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Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale., Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis., Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017., Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis., Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68])., Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

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Many genetic markers have been associated with variations in treatment response to analgesics, but none have been assessed in the context of combination therapies. In this study, the treatment effects of nortriptyline and morphine were tested for an association with genetic markers relevant to pain pathways. Treatment effects were determined for single and combination therapies. A total of 24 functional single nucleotide polymorphisms were tested within the gene loci of mu-opioid receptor (OPRM1) gene locus, ATP-Binding Cassette B1 Transporter (ABCB1), Cytochrome P450 gene family (CYP2C19 and CYP2D6), catecholamine inactivator Catechol-O-Methyl Transferase (COMT), and serotonin receptor 2A (HTR2A). Genotyping was performed in a population of neuropathic pain patients who previously participated in a clinical trial. For monotherapy, neither nortriptyline nor morphine responses were associated with single nucleotide polymorphisms. However, for nortriptyline + morphine combination therapy, the single nucleotide polymorphism rs1045642 within the drug efflux pump ABCB1 transporter significantly predicted analgesic response. The presence of the C allele accounted for 51% of pain variance in this subgroup in response to combination treatment. The T-allele homozygotes demonstrated only 20% improvement in pain scores, whereas the C-allele homozygotes 88%. There was no significant contribution of rs1045642 to the medication side effects under all treatment conditions. The UK Biobank data set was then used to validate this genetic association. Here, patients receiving similar combination therapy (opioid + tricyclic antidepressant) carrying the C allele of rs1045642 displayed 33% fewer body pain sites than patients without that allele, suggesting better pain control. In all, our results show a robust effect of the rs1045642 polymorphism in response to chronic pain treatment with a nortriptyline + morphine combination.

Functional traits have emerged as a key to understand species responses to environmental conditions. The concerted expression of multiple traits gives rise to the phenotype of each individual, which is the one interacting with the environment and evolving. However, patterns of trait covariation and how they vary in response to environmental conditions remain poorly understood, particularly at the intraspecific scale. Here, we have measured traits at different scales and in different organs, and analysed their covariation in a large number of conspecifics distributed in two contrasting environments. We expected significant correlations among traits, not only within clusters of traits as found in global, multispecies studies, but also among clusters, with more relationships within clusters, due to genetic constraints, and among clusters due to more coordinated phenotypes than community level, multispecies studies. We surveyed 100 Pinus sylvestris trees in a Mediterranean mountainous area distributed in two contrasting elevations. We measured 13 functional traits, in three clusters (leaf, stem and whole-plant traits), and analysed their variation and coordination. We found significant coordination among traits belonging to different clusters that reveals coordinated phenotypes. However, we found fewer correlations within trait clusters than initially expected. Trait correlation structures (number, intensity and type of correlations among traits) differed among individuals at different elevations. We observed more correlations within trait clusters at low elevation compared to those at high elevation. Moreover, the higher number of correlations among different trait clusters and the lower trait variation at the higher elevation suggests that variability decreases under more stressful conditions. Altogether, our results reveal that traits at intraspecific scale are coordinated in a broad network and not only within clusters of traits but also that this trait covariation is significantly affected by environmental conditions., Competing Interests: The authors have declared that no competing interests exist.

The dataset presented here was collected by the GenTree project (EU-Horizon 2020), which aims to improve the use of forest genetic resources across Europe by better understanding how trees adapt to their local environment. This dataset of individual tree-core characteristics including ring-width series and whole-core wood density was collected for seven ecologically and economically important European tree species: silver birch (Betula pendula), European beech (Fagus sylvatica), Norway spruce (Picea abies), European black poplar (Populus nigra), maritime pine (Pinus pinaster), Scots pine (Pinus sylvestris), and sessile oak (Quercus petraea). Tree-ring width measurements were obtained from 3600 trees in 142 populations and whole-core wood density was measured for 3098 trees in 125 populations. This dataset covers most of the geographical and climatic range occupied by the selected species. The potential use of it will be highly valuable for assessing ecological and evolutionary responses to environmental conditions as well as for model development and parameterization, to predict adaptability under climate change scenarios.

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives., (© 2019 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Background: In contrast with the negligible contribution of the forest understorey to the total aboveground phytobiomass of a forest, its share in annual litter production and nutrient cycling may be more important. Whether and how this functional role of the understorey differs across forest types and depends upon overstorey characteristics remains to be investigated., Methods: We sampled 209 plots of the FunDivEUROPE Exploratory Platform, a network of study plots covering local gradients of tree diversity spread over six contrasting forest types in Europe. To estimate the relative contribution of the understorey to carbon and nutrient cycling, we sampled non-lignified aboveground understorey biomass and overstorey leaf litterfall in all plots. Understorey samples were analysed for C, N and P concentrations, overstorey leaf litterfall for C and N concentrations. We additionally quantified a set of overstorey attributes, including species richness, proportion of evergreen species, light availability (representing crown density) and litter quality, and investigated whether they drive the understorey's contribution to carbon and nutrient cycling., Results and Conclusions: Overstorey litter production and nutrient stocks in litterfall clearly exceeded the contribution of the understorey for all forest types, and the share of the understorey was higher in forests at the extremes of the climatic gradient. In most of the investigated forest types, it was mainly light availability that determined the contribution of the understorey to yearly carbon and nutrient cycling. Overstorey species richness did not affect the contribution of the understorey to carbon and nutrient cycling in any of the investigated forest types., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Dietary biotin intake does not typically result in blood biotin concentrations that exceed interference thresholds for in vitro diagnostic tests. However, recent trends of high-dose biotin supplements and clinical trials of very high biotin doses for patients with multiple sclerosis have increased concerns about biotin interference with immunoassays. Estimates of the prevalence of high biotin intake vary, and patients may be unaware that they are taking biotin. Since 2016, 92 cases of suspected biotin interference have been reported to the US Food and Drug Administration. Immunoassays at greatest risk from biotin interference include thyroid and reproductive hormones, cardiac, and immunosuppressive drug tests. Several case studies have highlighted the challenge of biotin interference with thyroid hormone assays and the potential misdiagnosis of Graves' disease. Biotin interference should be suspected when immunoassay test results are inconsistent with clinical information; a clinically relevant biotin interference happens when the blood biotin concentration is high and the assay is sensitive to biotin. We propose a best practice workflow for laboratory scientists to evaluate discrepant immunoassay results, comprising: (1) serial dilution; (2) retesting after biotin clearance and/or repeat testing on an alternate platform; and (3) confirmation of the presence of biotin using depletion protocols or direct measurement of biotin concentrations. Efforts to increase awareness and avoid patient misdiagnosis should focus on improving guidance from manufacturers and educating patients, healthcare professionals, and laboratory staff. Best practice guidance for laboratory staff and healthcare professionals would also provide much-needed information on the prevention, detection, and management of biotin interference., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is the cause for long-term disability in more than 3 million patients in the US alone, with chronic pain being the most frequently reported complain. To date, predisposing mechanisms for chronic pain in TBI patients are largely unknown. Psychological disorders, including post-traumatic stress disorder, depression and anxiety following TBI are commonly reported comorbidities to post-traumatic pain. Long term consequences can be debilitating and affect quality of life even when the injury is mild. In this review, we present the most commonly reported chronic pain conditions across the spectrum of severity of TBI, mainly focusing on mild TBI. We discuss chronic post- traumatic headaches, widespread pain as well as post-traumatic central pain. We discuss pain in the context of injury severity and military versus civilian populations. We are only starting to understand the biological mechanisms behind post-traumatic pain and associated psychological distress following TBI, with genetic, biochemical and imaging studies pointing to the dopaminergic, neurotrophic factors and the role of Apolipoprotein. Physiological and neurological mechanisms are proposed to partially explain this interaction between post-traumatic pain and psychological distress. Nevertheless, the evidence for the role of structural brain damage remains incomplete and to a large extent debatable, as it is still difficult to establish clear causality between brain trauma and chronic pain. Finally, general aspects of management of chronic pain post-TBI are addressed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Molecular targeted compounds are emerging as a strategy to improve classical chemotherapy. Herein, we describe that using low dose of the multikinase inhibitor sorafenib improves cyclophosphamide antitumor activity by inhibiting angiogenesis, metastasis and promoting tumor healing in MDA-MB231 xenografts and the 4T1-12B syngeneic breast cancer metastasis model. Mechanistic studies in MDA-MB231 cells revealed that alkylation upregulates inflammatory genes/proteins such as COX-2, IL8, CXCL2 and MMP1 in a MEK1/2-ERK1/2-dependent manner. These proteins enrich the secretome of cancer cells, stimulating cell invasion and angiogenesis via autocrine and paracrine mechanisms. Sorafenib inhibits MEK1/2-ERK1/2 pathway thereby decreasing inflammatory genes and mitigating cell invasion and angiogenesis at basal and alkylation-induced conditions whereas NRF2 and ER stress pathways involved in alkylation survival are not affected. In non-invasive/non-angiogenic breast cancer cells (SKBR3 and MCF7), alkylation did not elicit inflammatory responses with the only sorafenib effect being ERK1/2-independent ROS-dependent cytotoxicity when using higher drug concentrations. In summary, our data show that alkylating agents may elicit inflammatory responses that seems to contribute to malignant progression in specific breast cancer cells. Identifying and targeting drivers of this phenotype may offer opportunities to optimize combined drug regimens between classical chemotherapeutics and targeted agents., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The Human Pain Genetics Database (HPGDB) is a comprehensive variant-focused inventory of genetic contributors to human pain. After curation, the HPGDB currently includes 294 studies reporting associations between 434 distinct genetic variants and various pain phenotypes. Variants were then submitted to a comprehensive analysis. First, they were validated in an independent high-powered replication cohort by testing the association of each variant with 10 different pain phenotypes (n = 1320-26,973). One hundred fifty-five variants replicated successfully (false discovery rate 20%) in at least one pain phenotype, and the association P values of the HPGDB variants were significantly lower compared with those of random controls. Among the 155 replicated variants, 21 had been included in the HPGDB because of their association with analgesia-related and 13 with nociception-related phenotypes, confirming analgesia and nociception as pathways of vulnerability for pain phenotypes. Furthermore, many genetic variants were associated with multiple pain phenotypes, and the strength of their association correlated between many pairs of phenotypes. These genetic variants explained a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. In addition, we found that HPGDB variants show many pleiotropic associations, indicating that genetic pathophysiological mechanisms are also shared among painful and nonpainful conditions. Finally, we demonstrated that the HPGDB data set is significantly enriched for functional variants that modify gene expression, are deleterious, and colocalize with open chromatin regions. As such, the HPGDB provides a validated data set that represents a valuable resource for researchers in the human pain field.

The importance of biodiversity in supporting ecosystem functioning is generally well accepted. However, most evidence comes from small-scale studies, and scaling-up patterns of biodiversity-ecosystem functioning (B-EF) remains challenging, in part because the importance of environmental factors in shaping B-EF relations is poorly understood. Using a forest research platform in which 26 ecosystem functions were measured along gradients of tree species richness in six regions across Europe, we investigated the extent and the potential drivers of context dependency of B-EF relations. Despite considerable variation in species richness effects across the continent, we found a tendency for stronger B-EF relations in drier climates as well as in areas with longer growing seasons and more functionally diverse tree species. The importance of water availability in driving context dependency suggests that as water limitation increases under climate change, biodiversity may become even more important to support high levels of functioning in European forests., (© 2017 John Wiley & Sons Ltd/CNRS.)

The present study investigated stress oxidative parameters and activities of enzymes of the energy metabolism in various brain structures. Rats were subjected to acute and long-term administration of gold nanoparticles (GNPs) with mean diameters of 10nm and 30nm. Adult (60days old) male Wistar rats received a single intraperitoneal injection (acute administration; 70μg·kg -1 ) or repeated injections once daily for 28days (long-term administration; 70μg·kg -1 ) of saline solution or GNPs (10nm or 30nm). Twenty-four hours after administration of the final dose, the animals were killed and the cerebral structures were isolated for enzyme analysis. In this study, we observed that the thiobarbituric acid-reactive species and carbonyl protein levels were decreased after acute administration of GNPs, whereas the superoxide dismutase activity was increased after acute and long-term of GNPs. The catalase activity was affected by the administration of GNPs. Furthermore, we have not found change in the citrate synthase activity. The succinate dehydrogenase, malate dehydrogenase, complexes I, II, II-III and IV, and creatine kinase activities were altered. These results indicate that inhibition energy metabolism can be caused by oxidative stress., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We performed a retrospective chart review of patients to determine if the Verigene Gram-negative blood culture (BC-GN) results would lead to earlier deescalation of empiric therapy for inpatients with GN bacteremia with Citrobacter spp., Enterobacter spp., Klebsiella spp., and Escherichia coli to appropriate targeted coverage. A total of 899 records were reviewed from April 2014 to February 2016 from three institutions within the Baylor Scott & White Health network. The cases were reviewed for initial antibiotic coverage, timing of Verigene results, change in antibiotic coverage, and how these changes related to the timing of Verigene results. The lab reported the BC-GN results and final conventional susceptibility results within 2.5 ± 1.3 and 73.6 ± 40.0 hours from the Gram stain, respectively. Overall, 29.1% of patients were transitioned from empiric to targeted therapy at 12.2 ± 13.5 hours in response to BC-GN results, which was significantly earlier ( P < 0.001) than results by conventional methods. After accounting for patients already on targeted therapy, polymicrobial infections, and patients deceased or lost to follow-up, we identified antibiotic stewardship opportunities in ∼28% of GN infections. Further subanalysis demonstrated site-specific differences in the uptake of stewardship recommendations, whereby 32.4%, 50.5%, and 15.0% of cases at different hospitals demonstrated the expected change in antibiotics. These results suggest that Verigene had the expected impact in a third of the cases and the results reporting algorithm minimized the real-time involvement of the pharmacist while maintaining optimal patient management. However, this impact varied substantially by clinical site and was tempered by variable initial antibiotic coverage and clinician response.

Background : Mild traumatic brain injury (mTBI) often results in post-concussion symptoms, chronic pain, and sleepiness. Genetic factors are thought to play an important role in poor prognosis. Aims : The aims of this study are to (1) document the prevalence of pain and post-concussion symptoms in mTBI patients in acute and chronic phases (2) determine whether candidate genes predispose to post-concussive symptoms and pain. Methods : Posttraumatic symptoms, evaluated using the Rivermead Post-Concussion Symptoms Questionnaire, and pain were assessed in 94 mTBI patients in the acute phase as well as in 22 healthy controls. Assessment was repeated in 36 patients after one year who agreed to participate in the follow-up visit. Gene polymorphisms and expression were assessed in mTBI patients and healthy controls. Results : In the acute phase, mTBI patients with pain (69%) presented more psychological symptoms and sleepiness and were less able to return to work than those without pain. At one year, 19% of mTBI patients had persistent pain and psychological distress. Two haplotypes (H2 and H3) in the brain-derived neurotrophic factor ( BDNF ) gene were shown to be respectively deleterious and protective against post-concussion symptoms and pain in both acute and chronic phases. Protective haplotype H3 was associated with a decreased expression of the anti-sense of BDNF ( BDNF-AS ). Deleterious haplotype H2 predicted the development of chronic pain at one year, whereas H3 was protective. Conclusions : This pilot study suggests a protective mechanism of a multilocus effect in BDNF , through BDNF-AS , against post-concussion symptoms and pain in the acute phase and possibly chronic pain at one year post-mTBI. The role of antisense RNA should be validated in larger cohorts., (© 2017 Samar Khoury, Julia Segal, Marc Parisien, Anne Noreau, Patrick Dion, Rodrigo Benavides, Jean-François Giguère, Ronald Denis, Inna Belfer, Luda Diatchenko, Guy A. Rouleau, and Gilles J. Lavigne. Published with license by Taylor & Francis Group, LLC.)

Previously reinforced responses can reappear when reinforcement is withdrawn from current responding. This is known as resurgence. Although resurgence of response topography, spacing, and patterns over time has been demonstrated, there is no evidence of resurgence of response duration. This experiment explored resurgence of response duration in humans. In Phase 1 a multiple schedule of reinforcement with two components was used. In each component a chained variable-interval 30s, variable-ratio 3 schedule was implemented. In the terminal link of the chained schedule, response durations between 0.1 and 0.5s were reinforced during one component, and between 2 and 8s in the other component. In Phase 2, response requirement during the terminal link of the chained schedule was inverted between components relative to Phase 1. In Phase 3 the chained schedule was changed to a variable-interval 30-s, extinction 30s. Resurgence of the durations trained during Phase 1 was observed. It was concluded that duration is a response dimension that reappears during extinction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Disentangling the mechanisms that shape community assembly across diversity gradients is a central matter in ecology. While many studies have explored community assembly through species average trait values, there is a growing understanding that intraspecific trait variation (ITV) can also play a critical role in species coexistence. Classic biodiversity theory hypothesizes that higher diversity at species-rich sites can arise from narrower niches relative to species-poor sites, which would be reflected in reduced ITV as species richness increases. To explore how ITV in woody plant communities changes with species richness, we compiled leaf trait data (leaf size and specific leaf area) in a total of 521 woody plant species from 21 forest communities that differed dramatically in species richness, ranging from boreal to tropical rainforests. At each forest, we assessed ITV as an estimate of species niche breadth and we quantified the degree of trait overlap among co-occurring species as a measure of species functional similarity. We found ITV was relatively invariant across the species richness gradient. In addition, we found that species functional similarity increased with diversity. Contrary to the expectation from classic biodiversity theory, our results rather suggest that neutral processes or equalizing mechanisms can be acting as potential drivers shaping community assembly in hyperdiverse forests.

The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.

An assemblage of tree species with different crown properties creates heterogeneous environments at the canopy level. Changes of functional leaf traits are expected, especially those related to light interception and photosynthesis. Chlorophyll a fluorescence (ChlF) properties in dark-adapted leaves, specific leaf area, leaf nitrogen content (N) and carbon isotope composition (δ13C) were measured on Picea abies (L.) H.Karst., Pinus sylvestris L. and Betula pendula Roth. in monospecific and mixed boreal forests in Europe, in order to test whether they were affected by stand species richness and composition. Photosynthetic efficiency, assessed by induced emission of leaf ChlF, was positively influenced in B. pendula by species richness, whereas P. abies showed higher photosynthetic efficiency in monospecific stands. Pinus sylvestris had different responses when it coexisted with P. abies or B. pendula. The presence of B. pendula, but not of P. abies, in the forest had a positive effect on the efficiency of photosynthetic electron transport and N in P. sylvestris needles, and the photosynthetic responses were positively correlated with an increase of leaf δ13C. These effects on P. sylvestris may be related to high light availability at the canopy level due to the less dense canopy of B. pendula. The different light requirements of coexisting species was the most important factor affecting the distribution of foliage in the canopy, driving the physiological responses of the mixed species. Future research directions claim to enhance the informative potential of the methods to analyse the responses of pure and mixed forests to environmental factors, including a broader set of plant species' functional traits and physiological responses., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Many experiments have shown that local biodiversity loss impairs the ability of ecosystems to maintain multiple ecosystem functions at high levels (multifunctionality). In contrast, the role of biodiversity in driving ecosystem multifunctionality at landscape scales remains unresolved. We used a comprehensive pan-European dataset, including 16 ecosystem functions measured in 209 forest plots across six European countries, and performed simulations to investigate how local plot-scale richness of tree species (α-diversity) and their turnover between plots (β-diversity) are related to landscape-scale multifunctionality. After accounting for variation in environmental conditions, we found that relationships between α-diversity and landscape-scale multifunctionality varied from positive to negative depending on the multifunctionality metric used. In contrast, when significant, relationships between β-diversity and landscape-scale multifunctionality were always positive, because a high spatial turnover in species composition was closely related to a high spatial turnover in functions that were supported at high levels. Our findings have major implications for forest management and indicate that biotic homogenization can have previously unrecognized and negative consequences for large-scale ecosystem multifunctionality.

There is considerable evidence that biodiversity promotes multiple ecosystem functions (multifunctionality), thus ensuring the delivery of ecosystem services important for human well-being. However, the mechanisms underlying this relationship are poorly understood, especially in natural ecosystems. We develop a novel approach to partition biodiversity effects on multifunctionality into three mechanisms and apply this to European forest data. We show that throughout Europe, tree diversity is positively related with multifunctionality when moderate levels of functioning are required, but negatively when very high function levels are desired. For two well-known mechanisms, 'complementarity' and 'selection', we detect only minor effects on multifunctionality. Instead a third, so far overlooked mechanism, the 'jack-of-all-trades' effect, caused by the averaging of individual species effects on function, drives observed patterns. Simulations demonstrate that jack-of-all-trades effects occur whenever species effects on different functions are not perfectly correlated, meaning they may contribute to diversity-multifunctionality relationships in many of the world's ecosystems.

New technologies offer rapid identification of organisms and antimicrobial resistance markers in blood cultures several hours faster than conventional methods. We sought to determine whether implementation of the Verigene® Gram-Positive Blood Culture (BC-GP) assay paired with a well-defined results reporting algorithm would lead to earlier deescalation of empiric therapy for inpatients with methicillin-sensitive Staphylococcus aureus (MSSA) and vancomycin-resistant Enterococcus (VRE) bacteremia. The algorithm design focused on lessening the demand for pharmacist time by using electronic communications where possible. Our study compared inpatients with MSSA and VRE bacteremia from the time period before (pre-BC-GP) and after (post-BC-GP) implementation of the assay on June 25, 2013. The time from blood draw to identification and susceptibility results was decreased by 36.4 hours (P < 0.001) in the post-BC-GP group. The mean time from collection to the first dose of optimal antibiotics was reduced in the post-BC-GP group by 18.9 hours (P = 0.004) overall, with a 20.6-hour reduction (P = 0.009) for patients with MSSA and a 20.7-hour reduction (P = 0.077) for patients with VRE. Additionally, the percent of patients on empiric therapy who were placed on optimal antibiotics at any time after the Gram stain result was available increased from 64% (45/70) pre-BC-GP to 80% (43/54) post-BC-GP. The BC-GP led to an increased rate of deescalation of empiric antibiotics and a reduction in the time to optimal antibiotics for patients with MSSA and VRE bacteremia.

Successful performance and execution of rapid diagnostics in a clinical laboratory hinges heavily on careful validation, accurate and timely communication of results, and real-time quality monitoring. Laboratories must develop strategies to integrate diagnostics with stewardship and evidence-based clinical practice guidelines. We present a collaborative SUCCESS model for execution and monitoring of rapid sepsis diagnostics to facilitate timely treatment. Six months after execution of the Verigene Gram-Positive Blood Culture (BC-GP) and the AdvanDx PNA-FISH assays, data were collected on 579 and 28 episodes of bacteremia and fungemia, respectively. Clinical testing was executed using a SUCCESS model comprising the following components: stewardship, utilization of resources, core strategies, concierge services, education, support, and surveillance. Stewardship needs were identified by evaluating the specialty services benefiting from new testing. Utilization of resources was optimized by reviewing current treatment strategies and antibiogram and formulary options. Core strategies consisted of input from infectious disease leadership, pharmacy, and laboratory staff. Concierge services included automated Micro-eUpdate and physician-friendly actionable reports. Education modules were user-specific, and support was provided through a dedicated 24/7 microbiology hotline. Surveillance was performed by daily audit by the director. Using the SUCCESS model, the turnaround time for the detailed report with actionable guidelines to the physician was ∼3 hours from the time of culture positivity. The overall correlation between rapid methods and culture was 94% (546/579). Discrepant results were predominantly contaminants such as a coagulase-negative staphylococci or viridans streptococci in mixed cultures. SUCCESS is a cost-effective and easily adaptable model for clinical laboratories with limited stewardship resources.

In the United States, sepsis is the leading cause of death in critically ill patients. The fatality rate for severe sepsis is about 40%, and treatment costs over $16 billion annually. It is critical to identify and treat the source of sepsis. While there are varying guidelines determining when to draw blood for culture, at Baylor University Medical Center at Dallas, blood cultures are ordered for patients with new onset of fever, immunosuppression, or a suspicion of an underlying infectious etiology. We conducted a retrospective study of patients who had blood cultures after hospital admission or in the emergency department in December 2013. We compared length of stay and outcomes of patients with positive versus negative blood cultures. There was no significant difference for length of stay or outcomes among patients with positive and negative blood cultures. For patients admitted from the emergency department, there was a longer length of stay for patients with positive cultures; however, the overall prognosis was not worse.

The use of gold nanoparticles is increasing in medicine; however, their toxic effects remain to be elucidated. Studies show that gold nanoparticles can cross the blood-brain barrier, as well as accumulate in the brain. Therefore, this study was undertaken to better understand the effects of gold nanoparticles on rat brains. DNA damage parameters were evaluated in the cerebral cortex of adult rats submitted to acute and chronic administration of gold nanoparticles of two different diameters: 10 and 30nm. During acute administration, adult rats received a single intraperitoneal injection of either gold nanoparticles or saline solution. During chronic administration, adult rats received a daily single injection for 28 days of the same gold nanoparticles or saline solution. Twenty-four hours after either single (acute) or last injection (chronic), the rats were euthanized by decapitation, their brains removed, and the cerebral cortices isolated for evaluation of DNA damage parameters. Our study showed that acute administration of gold nanoparticles in adult rats presented higher levels of damage frequency and damage index in their DNA compared to the control group. It was also observed that gold nanoparticles of 30nm presented higher levels of damage frequency and damage index in the DNA compared to the 10nm ones. When comparing the effects of chronic administration of gold nanoparticles of 10 and 30nm, we observed that occurred significant different index and frequency damage, comparing with control group. However, there is no difference between the 10 and 30nm groups in the levels of DNA damage for both parameters of the Comet assay. Results suggest that gold nanoparticles for both sizes cause DNA damage for chronic as well as acute treatments, although a higher damage was observed for the chronic one., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The clinical pathology laboratory database of a large tertiary hospital in Dallas, Texas, was searched for patients having a serum total cholesterol > 300 mg in a single month in 1993 and in 2013. In September 1993, 63 patients had a serum total cholesterol > 300 mg/dL (range 302-1515 [mean 431, median 349]), and in September 2013, 12 patients had serum total cholesterol levels > 300 mg/dL (range 303-442 [mean 334, median 316.5]), an 81% decline in the numbers of patients and a 23% decline in the average total cholesterol levels during the 20-year period.

We aimed to adapt the shared medical appointment (SMA) model to the care of pulmonary hypertension (PH) patients and evaluate patient satisfaction. Our SMA team included a PH specialist, a PH nurse, and one research fellow. Eight to twelve PH patients with a family member were invited during office visits and by phone calls. Attendance was verified and encouraged by phone calls and informational letters. The meetings started with a 30-minute presentation on various PH topics, which was followed by each patient's individual visit and a focused examination in front of the group, allowing group questions and interaction. Of the total number of patients (n = 53), 84% stated that they would attend a future SMA. The care provided was rated excellent to very good by 98% of the patients. Ninety-two percent stated that they improved their understanding of the disease and treatment options, and 59% acknowledged a preference for the group visit over the private visit. Twenty-five percent of patients stated that they were very likely to likely to some extent to agree to change or seek a change in treatment modality on the basis of conversation with other patients in the SMA. The majority of our patients expressed no privacy concerns before the meeting (76%), and even more expressed no such concerns afterward (88%). In conclusion, the SMA model allows PH patients to increase understanding of their disease process while integrating peer support, promoting social interaction, and addressing patients' emotional needs. Other (rare) pulmonary diseases may benefit from this model.

Predicting climate-driven changes in plant distribution is crucial for biodiversity conservation and management under recent climate change. Climate warming is expected to induce movement of species upslope and towards higher latitudes. However, the mechanisms and physiological processes behind the altitudinal and latitudinal distribution range of a tree species are complex and depend on each tree species features and vary over ontogenetic stages. We investigated the altitudinal distribution differences between juvenile and adult individuals of seven major European tree species along elevational transects covering a wide latitudinal range from southern Spain (37°N) to northern Sweden (67°N). By comparing juvenile and adult distributions (shifts on the optimum position and the range limits) we assessed the response of species to present climate conditions in relation to previous conditions that prevailed when adults were established. Mean temperature increased by 0.86 °C on average at our sites during the last decade compared with previous 30-year period. Only one of the species studied, Abies alba, matched the expected predictions under the observed warming, with a maximum abundance of juveniles at higher altitudes than adults. Three species, Fagus sylvatica, Picea abies and Pinus sylvestris, showed an opposite pattern while for other three species, such as Quercus ilex, Acer pseudoplatanus and Q. petraea, we were no able to detect changes in distribution. These findings are in contrast with theoretical predictions and show that tree responses to climate change are complex and are obscured not only by other environmental factors but also by internal processes related to ontogeny and demography., (© 2013 John Wiley & Sons Ltd.)

In recent years, access to information regarding acquisition and synthesis of newer designer drugs has been at an all-time high due largely to the Internet. As these drugs have become more prevalent, laboratory techniques have been developed and refined to identify and screen for this burgeoning population of drugs. This provides a unique opportunity for learning about many of these methods. Laboratory testing techniques and instrumentation are obscure to many health care professionals, yet their results are crucial. Here, we present a case of an overdose of an uncommon designer drug (2C-E) and discuss the basics of liquid chromatography and mass spectrometry, two important techniques used in isolating and identifying the drug. Although often overlooked and taken for granted, these techniques can play a pivotal role in the diagnosis and subsequent management of select patients.

Global change triggers shifts in forest composition, with warming and aridification being particularly threatening for the populations located at the rear edge of the species distributions. This is the case of Scots pine (Pinus sylvestris) in the Mediterranean Basin where uncertainties in relation to its dynamics under these changing scenarios are still high. We analysed the relative effect of climate on the recruitment patterns of Scots pine and its interactions with local biotic and abiotic variables at different spatial scales. Number of seedlings and saplings was surveyed, and their annual shoot growth measured in 96 plots located across altitudinal gradients in three different regions in the Iberian Peninsula. We found a significant influence of climate on demography and performance of recruits, with a non-linear effect of temperature on the presence of juveniles, and a positive effect of precipitation on their survival. Abundance of juveniles of P. sylvestris that underwent their first summer drought was skewed towards higher altitudes than the altitudinal mean range of the conspecific adults and the optimum elevation for seedlings' emergence. At local level, light availability did not influence juveniles' density, but it enhanced their growth. Biotic interactions were found between juveniles and the herb cover (competition) and between the number of newly emerged seedlings and shrubs (facilitation). Results also highlighted the indirect effect that climate exerts over the local factors, modulating the interactions with the pre-existing vegetation that were more evident at more stressful sites. This multiscale approach improves our understanding of the dynamics of these marginal populations and some management criteria can be inferred to boost their conservation under the current global warming.

Background: Splenic pseudoaneurysm is an uncommon disease. It occurs as a consequence of injury to the vascular wall, mostly inflammatory. The main symptom is gastrointestinal bleeding. The objective of this paper is to present the case of two patients with splenic pseudoaneurysm., Case Reports: The first case we present is a 26-year-old male with a history of idiopatic pancreatitis, pancreatic abscess and colonic fistula 3 years prior. The second case is a 20-year-old male with a history of chronic kidney disease with peritoneal dialysis interrupted due to fungal (Candida albicans) peritonitis. Both patients presented with signs of lower gastrointestinal bleeding. Endoscopic examinations (upper endoscopy and colonoscopy) were inconclusive. Tomographic studies showed the lesion. Arteriography with embolization was performed and was satisfactory in one case and partially satisfactory in the other case. Surgery was done with proximal and distal ligation of the lesion with splenectomy. Postoperative evolution was satisfactory. During the follow-up for 6 and 12 months, neither patient has presented signs of recurrent bleeding., Conclusions: This is a very rare lesion usually presenting after a history of pancreatitis or abdominal trauma. This lesion must be ruled out in patients with obscure gastrointestinal bleeding. Arteriography with embolization is the best diagnostic and probably therapeutic procedure. Surgery is warranted for hemodynamically unstable patients, embolization failure or rebleeding.

Background and Objectives: Preconditioning gas by humidification and warming the pneumoperitoneum improves laparoscopic outcomes. This prevents peritoneal desiccation and detrimental events related to traditional cold-dry gas. Few comparisons have been done comparing traditional cold-dry, heated-only, and humidified-warmed carbon dioxide., Methods: A prospective, controlled, randomized, double-blind study of laparoscopic gastric banding included 113 patients and compared traditional dry-cold (n=35) versus dry-heated (n=40), versus humidified-warm gas (n=38). Pain medications were standardized for all groups. Endpoints were recovery room length of stay, pain location, pain intensity, and total pain medications used postoperatively for up to 10 days., Results: The humidified-warmed group had statistically significant differences from the other 2 groups with improvement in all end points. The dry-heated group had significantly more pain medication use and increased shoulder and chest pain than the other 2 groups had., Conclusion: Using warm-humidified gas for laparoscopic gastric banding reduces shoulder pain, shortens recovery room length of stay, and decreases pain medication requirements for up to 10 days postoperatively. Dry-heated gas may cause additional complications as is indicated by the increase in pain medication use and pain intensity.

Background: splenectomy has been elected surgical procedure for multiple hematologic diseases, specially for Idiopathic Thrombocytopenic Purpura. The aim of this study was to compare the incidence of splenectomies in two different periods of time and to show decrease tendency during the most recent years., Methods: it was a retrospectively reviewed study from medical records of patients who underwent splenectomy at the Hospital de Especialidades Siglo XXI, between 1986 to 1990 and 1995 to 1999., Results: during the first period of time, the incidence of splenectomies for hospital admissions was 0.52%, and in the second 0.19%., Conclusions: the incidence of splenectomies performed at the Hospital de Especialidades Siglo XXI decreased in the second period of time, probably because there are new available treatments for hematologic diseases.

Objective: To describe the optical coherence tomography (OCT) features of optic disk melanocytoma., Design and Participants: Case series including 15 patients., Main Outcome Measures: OCT characteristics of the tumor., Results: The mean age of the patients was 42 years. By ophthalmoscopy, the mean basal diameter of the tumor was 2.7 mm, and by ultrasonography, the mean thickness was 1.8 mm. By OCT, the tumor showed a nodular appearance in 14 cases (93%). The tumor displayed a gradual sloping transition from normal retina into the mass, hyperreflectivity at its anterior tumor surface, and dense posterior shadowing with an optically empty appearance in all 15 cases (100%). Thicker tumors displayed thinner anterior hyperreflective borders and denser shadowing. There were no internal qualities of the tumor or disk visible by OCT due to dense shadowing. Other findings of OCT included vitreous seeds in 2 cases (13%) and adjacent retinal edema in 1 case (7%). There were no cases of retinal traction, subretinal fluid, macular edema, or epiretinal membrane in the macula., Conclusions: Optic disk melanocytoma shows characteristic features by OCT including a gradual transition from normal retina into nodular tumor, and the mass displays a bright anterior border layer with optically empty internal details.

Background: Most enterocutaneous fistulas are postoperative in origin. Sepsis, malnutrition, and hydroelectrolytic deficit are still the most important complications to which patients with postoperative enterocutaneous fistulas (PEF) are exposed. Knowledge of prognostic factors related to specific outcomes is essential for therapeutic decision-making processes., Methods: We reviewed files of all consecutive patients with PEF treated in our hospital during a 10-year period. Our aim was to identify factors related to spontaneous closure, need for operative treatment, and mortality. Univariate and multivariate analyses were performed., Results: A total of 174 patients were treated. The most frequent site of origin was the small bowel (90 patients: 48 jejunal, and 42 ileal), followed in frequency by the colon (50 patients). Postoperative enterocutaneous fistula closure was achieved in 151 patients (86%), being spontaneous in 65 (37%) and surgical in 86 (49%). Factors that significantly precluded spontaneous closure were jejunal site, multiple fistulas, sepsis, high output, and hydroelectrolytic deficit at diagnosis or referral. Origin of PEF at our hospital was the only factor significantly associated with spontaneous closure. The most frequent operative indication was PEF persistence without sepsis. Factors significantly associated with the need for operative treatment were high output, jejunal site, and multiple fistulas. Closure was achieved in 84% of patients who underwent operation. A total of 23 patients died (13%). Factors associated with mortality were serum albumin <3.0 g/dl (at diagnosis or referral), high output, hydroelectrolytic deficit, multiple fistulas, jejunal site, sepsis, and a complex fistulous tract., Conclusions: In spite of advances in management of PEF, the associated morbidity and mortality remain high. Among several variables influencing outcome, our multivariate analysis disclosed high output, jejunal site, multiple fistulas, and sepsis as independent adverse factors related to non-spontaneous closure, need for operative treatment, and/or death.

The surgical literature contains few reports about effects of hypothyroidism in patients with acute abdomen; has been reported that a glycoprotein infiltrate the lining of the bowel leading to denervation. We report the case of a woman with acute abdomen secondary to pyosalpynx with uncontrolled hypothyroidism postoperative complications.Hypothyroidism is called "big mimicker"because its clinic spectrum ranges from anasymptomatic subclinical condition to the rare,life-threatening myxedema coma, and thus can bea challenging diagnosis to make. Unrecognized hypothyroidism may lead to unnecessary surgery or even a potentially fatal outcome. A heightened awareness of this not so uncommon entity is mandatory

We have synthesized a novel analog of the general anesthetic etomidate in which the ethoxy group has been replaced by an azide group, and which can be used as a photolabel to identify etomidate binding sites. This acyl azide analog is a potent general anesthetic in both rats and tadpoles and, as with etomidate, is stereoselective in its actions, with the R(+) enantiomer being significantly more potent than the S(-) enantiomer. Its effects on alpha1beta2gamma2s GABA(A) receptors expressed in HEK-293 cells are virtually indistinguishable from the parent compound etomidate, showing stereoselective potentiation of GABA-induced currents, as well as direct mimetic effects at higher concentrations. In addition, a point mutation (beta2 N265M), which is known to attenuate the potentiating actions of etomidate, also blocks the effects of the acyl azide analog. We have investigated the utility of the analog to identify etomidate binding sites by using it to photolabel human serum albumin, a protein that binds approximately 75% of etomidate in human plasma and which is thought to play a major role in its pharmacokinetics. Using HPLC/mass spectrometry we have identified two anesthetic binding sites on HSA. One site is the well-characterized drug binding site I, located in HSA subdomain IIA, and the second site is also an established drug binding site located in subdomain IIIB, which also binds propofol. The acyl azide etomidate may prove to be a useful new photolabel to identify anesthetic binding sites on the GABA(A) receptor or other putative targets.

Purpose: To evaluate clinical features and risks for transformation of conjunctival primary acquired melanosis (PAM) into melanoma., Methods: Retrospective chart review and Kaplan-Meier estimates of times to PAM enlargement, recurrence, and transformation into melanoma., Main Outcome Measures: PAM enlargement, recurrence, and transformation into melanoma., Results: The mean patient age at diagnosis of PAM was 56 years; 62% were female and 96% Caucasian. The conjunctival quadrant(s) affected by PAM and its extent in clock hours were recorded. Initial management included observation in 62%, biopsy combined with cryotherapy in 34%, and other methods in 4%. Of PAM that was observed, Kaplan-Meier estimates at 10 years revealed PAM enlargement in 35% and transformation into melanoma in 12%. Of those that underwent incisional or excisional biopsy, 10-year estimates of PAM recurrence and transformation into melanoma were 58% and 11%, respectively. Progression to melanoma occurred in 0% of PAM without atypia, 0% of PAM with mild atypia, and 13% of PAM with severe atypia. Multivariable analysis revealed that the most significant factor for both PAM recurrence and progression to melanoma was extent of PAM in clock hours., Conclusion: PAM without atypia or with mild atypia shows 0% progression into melanoma, whereas PAM with severe atypia shows progression into melanoma in 13%. The greater the extent of PAM in clock hours, the greater the risk for transformation into melanoma.

Introduction: We report here a case of a patient with pseudotumor cerebri (PTC) associated with morbid obesity. PTC, also called benign intracranial hypertension, is a known complication of morbid obesity with resolution by reduction of obesity., Clinical Case: A 42-year-old female with morbid obesity and secondary PTC underwent a modified jejunocolonostomy., Results: The patient has lost 43% of excess body weight and the intracranial pressure is normal., Conclusions: PTC is a benign pathology, and the cause may be morbid obesity. Bariatric surgery is useful in the management of these patients for the resolution of this disease.

Objective: To assess the mortality related factors of patients after relaparotomy on demand., Background: In some patients, a relaparotomy after a primary laparotomy will be necessary, most due to acute complications. The relaparotomy can be planned or on demand based on the evolution of the patient. Which of these approaches is better is still a matter of debate., Material and Methods: Thirty three patients underwent relaparatomy on demand in a general surgery unit., Results: Of 51 relaparotomies, 98% were positive. Nineteen of the 33 patients died, resulting in a mortality rate of 58%. The factors associated with mortality were development of an intestinal fistula (p < 0.02), wound infection (p < 0.03), generalized peritonitis in the primary surgery (p < 0.001), urgent primary laparotomy (p < 0.003), development of multiple organ failure (p < 0.005), and respiratory insufficiency (p < 0.01)., Conclusions: Laparotomy on demand is useful in the treatment of patients with abdominal sepsis; however, the mortality is still very high.

Intestinal intussusception in adults is a very rare entity whose etiology differs greatly from its pediatric counterparts. Three adult patients with intestinal intussusception presented with intestinal obstruction and required surgery for its resolution. In each case a pathologic cause was found. They had intestinal polyps, two benign (lipoma and hamartomatous polyps) and one malignant (metastasis). Intestinal intussusception in adults usually has a pathologic cause. About half have a malignant etiology. Intestinal resection without reduction of the intussusception is the preferred surgical procedure.

Objective: The objective of this report is to describe the existence of a rare tumor that must be taken into consideration when studying the diagnosis of pancreatic tumors., Case Report: A 20-year-old female with abdominal pain as an only manifestation was seen. The diagnosis of a pancreatic head and body tumor was made. During surgery, we found a tumor in the head and body of the pancreas that measured approximately 10 x 7 cm; histopathologic study revealed a solid and cystic papillary epithelial neoplasm of the pancreas., Discussion: Frantz-Gruber tumor is a rare pancreatic tumor suspected during the evaluation of a young female with abdominal pain and confirmed during surgery. It is important to consider the existence of this tumor in the evaluation of patients with these characteristics; even if the tumor's biological behavior is benign Frantz-Gruber tumor is considered a low-grade malignant tumor

Psoas abscess is an uncommon disease with varied etiology. The most common pathogen in primary abscess is Staphylococcus aureus. Crohn's disease is the most common cause of a secondary abscess. Recently, drug abuse and HIV infection have become important risk factors in identification of a patient with psoas abscess. Mycobacterium tuberculosis is considered an extremely rare cause of psoas abscess, but it is reported in HIV patients. Physical presentation is insidious; classical symptoms are pain and fever. Computed tomography (CT) is the most important tool for diagnosis. Preferred treatment is percutaneous drainage guided by CT. Open surgical drainage should be reserved if percutaneous drainage fails, if possible by extraperitoneal approach; in secondary abscess, the transperitoneal approach is preferred to correct the possible disease.