Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. NCT04706429 and ISRCTN57145331.


Dorsal root potentials and ventral root reflexes evoked by nonmyelinated fibers.
Electrical stimulation of C-fibers in the cat superficial peroneal nerve, with the A-fibers either conducting or blocked by cold, evoked dorsal root potentials having the same polarity as those evoked by A-fibers. Ventral root reflexes evoked by A-fibers were facilitated by a pure C-volley in the same or another nerve, but dorsal root potentials evoked by A-fibers were reduced by isolated dorsal root potentials from C-fibers. In the absence of anesthetics, single C-volleys produced brisk and prolonged reflex discharges in ventral roots.


Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection.
To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251 (27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.


A new class of transcription factors mediates brassinosteroid-regulated gene expression in Arabidopsis.
Brassinosteroids (BRs) signal through a plasma membrane-localized receptor kinase to regulate plant growth and development. We showed previously that a novel protein, BES1, accumulates in the nucleus in response to BRs, where it plays a role in BR-regulated gene expression; however, the mechanism by which BES1 regulates gene expression is unknown. In this study, we dissect BES1 subdomains and establish that BES1 is a transcription factor that binds to and activates BR target gene promoters both in vitro and in vivo. BES1 interacts with a basic helix-loop-helix protein, BIM1, to synergistically bind to E box (CANNTG) sequences present in many BR-induced promoters. Loss-of-function and gain-of-function mutants of BIM1 and its close family members display BR response phenotypes. Thus, BES1 defines a new class of plant-specific transcription factors that cooperate with transcription factors such as BIM1 to regulate BR-induced genes.


Antidepressive treatment as a modulator of inflammatory process in patients with heart failure: effects on proinflammatory cytokines and acute phase protein levels.
Depression has been associated with increased inflammatory process. Although anti-depressive medication has anti-inflammatory effect in major depression, its role in patients with heart failure (HF) is unknown. In the present study we evaluated the impact of antidepressive medication on the expression of proinflammatory cytokines and acute phase response proteins, in patients with HF and major depression. The study population consisted of 250 patients with HF (154 suffering from major depression). Patients with major depression were under selective serotonin reuptake inhibitors (SSRIs, n=120) or tricyclic antidepressants (TCA) and/or serotonin/norepinephrine reuptake inhibitors (SNRIs) (n=34), for at least 6 months. Levels of TNF-alpha, IL-6, CRP and fibrinogen were not significantly different between HF patients with depression under treatment and those without depression (p=NS for all). However, TNF-alpha and CRP levels were significantly lower in patients receiving TCA/SNRI compared to patients receiving SSRIs or those without depression (p<0.05 for all). Similarly, patients under TCA/SNRI had significantly lower heart rate compared to those treated with SSRIs or those without depression. In multivariate analysis, treatment with SNRI/TCA was an independent predictor for log(TNF-alpha) (beta=0.036(SE:0.016) and log(CRP) (beta=0.099(SE:0.048), p=0.041). In the present study we demonstrate for the first time that treatment of patients with HF and major depression with TCAs/SNRIs, is associated with lower levels of TNF-alpha and CRP, suggesting that the type of antidepressive treatment may have a significant effect on the underlying inflammatory process.


Innovative measures to combat rare diseases in China: The national rare diseases registry system, larger-scale clinical cohort studies, and studies in combination with precision medicine research.
China is facing the great challenge of treating the world's largest rare disease population, an estimated 16 million patients with rare diseases. One effort offering promise has been a pilot national project that was launched in 2013 and that focused on 20 representative rare diseases. Another government-supported special research program on rare diseases - the "Rare Diseases Clinical Cohort Study" - was launched in December 2016. According to the plan for this research project, the unified National Rare Diseases Registry System of China will be established as of 2020, and a large-scale cohort study will be conducted from 2016 to 2020. The project plans to develop 109 technical standards, to establish and improve 2 national databases of rare diseases - a multi-center clinical database and a biological sample library, and to conduct studies on more than 50,000 registered cases of 50 different rare diseases. More importantly, this study will be combined with the concept of precision medicine. Chinese population-specific basic information on rare diseases, clinical information, and genomic information will be integrated to create a comprehensive predictive model with a follow-up database system and a model to evaluate prognosis. This will provide the evidence for accurate classification, diagnosis, treatment, and estimation of prognosis for rare diseases in China. Numerous challenges including data standardization, protecting patient privacy, big data processing, and interpretation of genetic information still need to be overcome, but research prospects offer great promise.


Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies.
Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab. Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups. In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group. Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.


Improving timeliness for acute asthma care for paediatric ED patients using a nurse driven intervention: an interrupted time series analysis.
Asthma is the most common chronic paediatric disease treated in the emergency department (ED). Rapid corticosteroid administration is associated with improved outcomes, but our busy ED setting has made it challenging to achieve this goal. Our primary aim was to decrease the time to corticosteroid administration in a large, academic paediatric ED. We conducted an interrupted time series analysis for moderate to severe asthma exacerbations of one to 18 year old patients. A multidisciplinary team designed the intervention of a bedside nurse initiated administration of oral dexamethasone, to replace the prior system of a physician initiated order for oral prednisone. Our baseline and intervention periods were 12 month intervals. Our primary process measure was the time to corticosteroid administration. Other process measures included ED length of stay, admission rate, and rate of emesis. The balance measures included rate of return visits to the ED or clinic within five days, as well as the proportion of discharged patients who were admitted within five days. No special cause variation occurred in the baseline period. The mean time to corticosteroid administration decreased significantly, from 98 minutes in the baseline period to 59 minutes in the intervention period (p < 0.01), and showed special cause variation improvement within two months after the intervention using statistical process control methodology. We sustained the improvement and demonstrated a stable process. The intervention period had a significantly lower admission rate (p<0.01) and emesis rate (p<0.01), with no unforeseen harm to patients found with any of our balance measures. In summary, the introduction of a nurse initiated, standardized protocol for corticosteroid therapy for asthma exacerbations in a paediatric ED was associated with decreased time to corticosteroid administration, admission rates, and post-corticosteroid emesis.


FEEDING EXPERIMENTS WITH BACTERIUM PULLORUM. THE TOXICITY OF INFECTED EGGS.
The problem of eradicating ovarian infection in the domestic fowl assumes still greater importance than heretofore, in the light of data recently acquired. Not only is it of great significance to eliminate the permanent carriers of Bacterium pullorum from all flocks of fowls from the standpoint of successful poultry breeding, but also because they constitute a possible source of danger to man. Eggs which harbor Bacterium pullorum in the yolk in large numbers may produce abnormal conditions, when fed, not only in young chicks, but in adult fowls, young rabbits, guinea pigs, and kittens. The toxicity for young rabbits is most pronounced, the infection usually resulting in the death of the animals. In kittens the most prominent symptoms are those of severe food-poisoning with members of the paratyphoid group of bacteria. The possibility of infected eggs causing serious disturbances in young children and in the sick and convalescent of all ages must therefore receive serious consideration. Ovarian infection of fowls is very common throughout this country. Hence, a large proportion of the marketed eggs are infected with Bacterium pullorum. When such eggs are allowed to remain in nests under broody hens, or in warm storage places, for comparatively few hours, they contain large numbers of the organism. Soft boiling, coddling, and frying on one side only do not necessarily render the yolks free from viable bacteria; therefore, eggs which have gone through these processes may, like raw eggs, be the cause of serious disturbances in persons who are particularly susceptible to such influences, and especially to infants. That no well authenticated instances of egg-poisoning of this kind are on record does not warrant the assumption that there have been no cases. The etiology of infantile stomach and intestinal disturbances is as yet too little understood; in fact, it may be said that many of these disorders have no known cause, and almost as much may be said regarding gastro-intestinal diseases in later life. Furthermore, since the ailments caused by infected eggs would not make themselves felt presumably until several days after their ingestion, little or no suspicion would fall upon the eggs. It may be said, too, that the wide distribution of ovarian infection in the domestic fowl has come about only in the last few years, hence its possible danger to man is one of recent development.


Molecular cloning, structure, and expression of dopamine-beta-hydroxylase from bovine adrenal medulla.
Dopamine-beta-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine to norepinephrine, remains the topic of many unanswered questions. We isolated DBH cDNA clones from a bovine adrenal medulla cDNA library in the vector lambda gt10. The longest cDNA had an open reading frame encoding an entire mature DBH 578 amino acid (64,808 dalton) polypeptide chain, though lacking a portion of the signal peptide. Additional 5' clones, obtained by the polymerase chain reaction, established the sequence of a 19 amino acid signal peptide. The mature protein sequence was 84% homologous to that of human pheochromocytoma DBH, including preservation of four potential copper ligand sites (HH or HXH) and substrate binding domains. There were no hydrophobic (putative membrane spanning) domains, other than the signal peptide. All available DBH peptide and protein sequence data can be accounted for by the cDNA-deduced 578 amino acid mature protein primary structure. Prokaryotic DBH expression yielded a 65-kilodalton DBH-immunoreactive peptide that differed from eukaryotic adrenal DBH only in N-linked, endoglycosidase F-sensitive glycosylation in the latter. Southern analysis suggested one DBH gene, whereas Northern analysis suggested a single 2.6 kbp tissue-specific DBH transcript. Comparison of the DBH primary structure with other reported sequences [Protein Identification Resource (PIR), New Atlas (NEWAT)] did not indicate that DBH is a member of any known gene family. The results suggest that a single DBH gene encodes a message specifying a single DBH polypeptide chain.


Do sexual ornaments demonstrate heightened condition-dependent expression as predicted by the handicap hypothesis?
The handicap hypothesis of sexual selection predicts that sexual ornaments have evolved heightened condition-dependent expression. The prediction has only recently been subject to experimental investigation. Many of the experiments are of limited value as they: (i) fail to compare condition dependence in sexual ornaments with suitable non-sexual trait controls; (ii) do not adequately account for body size variation; and (iii) typically consider no stress and extreme stress manipulations rather than a range of stresses similar to those experienced in nature. There is also a dearth of experimental studies investigating the genetic basis of condition dependence. Despite the common claim that sexual ornaments are condition-dependent, the unexpected conclusion from our literature review is that there is little support from well-designed experiments.


Reinvigorating the clinical examination for the 21st century.
At its most fundamental level, the clinical encounter between a patient and their doctor seeks to solve a mystery. Clinicians uncover clues through the history, physical examination, and ancillary tests to arrive at a diagnosis and develop a management plan. Despite advances in technology, the majority of clinical diagnoses are still reached through the history and physical examination without the use of laboratory and imaging tests. However, in the modern American hospital, clinicians spend as little as 12% of their time in direct contact with patients and their families. This has led to a decline in clinical examination skills and contributes to diagnostic error. There is a growing movement to return clinicians and trainees back to the bedside. In 2017, we formed the Society of Bedside Medicine to encourage innovation, education, and research on the role of the clinical encounter in 21st century medicine. Over the last 3 years, we have embraced the following 6 strategies to reinvigorate the practice of the clinical examination: 1) be present with the patient; 2) practice an evidence‑based approach to the physical exam; 3) create opportunities for intentional practice of the physical exam; 4) recognize the power of the physical examination beyond diagnosis; 5) use point‑of‑care technology to aid in diagnosis and reinforce skills; and 6) seek and provide specific feedback on physical examination skills. By employing these strategies in both teaching and practice, clinicians can maximize the value of time spent with patients and renew the importance of the clinical examination in 21st century practice.


Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor.
Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.


The Effects of Anesthesia on the Pediatric Developing Brain: Strategies to Reduce Anesthesia Use in Pediatric MRI and Nursing's Role in Driving Patient Safety.
To describe the physiological and biological principles of anesthesia for children; nonanesthesia practices; the state of the evidence of patient- and family-centered care strategies to reduce anesthesia use; and role of nursing in ensuring patient safety through reducing anesthesia use for pediatric magnetic resonance imaging (MRI). Integrative literature review. Review and synthesis of experimental and nonexperimental literature. Anesthesia use in pediatric MRI: 20 studies met inclusion criteria. Physiological and biological side effects of anesthesia in children are substantial. Of significance is the developing research on the extent to which anesthesia affects the developing brain of children. Nonanesthesia in pediatric MRI: 16 studies met inclusion criteria. Common themes were noted between patient- and family-centered care strategies and reducing anesthesia use in children requiring MRI. There are significant risks associated with anesthesia on the developing brain. Nurses play an important role in using patient-centered strategies to reduce pediatric anesthesia use and advocate for patient safety.


PsyPhy: A Psychophysics Driven Evaluation Framework for Visual Recognition.
By providing substantial amounts of data and standardized evaluation protocols, datasets in computer vision have helped fuel advances across all areas of visual recognition. But even in light of breakthrough results on recent benchmarks, it is still fair to ask if our recognition algorithms are doing as well as we think they are. The vision sciences at large make use of a very different evaluation regime known as Visual Psychophysics to study visual perception. Psychophysics is the quantitative examination of the relationships between controlled stimuli and the behavioral responses they elicit in experimental test subjects. Instead of using summary statistics to gauge performance, psychophysics directs us to construct item-response curves made up of individual stimulus responses to find perceptual thresholds, thus allowing one to identify the exact point at which a subject can no longer reliably recognize the stimulus class. In this article, we introduce a comprehensive evaluation framework for visual recognition models that is underpinned by this methodology. Over millions of procedurally rendered 3D scenes and 2D images, we compare the performance of well-known convolutional neural networks. Our results bring into question recent claims of human-like performance, and provide a path forward for correcting newly surfaced algorithmic deficiencies.


Focal Task-Specific Lower Limb Dystonia Only When Walking Stairs: Is It a New Disease Entity?
Introduction: Focal task-specific dystonia in the lower limb or foot often occurs only during walking, running, hiking, or cycling. Several medications and botulinum toxin injection are effective in patients with this disorder. The objective of this study was to understand the spectrum of focal task-specific dystonia in the lower limb only when walking stairs and to compare other types of task-specific dystonia. Methods: All original articles and case reports were collected and reviewed using PubMed. In addition, all video clips of published cases were evaluated, and patients' clinical findings analyzed. The present study included 12 patients described in previous studies and five new Asian patients found in the medical records. Results: Most of the patients were women, and the onset age was 42 years. Ten patients were classified as the Kicking type, including three patients with the rKicking type, and six patients were considered as the Lifting type; however, only one patient was not included in any of the types. Symptoms in most of the patients did not improve with any medications or botulinum toxin injection. The symptoms of most patients did not change over a long time. Conclusion: Most patients showed the dystonic symptom when walking downstairs rather than upstairs. Psychogenic dystonia is a disease differentially diagnosed with this dystonia. Unlike other types of focal task-specific dystonia, the response to treatment was disappointing because most of the medications and botulinum toxin injection were not effective. The prognosis is completely different from that of other types of focal task-specific dystonia.


A nonrigid kernel-based framework for 2D-3D pose estimation and 2D image segmentation.
In this work, we present a nonrigid approach to jointly solving the tasks of 2D-3D pose estimation and 2D image segmentation. In general, most frameworks that couple both pose estimation and segmentation assume that one has exact knowledge of the 3D object. However, under nonideal conditions, this assumption may be violated if only a general class to which a given shape belongs is given (e.g., cars, boats, or planes). Thus, we propose to solve the 2D-3D pose estimation and 2D image segmentation via nonlinear manifold learning of 3D embedded shapes for a general class of objects or deformations for which one may not be able to associate a skeleton model. Thus, the novelty of our method is threefold: first, we present and derive a gradient flow for the task of nonrigid pose estimation and segmentation. Second, due to the possible nonlinear structures of one's training set, we evolve the pre-image obtained through kernel PCA for the task of shape analysis. Third, we show that the derivation for shape weights is general. This allows us to use various kernels, as well as other statistical learning methodologies, with only minimal changes needing to be made to the overall shape evolution scheme. In contrast with other techniques, we approach the nonrigid problem, which is an infinite-dimensional task, with a finite-dimensional optimization scheme. More importantly, we do not explicitly need to know the interaction between various shapes such as that needed for skeleton models as this is done implicitly through shape learning. We provide experimental results on several challenging pose estimation and segmentation scenarios.


Gasless trans-axillary robotic thyroidectomy: the introduction and principle.
A historic review of the main stages of evolution of the minimally-invasive techniques in thyroid surgery. The endoscopic era is divided into direct and indirect approaches. Examples are the minimally invasive video-assisted thyroidectomy (MIVAT) and the minimally invasive lateral approach. The indirect approach is divided into transaxillary and chest/breast incisions. A brief historic review of the advent of robots to the medical and mainly surgical field. And finally, an introduction to transaxillary robotic thyroidectomy.


Heterogeneity in myeloproliferative neoplasms: Causes and consequences.
Myeloproliferative neoplasms (MPNs) are haematopoietic stem cell-derived clonal disorders characterised by proliferation of some or all myeloid lineages, depending on the subtype. MPNs are classically categorized into three disease subgroups; essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF). The majority (>85%) of patients carry a disease-initiating or driver mutation, the most prevalent occurring in the janus kinase 2 gene (JAK2 V617F), followed by calreticulin (CALR) and myeloproliferative leukaemia virus (MPL) genes. Although these diseases are characterised by shared clinical, pathological and molecular features, one of the most challenging aspects of these disorders is the diverse clinical features which occur in each disease type, with marked variability in risks of disease complications and progression to leukaemia. A remarkable aspect of MPN biology is that the JAK2 V617F mutation, often occurring in the absence of additional mutations, generates a spectrum of phenotypes from asymptomatic ET through to aggressive MF, associated with a poor outcome. The mechanisms promoting MPN heterogeneity remain incompletely understood, but contributing factors are broad and include patient characteristics (gender, age, comorbidities and environmental exposures), additional somatic mutations, target disease-initiating cell, bone marrow microenvironment and germline genetic associations. In this review, we will address these in detail and discuss their role in heterogeneity of MPN disease phenotypes. Tailoring patient management according to the multiple different factors that influence disease phenotype may prove to be the most effective approach to modify the natural history of the disease and ultimately improve outcomes for patients.


Measuring the influence of solution chemistry on the adhesion of au nanoparticles to mica using colloid probe atomic force microscopy.
Engineered nanoparticles are used increasingly in numerous commercial products, leading to concerns over their environmental fate and ecotoxicity. We report the adaptation of colloid probe atomic force microscopy (AFM) to quantitatively determine the adhesive behavior of gold nanoparticles (Au NPs) with mica, chosen as a model for sand, in various water chemistries. Au NP-covered polystyrene (PS) beads were prepared by a combined swelling-heteroaggregation (CSH) technique prior to attachment to tipless AFM cantilevers. Force measurements were performed over a range of solution conditions (pH, ionic strength (IS), and natural organic matter (NOM) content). Plain PS beads with no Au NPs were used as controls. In general, adhesion of Au NP-PS beads to mica were found to increase as IS increased while a rise in pH led to a decrease in adhesion. Plain PS beads were not observed to adhere to mica in any of the experimental solution conditions, and the PS force curves were unaffected by changes in the pH and electrolyte concentrations. In the presence of NOM, pull-off forces for Au NP-PS beads increased in magnitude when NaCl was added. In addition, the experimental approach force curves were not successfully described by the classical Derjaguin-Landau-Verwey-Overbeek (DLVO) theory of colloidal stability. To reconcile the discrepancy between theory and experiment, an extended DLVO (xDLVO) empirical model was used to account for the contribution of non-DLVO interactions (known collectively as structural forces) between the Au NPs and mica surfaces.


Construction of nano-scale cellular environments by coating a multilayer nanofilm on the surface of human induced pluripotent stem cells.
Interactions with peripheral environments, such as extracellular matrix (ECM) and other cells, and their balance play a crucial role in the maintenance of pluripotency and self-renewal of human pluripotent stem cells. In this study, we focused on a nano-sized artificial cellular environment that is directly attached to the cytoplasmic membrane as a facile method that can effect intercellular interactions at the single-cell level. We designed multilayered nanofilms that are self-assembled on the surface of human induced pluripotent stem cells (iPSCs), by repetitive adsorption of fibronectin and heparin or chondroitin sulfate. However, the surface modification process could also lead to the loss of cell-cell adhesion, which may result in apoptotic cell death. We investigated the proliferation and pluripotency of the iPSCs coated with the nanofilm in order to establish the suitable nanofilm structure and coating conditions. As a result, the cell viability reduced with the increase in the duration of the coating process, but the undifferentiated state and proliferation of the cells were maintained until 2 bilayers were coated. To suppress the dissociation-induced apoptosis, Y-27632, the Rho-associated kinase inhibitor (ROCKi), was added to the coating solution; this allowed the coating of up to 4 bilayers of the nanofilm onto the iPSCs. These results are expected to accelerate the pace of iPSC studies on 3-dimensional cultures and naïve pluripotency, in which the regulation of cellular interactions plays a critical role.


The relationship between grey-matter and ASD and ADHD traits in typical adults.
We tested whether in 85 healthy adults (18-29 years) there is a relationship between grey-matter (GM) volume and autism and ADHD symptom severity. The structural MRI findings and autism and ADHD self-reports revealed that autism and ADHD symptom severity was correlated with GM volume in the left inferior frontal gyrus. Autism symptom-severity was correlated with the left posterior cingulate, ADHD with the right parietal lobe, right temporal frontal cortex, bilateral thalamus, and left hippocampus/amygdala complex. Symptom severity of both disorders form a continuum extending into the general population, but it seems to be an oversimplification to typify psychiatric disorders such as autism and ADHD solely as extremes of brain structure abnormalities.


Prediction of plant promoters based on hexamers and random triplet pair analysis.
With an increasing number of plant genome sequences, it has become important to develop a robust computational method for detecting plant promoters. Although a wide variety of programs are currently available, prediction accuracy of these still requires further improvement. The limitations of these methods can be addressed by selecting appropriate features for distinguishing promoters and non-promoters. In this study, we proposed two feature selection approaches based on hexamer sequences: the Frequency Distribution Analyzed Feature Selection Algorithm (FDAFSA) and the Random Triplet Pair Feature Selecting Genetic Algorithm (RTPFSGA). In FDAFSA, adjacent triplet-pairs (hexamer sequences) were selected based on the difference in the frequency of hexamers between promoters and non-promoters. In RTPFSGA, random triplet-pairs (RTPs) were selected by exploiting a genetic algorithm that distinguishes frequencies of non-adjacent triplet pairs between promoters and non-promoters. Then, a support vector machine (SVM), a nonlinear machine-learning algorithm, was used to classify promoters and non-promoters by combining these two feature selection approaches. We referred to this novel algorithm as PromoBot. Promoter sequences were collected from the PlantProm database. Non-promoter sequences were collected from plant mRNA, rRNA, and tRNA of PlantGDB and plant miRNA of miRBase. Then, in order to validate the proposed algorithm, we applied a 5-fold cross validation test. Training data sets were used to select features based on FDAFSA and RTPFSGA, and these features were used to train the SVM. We achieved 89% sensitivity and 86% specificity. We compared our PromoBot algorithm to five other algorithms. It was found that the sensitivity and specificity of PromoBot performed well (or even better) with the algorithms tested. These results show that the two proposed feature selection methods based on hexamer frequencies and random triplet-pair could be successfully incorporated into a supervised machine learning method in promoter classification problem. As such, we expect that PromoBot can be used to help identify new plant promoters. Source codes and analysis results of this work could be provided upon request.


Risk of hip fracture in women with vertebral fracture.
In a population-based retrospective cohort study, Rochester women aged 35-69 years who were first diagnosed with one or more vertebral fractures in 1950-1979 were followed for the development of a subsequent hip fracture. The 336 women with no history of hip fracture at the time of their vertebral fracture experienced 52 proximal femur fractures in 4788 person-years of follow-up. The standardized morbidity ratio (SMR) of observed to expected hip fractures was 1.8 (95% CI, 1.3-2.4) and was higher for intertrochanteric than cervical femoral fractures (SMR, 2.3 versus 1.3; P = 0.07). Hip fracture risk among women with symptomatic vertebral fractures was slightly less than in those with asymptomatic vertebral fractures (SMR, 1.8 versus 2.3; not significant), and younger women had no higher risk of a subsequent hip fracture than women who were > or = 60 years of age at the time of their vertebral fracture (SMR, 1.4 versus 1.8; not significant). Alternative explanations are possible, but these data are consistent with heterogeneity in the pathogenesis of different osteoporotic fractures.


Is routine audiometric testing necessary for children with isolated preauricular lesions?
Preauricular lesions, including tags, pits, sinuses, and cysts are commonly seen. Some studies have shown increased incidence of hearing loss in these patients but other studies have failed to corroborate this finding. The purpose of this study is to evaluate the incidence of hearing loss in patients with isolated preauricular lesions. Retrospective chart review of all pediatric otolaryngology patients seen at a tertiary academic center between 2008 and 2014. All patients with the diagnosis code of 744.1 or 701.9 (preauricular skin tag) or 744.46, 744.47, or 744.89 (preauricular pit/fistula/cyst) were included in this study. Medical records were reviewed for clinical, demographic, and audiologic data. Ninety-nine patients, 46 males, 53 females, with preauricular lesions were identified. Twelve were found to have abnormal hearing. Five patients had conductive hearing loss due to underlying Eustachian tube dysfunction. Four patients had sensorineural hearing loss; three of these patients had an enlarged vestibular aqueduct and one patient did not have an identified cause. Three patients had sound field testing or abnormal otoacoustic emissions that suggested hearing loss with no further follow up. Children with isolated preauricular lesions with no history of otologic surgery or risk factors for hearing loss may not need audiologic evaluation outside of regular hearing screening. However, there does appear to be a higher association with Eustachian tube dysfunction in these children. Further studies will need to be done to determine whether or not there is an embryological correlation for this finding.


Building chessboard-like supramolecular structures on Au(111) surfaces.
We investigate an anthracene derivative, 3(5)-(9-anthryl) pyrazole (ANP), self-assembled on the Au(111) surface by means of scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. A chessboard-like network structure composed of ANP molecules is found, covering the whole Au(111) substrate. Our STM results and DFT calculations reveal that the formation of chessboard-like networks originates from a basic unit cell, a tetramer structure, which is formed by four ANP molecules connected through C-H…N hydrogen bonds. The hydrogen bonds inside each tetramer and the molecule-substrate interaction are fundamentally important in providing a driving force for formation of the supramolecular networks.


Even moderate cigarette smoking influences the pattern of circulating monocytes and the concentration of sICAM-1.
The pattern of circulating monocyte subtypes and the concentration of the soluble intercellular adhesion molecule-1 (ICAM-1) were compared in middle-aged female moderate smokers and lifetime non-smokers. Total leukocyte and monocyte counts were higher in smokers. The pattern of circulating monocytes of smokers was changed toward lower absolute counts of activated (CD16+/CD64+) monocytes and (CD16+/CD14+) monocyte-macrophages and higher counts of nonactivated monocytes. The serum concentration of soluble ICAM-1 was significantly higher in smokers than in non-smokers. It is supposed that even moderate cigarette smoking leads to an activation of the circulating monocytes and their increased adhesion to the endothelium.


Hyperbolic geometry of complex networks.
We develop a geometric framework to study the structure and function of complex networks. We assume that hyperbolic geometry underlies these networks, and we show that with this assumption, heterogeneous degree distributions and strong clustering in complex networks emerge naturally as simple reflections of the negative curvature and metric property of the underlying hyperbolic geometry. Conversely, we show that if a network has some metric structure, and if the network degree distribution is heterogeneous, then the network has an effective hyperbolic geometry underneath. We then establish a mapping between our geometric framework and statistical mechanics of complex networks. This mapping interprets edges in a network as noninteracting fermions whose energies are hyperbolic distances between nodes, while the auxiliary fields coupled to edges are linear functions of these energies or distances. The geometric network ensemble subsumes the standard configuration model and classical random graphs as two limiting cases with degenerate geometric structures. Finally, we show that targeted transport processes without global topology knowledge, made possible by our geometric framework, are maximally efficient, according to all efficiency measures, in networks with strongest heterogeneity and clustering, and that this efficiency is remarkably robust with respect to even catastrophic disturbances and damages to the network structure.


Biocompatibility of trypan blue with human corneal cells.
To quantify the toxicity of trypan blue on human corneal cells according to exposure time and concentration. Three in vitro experiments were performed. (1) We exposed cultured human corneal fibroblasts to trypan blue (0.0001% to 0.1%) in Eagle modified minimum essential medium (EMEM) or phosphate-buffered saline (PBS) for 15 minutes to 24 hours. Cytotoxicity was evaluated by Mosmann's colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MMT) assay. (2) We exposed human corneas in EMEM for 24 hours to trypan blue (0.001% to 0.1%). Fellow donor corneas served as controls. Endothelial survival was evaluated morphologically and by cell density assessment. (3) We morphologically compared the endothelial viability of human donor corneas after exposure to 0.1% trypan blue for 5 to 30 minutes with control corneas. In experiment 1, trypan blue in EMEM was not significantly toxic at concentrations of 0.005% or lower. Higher concentrations were toxic only after exposure to trypan blue for at least 6 hours. In PBS, significant toxicity was found after exposure to 0.1% trypan blue for 30 minutes or longer. Lower concentrations were toxic after longer exposures. In experiment 2, exposure to 0.01% and 0.1% trypan blue for 24 hours resulted in significant loss in cell density. At lower concentrations, the endothelium was affected only morphologically. In experiment 3, endothelial morphology changed in control corneas and after exposure to 0.1% trypan blue for as little as 5 minutes. After 30-minute exposure, morphologic deterioration was more pronounced. Trypan blue was toxic in vitro to corneal endothelium and corneal fibroblasts at higher concentrations and notably longer exposure times. Toxicity was less in EMEM than in PBS. Clinical Relevance At commonly used concentrations, both during cataract surgery and in the cornea bank, trypan blue is safe for corneal cells. At higher concentrations or longer exposures, however, caution is warranted.


Intravesical instillations and cancer-specific survival in patients with primary carcinoma in situ of the urinary bladder.
The aim of this study was to evaluate the use of intravesical treatment and cancer-specific survival of patients with primary carcinoma in situ (CIS). Data acquisition was based on the Swedish National Registry of Urinary Bladder Cancer by selecting all patients with primary CIS. The analysis covered gender, age, hospital type and hospital volume. Intravesical treatment and death due to bladder cancer were evaluated by multivariate logistic regression and multivariate Cox analysis, respectively. The study included 1041 patients (median age at diagnosis 72 years) with a median follow-up of 65 months. Intravesical instillation therapy was given to 745 patients (72%), and 138 (13%) died from bladder cancer during the observation period. Male gender [odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.13-2.17] and treatment at county (OR = 1.65, 95% CI 1.17-2.33), university (OR =2.12, 95% CI 1.48-3.03) or high-volume (OR = 1.92, 95% CI 1.34-2.75) hospitals were significantly associated with higher odds of intravesical instillations. The age category ≥80 years had a significantly lower chance of receiving intravesical therapy (OR = 0.44, 95% CI 0.26-0.74) and a significantly higher risk of dying from bladder cancer (hazard ratio = 3.03, 95% CI 1.71-5.35). Significantly more frequent use of intravesical treatment of primary CIS was found for males and for patients treated at county, university and high-volume hospitals. Age ≥80 years was significantly related to less intravesical treatment and poorer cancer-specific survival.


In situ structure determination at nanometer resolution using TYGRESS.
The resolution of subtomogram averages calculated from cryo-electron tomograms (cryo-ET) of crowded cellular environments is often limited owing to signal loss in, and misalignment of, the subtomograms. By contrast, single-particle cryo-electron microscopy (SP-cryo-EM) routinely reaches near-atomic resolution of isolated complexes. We report a method called 'tomography-guided 3D reconstruction of subcellular structures' (TYGRESS) that is a hybrid of cryo-ET and SP-cryo-EM, and is able to achieve close-to-nanometer resolution of complexes inside crowded cellular environments. TYGRESS combines the advantages of SP-cryo-EM (images with good signal-to-noise ratio and contrast, as well as minimal radiation damage) and subtomogram averaging (three-dimensional alignment of macromolecules in a complex sample). Using TYGRESS, we determined the structure of the intact ciliary axoneme with up to resolution of 12 Å. These results reveal many structural details that were not visible by cryo-ET alone. TYGRESS is generally applicable to cellular complexes that are amenable to subtomogram averaging.


Determinants within the turret and pore-loop domains of KCNQ3 K+ channels governing functional activity.
KCNQ1-5 (Kv7.1-7.5) subunits assemble to form a variety of functional K(+) channels in the nervous system, heart, and epithelia. KCNQ1 and KCNQ4 homomers and KCNQ2/3 heteromers yield large currents, whereas KCNQ2 and KCNQ3 homomers yield small currents. Since the unitary conductance of KCNQ3 is five- to 10-fold greater than that of KCNQ4 or KCNQ1, these differences are even more striking. To test for differential membrane protein expression, we performed biotinylation and total internal reflection fluorescence imaging assays; however, both revealed only small differences among the channels, leading us to investigate other mechanisms at work. We probed the molecular determinants governing macroscopic current amplitudes, with focus on the turret and pore-loop domains of KCNQ1 and KCNQ3. Elimination of the putative N289 glycosylation site in KCNQ1 reduced current density by approximately 56%. A chimera consisting of KCNQ3 with the turret domain (TD) of KCNQ1 increased current density by about threefold. Replacement of the proximal half of the TD in KCNQ3 with that of KCNQ1 increased current density by fivefold. A triple chimera containing the TD of KCNQ1 and the carboxy terminus of KCNQ4 yielded current density 10- or sixfold larger than wild-type KCNQ3 or KCNQ1, respectively, suggesting that the effects on current amplitudes of the TD and the carboxy-terminus are additive. Critical was the role of the intracellular TEA(+)-binding site. The KCNQ3 (A315T) swap increased current density by 10-fold, and the converse KCNQ1 (T311A) swap reduced it by 10-fold. KCNQ3 (A315S) also yielded greatly increased current amplitudes, whereas currents from mutant A315V channels were very small. The KCNQ3 (A315T) mutation increased the sensitivity of the channels to external Ba(2+) block by eight- to 28-fold, consistent with this mutation altering the structure of the selectivity filter. To investigate a structural hypothesis for the effects of these mutations, we performed homology modeling of the pore region of wild-type and mutant KCNQ3 channels, using KvAP as a template. The modeling suggests a critical stabilizing interaction between the pore helix and the selectivity filter that is absent in wild-type KCNQ3 and the A315V mutant, but present in the A315T and A315S mutants. We conclude that KCNQ3 homomers are well expressed at the plasma membrane, but that most wild-type channels are functionally silent, with rearrangements of the pore-loop architecture induced by the presence of a hydroxyl-containing residue at the 315 position "unlocking" the channels into a conductive conformation.


Extracellular vesicles from endothelial progenitor cells prevent steroid-induced osteoporosis by suppressing the ferroptotic pathway in mouse osteoblasts based on bioinformatics evidence.
Abnormal antioxidative capabilities were observed in the pathogenesis of steroid-induced osteoporosis (SIOP). Ferroptosis is a recently discovered type of cell death that is characterized by the overproduction of ROS in response to GPX4 and system Xc- downregulation, which is mediated by an Fe2+ fenton reaction. However, investigations focusing on the relationship between ferroptosis and steroid-induced bone disease remain limited. In the present study, high-dose dexamethasone was used to establish a mouse SIOP model, and extracellular vesicles extracted from bone marrow-derived endothelial progenitor cells (EPC-EVs) alleviated the pathological changes in SIOP via microtomography (micro-CT), with elevations in bone volume (BV), bone surface (BS), trabecular thickness (Tb.Th), and trabecular connectivity density (Conn-D) and decreases in trabecular separation (Tb.sp) and the structure model index (SMI). Histopathological analysis, such as haematoxylin and eosin (HE) and Masson staining, showed that EPC-EVs treatment increased the volume and density of the trabecular bone and bone marrow. RNA sequencing (RNA-seq) and bioinformatics analysis revealed subcellular biological alterations upon steroid and EPC-EVs treatment. Compared with the control, high-dose dexamethasone downregulated GPX4 and system XC-, and the Kyoto Encyclopedia of Genes and Genomes (KEGG)-based gene set enrichment analysis suggested that the ferroptotic pathway was activated. In contrast, combination treatment with EPC-EVs partly reversed the KEGG-mapped changes in the ferroptotic pathway at both the gene and mRNA expression levels. In addition, alterations in ferroptotic marker expression, such as SLC3A2, SLC7A11, and GPX4, were further confirmed by RNA-seq. EPC-EVs were able to reverse dexamethasone treatment-induced alterations in cysteine and several oxidative injury markers, such as malondialdehyde (MDA), glutathione (GSH), and glutathione disulphide (GSSG) (as detected by ELISA). In conclusion, EPC-EVs prevented mouse glucocorticoid-induced osteoporosis by suppressing the ferroptotic pathway in osteoblasts, which may provide a basis for novel therapies for SIOP in humans.


An obligately aerobic soil bacterium activates fermentative hydrogen production to survive reductive stress during hypoxia.
Oxygen availability is a major factor and evolutionary force determining the metabolic strategy of bacteria colonizing an environmental niche. In the soil, conditions can switch rapidly between oxia and anoxia, forcing soil bacteria to remodel their energy metabolism accordingly. Mycobacterium is a dominant genus in the soil, and all its species are obligate aerobes. Here we show that an obligate aerobe, the soil actinomycete Mycobacterium smegmatis, adopts an anaerobe-type strategy by activating fermentative hydrogen production to adapt to hypoxia. This process is controlled by the two-component system DosR-DosS/DosT, an oxygen and redox sensor that is well conserved in mycobacteria. We show that DosR tightly regulates the two [NiFe]-hydrogenases: Hyd3 (MSMEG_3931-3928) and Hyd2 (MSMEG_2719-2718). Using genetic manipulation and high-sensitivity GC, we demonstrate that Hyd3 facilitates the evolution of H2 when oxygen is depleted. Combined activity of Hyd2 and Hyd3 was necessary to maintain an optimal NAD(+)/NADH ratio and enhanced adaptation to and survival of hypoxia. We demonstrate that fermentatively-produced hydrogen can be recycled when fumarate or oxygen become available, suggesting Mycobacterium smegmatis can switch between fermentation, anaerobic respiration, and aerobic respiration. Hydrogen metabolism enables this obligate aerobe to rapidly meet its energetic needs when switching between microoxic and anoxic conditions and provides a competitive advantage in low oxygen environments.


Relationship between thromboelastography and long-term ischemic events as gauged by the response to clopidogrel in patients undergoing elective percutaneous coronary intervention.
Ischemic events after percutaneous coronary intervention (PCI) remain a major concern for patients with coronary heart disease (CHD). The aim of the current study was to investigate whether thromboelastography (TEG) was a satisfactory technique to measure platelet function in vitro in order to improve risk stratification and the individual response to antiplatelet therapy. The diagnostic and prognostic utility of the maximum amplitude of adenosine diphosphate induced platelet-fibrin clots (MAADP) was measured with TEG in 759 patients undergoing elective PCI. A 600-mg dose of clopidogrel was taken more than 12 h before surgery in addition to a maintenance dose of aspirin 100 mg/day and clopidogrel 75 mg/day for 2 y. Platelet-fibrin clot strength was also measured in this study. An MAADP > 34 mm significantly predicted ischemic events after PCI, as indicated by an area under the curve (AUC) of 0.79 (95% CI: 0.72-0.87, P < 0.05) according to receiver operating characteristic (ROC) curve analysis. The multivariate Cox proportional hazards model identified MAADP > 34 mm and an FBG level > 7.0 mmol/L as significant independent predictors of first ischemic events at the 2-year time point (P < 0.05). With adequate clopidogrel pretreatment, patients who underwent elective PCI and who experienced ischemic events could be diagnosed with a certain MAADP according to TEG. TEG could be a good tool to measure platelet function.


A U-shaped association between intensity of Internet use and adolescent health.
To examine the relationship between different Internet-use intensities and adolescent mental and somatic health. Data were drawn from the 2002 Swiss Multicenter Adolescent Survey on Health, a nationally representative survey of adolescents aged 16 to 20 years in post-mandatory school. From a self-administered anonymous questionnaire, 3906 adolescent boys and 3305 girls were categorized into 4 groups according to their intensity of Internet use: heavy Internet users (HIUs; >2 hours/day), regular Internet users (RIUs; several days per week and ≤ 2 hours/day), occasional users (≤ 1 hour/week), and non-Internet users (NIUs; no use in the previous month). Health factors examined were perceived health, depression, overweight, headaches and back pain, and insufficient sleep. In controlled multivariate analysis, using RIUs as a reference, HIUs of both genders were more likely to report higher depressive scores, whereas only male users were found at increased risk of overweight and female users at increased risk of insufficient sleep. Male NIUs and female NIUs and occasional users also were found at increased risk of higher depressive scores. Back-pain complaints were found predominantly among male NIUs. Our study provides evidence of a U-shaped relationship between intensity of Internet use and poorer mental health of adolescents. In addition, HIUs were confirmed at increased risk for somatic health problems. Thus, health professionals should be on the alert when caring for adolescents who report either heavy Internet use or very little/none. Also, they should consider regular Internet use as a normative behavior without major health consequence.


Recent advances in antibody-inducing poxviral and adenoviral vectored vaccine delivery platforms for difficult disease targets.
Viral vectored vaccine delivery platforms have traditionally been used for the induction of cellular rather than humoral immunity. However, in recent years, recombinant adenoviral and poxviral vectored vaccines have been optimized to induce B-cell responses, resulting in the demonstration of high-titer antibody responses in a wide variety of animal species. These approaches have now been translated, confirming the induction of substantial levels of antigen-specific IgG in a series of Phase I human clinical trials targeting HIV-1 and Plasmodium falciparum malaria. To further improve the induction of antibodies, mixed-modality regimens based on recombinant viral and protein/adjuvant vaccines are now being assessed. However, limited data exist about the underlying mechanisms mediating the induction of B-cell responses by these subunit vaccines and their ability to influence the qualitative aspects of vaccine-induced B-cell populations and immunoglobulin. Future studies in this area are needed to guide the rational design of antibody-inducing subunit vaccine strategies.


Plant density and life history traits of Aconitum spicatum in North-central Nepal: effects of elevation and anthropogenic disturbances.
Increasing cross-border trade of medicinal and aromatic plants (MAPs) has put heavy pressure on a considerable number of species in the Himalayas. One of the threatened species in Nepal is Aconitum spicatum. Unfortunately for this species and for many others, our knowledge on population ecology and performance across the distribution range is insufficient, hindering the formulation of species-specific management plans. We therefore studied density and population structure of A. spicatum and assessed variation in its life history traits among three populations (subalpine, lower alpine and alpine) along an elevation gradient (3,000-4,200 m a.s.l.) in Annapurna Conservation Area, north-central Nepal. The results show that human disturbances and topographic factors contributed to the variation in density and life history traits. The overall density ranged between 0.56 ± 0.09 (Mean ± SE) and 2.48 ± 0.24 plants/m2 with highest mean density in the lower alpine and lowest in the subalpine population. The subalpine population was also characterized by lower investment in reproductive structures with lowest seed mass and low seed viability and fecundity. Among the environmental variables tested, harvesting, animal droppings and fire appeared to be the most important factors affecting density of different life stages of A. spicatum. The prevailing harvesting pattern is destructive as it involves uprooting of the whole plant and this appears to be a main reason for low recruitment and reduced density of the subalpine population. The level of disturbance decreased with increasing elevation. In terms of reproductive effort, the alpine population performed best. Our results indicate that the viability of A. spicatum populations depends on controlling over-harvesting and pre-mature harvesting of tubers and protecting younger life stages from grazing, trampling and fire. We therefore recommend that when formulating management guidelines, measures aiming to mitigate such anthropogenic disturbances should be considered.


Barriers and facilitators to implementing workplace health and wellbeing services in the NHS from the perspective of senior leaders and wellbeing practitioners: a qualitative study.
The National Health Service (NHS) seems appropriately placed to be an exemplar employer in providing effective and proactive workplace health and wellbeing services for its staff. However, NHS staff sickness absence costs an estimated £2.4 billion. Evidence suggests staff health and wellbeing services delivered in the NHS can improve health, productivity and sickness absence and yet the adoption of these services remains a challenge, with few examples nationally. This research aimed to explore the perceptions of NHS senior leaders and health and wellbeing practitioners regarding barriers and facilitators to implementing workplace health and wellbeing services for staff in the NHS. Semi-structured interviews were conducted with NHS staff, consisting of four senior leaders, four heads of department and three health and wellbeing practitioners in one region of the UK. Interviews were transcribed verbatim and analysed using thematic analysis. Themes describe the experience of delivering workplace health and wellbeing services in the NHS, and barriers and facilitators to implementation from senior decision makers. Barriers to implementation of services include; a busy and pressurised environment, financial constraints and reluctance to invest in staff health and wellbeing. Barriers to staff engagement were also reported and include difficulty of access to health and wellbeing services and lack of time. Initiating services were facilitated by financial incentives, a supportive organisational structure and culture that takes a preventative, rather than reactive, approach to staff health and wellbeing. Facilitators to implementing health and wellbeing services include a coherent, strategic approach to implementation, effective communication and advertisement, being creative and innovative with resources and conducting a needs analysis and evaluation before, during and after implementation. Barriers to the successful initiation and implementation of health and wellbeing services in the NHS are numerous and range from front-line logistical issues with implementation to high-level strategic and financial constraints. Adopting a strategic and needs-led approach to implementation and ensuring thorough staff engagement are amongst a number of factors that facilitate implementation and help overcome barriers to initiation of wellbeing programmes in the NHS. There is a need for a culture that supports staff health and wellbeing in the NHS.


Natural quasicrystal with decagonal symmetry.
We report the first occurrence of a natural quasicrystal with decagonal symmetry. The quasicrystal, with composition Al71Ni24Fe5, was discovered in the Khatyrka meteorite, a recently described CV3 carbonaceous chondrite. Icosahedrite, Al63Cu24Fe13, the first natural quasicrystal to be identified, was found in the same meteorite. The new quasicrystal was found associated with steinhardtite (Al38Ni32Fe30), Fe-poor steinhardtite (Al50Ni40Fe10), Al-bearing trevorite (NiFe2O4) and Al-bearing taenite (FeNi). Laboratory studies of decagonal Al71Ni24Fe5 have shown that it is stable over a narrow range of temperatures, 1120 K to 1200 K at standard pressure, providing support for our earlier conclusion that the Khatyrka meteorite reached heterogeneous high temperatures [1100 < T(K) ≤ 1500] and then rapidly cooled after being heated during an impact-induced shock that occurred in outer space 4.5 Gya. The occurrences of metallic Al alloyed with Cu, Ni, and Fe raises new questions regarding conditions that can be achieved in the early solar nebula.


British Heart Foundation surveys (1987 and 1989) of United Kingdom treatment policies for acute myocardial infarction.
Consultant physicians and cardiologists were surveyed early in 1987 and 1989 to document the management policies for the treatment of acute myocardial infarction in United Kingdom hospitals and to assess the influence of major clinical trials on these policies. The response rate to both these surveys was high (84% (1178 physicians) in 1987 and 76% (982 physicians) in 1989). The percentage of physicians that reported using antiplatelet therapy "routinely" in acute myocardial infarction rose from 9% in 1987 to 84% in 1989 while those who reported using it "rarely or never" fell from 42% to 3%. Similarly, "routine" use of fibrinolytic therapy rose from 2% to 68%, and use "rarely or never" fell from 53% to 3%. This increase in the reported use of fibrinolytic therapy was accompanied by greater certainty about its efficacy and relative safety and by a general widening of the indications for its use. The use of other treatments in acute myocardial infarction (for example, the general use of anticoagulants, beta blockers, nitrates, calcium antagonists, or prophylactic antiarrhythmic agents) seemed to change little during this period, although the routine use of coronary angiography and oral anticoagulants after fibrinolytic therapy fell substantially between 1987 and 1989 (from 23% to 4%, and from 24% to 7% respectively). Fibrinolytic and antiplatelet therapy were accepted into the routine management of myocardial infarction during a relatively short period that coincided with the reporting of several positive controlled trial results. Clinical trials have rarely been seen to have had such a great impact on practice. In this case the rapid acceptance of the trial results may have been due to the consistency and reliability of the estimates of the size of the benefits (and risks) of therapy seen in these unusually large studies.


The planktonic stages of the salmon louse (Lepeophtheirus salmonis) are tolerant of end-of-century pCO2 concentrations.
The copepod Lepeophtheirus salmonis is an obligate ectoparasite of salmonids. Salmon lice are major pests in salmon aquaculture and due to its economic impact Lepeophtheirus salmonis is one of the most well studied species of marine parasite. However, there is limited understanding of how increased concentration of pCO2 associated with ocean acidification will impact host-parasite relationships. We investigated the effects of increased pCO2 on growth and metabolic rates in the planktonic stages, rearing L. salmonis from eggs to 12 days post hatch copepodids under three treatment levels: Control (416 µatm), Mid (747 µatm), and High (942 µatm). The pCO2 treatment had a significant effect on oxygen consumption rate with the High treatment animals exhibiting the greatest respiration. The treatments did not have a significant effect on the other biological endpoints measured (carbon, nitrogen, lipid volume, and fatty acid content). The results indicate that L. salmonis have mechanisms to compensate for increased concentration of pCO2and that populations will be tolerant of projected future ocean acidification scenarios. The work reported here also describes catabolism during the lecithotrophic development of L. salmonis, information that is not currently available to parameterize models of dispersal and viability of the planktonic free-living stages.


Ultrasonography versus chest radiography after chest tube removal for the detection of pneumothorax.
Bedside ultrasound technology is an innovative, cost-effective, safe, and reproducible method used to make efficient decisions that directly affect the care of critical care patients. To validate the use of ultrasound technology when compared with the use of standard chest radiography for the detection of pneumothorax following chest tube removal. A prospective observational comparison study of 50 cardiothoracic patients with surgically placed pleural chest tubes was conducted. The accuracy of bedside ultrasound technology was compared with standard chest radiography to detect pneumothorax. The sample kappa statistic was 1.000, indicating a perfect agreement between bedside ultrasonography and chest radiography in the detection of pneumothorax. Completion of the bedside ultrasound procedure took significantly less time than chest radiography. Bedside ultrasound technology is as accurate as chest radiography in detecting pneumothorax following chest tube removal and can save institutions' time and money.


Serotonergic neurons signal reward and punishment on multiple timescales.
Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We 'tagged' serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales.


Protective effect of stem bark of Ceiba pentandra linn. against paracetamol-induced hepatotoxicity in rats.
The present study reports protective activity of ethyl acetate fraction of methanol extract of stem bark of Ceiba pentandra against paracetamol-induced liver damage in rats. The ethyl acetate fraction (400 mg/kg) was administered orally to the rats with hepatotoxicity induced by paracetamol (3 gm/kg). Silymarin (100 mg/kg) was used as positive control. High performance thin layer chromatography (HPTLC) fingerprinting of ethyl acetate fraction revealed presence of its major chemical constituents. A significant (P < 0.05) reduction in serum enzymes GOT (ALT), aspartate aminotransferase (AST), GPT alkaline phosphatase (ALP), total bilirubin content and histopathological screening in the rats treated gave indication that ethyl acetate fraction of methanolic extract of Ceiba pentandra possesses hepatoprotective potential against paracetamol-induced hepatotoxicity in rats.


Testosterone enhancement of the nerve cell body response to injury: evidence using in situ hybridization and ribosomal DNA probes.
In axotomized peripheral motoneurons capable of successful regeneration, one of the earliest morphological indicators of the injury response occurs within the nucleolus. In the initial part of this investigation, we mapped the nucleolar response of injured adult hamster facial motoneurons from a molecular perspective, utilizing in situ hybridization and ribosomal DNA probes complementary to stable rRNA. Recently, we have discovered that the gonadal steroid, testosterone propionate (TP), accelerates recovery from facial paralysis in the hamster by increasing the rate of regeneration of the fastest regrowing axons. In the second part of this study, the hypothesis that TP accomplishes these effects on facial nerve regeneration through an enhancement of the nerve cell body response to injury was tested using in situ hybridization and rDNA probes. Adult intact male hamsters were subjected to right facial nerve axotomies at the stylomastoid foramen. One-half of the axotomized animals received subcutaneous implants of TP, with the remainder sham implanted. In situ hybridization with tritiated rDNA probes was accomplished and levels of hybridizable rRNA assessed both qualitatively and quantitatively. Axotomy alone induced an upregulation in rRNA levels, with peak changes occurring by 24 hr postoperative and continuing through postoperative day 4. These molecular changes in the nucleolar response preceded, by a full day, any morphological signs of the nucleolar reactive pattern previously found in this cell type, and, as such, point to the usefulness of in situ hybridization as a tool to identify the earliest events associated with the axon reaction. A secondary smaller increase in rRNA levels was observed during the later stages of regeneration. TP significantly augmented the ribosomal response to injury, with levels of rRNA increased as early as 6 hr and the magnitude of the response greater than that occurring following axotomy alone. These results provide the first mechanistic step in the identification of the cellular processes underlying gonadal steroid augmentation of neuronal reparative processes. We conclude that TP accelerates the "switch" from a normal to a reparative state and suggest that this priming effect may be causally related to the differential effects of TP on the regenerative properties of this cell type.


Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney.
During kidney development and in response to inductive signals, the metanephric mesenchyme aggregates, becomes polarized, and generates much of the epithelia of the nephron. As such, the metanephric mesenchyme is a renal progenitor cell population that must be replenished as epithelial derivatives are continuously generated. The molecular mechanisms that maintain the undifferentiated state of the metanephric mesenchymal precursor cells have not yet been identified. In this paper, we report that functional inactivation of the homeobox gene Six2 results in premature and ectopic differentiation of mesenchymal cells into epithelia and depletion of the progenitor cell population within the metanephric mesenchyme. Failure to renew the mesenchymal cells results in severe renal hypoplasia. Gain of Six2 function in cortical metanephric mesenchymal cells was sufficient to prevent their epithelial differentiation in an organ culture assay. We propose that in the developing kidney, Six2 activity is required for maintaining the mesenchymal progenitor population in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud.


Femoral neck-shaft angle in humans: variation relating to climate, clothing, lifestyle, sex, age and side.
The femoral neck-shaft angle (NSA) varies among modern humans but measurement problems and sampling limitations have precluded the identification of factors contributing to its variation at the population level. Potential sources of variation include sex, age, side (left or right), regional differences in body shape due to climatic adaptation, and the effects of habitual activity patterns (e.g. mobile and sedentary lifestyles and foraging, agricultural, and urban economies). In this study we addressed these issues, using consistent methods to assemble a global NSA database comprising over 8000 femora representing 100 human groups. Results from the analyses show an average NSA for modern humans of 127° (markedly lower than the accepted value of 135°); there is no sex difference, no age-related change in adults, but possibly a small lateral difference which could be due to right leg dominance. Climatic trends consistent with principles based on Bergmann's rule are evident at the global and continental levels, with the NSA varying in relation to other body shape indices: median NSA, for instance, is higher in warmer regions, notably in the Pacific (130°), whereas lower values (associated with a more stocky body build) are found in regions where ancestral populations were exposed to colder conditions, in Europe (126°) and the Americas (125°). There is a modest trend towards increasing NSA with the economic transitions from forager to agricultural and urban lifestyles and, to a lesser extent, from a mobile to a sedentary existence. However, the main trend associated with these transitions is a progressive narrowing in the range of variation in the NSA, which may be attributable to thermal insulation provided by improved cultural buffering from climate, particularly clothing.


A Healthy Mind for Problematic Internet Use.
This article designed and tested a cognitive behavioral-based preventive intervention program for youths with problematic Internet use (PIU) behavior. The program is the Psychological Intervention Program-Internet Use for Youth (PIP-IU-Y). A cognitive-based therapy approach was adopted. A total of 45 secondary students from four schools completed the intervention program that was conducted in a group format by registered school counselors. Three sets of self-reported data on Problematic Internet Use Questionnaire (PIUQ), Social Interaction Anxiety Scale (SIAS), and Depression Anxiety Stress Scale (DASS) were collected at three time points: 1 week before the intervention, immediately after the last intervention session, and 1 month after the intervention. Paired t-test results showed that the program was effective in preventing negative progression into more serious Internet addiction stages, and reducing anxiety and stress and interaction phobia of the participants. The effect was evident immediately at the end of the intervention session and was maintained 1 month after the intervention. This study is among the first to develop and test a preventive intervention program for youths with PIU. The effectiveness of our program in preventing negative progression of PIU and its symptoms in problematic users has led us to postulate that the program will also prevent normal users from developing serious symptoms. The majority of the intervention programs reported in the literature merely tailor to those who already have problems.


A High-Throughput Screening Platform Identifies Novel Combination Treatments for Malignant Peripheral Nerve Sheath Tumors.
Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that are the leading cause of mortality in patients with Neurofibromatosis type 1 (NF1). Single chemotherapeutic agents have shown response rates ranging from 18% to 44% in clinical trials, so there is still a high medical need to identify chemotherapeutic combination treatments that improve clinical prognosis and outcome. We screened a collection of compounds from the NCATS Mechanism Interrogation PlatE (MIPE) library in three MPNST cell lines, using cell viability and apoptosis assays. We then tested whether compounds that were active as single agents were synergistic when screened as pairwise combinations. Synergistic combinations in vitro were further evaluated in patient-derived orthotopic xenograft/orthoxenograft (PDOX) athymic models engrafted with primary MPNST matching with their paired primary-derived cell line where synergism was observed. The high-throughput screening identified 21 synergistic combinations, from which four exhibited potent synergies in a broad panel of MPNST cell lines. One of the combinations, MK-1775 with Doxorubicin, significantly reduced tumor growth in a sporadic PDOX model (MPNST-SP-01; sevenfold) and in an NF1-PDOX model (MPNST-NF1-09; fourfold) and presented greater effects in TP53 mutated MPNST cell lines. The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume in vivo at noncytotoxic doses. Our results support the utility of our screening platform of in vitro and in vivo models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacologic option for the treatment of these tumors.


Recovery from Repeated Sudden Hearing Loss in a Patient with Takayasu's Arteritis Treated with Hyperbaric Oxygen Therapy: The First Report in the Literature.
Hearing loss has been rarely reported in Takayasu's arteritis, may present as Sudden Sensorineural Hearing Loss, and usually responds well to corticosteroid therapy. Hyperbaric Oxygen Therapy is commonly used as a supplementary treatment to corticosteroids for Sudden Sensorineural Hearing Loss. We present the case of a 36-year-old woman with Takayasu's arteritis who had two episodes of sudden hearing loss involving one ear at a time with an 11-month delay between each episode. During the first episode, the patient was treated with high-dose intramuscular corticosteroids with a temporary improvement of auditory threshold that deteriorated 14 days after cessation of therapy. In the second episode, Hyperbaric Oxygen Therapy was associated with corticosteroids, with improvements in both ears, including the one that was unresponsive in the long term to previous pharmacologic therapy. In this case, Hyperbaric Oxygen Therapy could have acted synergically with corticosteroids playing a role in hearing restoration.


Predictors of reperfusion delay in patients with ST elevation myocardial infarction self-transported to the hospital (from the American Heart Association's Mission: Lifeline Program).
Primary percutaneous coronary intervention for ST elevation myocardial infarction (STEMI) is beneficial if performed in a timely manner. Self-transport patients with STEMI have prolonged treatment times compared with Emergency Medical Services-transported patients. This study evaluated self-transport patients with STEMI undergoing primary percutaneous coronary intervention to identify factors associated with prolonged door-to-balloon (D2B) times. From January 2007 to March 2011, data for 13,379 self-transport patients with STEMI treated at 432 hospitals in the Acute Coronary Treatment Intervention Outcomes Network Registry-Get With The Guidelines Registry were evaluated. Patients with a D2B time >90 minutes were compared with those with D2B time ≤90 minutes. Factors associated with prolonged D2B (>90 minutes) were explored using logistic generalized estimating equations. The median (twenty-fifth, seventy-fifth percentiles) D2B time for the entire cohort was 72 minutes (58, 86), and 19% had a D2B time of >90 minutes. Over the study period, there was a significant increase in the percentage of patients achieving D2B time ≤90 minutes. There were significant baseline differences between patients with D2B time ≤ versus >90 minutes. The main factors associated with prolonged treatment time were off-hour presentation (weekends and 7 p.m. to 7 a.m. weekdays), not obtaining an electrocardiogram within 10 minutes of hospital arrival, previous coronary artery bypass surgery, black race, older age, and female gender. In conclusion, although prolonged delay from arrival to electrocardiographic acquisition is a modifiable factor contributing to prolonged D2B times among self-transport patients with STEMI, additional factors (age, race, and gender) indicate that historic disparities for cardiovascular care still persist in terms of contemporary metrics for STEMI reperfusion.


In The Affordable Care Act's Shadow: The Fate Of The Children's Health Insurance Program.
The Children's Health Insurance Program (CHIP) is a success story. CHIP has contributed greatly to ensuring affordable insurance and access to medical services for millions of children. The 2015 two-year extension of CHIP funding appeared to confirm its longstanding status as a bipartisan program. Yet that appearance obscures important changes in CHIP politics. In recent years, there have been calls to end the program, and its bipartisan coalition has frayed. In this article we analyze CHIP's funding extension, explore its shifting political environment, and discuss the implications for the program's future.


Setting time and expansion in different soaking media of experimental accelerated calcium-silicate cements and ProRoot MTA.
The setting time and the expansion in deionized water, phosphate-buffered saline (PBS), 20% fetal bovine serum (FBS)/80% PBS or hexadecane oil of experimental accelerated calcium-silicate cements and ProRoot MTA were evaluated. Different compounds such as sodium fluoride, strontium chloride, hydroxyapatite, and tricalcium phosphate were separately added to a basic experimental calcium-silicate cement to test their effect on setting and expansion. The initial and final setting times were determined using appropriate Gilmore needles. A linear variable differential transformer (LVDT) device was used to test the restricted hygroscopic linear expansion over 180 minutes of cements immersed in different solutions. Results were statistically compared using a 2-way ANOVA test (cement type versus solution type). All experimental cements showed initial setting times between 28 and 45 minutes and final setting times between 52 and 80 minutes. MTA showed a final setting time of 170 minutes. Final setting time of all experimental cements was faster than MTA. All cements showed slight (0.04%-0.77%) expansion in water, PBS, or FBS/PBS. Only fluoride-containing cement showed a significant expansion in water (6.68%) and in PBS (6.72%). The PBS/FBS contamination significantly reduced the expansion of fluoride-containing cement (2.98%) and MTA (0.07%). In contrast, cements showed a slight shrinkage when immersed in hexadecane, especially fluoride-containing cement. The study demonstrated that: (1) the setting time of calcium-silicate cements may be effectively reduced; (2) the expansion is a water dependent mechanism owing to water uptake, because no expansion occurred in cements immersed in oil; (3) a correlation between setting time and expansion in water and PBS exists; (4) fluorine-containing cement showed a significant expansion in water and in PBS; (5) the immersion in FBS/PBS strongly reduced the expansion of MTA and fluoride-doped cement suggesting that fluid contamination (ie, blood) during surgical procedures may greatly affect the expansion of some calcium-silicate cements.


Design of MARQUIS2: study protocol for a mentored implementation study of an evidence-based toolkit to improve patient safety through medication reconciliation.
The first Multi-center Medication Reconciliation Quality Improvement Study (MARQUIS1) demonstrated that implementation of a medication reconciliation best practices toolkit decreased total unintentional medication discrepancies in five hospitals. We sought to implement the MARQUIS toolkit in more diverse hospitals, incorporating lessons learned from MARQUIS1. MARQUIS2 is a pragmatic, mentored implementation QI study which collected clinical and implementation outcomes. Sites implemented a revised toolkit, which included interventions from these domains: 1) best possible medication history (BPMH)-taking; 2) discharge medication reconciliation and patient/caregiver counseling; 3) identifying and defining clinician roles and responsibilities; 4) risk stratification; 5) health information technology improvements; 6) improved access to medication sources; 7) identification and correction of real-time discrepancies; and, 8) stakeholder engagement. Eight hospitalists mentored the sites via one site visit and monthly phone calls over the 18-month intervention period. Each site's local QI team assessed opportunities to improve, implemented at least one of the 17 toolkit components, and accessed a variety of resources (e.g. implementation manual, webinars, and workshops). Outcomes to be assessed will include unintentional medication discrepancies per patient. A mentored multi-center medication reconciliation QI initiative using a best practices toolkit was successfully implemented across 18 medical centers. The 18 participating sites varied in size, teaching status, location, and electronic health record (EHR) platform. We introduce barriers to implementation and lessons learned from MARQUIS1, such as the importance of utilizing dedicated, trained medication history takers, simple EHR solutions, clarifying roles and responsibilities, and the input of patients and families when improving medication reconciliation.


Pharmacologic treatment of constipation: what is new?
Constipation is a common gastrointestinal disease affecting 2-27% of the population in Western hemisphere. Approximately in half of patients the diagnosis of functional constipation is made after having ruled out secondary causes. Treatment of chronic functional constipation primarily addresses education on toilet habits, dietary advice, and patient reassurance. Further therapies are guided according to functional subtype slow-transit constipation, dyssynergic defecation, and constipation-predominant irritable bowel syndrome (IBS-C). Traditionally, the pharmacologic treatment of constipation uses primarily bulking agents and/or laxatives (osmotic or secretory). However, often these therapies do not provide the desired improvement, have a short-lived efficacy and/or are accompanied by side-effects such as bloating and abdominal cramps. Thus, there is a clinical need for new, more potent drugs particularly for patients who are not satisfactorily treated by conventional therapies. This review discusses recent developments in the pharmacologic treatment of chronic constipation including recently FDA-approved lubiprostone, emerging 5-HT receptors modifiers, investigational substances, and probiotics.


Falls From the O.R. or Procedure Table.
Patient safety secured by constant vigilance remains a primary responsibility of every anesthesia professional. Although significant attention has been focused on patient falls occurring before and after surgery, a potentially catastrophic complication is when patients fall off an operating room or procedure table during anesthesia care. Because such events are (fortunately) uncommon, and because very little information is published in our literature, we queried 2 independent closed claims databases (the American Society of Anesthesiologists Closed Claims Project and the secure records of a private, anesthesia specialty-specific liability insurer) for information. We acquired documentation of patient events where a fall occurred during anesthesia care, noting the surrounding conditions of the provider, the patient, and the environment at the time of the event. We identified 21 claims (1.2% of cases) from the American Society of Anesthesiologists Closed Claims Project, while information from a private liability insurer identified falls in only 0.07% of cases. The percentage of these patients under general, regional, or monitored anesthesia care anesthesia was 71.5%, 19.5%, and 9.5%, respectively. To educate personnel about these uncommon events, we summarized this cohort with illustrative examples in a series of mini-case reports, noting that both inpatients and outpatients undergoing a broad array of procedures with various anesthetic techniques within and outside operating rooms may be vulnerable to patient falls. Based on detailed reports, we created 2 supplementary videos to further illuminate some of the unique mechanisms by which these events and their resulting injuries occur. When such information was available, we also noted the associated liability costs of defending and settling malpractice claims associated with these events. Our goal is to inform anesthesia and perioperative personnel about the common patient, provider, and environmental risk factors that appear to contribute to these mishaps, and suggest key strategies to mitigate the risks.


Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.
Alterations in glutamatergic neurotransmission may be fundamental to the pathophysiology of schizophrenia, and the glutamatergic system is a target for novel therapeutic interventions in the disorder. To investigate the nature of brain glutamate alterations in schizophrenia by conducting a meta-analysis of glutamate proton magnetic resonance (MRS) spectroscopy studies. The MEDLINE database was searched for studies published from January 1, 1980, to April 1, 2015. Search terms included magnetic resonance spectroscopy, schizophrenia, psychosis, clinical or genetic high risk, and schizoaffective. Inclusion criteria were single voxel 1H-MRS studies reporting glutamate, glutamine or Glx values for a patient or risk group in comparison to a healthy volunteer group. Fifty-nine studies were identified, which included 1686 patients and 1451 healthy individuals serving as controls. A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were determined for glutamate, glutamine, and Glx in brain regions that had been examined in at least 3 different studies. A secondary analysis grouped studies into those examining patients at different stages of illness (high risk, first-episode psychosis, or chronic schizophrenia). Effects of age, antipsychotic dose, and symptom severity were determined using meta-regression. In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus (g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia (g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe (g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in individuals at high risk for schizophrenia (g = 0.26; 95% CI, 0.05-0.46) but not in those with first-episode psychosis or chronic schizophrenia, whereas elevated Glx in the medial temporal lobe was seen with chronic schizophrenia (g = 0.40; 95% CI, 0.08-0.71) but not in the high-risk or first-episode groups. Meta-regression found no association with age, symptom severity, or antipsychotic dose. Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.


The murine Hox-2 cluster of homeo box containing genes maps distal on chromosome 11 near the tail-short (Ts) locus.
Two probes derived from a mouse recombinant lambda-clone (H24.1), that contains a sequence closely homologous to the Drosophila antennapedia homeo box, were mapped to mouse chromosome (MMU) 11 by filter hybridization of somatic cell hybrid DNA. This sequence is highly homologous to a human homeo box gene (HOX2) and appears to represent one of the two genes in the Hox-2 cluster previously assigned to MMU 11. To regionally map the Hox-2 cluster, we have carried out in situ hybridization of the two H24.1 probes and of an independently isolated Hox-2 probe. The autoradiographic silver grain distributions were similar in all three experiments with a peak over band 11D. This region contains the locus for the tail-short (Ts) mutation which causes skeletal abnormalities in heterozygotes and early embryonic death in homozygotes.


Why and how to include parents in the treatment of adolescents presenting Internet gaming disorder?
Clinicians and researchers are increasingly interested in investigating excessive use of video gaming recently named Internet gaming disorder (IGD). As is the case with extensively researched adolescent problem behaviors such as substance use disorder, several studies associate IGD with the young person's family environment and the parent-adolescent relationship in particular. Evidence-based treatments for a range of adolescent clinical problems including behavioral addictions demonstrate efficacy, the capacity for transdiagnostic adaptation, and lasting impact. However, less attention has been paid to developing and testing science-based interventions for IGD, and at present most tested interventions for IGD have been individual treatments (cognitive behavioral therapy). This article presents the rationale for a systemic conceptualization of IGD and a therapeutic approach that targets multiple units or subsystems. The IGD treatment program is based on the science-supported multidimensional family therapy approach (MDFT). Following treatment development work, the MDFT approach has been adapted for IGD. The article discusses recurring individual and family-based clinical themes and therapeutic responses in the MDFT-IGD clinical model, which tailors interventions for individuals and subsystems within the young person's family. Basic science developmental research can inform conceptualization of IGD and a systemic logic model of intervention and change. This paper aims to expand treatment theorizing and intervention approaches for practitioners working with frequently life-altering behaviors of excessive Internet gaming. We operationalize this aim by addressing the question of why and how parents should be involved in youth IGD treatment.


Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.
Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.