) government topics predominated coverage; (2) government action and negative health effects topics tended not to occur together in stories; (3) tobacco stories were fairly prominently placed in newspapers; (4) opinion news items tended to favour tobacco control policies, while news and feature stories were evenly split between positive and negative stories; and (5) tobacco coverage in the southeast, which is the country's major tobacco producing region, did not differ from the rest of the country. Results suggest mixed support in news coverage for tobacco control efforts in the United States. The modest amount of news coverage of tobacco is troubling, particularly because so few news stories were found on TV, which is a more important news source for Americans than newspapers. When tobacco was covered, government themed stories, which often did not include mentions of negative health effects, were typical, suggesting that media coverage does not reinforce the reason for tobacco control efforts. However, some results were encouraging. For example, when newspapers did cover tobacco, they accorded the stories relatively high prominence, thus increasing the chance that readers would see tobacco stories when they were published.


The Muranga Teleophthalmology Study: Comparison of Virtual (Teleglaucoma) with in-Person Clinical Assessment to Diagnose Glaucoma.
While the effectiveness of teleophthalmology is generally accepted, its ability to diagnose glaucomatous eye disease remains relatively unknown. This study aimed to compare a web-based teleophthalmology assessment with clinical slit lamp examination to screen for glaucoma among diabetics in a rural African district. Three hundred and nine diabetic patients underwent both the clinical slit lamp examination by a comprehensive ophthalmologist and teleglaucoma (TG) assessment by a glaucoma subspecialist. Both assessments were compared for any focal glaucoma damage; for TG, the quality of photographs was assessed, and vertical cup-to-disk ratio (VCDR) was calculated in a semi-automated manner. In patients with VCDR > 0.7, the diagnostic precision of the Frequency Doubling Technology (FDT) C-20 screening program was assessed. Of 309 TG assessment photos, 74 (24%) were deemed unreadable due to media opacities, patient cooperation, and unsatisfactory photographic technique. While the identification of individual optic nerve factors showed either fair or moderate agreement, the ability to diagnose glaucoma based on the overall assessment showed moderate agreement (Kappa [κ] statistic 0.55% and 95% confidence interval [CI]: 0.48-0.62). The use of FDT to detect glaucoma in the presence of disc damage (VCDR > 0.7) showed substantial agreement (κ statistic of 0.84 and 95% CI 0.79-0.90). A positive TG diagnosis of glaucoma carried a 77.5% positive predictive value, and a negative TG diagnosis carried an 82.2% negative predicative value relative to the clinical slit lamp examination. There was moderate agreement between the ability to diagnose glaucoma using TG relative to clinical slit lamp examination. Poor quality photographs can severely limit the ability of TG assessment to diagnose optic nerve damage and glaucoma. Although further work and validation is needed, the TG approach provides a novel, and promising method to diagnose glaucoma, a major cause of ocular morbidity throughout the world.


Structural properties of the Caenorhabditis elegans neuronal network.
Despite recent interest in reconstructing neuronal networks, complete wiring diagrams on the level of individual synapses remain scarce and the insights into function they can provide remain unclear. Even for Caenorhabditis elegans, whose neuronal network is relatively small and stereotypical from animal to animal, published wiring diagrams are neither accurate nor complete and self-consistent. Using materials from White et al. and new electron micrographs we assemble whole, self-consistent gap junction and chemical synapse networks of hermaphrodite C. elegans. We propose a method to visualize the wiring diagram, which reflects network signal flow. We calculate statistical and topological properties of the network, such as degree distributions, synaptic multiplicities, and small-world properties, that help in understanding network signal propagation. We identify neurons that may play central roles in information processing, and network motifs that could serve as functional modules of the network. We explore propagation of neuronal activity in response to sensory or artificial stimulation using linear systems theory and find several activity patterns that could serve as substrates of previously described behaviors. Finally, we analyze the interaction between the gap junction and the chemical synapse networks. Since several statistical properties of the C. elegans network, such as multiplicity and motif distributions are similar to those found in mammalian neocortex, they likely point to general principles of neuronal networks. The wiring diagram reported here can help in understanding the mechanistic basis of behavior by generating predictions about future experiments involving genetic perturbations, laser ablations, or monitoring propagation of neuronal activity in response to stimulation.


Control of Postharvest Botrytis Fruit Rot with Preharvest Fungicide Applications in Annual Strawberry.
The control of postharvest Botrytis fruit rot was evaluated during 1997-98 and 1998-99. Weekly applications of captan and thiram were examined at two or three different rates, respectively. Iprodione applications were combined with the captan and thiram treatments and also applied alone for two peak bloom periods. Strawberry fruit were harvested and graded twice weekly for marketable yield and preharvest incidence of Botrytis fruit rot. For postharvest evaluations, fruit from four harvests were selected and stored at 4°C, and Botrytis fruit rot incidence was recorded over 14 days of storage. Fungicide treatments reduced the incidence of preharvest Botrytis fruit rot and increased marketable yield. The incidence of postharvest Botrytis fruit rot was significantly affected by harvest date, length of time in storage, and fungicide treatment. The highest rate captan and thiram treatments had the least Botrytis fruit rot and the longest storage life. Reduced-rate captan and thiram treatments generally did not provide the same control as their respective high-rate treatments. Iprodione added to either the captan or thiram treatments did not consistently reduce the preharvest or postharvest incidence of Botrytis fruit rot or increase yield. Regular, full-rate fungicide treatments appear to be necessary to control Botrytis fruit rot in Florida and to provide the storage life necessary to reach distant markets.


Underdetermination and incommensurability in contemporary epidemiology.
In the shadowy world between philosophy of science and ethics lie the paired concepts of underdetermination and incommensurability. Typically, scientific evidence underdetermines the hypotheses tested in research studies, providing neither proof nor disproof. As a result, scientists must judge the weight of the evidence, and in doing so, bring scientific and extrascientific values to bear in their approaches to assessing and interpreting the evidence. When different scientists employ very different values, their views are said to be incommensurable. Less prominent differences represent partial incommensurabilities. The definitions and analyses provided by McMullin and by Veatch and Stempsey lay the foundation for the description of partial incommensurabilities in the current practice of assessing and interpreting epidemiologic evidence. This practice is called "causal inference" and is undertaken for the purpose of making causal conclusions and public health recommendations from population-based studies of exposures and diseases. Following the work of Bayley and Longino, several suggestions are examined for dealing with the partial incommensurabilities found in the general practice of causal inference in contemporary epidemiology. Two specific examples illustrate these ideas: studies on the relationship between induced abortion and breast cancer and those on the relationship between moderate alcohol consumption and breast cancer.


Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay.
Ketamine and two of its metabolites were determined up to 24 hours by a sensitive and specific gas chromatographic mass fragmentographic (GCMF) assay in the plasma of seven premedicated surgical patients. Each patient received ketamine in a dose between 2.0 and 2.2 mg/kg given intravenously over a 30-second period. Plasma levels of ketamine varied from 9,000 to 25,800 ng/ml 1 minute after injection to approximately 1,000 ng/ml when the patients began to recover consciousness. Within the next 24 hours, the patients had a complex logarithmic decline after injection. The data suggest rather complex pharmacokinetics with multiple compartments. Ketamine metabolites I and II were also found in the plasma over comparable periods of time. Ketamine metabolite I levels ranged from a high of 245 to 668 ng/ml within 30 minutes after ketamine administration to as low as 15 ng/ml 24 hours later. Ketamine metabolite II levels were lower with a peak of 515 ng/ml in approximately 60 minutes to 13 to 27 ng/ml 24 hours later. Recovery from anesthesia was related to the first two phases of rapid redistribution of ketamine. The plasma levels of the two ketamine metabolites were first detectable approximately 5 minutes after ketamine injection. Their relatively low levels throughout ketamine anesthesia and postanesthesia do not correlate with recovery from anesthesia. CSTRIP and NONLIN analysis indicated that a three-exponential equation best approximated the data obtained. It is concluded that a three-compartment open model best approximates ketamine pharmacokinetics in these patients.


Phytoestrogens and thyroid cancer risk: the San Francisco Bay Area thyroid cancer study.
Epidemiological and pathological data suggest that thyroid cancer may well be an estrogen-dependent disease. The relationship between thyroid cancer risk and dietary phytoestrogens, which can have both estrogenic and antiestrogenic properties, has not been previously studied. We present data from a multiethnic population-based case-control study of thyroid cancer conducted in the San Francisco Bay Area. Of 817 cases diagnosed between 1995 and 1998 (1992 and 1998 for Asian women), 608 (74%) were interviewed. Of 793 controls identified through random-digit dialing, 558 (70%) were interviewed. Phytoestrogen consumption was assessed via a food-frequency questionnaire and a newly developed nutrient database. The consumption of traditional and nontraditional soy-based foods and alfalfa sprouts were associated with reduced risk of thyroid cancer. Consumption of "western" foods with added soy flour or soy protein did not affect risk. Of the seven specific phytoestrogenic compounds examined, the isoflavones, daidzein and genistein [odds ratio (OR), 0.70; 95% confidence interval (CI), 0.44-1.1; and OR, 0.65, 95% CI, 0.41-1.0, for the highest versus lowest quintile of daidzein and genistein, respectively] and the lignan, secoisolariciresinol (OR, 0.56; 95% CI, 0.35-0.89, for the highest versus lowest quintile) were most strongly associated with risk reduction. Findings were similar for white and Asian women and for pre- and postmenopausal women. Our findings suggest that thyroid cancer prevention via dietary modification of soy and/or phytoestrogen intake in other forms may be possible but warrants further research at this time.


Time to rethink sleep quality: PSQI scores reflect sleep quality on workdays.
The Pittsburgh Sleep Quality Index (PSQI) is the most common measure of sleep quality. Its questions refer to "usual" sleep habits during the last month. Considering how different sleep-wake behavior can be between workdays and work-free days, we hypothesized that sleep quality should show similar differences. We investigated these potential differences in a cross-sectional online study using the original and two adapted versions of the PSQI that replaced "usual" by explicitly referring to sleep on workdays or work-free days. Additionally, we investigated how these scores relate to chronotype and social jetlag assessed by the Munich ChronoType Questionnaire. Participants were recruited online, they had to be older than 18 years, following regular weekly work schedules, and they should not be shift workers. Repeated-measures analysis of variance was used to compare the three different versions of the PSQI (usual, work, and work-free). To find out whether PSQI score differences could be predicted by chronotype and/or social jetlag a mediation analysis was carried out. Workday PSQI scores were similar to the original "usual" scores, two points higher than the PSQI score on work-free days and above the cutoff designating poor sleep quality. PSQI components and time variables also differed between workdays and work-free days. Chronotype correlated with the difference between PSQI scores on workdays and on work-free days, an association mediated by social jetlag. Our results suggest that the original PSQI predominantly reports sleep quality on workdays and that work schedules may affect sleep quality. The mediation of social jetlag on the association of chronotype and PSQI score differences could mean that not chronotype per se, but rather the collision of an individuals' chronotype with fixed work schedules explains the differences between sleep on workdays and work-free days. Understanding how sleep quality differs between workdays and work-free days, how this difference can adequately be assessed through directing participants to focus on their sleep specifically on workdays vs. work-free days, and how circadian factors modulate this difference, is crucial to improve sleep quality.


PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus.
The efficacy, tolerability, and safety of the prophylactic treatment of hepatitis C virus (HCV) after liver transplantation (LT) with peginterferon alfa-2a and ribavirin are not known. LT recipients with HCV were randomized to peginterferon alfa-2a/ribavirin treatment or observation 10 to 26 weeks post-LT. Prophylaxis patients received peginterferon alfa-2a (135 μg/week for 4 weeks and then 180 μg/week for 44 weeks) plus ribavirin (the initial dose of 400 mg/day was escalated to 1200 mg/day). Observation patients received the same regimen only upon significant HCV recurrence (histological activity index ≥ 3 and/or fibrosis score ≥ 2). The primary endpoint was the proportion of patients with histological evidence of significant HCV recurrence 120 weeks after randomization. In all, 115 patients were randomized (prophylaxis arm, n = 55; observation arm, n = 60). Sustained virological response was achieved by 12 of 54 prophylaxis patients (22.2%) and by 3 of 14 observation patients who switched to treatment (21.4%). On an intent-to-treat basis, significant HCV recurrence at 120 weeks was similar in the prophylaxis (61.8%) and observation arms (65.0%, P = 0.725). The patient and graft survival rates and the rates of biopsy-proven acute cellular rejection were similar in the 2 study arms. Approximately 70% of the treated patients in both arms had at least one dose reduction for safety reasons. The most common adverse event leading to treatment withdrawal was anemia. Because of the safety profile of peginterferon alfa-2a/ribavirin and the lack of a clear benefit in terms of HCV recurrence and patient or graft survival, this study does not support the routine use of prophylactic antiviral therapy.


Electrophysiological Characterization of Transport Across Outer-Membrane Channels from Gram-Negative Bacteria in Presence of Lipopolysaccharides.
Multi-drug resistance in Gram-negative bacteria is often associated with low permeability of the outer membrane. To investigate the role of membrane channels in the uptake of antibiotics, we present an approach using fusion of native outer membrane vesicles (OMVs) into a planar lipid bilayer, allowing characterization of membrane protein channels in their native environment. Two major membrane channels from E. coli, OmpF and OmpC, were overexpressed from the host and the corresponding OMVs were collected. Each OMV fusion surprisingly revealed only single or few channel activities. The asymmetry of the OMVs translates after fusion into the lipid membrane with the lipopolysaccharides (LPS) dominantly present at the side of OMV addition. Compared to the conventional reconstitution method, the channels fused from OMVs containing LPS have similar conductance but a much broader distribution and significantly lower permeation. We suggest using outer membrane vesicles for functional and structural studies of membrane channels in the native membrane.


Genistein exerts neuroprotective effect on focal cerebral ischemia injury in rats.
Brain ischemia and treatment are one of the important topics in neurological science. Free oxygen radicals and inflammation formed after ischemia are accepted as the most important causes of damage. Currently, there are studies on many chemopreventive agents to prevent cerebral ischemia damage. Our aim is to research the preventive effect of the active ingredient in genistein, previously unstudied, on oxidative damage in cerebral ischemia. Rats were randomly divided into three groups: control group (no medication or surgical procedure), ischemia group, and artery ischemia+genistein group, sacrificed at 24 h after ischemia. The harvested brain tissue from the right hemisphere was investigated histopathologically and for tissue biochemistry. Superoxide dismutase and nuclear respiratory factor 1 values decreased after ischemia and they increased after genistein treatment, while increased malondialdehyde levels after ischemia reduced after treatment. Apoptosis-related cysteine peptidase caspase-3 and caspase-9 values increased after ischemia, but reduced after treatment. Our study revealed that genistein treatment in cerebral ischemia reduced oxidative stress and neuronal degeneration. We believe that genistein treatment may be an alternative treatment method.


Identification of Metabolically Quiescent Leishmania mexicana Parasites in Peripheral and Cured Dermal Granulomas Using Stable Isotope Tracing Imaging Mass Spectrometry.
Leishmania are sandfly-transmitted protists that induce granulomatous lesions in their mammalian host. Although infected host cells in these tissues can exist in different activation states, the extent to which intracellular parasites stages also exist in different growth or physiological states remains poorly defined. Here, we have mapped the spatial distribution of metabolically quiescent and active subpopulations of Leishmania mexicana in dermal granulomas in susceptible BALB/c mice, using in vivo heavy water labeling and ultra high-resolution imaging mass spectrometry. Quantitation of the rate of turnover of parasite and host-specific lipids at high spatial resolution, suggested that the granuloma core comprised mixed populations of metabolically active and quiescent parasites. Unexpectedly, a significant population of metabolically quiescent parasites was also identified in the surrounding collagen-rich, dermal mesothelium. Mesothelium-like tissues harboring quiescent parasites progressively replaced macrophage-rich granuloma tissues following treatment with the first-line drug, miltefosine. In contrast to the granulomatous tissue, neither the mesothelium nor newly deposited tissue sequestered miltefosine. These studies suggest that the presence of quiescent parasites in acute granulomatous tissues, together with the lack of miltefosine accumulation in cured lesion tissue, may contribute to drug failure and nonsterile cure.IMPORTANCE Many microbial pathogens switch between different growth and physiological states in vivo in order to adapt to local nutrient levels and host microbicidal responses. Heterogeneity in microbial growth and metabolism may also contribute to nongenetic mechanisms of drug resistance and drug failure. In this study, we have developed a new approach for measuring spatial heterogeneity in microbial metabolism in vivo using a combination of heavy water (2H2O) labeling and imaging mass spectrometry. Using this approach, we show that lesions contain a patchwork of metabolically distinct parasite populations, while the underlying dermal tissues contain a large population of metabolically quiescent parasites. Quiescent parasites also dominate drug-depleted tissues in healed animals, providing an explanation for failure of some first line drugs to completely eradicate parasites. This approach is broadly applicable to study the metabolic and growth dynamics in other host-pathogen interactions.


Sarcopenia: assessment of disease burden and strategies to improve outcomes.
Life expectancy is increasing worldwide, with a resultant increase in the elderly population. Aging is characterized by the progressive loss of skeletal muscle mass and strength - a phenomenon called sarcopenia. Sarcopenia has a complex multifactorial pathogenesis, which involves not only age-related changes in neuromuscular function, muscle protein turnover, and hormone levels and sensitivity, but also a chronic pro-inflammatory state, oxidative stress, and behavioral factors - in particular, nutritional status and degree of physical activity. According to the operational definition by the European Working Group on Sarcopenia in Older People (EWGSOP), the diagnosis of sarcopenia requires the presence of both low muscle mass and low muscle function, which can be defined by low muscle strength or low physical performance. Moreover, biomarkers of sarcopenia have been identified for its early detection and for a detailed identification of the main pathophysiological mechanisms involved in its development. Because sarcopenia is associated with important adverse health outcomes, such as frailty, hospitalization, and mortality, several therapeutic strategies have been identified that involve exercise training, nutritional supplementation, hormonal therapies, and novel strategies and are still under investigation. At the present time, only physical exercise has showed a positive effect in managing and preventing sarcopenia and its adverse health outcomes. Thus, further well-designed and well-conducted studies on sarcopenia are needed.


The Weight of a Term: "Substantial Evidence" and Buried Data.
When Congress amended the Food, Drug, and Cosmetic Act in 1962 to ensure the efficacy of drugs before they reach the market, it imposed a standard of evidence distinctly weaker than the reasonable one of preponderance. The difference is material. Some drugs now on the market may or may not have a preponderance of trial evidence of efficacy. An obstacle to a finding of efficacy is the well-known nemesis of drug makers with a definite interest in favorable trials: the placebo effect. Trials where the placebo effect runs high are vulnerable to negative findings, and trials with such findings all too often find their way to burial sites like regulatory archives. Publication bias-the preferential reporting of positive findings-has been abetted by a regulatory standard that does not require a preponderance of evidence and discounts negative trials, provided only that two trials show positive results.


Comparative in vitro cytotoxicity study of silver nanoparticle on two mammalian cell lines.
In this study the cytotoxic effect of commercially available silver (Ag) nanoparticle was evaluated using human dermal and cervical cancer cell lines. Prior to the cellular studies a full particle size characterisation was carried out using Dynamic Light Scattering (DLS), Transmission Electron Microscopy and Scanning Electron Microscopy in distilled water and cell culture media. The Zeta Potential (ZP) associated with the Ag nanoparticle was also determined in order to assess its stability in the solutions and its possible interaction with the media. The DLS and ZP study have suggested interaction of Ag nanoparticles with the media, which can lead to secondary toxicity. The toxic effects of Ag nanoparticles were then evaluated using different cytotoxic endpoints namely the lysosomal activity, mitochondrial metabolism, basic cellular metabolism, cellular protein content and cellular proliferative capacity. The cytotoxic effect of Ag nanoparticle was dependant on dose, exposure time and on the cell line tested. Further investigation was carried out on HeLa and HaCaT cell lines to elucidate the mechanism of its cytotoxicity. The Ag nanoparticle was noted to induce elevated levels of oxidative stress, glutathione depletion and damage to the cell membrane as found from the adenylate kinase assay and that leads to the apoptosis. Overall, significant differences were observed between the sensitivity of the two cell lines which can be understood in terms of their natural antioxidant levels.


Flexible Strategies for Coping with Rainfall Variability: Seasonal Adjustments in Cropped Area in the Ganges Basin.
One of the main manifestations of climate change will be increased rainfall variability. How to deal with this in agriculture will be a major societal challenge. In this paper we explore flexibility in land use, through deliberate seasonal adjustments in cropped area, as a specific strategy for coping with rainfall variability. Such adjustments are not incorporated in hydro-meteorological crop models commonly used for food security analyses. Our paper contributes to the literature by making a comprehensive model assessment of inter-annual variability in crop production, including both variations in crop yield and cropped area. The Ganges basin is used as a case study. First, we assessed the contribution of cropped area variability to overall variability in rice and wheat production by applying hierarchical partitioning on time-series of agricultural statistics. We then introduced cropped area as an endogenous decision variable in a hydro-economic optimization model (WaterWise), coupled to a hydrology-vegetation model (LPJmL), and analyzed to what extent its performance in the estimation of inter-annual variability in crop production improved. From the statistics, we found that in the period 1999-2009 seasonal adjustment in cropped area can explain almost 50% of variability in wheat production and 40% of variability in rice production in the Indian part of the Ganges basin. Our improved model was well capable of mimicking existing variability at different spatial aggregation levels, especially for wheat. The value of flexibility, i.e. the foregone costs of choosing not to crop in years when water is scarce, was quantified at 4% of gross margin of wheat in the Indian part of the Ganges basin and as high as 34% of gross margin of wheat in the drought-prone state of Rajasthan. We argue that flexibility in land use is an important coping strategy to rainfall variability in water stressed regions.


Association of Adding Aspirin to Warfarin Therapy Without an Apparent Indication With Bleeding and Other Adverse Events.
It is not clear how often patients receive aspirin (acetylsalicylic acid) while receiving oral anticoagulation with warfarin sodium without a clear therapeutic indication for aspirin, such as a mechanical heart valve replacement, recent percutaneous coronary intervention, or acute coronary syndrome. The clinical outcomes of such patients treated with warfarin and aspirin therapy compared with warfarin monotherapy are not well defined to date. To evaluate the frequency and outcomes of adding aspirin to warfarin for patients without a clear therapeutic indication for combination therapy. A registry-based cohort study of adults enrolled at 6 anticoagulation clinics in Michigan (January 1, 2010, to December 31, 2017) who were receiving warfarin therapy for atrial fibrillation or venous thromboembolism without documentation of a recent myocardial infarction or history of valve replacement. Aspirin use without therapeutic indication. Rates of any bleeding, major bleeding events, emergency department visits, hospitalizations, and thrombotic events at 1, 2, and 3 years. Of the study cohort of 6539 patients (3326 men [50.9%]; mean [SD] age, 66.1 [15.5] years), 2453 patients (37.5%) without a clear therapeutic indication for aspirin were receiving combination warfarin and aspirin therapy. Data from 2 propensity score-matched cohorts of 1844 patients were analyzed (warfarin and aspirin vs warfarin only). At 1 year, patients receiving combination warfarin and aspirin compared with those receiving warfarin only had higher rates of overall bleeding (cumulative incidence, 26.0%; 95% CI, 23.8%-28.3% vs 20.3%; 95% CI, 18.3%-22.3%; P < .001), major bleeding (5.7%; 95% CI, 4.6%-7.1% vs 3.3%; 95% CI, 2.4%-4.3%; P < .001), emergency department visits for bleeding (13.3%; 95% CI, 11.6%-15.1% vs 9.8%; 95% CI, 8.4%-11.4%; P = .001), and hospitalizations for bleeding (8.1%; 6.8%-9.6% vs 5.2%; 4.1%-6.4%; P = .001). Rates of thrombosis were similar, with a 1-year cumulative incidence of 2.3% (95% CI, 1.6%-3.1%) for those receiving combination warfarin and aspirin therapy compared with 2.7% (95% CI, 2.0%-3.6%) for those receiving warfarin alone (P = .40). Similar findings persisted during 3 years of follow-up as well as in sensitivity analyses. Compared with warfarin monotherapy, receipt of combination warfarin and aspirin therapy was associated with increased bleeding and similar observed rates of thrombosis. Further research is needed to better stratify which patients may benefit from aspirin while anticoagulated with warfarin for atrial fibrillation or venous thromboembolism; clinicians should be judicious in selecting patients for combination therapy.


Influenza virus infection elicits protective antibodies and T cells specific for host cell antigens also expressed as tumor-associated antigens: a new view of cancer immunosurveillance.
Most tumor-associated antigens (TAA) are self-molecules that are abnormally expressed in cancer cells and become targets of antitumor immune responses. Antibodies and T cells specific for some TAAs have been found in healthy individuals and are associated with lowered lifetime risk for developing cancer. Lower risk for cancer has also been associated with a history of febrile viral diseases. We hypothesized that virus infections could lead to transient expression of abnormal forms of self-molecules, some of which are TAAs; facilitated by the adjuvant effects of infection and inflammation, these molecules could elicit specific antibodies, T cells, and lasting immune memory simultaneously with immunity against viral antigens. Such infection-induced immune memory for TAA would be expected to provide life-long immune surveillance of cancer. Using influenza virus infection in mice as a model system, we tested this hypothesis and demonstrated that influenza-experienced mice control 3LL mouse lung tumor challenge better than infection-naive control mice. Using 2D-difference gel electrophoresis and mass spectrometry, we identified numerous molecules, some of which are known TAAs, on the 3LL tumor cells recognized by antibodies elicited by two successive influenza infections. We studied in detail immune responses against glyceraldehyde-3-phosphate dehydrogenase (GAPDH), histone H4, HSP90, malate dehydrogenase 2, and annexin A2, all of which were overexpressed in influenza-infected lungs and in tumor cells. Finally, we show that immune responses generated through vaccination against peptides derived from these antigens correlated with improved tumor control.


Validation of a new classifier for the automated analysis of the human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer specimens.
Amplification of the human epidermal growth factor receptor 2 (HER2) is a prognostic marker for poor clinical outcome and a predictive marker for therapeutic response to targeted therapies in breast cancer patients. With the introduction of anti-HER2 therapies, accurate assessment of HER2 status has become essential. Fluorescence in situ hybridization (FISH) is a widely used technique for the determination of HER2 status in breast cancer. However, the manual signal enumeration is time-consuming. Therefore, several companies like MetaSystem have developed automated image analysis software. Some of these signal enumeration software employ the so called "tile-sampling classifier", a programming algorithm through which the software quantifies fluorescent signals in images on the basis of square tiles of fixed dimensions. Considering that the size of tile does not always correspond to the size of a single tumor cell nucleus, some users argue that this analysis method might not completely reflect the biology of cells. For that reason, MetaSystems has developed a new classifier which is able to recognize nuclei within tissue sections in order to determine the HER2 amplification status on nuclei basis. We call this new programming algorithm "nuclei-sampling classifier". In this study, we evaluated the accuracy of the "nuclei-sampling classifier" in determining HER2 gene amplification by FISH in nuclei of breast cancer cells. To this aim, we randomly selected from our cohort 64 breast cancer specimens (32 nonamplified and 32 amplified) and we compared results obtained through manual scoring and through this new classifier. The new classifier automatically recognized individual nuclei. The automated analysis was followed by an optional human correction, during which the user interacted with the software in order to improve the selection of cell nuclei automatically selected. Overall concordance between manual scoring and automated nuclei-sampling analysis was 98.4% (100% for nonamplified cases and 96.9% for amplified cases). However, after human correction, concordance between the two methods was 100%. We conclude that the nuclei-based classifier is a new available tool for automated quantitative HER2 FISH signals analysis in nuclei in breast cancer specimen and it can be used for clinical purposes.


Should heart failure be regarded as a terminal illness requiring palliative care? A study of heart failure patients', carers' and clinicians' understanding of heart failure prognosis and its management.
Communication and planning for heart failure (HF) care near the end of life is known to be complex. Little is known about how the patient experience of palliative assessment and communication needs change over time, and how this might inform management. Our aim was to explore experiences of giving or receiving a prognosis and advanced palliative care planning (ACP) for those with HF. We carried out a longitudinal grounded theory study, employing in-depth interviews with 14 clinicians (primary and secondary care) and observations of clinic and home appointments, followed by a series of interviews with 13 patients with HF and 9 carers. Overall, the majority of participants rejected notions of HF as a terminal illness in favour of a focus on day-to-day management and maintenance, despite obvious deterioration in disease stage and needs over time. Clinicians revealed frustration about the uncertain nature of HF prognosis, leading to difficulties in planning. Others highlighted the need to deliver problem-based, individualised care but felt constrained sometimes by the lack of multidisciplinary ACP. Patients reported an absence of prognostic discussions with clinicians. This is the first study exploring the experiences of prognostic communication at all stages of HF. Findings raise questions regarding the pragmatic utility of the concept of HF as a terminal illness and have implications for future HF care pathway development. Findings support the incorporation of a problem-based approach to management, which recognises the importance of everyday functioning for patients and carers as well as the opportunity for ACP.


The benefits and limitations of robotic assisted transhiatal esophagectomy for esophageal cancer.
Robotic-assisted transhiatal esophagectomy (RATE) is a minimally invasive approach to total esophagectomy with less morbidity but equivalent efficacy when compared with the traditional open approach. The robotic platform offers numerous technical advantages that assist with the esophageal dissection, which allows the procedure to be completed without entry into the thoracic cavity. The major criticism of the transhiatal approach is that it forfeits the ability of the surgeon to perform a formal lymphadenectomy, but this does not appear to affect long-term survival.


Individualization of Treatment Improves the Survival of Children With High-Risk Solid Tumors: Comparative Patient Series Analysis in a Real-Life Scenario.
Introduction: The individualization of treatment is attractive, especially in children with high-risk cancer. In such a rare and very heterogeneous group of diseases, large population-based clinical randomized trials are not feasible without international collaboration. We therefore propose comparative patient series analysis in a real-life scenario. Methods: Open cohort observational study, comparative analysis. Seventy patients with high-risk solid tumors diagnosed between 2003 and 2015 and in whom the treatment was individualized either empirically or based on biomarkers were analyzed. The heterogeneity of the cohort and repeated measurements were advantageously utilized to increase effective sample size using appropriate statistical tools. Results: We demonstrated a beneficial effect of empirically given low-dose metronomic chemotherapy (HR 0.46 for relapses, p = 0.017) as well as various repurposed or targeted agents (HR 0.15 for deaths, p = 0.004) in a real-life scenario. However, targeted agents given on the basis of limited biological information were not beneficial. Conclusions: Comparative patient series analysis provides institutional-level evidence for treatment individualization in high-risk pediatric malignancies. Our findings emphasize the need for a comprehensive, multi omics assessment of the tumor and the host as well whenever molecularly driven targeted therapies are being considered. Low-dose metronomic chemotherapy or local control of the disease may be a more rational option in situations where targeted treatment cannot be justified by robust evidence and comprehensive biological information. "Targeted drugs" may be given empirically with a realistic benefit expectation when based on robust rationale.


General health and tobacco habits among middle-aged Swedes.
Convincing scientific evidence exists that smoking has devastating effects on health. The use of smokeless tobacco (snuff) as a tobacco habit has been reported to be considerably less harmful, and has been suggested as an aid to smoking cessation, among other things. Cross-sectional data on general health and tobacco habits were obtained through a self-administered mail questionnaire in 2002 representing 50-year-old (n = 6236) and 60-year-old (n = 6232) Swedes in two counties. Participation rates were 70.2 and 75.7% in the both age cohorts, respectively. Of all participants 46.2% were male and 53.8% female. A general health index encompassing five items (score 0-5) was designed, with the best general health attributed to those scoring 5. Male daily smokers accounted for 15.6% of the 50-year-olds and 18.7% of the 60-years-olds compared with 21.1 and 16.6%, respectively, for females. Corresponding figures for daily snuffing were 21.1 and 11.9% for men and 1.7 and 0.4% for women. When adjusting for age, sex, place of living, social network, education, and marital status, and related to subjects who never used tobacco, 'best general health' score 5, significant differences were found for ex-smokers (OR 0.82; 95% CI 0.74-0.90; P < 0.001) and ex-snuffers (OR 0.74; 95% CI 0.61-0.90; P < 0.01). Those who have stopped smoking or snuffing seem to be in a vulnerable condition with respect to general health and in need of extra support and health-promoting activities.


Osteopathic musculoskeletal examination and subarachnoid anesthetic administration in a patient with severe scoliosis.
Physicians primarily use palpation of anatomical landmarks to guide the placement of needles when administering neuraxial anesthetics. For patients with anatomical abnormalities such as scoliosis, it is also important for physicians to understand Fryette mechanics and spinal curvature anatomy, as well as preprocedural radiography and ultrasonography, to ensure accuracy in neuraxial anesthetic procedures. The authors report the case of a patient with severe scoliosis who required neuraxial anesthesia for total hip arthroplasty. Using palpation and imaging, his physicians were able to successfully administer a subarachnoid anesthetic injection on the first attempt. The authors discuss considerations for improving success rates of neuraxial anesthetic administration in these patients.


The acute and sensitization effects of tumor necrosis factor-α: implications for immunotherapy as well as psychiatric and neurological conditions.
In addition to their role as signaling molecules of the immune system, cytokines may participate in central neurotransmission. Variations of the central and/or peripheral levels of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-β (IL-1β), impact on neuroendocrine processes as well as central neurotransmitter activity. To a considerable extent, these effects are reminiscent of those elicited by psychogenic stressors. The current review describes recent findings consistent with a role for these cytokines in the neurochemical and behavioral manifestations of clinical depression, as well as the cellular death associated with cerebral ischemia. Moreover, the increasing use of cytokines in the immunotherapeutic treatment of various autoimmune diseases (e.g. rheumatoid arthritis) and cancers prompted us to consider the potential role of central processes in subserving the mood-related side-effects elicited by these treatments. Finally, a single administration of TNF-α has been shown to elicit a time-dependent sensitization effect, wherein the behavioral and neurochemical responses elicited by later cytokine treatment are greatly enhanced. Thus, particular attention was devoted to the possibility that elevated levels of TNF-α, through either exogenous (e.g. immunotherapy) or endogenous (e.g. brain damage or stressors) means may sensitize neurotransmitter or second messenger pathways important for the pathology. Given the time-dependent nature of cytokine sensitization effects, the schedule of cytokine administration during immunotherapy, or the timing of cytokine up-regulation in response to traumatic or stressful events may favor the development of sensitized central processes, which may influence clinical outcome.


The key to controlling the morphologies of quantum nanocrystals: spherical carborane ligands.
By minor structure modification of spherical carborane ligands, in a similar synthetic procedure, large morphological changes are produced in Quantum Nanocrystals (QNCs). The spheres are icosahedral C2B10H12 molecules with binding sites on the carbon, and the QNCs produced are Quantum Dots, Rods, Rings and Tetrapods. These QNCs demonstrated high stability and impeccable emissive properties for more than a year.


AZT myopathy and HIV-1 polymyositis: one disease or two?
This paper discusses the association between inflammatory and mitochondrial pathologies in patients with HIV-1/AIDS treated with zidovudine (AZT). We present the clinical and pathological details of a 52-year-old HIV-1 positive male who presented with progressive muscle weakness. We also review the current literature and address the debated pathogenesis of the inflammatory pathology. Muscle biopsy revealed evidence of both HIV-1 polymyositis and AZT myopathy. Six months after initiation of corticosteroid therapy and discontinuation of AZT, the patient's symptoms had greatly improved. The biopsy was repeated to show that both pathologies had resolved. The perceived overlap in the pathological spectra of HIV-1 polymyositis and AZT myopathy has produced some debate on causation and treatment. Unfortunately, there have been very few reports where a repeat biopsy following a drug washout period confirmed resolution of the pathology. Furthermore, affected patients have not been treated in a uniform fashion. Whether this represents one disease or two remains uncertain. The clinical relevance of this issue lies in the potential for harm from the unnecessary use of corticosteroids. This question may be best addressed by a randomized clinical trial.


Dynamics of the firing probability of noisy integrate-and-fire neurons.
Cortical neurons in vivo undergo a continuous bombardment due to synaptic activity, which acts as a major source of noise. Here, we investigate the effects of the noise filtering by synapses with various levels of realism on integrate-and-fire neuron dynamics. The noise input is modeled by white (for instantaneous synapses) or colored (for synapses with a finite relaxation time) noise. Analytical results for the modulation of firing probability in response to an oscillatory input current are obtained by expanding a Fokker-Planck equation for small parameters of the problem - when both the amplitude of the modulation is small compared to the background firing rate and the synaptic time constant is small compared to the membrane time constant. We report here the detailed calculations showing that if a synaptic decay time constant is included in the synaptic current model, the firing-rate modulation of the neuron due to an oscillatory input remains finite in the high-frequency limit with no phase lag. In addition, we characterize the low-frequency behavior and the behavior of the high-frequency limit for intermediate decay times. We also characterize the effects of introducing a rise time to the synaptic currents and the presence of several synaptic receptors with different kinetics. In both cases, we determine, using numerical simulations, an effective decay time constant that describes the neuronal response completely.


Hemorrhage and blood loss-induced anemia associated with an acquired coagulation factor VIII inhibitor in a Thoroughbred mare.
A 23-year-old Thoroughbred mare was evaluated because of a coagulopathy causing hemoperitoneum, hematomas, and signs of blood loss-induced anemia. The mare had tachycardia, pallor, hypoperfusion, and a large mass in the right flank. The mass was further characterized ultrasonographically as an extensive hematoma in the body wall with associated hemoabdomen. Coagulation testing revealed persistent, specific prolongation of the activated partial thromboplastin time (> 100 seconds; reference interval, 24 to 44 seconds) attributable to severe factor VIII deficiency (12%; reference interval, 50% to 200%). On the basis of the horse's age, lack of previous signs of a bleeding diathesis, and subsequent quantification of plasma factor VIII inhibitory activity (Bethesda assay titer, 2.7 Bethesda units/mL), acquired hemophilia A was diagnosed. The medical history did not reveal risk factors or underlying diseases; thus, the development of inhibitory antibodies against factor VIII was considered to be idiopathic. The mare was treated with 2 transfusions of fresh whole blood and fresh-frozen plasma. Immunosuppressive treatment consisting of dexamethasone and azathioprine was initiated. Factor VIII deficiency and signs of coagulopathy resolved, and the inhibitory antibody titer decreased. The mare remained healthy with no relapse for at least 1 year after treatment. Horses may develop inhibitory antibodies against factor VIII that cause acquired hemophilia A. A treatment strategy combining transfusions of whole blood and fresh-frozen plasma and administration of immunosuppressive agents was effective and induced sustained remission for at least 1 year in the mare described here.


Effect of acute moderate exercise on induced inflammation and arterial function in older adults.
Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.


Role of PAI-1 in hepatic steatosis and dyslipidemia.
Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.


ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes.
An indolent non-healing wound and insulin and/or insulin-like growth factor (IGF1) resistance are cardinal features of diabetes, inflammation and hypercortisolemia. Little is known about why these phenomena occur in so many contexts. Do the various triggers that induce insulin and/or IGF1 resistance and retard wound healing act through a common mechanism? Cultured dermal fibroblasts from rats and full-thickness excisional wounds were used as models to test the premise that reactive oxygen species (ROS) play a causal role in the development of IGF1 resistance and impaired wound healing under different but pathophysiologically relevant clinical settings, including diabetes, dexamethasone-induced hypercortisolemia and TNFα-induced inflammation. In normal fibroblasts, IGF1 initiated a strong degree of phosphorylation of insulin receptor substrate 1 (IRS1) (Tyr612) and Akt (Ser473), concomitantly with increased PI3K activity. This phenomenon seemed to be attenuated in fibroblasts that had phenotypic features of diabetes, inflammation or hypercortisolemia. Notably, these cells also exhibited an increase in the activity of the ROS-phospho-JNK (p-JNK)-p-IRS1 (Ser307) axis. The above-mentioned defects were reflected functionally by attenuation in IGF1-dependent stimulation of key fibroblast functions, including collagen synthesis and cell proliferation, migration and contraction. The effects of IGF1 on glucose disposal and cutaneous wound healing were also impaired in diabetic or hypercortisolemic rats. The ROS suppressors EUK-134 and α-lipoic acid, or small interfering RNA (siRNA)-mediated silencing of JNK expression, restored IGF1 sensitivity both in vitro and in vivo, and also ameliorated the impairment in IGF1-mediated wound responses during diabetes, inflammation and hypercortisolemia. Our data advance the notion that ROS constitute a convergence nexus for the development of IGF1 resistance and impaired wound healing under different but pathophysiologically relevant clinical settings, with a proof of concept for the beneficial effect of ROS suppressors.


Statistical assessment of time-varying dependency between two neurons.
The joint peristimulus time histogram (JPSTH) provides a visual representation of the dynamics of correlated activity for a pair of neurons. There are many ways to adjust the JPSTH for the time-varying firing-rate modulation of each neuron, and then to define a suitable measure of time-varying correlated activity. Our approach is to introduce a statistical model for the time-varying joint spiking activity so that the joint firing rate can be estimated more efficiently. We have applied an adaptive smoothing method, which has been shown to be effective in capturing sudden changes in firing rate, to the ratio of joint firing probability to the probability of firing predicted by independence. A bootstrap procedure, applicable to both Poisson and non-Poisson data, was used to define a statistical significance test of whether a large ratio could be attributable to chance alone. A numerical simulation showed that the bootstrap-based significance test has very nearly the correct rejection probability, and can have markedly better power to detect departures from independence than does an approach based on testing contiguous bins in the JPSTH. In a companion paper, we show how this formulation can accommodate latency and time-varying excitability effects, which can confound spike timing effects.


Low workload as a trigger of sick leave: results from a Swedish case-crossover study.
To investigate if exposure to an unusually low workload when ill can trigger taking sick leave. A case-crossover design was applied to 546 sick-leave spells obtained from a cohort of 1430 employees within six Swedish workplaces. New sick-leave spells were reported from the workplaces during 3 to 12 months follow-up. Exposure was assessed in structured participant interviews at sick leave. Case and control periods from the same individual were sampled according to the matched-pair and usual-frequency approaches. Results are presented as odds ratios with surrounding 95% confidence intervals. The odds ratio of sick leave on a day with an unusually low workload was 2.57 (confidence interval, 1.07-6.16). Becoming ill on a day with a lower workload than usual can trigger the decision to take sick leave.


Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer's Disease.
Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer's disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.


Loss of control increases belief in precognition and belief in precognition increases control.
Every year thousands of dollars are spent on psychics who claim to "know" the future. The present research questions why, despite no evidence that humans are able to psychically predict the future, do people persist in holding irrational beliefs about precognition? We argue that believing the future is predictable increases one's own perceived ability to exert control over future events. As a result, belief in precognition should be particularly strong when people most desire control-that is, when they lack it. In Experiment 1 (N = 87), people who were experimentally induced to feel low in control reported greater belief in precognition than people who felt high in control. Experiment 2 (N = 53) investigated whether belief in precognition increases perceived control. Consistent with this notion, providing scientific evidence that precognition is possible increased feelings of control relative to providing scientific evidence that precognition was not possible. Experiment 3 (N = 132) revealed that when control is low, believing in precognition helps people to feel in control once more. Prediction therefore acts as a compensatory mechanism in times of low control. The present research provides new insights into the psychological functions of seemingly irrational beliefs, like belief in psychic abilities.


A public health approach to address the mental health burden of youth in situations of political violence and humanitarian emergencies.
This paper describes how socio-ecological theory and a syndemic health systems and public health approach may help address the plight of youth in situations of political violence and humanitarian emergencies. We describe the treatment gap caused by discrepancies in epidemiological prevalence rates, individual and family needs, and available human and material resources. We propose four strategies to develop a participatory public health approach for these youth, based on principles of equity, feasibility, and a balance between prevention and treatment. The first strategy uses ecological and transgenerational resilience as a theoretical framework to facilitate a systems approach to the plight of youth and families. This theoretical base helps to engage health care professionals in a multisectoral analysis and a collaborative public health strategy. The second strategy is to translate pre-program assessment into mental health and psychosocial support (MHPSS) priorities. Defining priorities helps to develop programs and policies that align with preventive and curative interventions in multiple tiers of the public health system. The third is a realistic budgetary framework as a condition for the development of sustainable institutional capacity including a monitoring system. The fourth strategy is to direct research to address the knowledge gap about effective practices for youth mental health in humanitarian settings.


Are all risks equal? Early experiences of poverty-related risk and children's functioning.
Using cumulative risk and latent class analysis (LCA) models, we examined how exposure to deep poverty (income-to-needs ratio <0.50) and 4 poverty-related risks (i.e., single-parent household, residential crowding, caregiver depression, and multiple life stressors) in preschool is related to children's future difficulty in school in a longitudinal sample of 602 Head Start-enrolled, low-income families. Results from the LCA revealed 4 risk profiles: low risk, deep poverty and single, single and stressed, and deep poverty and crowded household. Tests of measurement invariance across racial/ethnic groups established that, although patterns of risk are similar across groups (i.e., risks covary in the same way), the prevalence of risk profiles differs. African American families were overrepresented in the "deep poverty and single" profile while Latino and White families were overrepresented in the "deep poverty and crowded" profile. Finally, children's third grade functioning in 3 domains (i.e., academic performance, behavior problems, and self-regulatory skills) was predicted using a cumulative risk index and LCA-identified risk profiles. Both approaches demonstrated that children who experienced higher levels of risk in preschool had worse school performance than children with low levels of risk. However, LCA also revealed that children who experienced "single and stressed" family settings had more behavior problems than low-risk children while children who experienced "deep poverty and crowded" family settings had worse academic performance. The results indicate that all risks are not equal for children's development and highlight the utility of LCA for tailoring intervention efforts to best meet the needs of target populations.


Assessment of Queries Received by the Drug Information Center at King Saud Medical City.
The complexity of drug therapies has increased the need to evaluate the drug information scientifically. In this regard, the aim of drug information centers (DICs) is to promote rational use of drugs in a health-care setting. DI pharmacists play a vital role in providing the necessary and reliable information on drugs to promote the concept of rational drug use, eventually leading to a better patient outcome. The objective of the present study was to assess the drug-related queries received by the DIC at the King Saud Medical City (KSMC) from health-care professionals working in a large tertiary care setting. A retrospective analysis was conducted from February 2016 to January 2017. Data were collected using the DI request form, available in both printed and electronic formats for use by the health-care professionals. Descriptive statistics were used to calculate frequencies and percentages. Data analysis was performed using the Statistical Package of the Social Sciences software, version 16.0. The current study received a total of 139 queries that were answered by the DIC pharmacists over a period of 1 year. The majority of queries were asked by pharmacists (61.2%), followed by physicians (23.7%) and nurses (10.10%). About half of the queries were related to the dosage and administration of the drugs. Lexicomp® acted as the common resource of information. DIC has been instrumental in the dissemination of drug-related information to health-care professionals since its inception in February 2016, resulting in the provision of quality health care to the patients. However, based on yearly queries, there still exists a need to increase the awareness of health-care professionals about the DIC at KSMC, which will urge them to take drug consultation from DIC pharmacists and promote patient safety.


Synovial response to intraarticular injections of hyaluronate in frozen shoulder: a quantitative assessment with dynamic magnetic resonance imaging.
To clarify the response of frozen shoulder (FS) to intraarticular injections of high-molecular-weight sodium hyaluronate (HA), a mixture of 2.5 ml of HA and 1.5 ml of 1% lidocaine was injected into the glenohumeral joint of 11 patients with FS, 8 of whom received five weekly injections. The patients were assessed using the Japanese Orthopaedic Association shoulder score (JOA score) before the first injection, 1 week after the first injection, and 1 week after the final injection. Following each clinical evaluation, the patients underwent dynamic magnetic resonance imaging enhanced with Gd-DTPA, and the coefficient of enhancement (CE) in the glenohumeral synovium was calculated, with the examiners blinded to the clinical information. The JOA score tended to be greater and the CE smaller after injection than before injection. The changes in the CE following both single and repeated injections were negatively correlated with changes in the JOA score. Thus, clinical improvement in patients with FS was associated with a decrease in the CE. Because the CE depends on the degree of synovitis, the therapeutic effect of intraarticular HA injection for FS results, at least in part, from suppression of synovitis in the glenohumeral joint through an antiinflammatory effect.


[Pediatric cancer: analysis of hospital records].
To analyze pediatric cancer hospital records regarding the occurrence of new cases; to verify the relation between sex, age, race, origin and the disease clinical extension; to describe the mortality of children with cancer; to explore the association of new cases with proposed demographic variables, disease clinical extension and vital status. Observational, descriptive, longitudinal study in children up to 14 years old, from Santa Catarina. Three hundred and seventy-one new cases of cancer were treated in a regional reference outpatient clinic (1994-98) and recorded according to the International Classification of Childhood Cancer. Multiple Correspondence Analysis was applied to evaluate the categorical variables. Three-hundred and seventy-one new cases of cancer were recorded with constant distribution in each year. Cancer affected preschoolers (41.5%) and males (55.8%). Leukemia was observed in 36.6% of the cases. Non-localized stage on the diagnosis occurred in 55.7%. The death occurred in 55.7% of the cases with non-localized disease and 16.3% with localized disease. At the end of the study 58.8% of the children were alive. We observed more cases of cancer at pre-school age and among male subjects. Leukemia is the most frequent type of cancer. Non-localized disease predominates on the diagnosis. The death frequency is higher in the group with non-localized disease. There is direct association with non-localized disease, living vital status, school age, adolescent age, female, and for non-localized disease with death vital status, infant age, pre-school age and male.