Assessing the Consequences of Implementing Graphic Warning Labels on Cigarette Packs for Tobacco-Related Health Disparities.
Population-level communication interventions, such as graphic warning labels (GWLs) on cigarette packs, have the potential to reduce or exacerbate tobacco-related health disparities depending on their effectiveness among disadvantaged sub-populations. This study evaluated the likely impact of nine GWLs proposed by the US Food and Drug Administration on (1) African American and (2) Hispanic smokers, who disproportionately bear the burden of tobacco-related illness, and (3) low education smokers, who have higher smoking rates. Data were collected online from current smokers randomly assigned to see GWLs (treatment) or the current text-only warning labels (control). Participants were stratified by age (18-25; 26+) in each of four groups: general population (n = 1246), African Americans (n = 1200), Hispanics (n = 1200), and low education (n = 1790). We tested the effectiveness of GWLs compared to text-only warning labels using eight outcomes that are predictive of quitting intentions or behaviors including negative emotion, intentions to hold back from smoking, intentions to engage in avoidance behaviors, and intentions to quit. Across all outcomes, GWLs were significantly more effective than text-only warning labels more often than expected by chance. Results suggested that African Americans, Hispanics and smokers with low education did not differ from the general population of smokers in their reactions to any of the nine individual GWLs. The nine GWLs were similarly effective for disadvantaged sub-populations and the general population of smokers. Implementation of GWLs is therefore unlikely to reduce or exacerbate existing tobacco-related health disparities, but will most likely uniformly increase intentions and behaviors predictive of smoking cessation.


Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance.
Statins are potent inhibitors of hydroxyl-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, and have emerged as potential anti-cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)-10, transforming growth factor (TGF)-beta and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (T(reg)) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-beta and IDO production and the proliferation of T(regs) using several cancer cell lines, and Lewis lung cancer (3LL) cells-inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI-H292). The production of the immune regulatory markers IL-10, TGF-beta in 3LL and NCI-H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin-treated mice groups. Therefore, while simvastatin had an anti-proliferative effect, it also exhibited immune tolerance-promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth.


Microbial gene identification using interpolated Markov models.
This paper describes a new system, GLIMMER, for finding genes in microbial genomes. In a series of tests on Haemophilus influenzae , Helicobacter pylori and other complete microbial genomes, this system has proven to be very accurate at locating virtually all the genes in these sequences, outperforming previous methods. A conservative estimate based on experiments on H.pylori and H. influenzae is that the system finds >97% of all genes. GLIMMER uses interpolated Markov models (IMMs) as a framework for capturing dependencies between nearby nucleotides in a DNA sequence. An IMM-based method makes predictions based on a variable context; i.e., a variable-length oligomer in a DNA sequence. The context used by GLIMMER changes depending on the local composition of the sequence. As a result, GLIMMER is more flexible and more powerful than fixed-order Markov methods, which have previously been the primary content-based technique for finding genes in microbial DNA.


Nanoscale spatial dependence of avidity in an IgG1 antibody.
Antibodies are secreted proteins that are crucial to recognition of pathogens by the immune system and are also efficient pharmaceuticals. The affinity and specificity of target recognition can increase remarkably through avidity effects, when the antibody can bind a multivalent antigen through more than one epitope simultaneously. A key goal of antibody engineering is thus to optimize avidity, but little is known about the nanoscale spatial dependence of avidity in antibodies. Here, we develop a set of anti-parallel coiled-coils spanning from 7 to 20 nm and validate their structure using biophysical techniques. We use the coiled-coils to control the spacing between two epitopes, and measure how antigen spacing affects the stability of the bivalent antibody:antigen complex. We find a maximal avidity enhancement at a spacing of 13 nm. In contrast to recent studies, we find the avidity to be relatively insensitive to epitope spacing near the avidity maximum as long as it is within the spatial tolerance of the antibody. We thus only see a ~ twofold variation of avidity in the range from 7 to 20 nm. The coiled-coil systems developed here may prove a useful protein nanocaliper for profiling the spatial tolerance and avidity profile of bispecific antibodies.


D-TACC: a novel centrosomal protein required for normal spindle function in the early Drosophila embryo.
We identify Drosophila TACC (D-TACC) as a novel protein that is concentrated at centrosomes and interacts with microtubules. We show that D-TACC is essential for normal spindle function in the early embryo; if D-TACC function is perturbed by mutation or antibody injection, the microtubules emanating from centrosomes in embryos are short and chromosomes often fail to segregate properly. The C-terminal region of D-TACC interacts, possibly indirectly, with microtubules, and can target a heterologous fusion protein to centrosomes and microtubules in embryos. This C-terminal region is related to the mammalian transforming, acidic, coiled-coil-containing (TACC) family of proteins. The function of the TACC proteins is unknown, but the genes encoding the known TACC proteins are all associated with genomic regions that are rearranged in certain cancers. We show that at least one of the mammalian TACC proteins appears to be associated with centrosomes and microtubules in human cells. We propose that this conserved C-terminal 'TACC domain' defines a new family of microtubule-interacting proteins.


The contemporary role and impact of urine-based biomarkers in bladder cancer.
Despite advances in the surgical and medical treatment of bladder cancer, there have only been minor improvements in mortality and morbidity rates over the past decades. Urine-based markers help to improve diagnosing bladder cancer with the aim of complementing or probably in future replacing cystoscopy. Biomarkers may allow individualized risk stratification and support decision-making regarding therapy and follow-up. This review summarizes the existing urine-based biomarkers in bladder cancer. We conducted a comprehensive review of the literature. We conducted a PubMed/Medline based research on English language articles and selected original articles and review articles that provided both description and assessment of urinary markers at time of screening, initial diagnosis, monitoring and prognostic evaluation of urothelial bladder cancer. Our research covered studies published between 2000 and 2017. The aim of this study was to give clinicians keys to understand the existing or promising urinary markers that may become alternatives to cytology/cystoscopy pair in the near future. Many urinary markers are now available, often with superior sensitivity to cytology. Their uses have been evaluated in numerous clinical situations in addition to the time of initial diagnosis and surveillance such as cases of isolated macroscopic hematuria or atypical cytology discordant with the rest of the explorations. However, their superiority over the cytology/cystoscopy association is not demonstrated. These new markers are lacking for the most part of standardization and simplicity making their use in common practice difficult. the types and forms of these new markers are very heterogeneous among themselves and between the studies that evaluate them. Well-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of urine- and blood-based biomarkers into clinical decision-making will be of value for bladder cancer detection and screening in the future.


Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study.
To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status. In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis. Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33·0%] of 379 patients) and enthesitis-related arthritis (113 [29·8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56·7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31·5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19·1%] of 845 patients) and southern Europe (450 [18·8%] of 2400) and lowest in Latin America (54 [6·4%] of 849), Africa and Middle East (71 [5·9%] of 1209), and southeast Asia (19 [5·0%] of 379). Median age at disease onset was lower in southern Europe (3·5 years, IQR 1·9-7·3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lower-resource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis. IRCCS Istituto Giannina Gaslini.


EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria.
An autoimmune subset of chronic spontaneous urticaria is increasingly being recognized internationally, based on laboratory and clinical evidence that has accrued over the last 20 years. This evidence has been reviewed by a taskforce of the Dermatology section of the European Academy of Allergy and Clinical Immunology. Functional autoantibodies in chronic urticaria (CU) patient sera have been demonstrated against IgE and FcεRIα by basophil and mast cell histamine release assays and by basophil activation assays. Antibody specificity has been confirmed by immunoassay, but there is a poor correlation between functionality and immunoreactivity. Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Functionality of CU sera appears to be complement dependent on mast cells but not exclusively on basophils. Basophil activation by CU sera is predominantly restricted to IgG1 and IgG3 subclasses. Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA-DR4 haplotype and the good response of CU patients to immunotherapies. It was proposed that a study should be undertaken to prospectively validate potentially relevant clinical criteria (from the history, examination and routinely available clinical investigations) against a new 'gold standard' for the diagnosis of ACU (positive autoreactivity, functional bioassay and immunoassay) to define preliminary criteria sets for the diagnosis of ACU based on clinical and laboratory features with highest individual sensitivity and specificity.


Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium.
Nonoxynol-9 (N-9) containing spermicides and other N-9 containing products are commonly used as lubricants during rectal intercourse. We have previously demonstrated that rectal application of N-9 products in mice can cause exfoliation of epithelial cells, increasing the probability of infection by HSV-2. To determine if N-9-containing products would have a similar effect on the rectal epithelium in humans, the application of K-Y Plus and ForPlay, both over-the-counter (OTC) N-9 products, were compared to the application of two formulations, carrageenan and methyl cellulose, that do not contain N-9. The effects of each formulation were evaluated in 4 human participants. Light and electron microscope examination of rectal lavage specimens collected 15 min post application of N-9 products revealed the presence of sheets of epithelium. Each sheet contained hundreds of epithelial cells that included columnar and goblet cells, varieties of cells typical of rectal epithelial morphology. Sheets of epithelium were not observed in rectal lavage specimens collected 8 to 12 hr post N-9 product use or in either of the timed lavages involving non-N-9 containing formulations. In addition, no sheets of epithelial cells were observed in the baseline lavage specimens. We conclude that the rectal use of N-9-containing products causes a rapid exfoliation of extensive areas of the rectal epithelium. Exfoliation of the epithelium is no longer observed at 8 hr. It is reasonable to assume that the loss of the protective epithelium would render a person more at risk for infection by HIV and other sexually transmitted pathogens. We, therefore, caution against the use of N-9-containing products during rectal intercourse.


Multilevel factorial experiments for developing behavioral interventions: power, sample size, and resource considerations.
Factorial experimental designs have many potential advantages for behavioral scientists. For example, such designs may be useful in building more potent interventions by helping investigators to screen several candidate intervention components simultaneously and to decide which are likely to offer greater benefit before evaluating the intervention as a whole. However, sample size and power considerations may challenge investigators attempting to apply such designs, especially when the population of interest is multilevel (e.g., when students are nested within schools, or when employees are nested within organizations). In this article, we examine the feasibility of factorial experimental designs with multiple factors in a multilevel, clustered setting (i.e., of multilevel, multifactor experiments). We conduct Monte Carlo simulations to demonstrate how design elements-such as the number of clusters, the number of lower-level units, and the intraclass correlation-affect power. Our results suggest that multilevel, multifactor experiments are feasible for factor-screening purposes because of the economical properties of complete and fractional factorial experimental designs. We also discuss resources for sample size planning and power estimation for multilevel factorial experiments. These results are discussed from a resource management perspective, in which the goal is to choose a design that maximizes the scientific benefit using the resources available for an investigation.


Re-conceptualizing ASD Within a Dimensional Framework: Positive, Negative, and Cognitive Feature Clusters.
Introduction of the National Institute of Mental Health's Research Domain Criteria and revision of diagnostic classification for Autism Spectrum Disorder in the latest diagnostic manual call for a new way of conceptualizing heterogeneous ASD features. We propose a novel conceptualization of ASD, borrowing from the schizophrenia literature in clustering ASD features along positive, negative, and cognitive dimensions. We argue that this dimensional conceptualization can offer improved ability to classify, diagnose, and treat, to apply and predict response to treatment, and to explore underlying neural and genetic alterations that may contribute to particular feature clusters. We suggest the proposed conceptualization can advance the field in a manner that may prove clinically and biologically useful for understanding and addressing heterogeneity within ASD.


Computed Tomography and Optical Imaging of Osteogenesis-angiogenesis Coupling to Assess Integration of Cranial Bone Autografts and Allografts.
A major parameter determining the success of a bone-grafting procedure is vascularization of the area surrounding the graft. We hypothesized that implantation of a bone autograft would induce greater bone regeneration by abundant blood vessel formation. To investigate the effect of the graft on neovascularization at the defect site, we developed a micro-computed tomography (µCT) approach to characterize newly forming blood vessels, which involves systemic perfusion of the animal with a polymerizing contrast agent. This method enables detailed vascular analysis of an organ in its entirety. Additionally, blood perfusion was assessed using fluorescence imaging (FLI) of a blood-borne fluorescent agent. Bone formation was quantified by FLI using a hydroxyapatite-targeted probe and µCT analysis. Stem cell recruitment was monitored by bioluminescence imaging (BLI) of transgenic mice that express luciferase under the control of the osteocalcin promoter. Here we describe and demonstrate preparation of the allograft, calvarial defect surgery, µCT scanning protocols for the neovascularization study and bone formation analysis (including the in vivo perfusion of contrast agent), and the protocol for data analysis. The 3D high-resolution analysis of vasculature demonstrated significantly greater angiogenesis in animals with implanted autografts, especially with respect to arteriole formation. Accordingly, blood perfusion was significantly higher in the autograft group by the 7(th) day after surgery. We observed superior bone mineralization and measured greater bone formation in animals that received autografts. Autograft implantation induced resident stem cell recruitment to the graft-host bone suture, where the cells differentiated into bone-forming cells between the 7(th) and 10(th) postoperative day. This finding means that enhanced bone formation may be attributed to the augmented vascular feeding that characterizes autograft implantation. The methods depicted may serve as an optimal tool to study bone regeneration in terms of tightly bounded bone formation and neovascularization.


A kernel machine method for detecting effects of interaction between multidimensional variable sets: an imaging genetics application.
Measurements derived from neuroimaging data can serve as markers of disease and/or healthy development, are largely heritable, and have been increasingly utilized as (intermediate) phenotypes in genetic association studies. To date, imaging genetic studies have mostly focused on discovering isolated genetic effects, typically ignoring potential interactions with non-genetic variables such as disease risk factors, environmental exposures, and epigenetic markers. However, identifying significant interaction effects is critical for revealing the true relationship between genetic and phenotypic variables, and shedding light on disease mechanisms. In this paper, we present a general kernel machine based method for detecting effects of the interaction between multidimensional variable sets. This method can model the joint and epistatic effect of a collection of single nucleotide polymorphisms (SNPs), accommodate multiple factors that potentially moderate genetic influences, and test for nonlinear interactions between sets of variables in a flexible framework. As a demonstration of application, we applied the method to the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to detect the effects of the interactions between candidate Alzheimer's disease (AD) risk genes and a collection of cardiovascular disease (CVD) risk factors, on hippocampal volume measurements derived from structural brain magnetic resonance imaging (MRI) scans. Our method identified that two genes, CR1 and EPHA1, demonstrate significant interactions with CVD risk factors on hippocampal volume, suggesting that CR1 and EPHA1 may play a role in influencing AD-related neurodegeneration in the presence of CVD risks.


[Vagueness and the directionality of verbal probability expressions: the properties of probability information and their effects on decision making].
We examined the relationship between two properties of verbal probability (VP) expressions, "vagueness" and "directionality", and investigated the effects of these properties on decision making. Vagueness is defined as its imprecise characteristic of uncertainty expressions in VP, whereas the directionality is communicative functions which cause one to focus on the occurrence or non-occurrence of the target event described by VP. Experiment 1 contrasted a disagreement in the literature as to whether one can predict the directionality from vagueness properties, and our analyses resolved the conflict by showing the ineffectiveness of the vagueness in predicting the directionality. Experiment 2 administered decision tasks involving VP and numerical translation tasks of VP. We discovered that the directionality affects only on decision tasks. The results of Experiments 1 and 2 indicated that the directionality is distinct characteristic from the vagueness of VP, and these properties affect decisions independently. Implications are discussed.


Determination of pore space shape and size in porous systems using NMR diffusometry. Beyond the short gradient pulse approximation.
The influence of finite length gradient pulses on NMR diffusion experiments on liquids confined to diffuse between two parallel planes is investigated. It is experimentally verified that the pore size decreases when determined using finite gradient pulses if the results are analyzed within the short gradient pulse approximation. The results are analyzed using the matrix formulation. The observed minima in the echo decay profiles are considerably less sharp than theoretical analysis would indicate and we suggest that this is due to the presence of a distribution of pore sizes in the sample. In addition, effects due to the presence of background gradients are discussed. It is argued that effects due to the finite length gradient pulses are relatively minor and in realistic applications the effects due to inhomogeneities in pore sizes and effects due to background gradients will constitute more serious problems in pore size determinations by means of NMR diffusometry.


Functionalization of titanium oxide surfaces by means of poly(alkyl-phosphonates).
The use of a multiple attachment sites strategy is considered in order to improve the stability of monomolecular adlayers. The hypothesis was tested in the case of PEG-ylated compounds carrying phosphonate groups, known for their affinity toward titanium oxide surfaces. As a result, a new class of co- and terpolymers were synthesized by free-radical polymerization of three different monomers: dialkyl(methacryloyloxyalkyl)phosphonates, PEG methyl ether methacrylate, and/or butyl methacrylate monomers. Adlayers were formed following a simple dip-and-rinse protocol using diluted aqueous polymer solutions and were characterized by evaluating their thicknesses with variable angle spectroscopic ellipsometry (VASE) and their elemental compositions with X-ray photoelectron spectroscopy (XPS). The same techniques were used to determine changes of the adlayer as a function of exposure to electrolytes at different pH values and to monitor nonspecific protein adsorption upon serum exposures. The results indicated that the poly(alkyl-phosphonate)-based adlayers combine multiple site attachment of phosphonic groups and presentation of PEG side chains to the aqueous environment, resulting in both improved stability over a wide pH range in comparison to the tested reference surfaces and excellent resistance to protein adsorption when exposed to full human serum.


An Overview of Sleep as an Experimental Variable (1940-1959).
Less than one half of 1 percent of the psychological literature relates to sleep. Although there has been a relative decline in such research, the central nervous system and pathological aspects have recently received increased attention. The United States is producing less than 17 percent of the research on sleep.


[Patient-related independent clinical risk factors for early complications following interventional pulmonology procedures].
To investigate the early complication rate and identify patient-related independent clinical risk factors for early complications in patients following interventional pulmonology procedures. In the period from December 2014 to December 2015, sufficient data of Peking University First Hospital Respiratory and Critical Care Medicine Department for analysis were identified in 218 subjects. Interventional pulmonology procedures were performed in all the patients. Early complications after the procedures were defined as newly respiratory failure, arrhythmia requiring treatment, severe hemoptysis, pneumothorax, pneumomediastinum, pulmonary edema, tracheoesophageal fistulae, bronchopleural fistulae, acute coronary syndrome, acute cerebrovascular accident, and death. Patient-related clinical risk factors were defined as coronary atherosclerotic heart disease, cerebral infarction, diabetes mellitus, cirrhosis, chronic kidney disease, arrhythmia, asthma, chronic obstructive pulmonary disease, hypertension, and previous interventional pulmonology treatment. The patient-related independent clinical risk factors which had close relations to the occurrence of early complications were analyzed by multivariate statistical analysis with Logistic regression. There were 56.4% male and 43.6% female subjects in this study. There were 10.6% current smokers, 26.6% former smokers, and 62.8% non-smokers. The overall early complication rate was 8.3%. In all the subjects groups, the patient-related independent clinical risk factors for the early complication rate were coronary atherosclerotic heart disease (B=1.545, P=0.006, OR=4.686, 95% CI 1.568-14.006), chronic obstructive pulmonary disease (B=1.037, P=0.049, OR=2.820, 95% CI 1.675-11.790), and current smoking status (B=1.412, P=0.032, OR=4.139, 95% CI 1.134-15.109); for the newly respiratory failure rates were coronary atherosclerotic heart disease (B=2.207, P=0.004, OR=9.087, 95% CI 2.028-40.714), chronic obstructive pulmonary disease (B=1.646, P=0.048, OR=5.188, 95% CI 1.783-34.375), and lesions involving three central airways (B=1.899, P=0.032, OR=6.680, 95% CI 1.182-37.740). In the malignant group, the patient-related independent clinical risk factor for the early complication rate was current smoking status (B=2.953, P=0.006, OR=19.161, 95% CI 2.360-155.572). In the benign group, the patient-related independent clinical risk factor for the early complication rate was only coronary atherosclerotic heart disease (B=1.976, P=0.022, OR=7.214, 95% CI 1.324-39.298). Closer monitoring of patients with identified clinical risk factors is advisable prior and immediately after interventional pulmonology procedures. In order to avoid or minimize early complications, special attention should be directed toward patients who are current smokers, or patients with lesions involving three central airways, or with coronary atherosclerotic heart disease or chronic obstructive pulmonary disease.


Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.
Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs. To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs. PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model. Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events. Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001). In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.


Structural basis for the drug extrusion mechanism by a MATE multidrug transporter.
Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H(+) or Na(+) across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H(+)-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1-3.0 Å resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.


Clinical characterization of Lassa fever: A systematic review of clinical reports and research to inform clinical trial design.
Research is urgently needed to reduce the morbidity and mortality of Lassa fever (LF), including clinical trials to test new therapies and to verify the efficacy and safety of the only current treatment recommendation, ribavirin, which has a weak clinical evidence base. To help establish a basis for the development of an adaptable, standardised clinical trial methodology, we conducted a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has historically been defined and assessed in the scientific literature. Primary clinical studies and reports of patients with suspected and confirmed diagnosis of LF published in the peer-reviewed literature before 15 April 2021 were included. Publications were selected following a two-stage screening of abstracts, then full-texts, by two independent reviewers at each stage. Data were extracted, verified, and summarised using descriptive statistics. 147 publications were included, primarily case reports (36%), case series (28%), and cohort studies (20%); only 2 quasi-randomised studies (1%) were found. Data are mostly from Nigeria (52% of individuals, 41% of publications) and Sierra Leone (42% of individuals, 31% of publications). The results corroborate the World Health Organisation characterisation of LF presentation. However, a broader spectrum of presenting symptoms is evident, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. The overall case fatality ratio was 30% in laboratory-confirmed cases (1896/6373 reported in 109 publications). Systematic review is an important tool in the clinical characterisation of diseases with limited publications. The results herein provide a more complete understanding of the spectrum of disease which is relevant to clinical trial design. This review demonstrates the need for coordination across the LF research community to generate harmonised research methods that can contribute to building a strong evidence base for new treatments and foster confidence in their integration into clinical care.


Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital.
Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs. A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring. A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001). OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.


How do methods of non-fatal self-harm relate to eventual suicide?
Methods used at an index episode of non-fatal self-harm may predict risk of future suicide. Little is known of suicide risk associated with most recent non-fatal method, and whether or not change in method is important. A prospective cohort of 30,202 patients from the Multicentre Study of Self-harm in England presenting to six hospitals with self-harm, 2000-2007, was followed up to 2010 using national death registers. Risks of suicide (by self-poisoning, self-injury, and all methods) associated with recent method(s) of non-fatal self-harm were estimated using Cox models. Suicide occurred in 378 individuals. Cutting, hanging/asphyxiation, CO/other gas, traffic-related and other self-injury at the last episode of self-harm were associated with 1.8 to 5-fold increased risks (vs. self-poisoning) of subsequent suicide, particularly suicide involving self-injury. All methods of self-harm had similar risks of suicide by self-poisoning. One-third who died by suicide used the same method for their last self-harm and for suicide, including 41% who self-poisoned. No specific sequences of self-poisoning, cutting or other self-injury in the last two non-fatal episodes were associated with suicide in individuals with repeated self-harm. Data were for hospital presentations only, and lacked a suicide intent measure. Method of self-harm may aid identification of individuals at high risk of suicide. Individuals using more dangerous methods (e.g. hanging, CO/other gas) should receive intensive follow-up. Method changes in repeated self-harm were not associated with suicide. Our findings reinforce national guidance that all patients presenting with self-harm, regardless of method, should receive a psychosocial assessment.


Prolactin as a mammalian mitogen and tumor promoter.
Cellular proliferation and differentiation of the mammalian mammary gland requires a medley of hormones including the anterior pituitary hormone, PRL. Recent evidence extends the role of PRL as a mammalian mitogen to cells in several physiological systems not directly involved in reproductive functions, such as liver and lymphocytes. PRL administration induces biochemical markers expressed during the G1 phase of cell cycle and activates DNA synthesis in rat liver. Chronic PRL treatment causes hepatomegaly, reflecting its stimulation of the proliferative process. In vitro, a lactogen-dependent cell line, the Nb2 rat node lymphoma cell, serves as a useful paradigm to study PRL action on mitogenesis. These cells, when cultured in the presence of lactogens, proliferate in a dose-dependent manner. The effects of various pharmacological agents on discrete phases of the cell cycle may be readily assessed in these cells since PRL-stimulated entry into cycle is signalled by an elevation of ODC activity at 6 hr and entry into S-phase at 6-12 hr. The parallel effects of phorbol ester tumor promoters and PRL on cell cycle progression in Nb2 lymphoma cells and in hepatic proliferation suggest that PRL may likewise mediate proliferation in aberrant growth conditions such as neoplasia. The data presented support the hypothesis that PRL is capable of promoting hepatocarcinogenesis. Its chronic administration after a hepatic initiating agent stimulated the development of histochemical and biochemical markers characteristic of preneoplasia. Further, the effect of PRL was comparable to that of the hepatocarcinogen when either was administered alone. Thus, hyperprolactinemia may serve to promote the development of hepatic tumors. Phorbol esters are thought to promote tumorigenesis by directly activating PKC. In the Nb2 lymphoma cell model, tumor promoting phorbol esters mimic the effects of PRL. Similarly, PRL-stimulated enzyme induction in liver is mirrored by phorbol ester treatment, and inhibitors of PKC block PRL-stimulated mitogenesis in Nb2 cells. Further, PRL or TPA administration to rats causes translocation of PKC activity from the hepatic cytosol to the membrane fraction, reflecting kinase activation. Therefore, PRL activation of PKC appears to be a physiological phenomenon of general significance, occurring as the result of lactogen receptor stimulation and serving to transmit intracellular signals linked to the regulation of mitogenesis. Further study is required to more fully define the scope of PRL-mediated mitogenic actions as well as its effects on the expression of differentiated products in tissues and cells.


Impact of the time window on plasma volume measurement with indocyanine green.
Recent reports have questioned the accuracy of the indocyanine green dilution technique for measuring plasma volume. Our objective was to evaluate the impact of different time windows for monoexponential extrapolation. We retrospectively analysed 31 indocyanine green decay curves to investigate the problem in principle (group 1) and prospectively performed another 21 plasma volume measurements to estimate its practical impact (group 2). To monoexponentially extrapolate back to the specific extinction at the time of dye injection, two different time windows were applied to each decay curve, comparing the plasma volumes resulting from sampling within a short (<or=5 min) versus a longer (>5 min) period of time. Extrapolating back from the longer period led to a higher apparent plasma volume relative to the shorter period in both groups, the difference being 348 +/- 171 ml (group 1) and 384 +/- 131 ml (group 2; mean +/- SD; p < 0.05 each). This result was due to a reliable monoexponentiality of decay only up to the 5th min after dye injection. Thus, to estimate the initial distribution space of indocyanine green via monoexponential extrapolation, the first linear kinetic of indocyanine green decay should be taken.


SURF'S UP! - protein classification by surface comparisons.
Large-scale genome sequencing and structural genomics projects generate numerous sequences and structures for 'hypothetical' proteins without functional characterizations. Detection of homology to experimentally characterized proteins can provide functional clues, but the accuracy of homology-based predictions is limited by the paucity of tools for quantitative comparison of diverging residues responsible for the functional divergence. SURF'S UP! is a web server for analysis of functional relationships in protein families, as inferred from protein surface maps comparison according to the algorithm. It assigns a numerical score to the similarity between patterns of physicochemical features(charge, hydrophobicity) on compared protein surfaces. It allows recognizing clusters of proteins that have similar surfaces, hence presumably similar functions. The server takes as an input a set of protein coordinates and returns files with "spherical coordinates" of proteins in a PDB format and their graphical presentation, a matrix with values of mutual similarities between the surfaces, and the unrooted tree that represents the clustering of similar surfaces, calculated by the neighbor-joining method. SURF'S UP! facilitates the comparative analysis of physicochemical features of the surface, which are the key determinants of the protein function. By concentrating on coarse surface features, SURF'S UP! can work with models obtained from comparative modelling. Although it is designed to analyse the conservation among homologs, it can also be used to compare surfaces of non-homologous proteins with different three-dimensional folds, as long as a functionally meaningful structural superposition is supplied by the user. Another valuable characteristic of our method is the lack of initial assumptions about the functional features to be compared. SURF'S UP! is freely available for academic researchers at http://asia.genesilico.pl/surfs_up/.


Sevoflurane Protects Hepatocytes From Ischemic Injury by Reducing Reactive Oxygen Species Signaling of Hepatic Stellate Cells: Translational Findings Based on a Clinical Trial.
Randomized controlled trials (RCTs) data demonstrate that sevoflurane postconditioning improves clinical outcomes of liver resection with inflow occlusion, presumably due to hepatocyte protection from ischemic injury. However, mechanisms remain unclear. This study examines liver biopsy samples obtained in an RCT of sevoflurane postconditioning to test the hypothesis that sevoflurane attenuates hepatocyte apoptosis. Messenger ribonucleic acid (mRNA) of pro- and antiapoptotic regulators Bax and B-cell lymphoma 2 (Bcl2) was examined in hepatic biopsies obtained during the RCT. Hepatic stellate cells (HSCs) and hepatocytes were exposed to hypoxia/reoxygenation (H/R) in vitro to evaluate the effect of sevoflurane postconditioning on apoptosis. The role of HSC as a potential apoptosis trigger in hepatocytes through the production of reactive oxygen species induced by H/R was explored by transferring supernatants from H/R-exposed HSC to hepatocytes as target cells. In patients of the RCT, the Bax/Bcl2 mRNA ratio in liver tissue was markedly decreased in the sevoflurane arm (25% ± 21% reduction; P = .001). In vitro, H/R increased reactive oxygen species production in HSC by 33% ± 16% (P = .025), while it was abolished in the presence of sevoflurane (P < .001). In hepatocytes, caspase was minimally activated by H/R. However, incubation of hepatocytes with supernatants of HSC, previously exposed to H/R, increased caspase activity by 28% ± 13% (P < .001). When exposed to supernatants from HSC undergoing sevoflurane postconditioning, caspase activation in hepatocytes was reduced by 20% ± 9% (P < .001), similarly to the sevoflurane effect on the BAX/Bcl2 mRNA ratio in the liver samples. The study shows that sevoflurane postconditioning affects apoptosis of hepatocytes after ischemia-reperfusion injury in patients. It also demonstrates that HSC may be the effector cells of sevoflurane protection.


Structure and post-translational modifications of the web silk protein spidroin-1 from Nephila spiders.
Spidroin-1 is one of the major ampullate silk proteins produced by spiders for use in the construction of the frame and radii of orb webs, and as a dragline to escape from predators. Only partial sequences of spidroin-1 produced by Nephila clavipes have been reported up to now, and there is no information on post-translational modifications (PTMs). A gel-based mass spectrometry strategy with ETD and CID fragmentation methods were used to sequence and determine the presence/location of any PTMs on the spidroin-1. Sequence coverage of 98.06%, 95.05%, and 98.37% were obtained for N. clavipes, Nephila edulis and for Nephila madagascariensis, respectively. Phosphorylation was the major PTM observed with 8 phosphorylation sites considered reliable on spidroin-1 produced by N. clavipes, 4 in N. madagascariensis and 2 for N. edulis. Dityrosine and 3,4-dihydroxyphenylalanine (formed by oxidation of the spidroin-1) were observed, although the mechanism by which they are formed (i.e. exposure to UV radiation or to peroxidases in the major ampullate silk gland) is uncertain. Herein we present structural information on the spidroin-1 produced by three different Nephila species; these findings may be valuable for understanding the physicochemical properties of the silk proteins and moreover, future designs of recombinantly produced spider silk proteins. Biotechnological significance The present investigation shows for the first time spidroin structure and post-translational modifications observed on the major ampullate silk spidroin-1. The many site specific phosphorylations (localized within the structural motifs) along with the probably photoinduction of hydroxylations may be relevant for scientists in material science, biology, biochemistry and environmental scientists. Up to now all the mechanical properties of the spidroin have been characterized without any consideration about the existence of PTMs in the sequence of spidroins. Thus, these findings for major ampullate silk spidroin-1 from Nephila spiders provide the basis for mechanical-elastic property studies of silk for biotechnological and biomedical potential applications. This article is part of a Special Issue entitled: Proteomics of non-model organisms.


Novel decorin mutation in a Chinese family with congenital stromal corneal dystrophy.
The aim of this study was to characterize the congenital stromal corneal dystrophy (CSCD) pathological and clinical phenotype in a Chinese family with a novel mutation of decorin and its possible molecular pathogenesis. Molecular genetic analyses were performed on 5 patients with CSCD. Clinical characteristics, optical coherence tomography, and confocal microscopic study were evaluated. The corneal specimens from patients with CSCD were sent for light and electron microscopic evaluation. A protein modeling study was carried out to assess the effect of the mutation on the protein structure. Sequencing analysis of DCN revealed that all patients with CSCD were heterozygous for a 1-bp deletion at nucleotide 962 (c.962delA) in exon 8. This causes a premature termination of the decorin protein by frameshift, causing the deletion of 33 amino acids in the C-terminal end of the decorin protein. Optical coherence tomography and confocal microscopic study demonstrated that the corneal lamellar structure was disrupted and that this is more severe in the anterior and posterior central stroma. Histopathological study showed that electron-lucent zones were present between the normal-appearing collagen lamellae in the patients with CSCD. Abnormally thinned collagen filaments were identified in the electron-lucent zones, which could be due to abnormal decorin binding to the collagen microfibrils. Protein modeling studies involving wild-type and mutant protein indicated that mutant decorin might be unable to bind to all 4 collagen microfibrils as the normal decorin would. We present the clinical, histopathological, and molecular genetic assessment of a Chinese family with CSCD in which a novel DCN mutation was identified. Our findings add to the allelic heterogeneity of this rare form of inherited corneal disease.


Oocyte Activation and Fertilisation: Crucial Contributors from the Sperm and Oocyte.
This chapter intends to summarise the importance of sperm- and oocyte-derived factors in the processes of sperm-oocyte binding and oocyte activation. First, we describe the initial interaction between sperm and the zona pellucida, with particular regard to acrosome exocytosis. We then describe how sperm and oocyte membranes fuse, with special reference to the discovery of the sperm protein IZUMO1 and its interaction with the oocyte membrane receptor JUNO. We then focus specifically upon oocyte activation, the fundamental process by which the oocyte is alleviated from metaphase II arrest by a sperm-soluble factor. The identity of this sperm factor has been the source of much debate recently, although mounting evidence, from several different laboratories, provides strong support for phospholipase C ζ (PLCζ), a sperm-specific phospholipase. Herein, we discuss the evidence in support of PLCζ and evaluate the potential role of other candidate proteins, such as post-acrosomal WW-binding domain protein (PAWP/WBP2NL). Since the cascade of downstream events triggered by the sperm-borne oocyte activation factor heavily relies upon specialised cellular machinery within the oocyte, we also discuss the critical role of oocyte-borne factors, such as the inositol trisphosphate receptor (IP3R), protein kinase C (PKC), store-operated calcium entry (SOCE) and calcium/calmodulin-dependent protein kinase II (CaMKII), during the process of oocyte activation. In order to place the implications of these various factors and processes into a clinical context, we proceed to describe their potential association with oocyte activation failure and discuss how clinical techniques such as the in vitro maturation of oocytes may affect oocyte activation ability. Finally, we contemplate the role of artificial oocyte activating agents in the clinical rescue of oocyte activation deficiency and discuss options for more endogenous alternatives.


Double emulsions for the compatibilization of hydrophilic nanocellulose with non-polar polymers and validation in the synthesis of composite fibers.
A route for the compatibilization of aqueous dispersions of cellulose nanofibrils (CNFs) with a non-polar polymer matrix is proposed to overcome a major challenge in CNF-based material synthesis. Non-ionic surfactants were used in CNF aqueous dispersions equilibrated with an organic phase (for demonstration, a polystyrene solution, PS, was used). Stable water-in-oil-in-water (W/O/W) double emulsions were produced as a result of the compromise between composition and formulation variables. Most remarkably, the proposed route for CNF integration with hydrophobic polymers removed the need for drying or solvent-exchange of the CNF aqueous dispersion prior to processing. The rheological behavior of the double emulsions showed strong shear thinning behavior and facilitated CNF-PS co-mixing in solid nanofibers upon electrospinning. The morphology and thermal properties of the resultant nanofibers revealed that CNFs were efficiently integrated in the hydrophobic matrix which was consistent with the high interfacial area of the precursor double emulsion. In addition, the morphology and quality of the composite nanofibers can be controlled by the conductivity (ionic strength) of the CNF dispersion. Overall, double emulsion systems are proposed as a novel, efficient and scalable platform for CNF co-processing with non-polar systems and they open up the possibility for the redispersion of CNFs after removal of the organic phase.


Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and systematic review and guideline methodologists. Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without significant conflicts of interest participated in making recommendations. Panelists specified the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources and evidence permitted, they created standardized tables that present the quality of the evidence and key results in a transparent fashion. One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality of evidence and strength of recommendations were based on approaches developed by the Grades of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated with these states based on an additional systematic review of evidence regarding patient values and preferences for antithrombotic therapy. These ratings guided value and preference decisions underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance. AT9 methodology reflects the current science of evidence-based clinical practice guideline development, with reliance on high-quality systematic reviews, a standardized process for quality assessment of individual studies and the body of evidence, an explicit process for translating the evidence into recommendations, disclosure of financial as well as intellectual conflicts of interest followed by management of disclosed conflicts, and extensive peer review.


Integrative Taxonomy Recognizes Evolutionary Units Despite Widespread Mitonuclear Discordance: Evidence from a Rotifer Cryptic Species Complex.
Mitonuclear discordance across taxa is increasingly recognized as posing a major challenge to species delimitation based on DNA sequence data. Integrative taxonomy has been proposed as a promising framework to help address this problem. However, we still lack compelling empirical evidence scrutinizing the efficacy of integrative taxonomy in relation to, for instance, complex introgression scenarios involving many species. Here, we report remarkably widespread mitonuclear discordance between about 15 mitochondrial and 4 nuclear Brachionus calyciflorus groups identified using different species delimitation approaches. Using coalescent-, Bayesian admixture-, and allele sharing-based methods with DNA sequence or microsatellite data, we provide strong evidence in support of hybridization as a driver of the observed discordance. We then describe our combined molecular, morphological, and ecological approaches to resolving phylogenetic conflict and inferring species boundaries. Species delimitations based on the ITS1 and 28S nuclear DNA markers proved a more reliable predictor of morphological variation than delimitations using the mitochondrial COI gene. A short-term competition experiment further revealed systematic differences in the competitive ability between two of the nuclear-delimited species under six different growth conditions, independent of COI delimitations; hybrids were also observed. In light of these findings, we discuss the failure of the COI marker to estimate morphological stasis and morphological plasticity in the B. calyciflorus complex. By using B. calyciflorus as a representative case, we demonstrate the potential of integrative taxonomy to guide species delimitation in the presence of mitonuclear phylogenetic conflicts.


Maternal experiences of peanut avoidance during pregnancy/lactation: an in-depth qualitative study.
In 1998 the Department of Health Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment issued a report to British general practitioners, which advised that pregnant mothers with a family history of atopy may wish to avoid peanuts during pregnancy/lactation. To explore the lived-in experience of mothers who avoided/did not avoid peanuts during pregnancy/lactation in the light of the information issued. A qualitative approach, using unstructured in-depth interviews to explore what it was like for mothers to have a particular experience. A purposive sample frame was designed to ensure a maximum variation of participants. Forty-two interviews were conducted: 25 participants avoided peanuts; 15 with a family history of atopy and 10 with no such history. Seventeen participants did not avoid peanuts; 10 with a family history of atopy and seven with no such history. Emergent themes included: variations in information provision, a lack of clarity in relation to information and advice about peanut avoidance, the risks entailed and the introduction of peanuts to the developing child's diet; the importance of atopy in influencing participants' decisions to avoid peanuts and the importance of individual's choice in the decision making process. There was a significant difference in family size with respect to avoidance behaviour with 'avoider' families being smaller (p = 0.007). Avoidance was more likely in single child families (71% vs. 53%) although this difference was not significant. Improvements to the experience of avoidance and/or non-avoidance were primarily focused around provision of information and advice. In particular, a need for clear, consistent factual information and advice about the real risks associated with peanut consumption during pregnancy/lactation, and to whom these risks apply.


Development of cell type-specific connectivity patterns of converging excitatory axons in the retina.
To integrate information from different presynaptic cell types, dendrites receive distinct patterns of synapses from converging axons. How different afferents in vivo establish specific connectivity patterns with the same dendrite is poorly understood. Here, we examine the synaptic development of three glutamatergic bipolar cell types converging onto a common postsynaptic retinal ganglion cell. We find that after axons and dendrites target appropriate synaptic layers, patterns of connections among these neurons diverge through selective changes in the conversion of axo-dendritic appositions to synapses. This process is differentially regulated by neurotransmission, which is required for the shift from single to multisynaptic appositions of one bipolar cell type but not for maintenance and elimination, respectively, of connections from the other two types. Thus, synaptic specificity among converging excitatory inputs in the retina emerges via differential synaptic maturation of axo-dendritic appositions and is shaped by neurotransmission in a cell type-dependent manner.


Targeted deletion of Sost distal enhancer increases bone formation and bone mass.
The Wnt antagonist Sost has emerged as a key regulator of bone homeostasis through the modulation of Lrp4/5/6 Wnt coreceptors. In humans, lack of Sclerostin causes sclerosteosis and van Buchem (VB) disease, two generalized skeletal hyperostosis disorders that result from hyperactive Wnt signaling. Unlike sclerosteosis, VB patients lack SOST coding mutations but carry a homozygous 52 kb noncoding deletion that is essential for the transcriptional activation of SOST in bone. We recently identified a putative bone enhancer, ECR5, in the VB deletion region, and showed that the transcriptional activity of ECR5 is controlled by Mef2C transcription factor in vitro. Here we report that mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates. We conclude that the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton.


Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.
Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons. Deficiencies in their catabolic pathways give rise to a large and well-studied group of inherited disorders, the lysosomal storage diseases. Although many glycosphingolipid catabolic defects have been defined, only one proven inherited disease arising from a defect in ganglioside biosynthesis is known. This disease, because of defects in the first step of ganglioside biosynthesis (GM3 synthase), results in a severe epileptic disorder found at high frequency amongst the Old Order Amish. Here we investigated an unusual neurodegenerative phenotype, most commonly classified as a complex form of hereditary spastic paraplegia, present in families from Kuwait, Italy and the Old Order Amish. Our genetic studies identified mutations in B4GALNT1 (GM2 synthase), encoding the enzyme that catalyzes the second step in complex ganglioside biosynthesis, as the cause of this neurodegenerative phenotype. Biochemical profiling of glycosphingolipid biosynthesis confirmed a lack of GM2 in affected subjects in association with a predictable increase in levels of its precursor, GM3, a finding that will greatly facilitate diagnosis of this condition. With the description of two neurological human diseases involving defects in two sequentially acting enzymes in ganglioside biosynthesis, there is the real possibility that a previously unidentified family of ganglioside deficiency diseases exist. The study of patients and animal models of these disorders will pave the way for a greater understanding of the role gangliosides play in neuronal structure and function and provide insights into the development of effective treatment therapies.


Nicotine receptor subtype-specific effects on auditory evoked oscillations and potentials.
Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity. We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma. These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2 receptors. Event-related gamma is strongly influenced by activation of α4β2, but not α7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes.


Altered responsiveness to TGF-β results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage.
Previous studies have indicated that transforming growth factor β (TGF-β) signaling has a critical role in cartilage homeostasis and repair, yet the mechanisms of TGF-β's chondroprotective effects are not known. Our objective in this study was to identify downstream targets of TGF-β that could act to maintain biochemical and biomechanical properties of cartilage. Tibial joints from 20-week-old mice that express a dominant-negative mutation of the TGF-β type II receptor (DNIIR) were graded histologically for osteoarthritic changes and tested by indentation to evaluate their mechanical properties. To identify gene targets of TGF-β, microarray analysis was performed using bovine articular chondrocytes grown in micromass culture that were either treated with TGF-β or left untreated. Phosphoadenosine phosphosynthetase 2 (PAPSS2) was identified as a TGF-β-responsive gene. Papss2 expression is crucial for proper sulfation of cartilage matrix, and its deficiency causes skeletal defects in mice and humans that overlap with those seen in mice with mutations in TGF-β-signaling genes. Regulation of Papss2 was verified by real time RT-PCR and Western blot analyses. Alterations in sulfation of glycosaminoglycans were analyzed by critical electrolyte concentration and Alcian blue staining and immunofluorescence for chondroitin-4-sulfate, unsulfated chondroitin and the aggrecan core protein. DNIIR mutants showed reduced mechanical properties and osteoarthritis-like changes when compared to wild-type control mice. Microarray analysis identified a group of genes encoding matrix-modifying enzymes that were regulated by TGF-β. Papss2 was upregulated in bovine articular chondrocytes after treatment with TGF-β and downregulated in cartilage from DNIIR mice. Articular cartilage in DNIIR mice demonstrated reduced Alcian blue staining at critical electrolyte concentrations and reduced chondroitin-4-sulfate staining. Staining for unsulfated chondroitin sulfate was increased, whereas staining for the aggrecan core protein was comparable in DNIIR and wild-type mice. TGF-β maintains biomechanical properties and regulates expression of Papss2 and sulfation of glycosaminoglycans in mouse articular cartilage.


Combining urban scaling and polycentricity to explain socio-economic status of urban regions.
The fast pace of urbanisation may benefit or be detrimental to the socio-economic status of urban areas. Understanding how the configuration of urban areas influences the socio-economic status of their inhabitants is of crucial importance for urban planning. In theory, urban scaling laws and polycentric development are two well-known concepts developed to increase our understanding of urbanisation and its socio-economic effects. In practice, however, they fall short to explain the socio-economic status of urban regions. The urban scaling concept is constructed from a theoretical perspective, but functional relationships between urban centres are not taken into account in scaling models. In contrast, the concept of polycentricity is developed from a practical perspective and incorporates the socio-economic effect of relationships between urban centres in the process of urban development. However, polycentricity lacks a theoretical foundation, which would explain the socio-economic status of urban regions. In this study, we assess whether combining both concepts improves the ability to explain personal incomes in metropolitan areas in Switzerland. We first delineated metropolitan areas by implementing a modularity maximisation algorithm on the settlement network. Nodes in this network are Swiss municipalities and links are inter-municipal commuter flows. We found a strong relationship between the hierarchical organisation of functional connections within metropolitan areas and the socio-economic status of these areas. Both concepts were complementary and combining them proved to enhance the ability to explain socio-economic status. The combined model is a theoretical progress, which complements the traditional approaches and increases our understanding of cities and urbanisation processes.


Enhancement of dye regeneration kinetics in dichromophoric porphyrin-carbazole triphenylamine dyes influenced by more exposed radical cation orbitals.
Reduction kinetics of oxidized dyes absorbed on semiconductor surfaces and immersed in redox active electrolytes has been mainly modeled based on the free energy difference between the oxidation potential of the dye and the redox potential of the electrolyte. Only a few mechanisms have been demonstrated to enhance the kinetics by other means. In this work, the rate constant of the reduction of oxidized porphyrin dye is enhanced by attaching non-conjugated carbazole triphenylamine moiety using iodine/triiodide and tris(2,2'-bispyridinium)cobalt II/III electrolytes. These results are obtained using transient absorption spectroscopy by selectively probing the regeneration kinetics at the porphyrin radical cation and the carbazole triphenylamine radical cation absorption wavelengths. The enhancement in the reduction kinetics is not attributed to changes in the driving force, but to the more exposed dye cation radical orbitals of the dichromophoric dye. The results are important for the development of high efficiency photo-electrochemical devices with minimalized energy loss at electron transfer interfaces.


Mechanical and Geometric Performance of PLA-Based Polymer Composites Processed by the Fused Filament Fabrication Additive Manufacturing Technique.
In this work, the effect of short carbon fibre (CF) on the mechanical and geometric properties of 3D printed polylactic acid (PLA) composite parts processed using the Fused Filament Fabrication (FFF) technique have been analysed. Tensile, flexural and interlaminar shear strength (ILSS) tests were performed to obtain the mechanical performance of the different samples. The surface quality and geometric accuracy of the printed specimens were also evaluated. Finally, Scanning Electron Microscope (SEM) images of the printed samples are analysed. The results revealed that the addition of carbon fibres effectively improved all assessed mechanical properties of PLA-CF composites as compared to the neat PLA. In particular, Flat PLA-CF samples showed an average increase in tensile performance of 47.1% for the tensile strength and 179.9% for the tensile stiffness in comparison to the neat PLA. From the flexural behaviour point of view, Flat PLA-CF samples revealed an increase in average flexural strength and stiffness of 89.75% and 230.95%, respectively in comparison to the neat PLA. Furthermore, PLA-CF samples depicted the best ILSS performance. In general, the use of short carbon fibre as reinforcement did not affect the dimensional accuracy of the PLA-CF samples, and even improved the surface roughness in certain cases, particularly in Flat and On-edge orientations.


Continuous spinal anesthesia versus combined spinal epidural block for major orthopedic surgery: prospective randomized study.
In major orthopedic surgery of the lower limbs, continuous spinal anesthesia (CSA) and combined spinal epidural anesthesia (CSE) are safe and reliable anesthesia methods. In this prospective randomized clinical study, the blockading properties and side effects of CSA were compared with single interspace CSE, among patients scheduled for major hip or knee surgery. Prospective clinical study conducted at the Institute for Regional Anesthesia, Hospital de Base, São José do Rio Preto. 240 patients scheduled for hip arthroplasty, knee arthroplasty or femoral fracture treatment were randomly assigned to receive either CSA or CSE. Blockades were performed in the lateral position at the L3-L4 interspace. Puncture success, technical difficulties, paresthesia, highest level of sensory and motor blockade, need for complementary doses of local anesthetic, degree of technical difficulties, cardiocirculatory changes and postdural puncture headache (PDPH) were recorded. At the end of the surgery, the catheter was removed and cerebrospinal fluid leakage was evaluated. Seven patients were excluded (three CSA and four CSE). There was significantly lower incidence of paresthesia in the CSE group. The resultant sensory blockade level was significantly higher with CSE. Complete motor blockade occurred in 110 CSA patients and in 109 CSE patients. Arterial hypotension was observed significantly more often in the CSE group. PDPH was observed in two patients of each group. Our results suggest that both CSA and CSE provided good surgical conditions with low incidence of complications. The sensory blockade level and hemodynamic changes were lower with CSA.


Pregnancy and HIV disease progression: a systematic review and meta-analysis.
To assess whether pregnancy accelerates HIV disease progression. Studies comparing progression to HIV-related illness, low CD4 count, AIDS-defining illness, HIV-related death, or any death in HIV-infected pregnant and non-pregnant women were included. Relative risks (RR) for each outcome were combined using random effects meta-analysis and were stratified by antiretroviral therapy (ART) availability. 15 studies met the inclusion criteria. Pregnancy was not associated with progression to HIV-related illness [summary RR: 1.32, 95% confidence interval (CI): 0.66-2.61], AIDS-defining illness (summary RR: 0.97, 95% CI: 0.74-1.25) or mortality (summary RR: 0.97, 95% CI: 0.62-1.53), but there was an association with low CD4 counts (summary RR: 1.41, 95% CI: 0.99-2.02) and HIV-related death (summary RR: 1.65, 95% CI: 1.06-2.57). In settings where ART was available, there was no evidence that pregnancy accelerated progress to HIV/AIDS-defining illnesses, death and drop in CD4 count. In settings without ART availability, effect estimates were consistent with pregnancy increasing the risk of progression to HIV/AIDS-defining illnesses and HIV-related or all-cause mortality, but there were too few studies to draw meaningful conclusions. In the absence of ART, pregnancy is associated with small but appreciable increases in the risk of several negative HIV outcomes, but the evidence is too weak to draw firm conclusions. When ART is available, the effects of pregnancy on HIV disease progression are attenuated and there is little reason to discourage healthy HIV-infected women who desire to become pregnant from doing so.


Enhanced External Counterpulsation Therapy: Past, Present, and Future.
External counterpulsation therapy was first developed over half a century ago as a resuscitative tool to support the failing heart and was based on hemodynamic principles of the intraaortic balloon pump. Over the course of last few decades, it has evolved into the modern enhanced external counterpulsation (EECP) therapy, which has proven to be a safe, effective, and low-cost noninvasive treatment for patients with debilitating angina and chronic heart failure who are poor candidates for revascularization procedures and have suboptimal results from other therapies. Numerous studies have shown EECP to be efficacious in patients with chronic angina, with its effects lasting for several years after completion of therapy. Besides being safe in patients with coexisting left ventricular dysfunction, there is emerging evidence that EECP therapy may result in improvement in exercise capacity and oxygen consumption in heart failure patients. Several mechanisms have been postulated to explain the therapeutic effects of EECP, including improvement in endothelial function, promotion of angiogenesis and new collaterals, reduction in atherosclerotic burden, improvement in ventricular function, and peripheral training effects analogous to that of exercise. With greater understanding of these complex mechanisms, possible applications of EECP have broadened in recent years, with its use being studied in conditions like hepatorenal syndrome, erectile dysfunction, and restless leg syndrome. This review article offers a historical perspective on the origins of EECP, an overview of our current understanding of its physiological effects, and a glimpse at its future utilization in clinical practice.


Outcome in patients with religious delusions.
We read with interest the recent report on the definition, diagnosis, and clinical implications of religious delusions (RD).1 In our sample of 929 delusional schizophrenia patients who had been admitted to two psychiatric hospitals in Germany between 2010 and 2014, 138 patients (15%) reported RD. In 569 cases, information on religious affiliation was available. Patients with religious affiliation did not differ from patients without religious affiliation in the frequency of RD [χ2(1,569)= 0.02, p= 0.885]. Furthermore, patients with RD did not differ from patients with other types of delusion (OD) in the duration of hospitalisation [t(924)= -0.39, p= 0.695], or the number of hospitalisations [t(927)= -0.92, p= 0.358]. Additionally, in 185 cases, information on Clinical Global Impressions (CGI) and Global Assessment of Functioning (GAF) was available at the beginning and end of the hospital stay. By CGI-scores, no difference was seen in morbidity of subjects with RD relative to subjects with OD on admission [t(183)= -0.78, p= 0.437] and discharge t(183)= -1.10, p= .273 . Likewise, GAF-scores on admission did not differ in these groups [t(183)= 1.50, p= 0.135]. However, a trend was noted for lower GAF-scores on discharge in subjects with RD [t(183)= 1.91, p= .057, d= 0.39, CI 95% (-0.12-0.78)]. While RD have often been associated with a poorer prognosis in schizophrenia,2,3 we argue that this need not apply to all domains. Mohr et al4 reported that patients with RD were less likely to maintain psychiatric treatment, but did not have a more severe clinical status than patients with OD. Iyassu et al5 found higher levels of positive, but also lower levels of negative symptoms in patients with RD compared to patients with OD. Groups did not differ in terms of length of illness or level of medication. Siddle et al6 reported higher symptom scores in patients with RD at their first presentation, but a similar response to treatment when compared to patients with OD after 4 weeks of treatment. Furthermore, Ellersgaard et al7 iindicated that first-episode psychosis patients with RD at baseline were more likely to be non-delusional at follow-ups conducted after years 1, 2 and 5 when compared to patients with OD at baseline. We conclude that RD may thus interfere with short-term clinical outcome. With regard to long-term effects more favourable observations exist8 and the interplay of psychotic delusions with non-psychotic beliefs still warrants further research.


Stem cell-based bone and dental regeneration: a view of microenvironmental modulation.
In modern medicine, bone and dental loss and defects are common and widespread morbidities, for which regenerative therapy has shown great promise. Mesenchymal stem cells, obtained from various sources and playing an essential role in organ development and postnatal repair, have exhibited enormous potential for regenerating bone and dental tissue. Currently, mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering. Nevertheless, the efficacy of MSC-based regeneration is not always fulfilled, especially in diseased microenvironments. Specifically, the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs, both as donors and recipients. Accordingly, approaches targeting a diseased microenvironment have been established, including improving the diseased niche to restore endogenous MSCs, enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies. Moreover, the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy. In this review, we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment, emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.


Patterns and Disparities in Human Papillomavirus (HPV) Vaccine Uptake for Young Female Adolescents among U.S. States: NIS-Teen (2008-2016).
Several studies have reported differential vaccine uptake outcomes that are associated with sociodemographic and socioeconomic characteristics, as well as provider type. However, none has examined a trend over a multiple-year span. In this study, we utilize a longitudinal data-based approach to examine state-level human papillomavirus (HPV) vaccine trends and their influences over time. We analyzed National Immunization Survey - Teen data (2008-2016) to estimate HPV vaccine initiation rate in young female adolescent ages 13-17 years old among U.S. States. We identified growth patterns using the latent class growth method and explored state-level characteristics, including socioeconomic and sociodemographic attributes, and health legislation and policy-related programs among patterns. We identified three growth patterns, which showed gradually increasing vaccination trends but different baseline HPV uptake rates (high, moderate, low). States within Pattern 1 (highest HPV vaccination rates) included the lowest percentage of families with incomes below federal poverty level, the highest percentage of bachelor's degree or higher, and the lowest number of uninsured, while states within Pattern 3 (lowest HPV vaccination rates) included families with socioeconomic attributes along the opposite end of the spectrum. Latent class growth models are an effective tool to be able to capture health disparities in heterogeneity among states in relation to HPV vaccine uptake trajectories. These findings might lead to designing and implementing effective interventions and changes in policies and health care coverage to promote HPV vaccination uptake for states represented under the lowest trajectory pattern.


Optimal eigenanalysis for the treatment of aerosols in the retrieval of atmospheric composition from transmission measurements.
The separation of the individual contributions of aerosol and gases to the total attenuation of radiation through the atmosphere has been the subject of much scientific investigation since remote sensing experiments first began. We describe a new scheme to account for the spectral variation of the aerosol extinction in the inversion of transmission data from occultation measurements. Because the spectral variation of the aerosol extinction is generally unknown,the inversion problem is underdetermined and cannot be solved without a reduction in the number of unknowns in the set of equations used to describe the attenuation at each wavelength. This reduction can be accomplished by a variety of methods, including use of a priori information, the parameterization of the aerosol spectral attenuation, and the specification of the form of the aerosol size distribution. We have developed and implemented a parameterization scheme based on existing empirical and modeled information about the microphysical properties of aerosols. This scheme employs the eigenvectors from an extensive set of simulations to parameterize the aerosol extinction coefficient for incorporation into the inversion algorithm. We examine the accuracy of our method using data sets containing over 24,000 extinction spectra and compare it with that of another scheme that is currently implemented in the Polar Ozone and Aerosol Measurement (POAM) satellite experiment. In simulations using 80 wavelengths in the UV-visible-near-IR spectral range of the Stratospheric Aerosol and Gas Experiment III (SAGE) instrument, we show that, for our optimal parameterization, errors below 1% are observed in 80% of cases, whereas only approximately 20% of all cases are as accurate as this in a quadratic parameterization employing the logarithm of the wavelength.


Redox-responsive polyanhydride micelles for cancer therapy.
Biodegradable polyanhydrides possess unique features like those that they can predominantly undergo surface erosion, and the payloads can be released by a steady speed. However, there is little work that has been published to describe the polyanhydride micelles with redox-responsiveness as a nanocarrier for drug delivery. In this study, we develop one type of new amphiphilic polyanhydride copolymer containing disulfide bonds between the hydrophilic and hydrophobic segments. The copolymer can self-assemble into stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 69 nm. The disassembly behaviors of the micelles triggered by glutathione are evaluated from the changes of the micellar size, morphology and molecular weight. An approximate zero-order in vitro drug release mode with a fast speed can be achieved in a reducing and acid environment similar with that of tumor cells. In vitro cytotoxicity analysis demonstrate that the Cur-loaded micelles are of great efficiency in inhibiting the growth of cancer cells due to the rapidly intracellular delivery of therapeutic agent. Both the qualitative and quantitative results of the antitumor activity in 4T1 tumor-bearing BALB/c mice reveal that the redox-responsive micelles have a more significant therapeutic effect to artificial solid tumor compared to the redox-insensitive micelles. This study provides a new insight into the biomedical application of polyanhydrides in drug delivery.


A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients.
Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)-they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1-2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.


Inadequate sleep as a risk factor for obesity: analyses of the NHANES I.
Sleep deprivation has been hypothesized to contribute toward obesity by decreasing leptin, increasing ghrelin, and compromising insulin sensitivity. This study examines cross-sectional and longitudinal data from a large United States sample to determine whether sleep duration is associated with obesity and weight gain. Longitudinal analyses of the 1982-1984, 1987, and 1992 NHANES I Followup Studies and cross-sectional analysis of the 1982-1984 study. Probability sample of the civilian noninstitutionalized population of the United States. Sample sizes of 9,588 for the cross-sectional analyses, 8,073 for the 1987, and 6,981 for the 1992 longitudinal analyses. Measured weight in 1982-1984 and self-reported weights in 1987 and 1992. Subjects between the ages of 32 and 49 years with self-reported sleep durations at baseline less than 7 hours had higher average body mass indexes and were more likely to be obese than subjects with sleep durations of 7 hours. Sleep durations over 7 hours were not consistently associated with either an increased or decreased likelihood of obesity in the cross-sectional and longitudinal results. Each additional hour of sleep at baseline was negatively associated with change in body mass index over the follow-up period, but this association was small and statistically insignificant. These findings support the hypothesis that sleep duration is associated with obesity in a large longitudinally monitored United States sample. These observations support earlier experimental sleep studies and provide a basis for future studies on weight control interventions that increase the quantity and quality of sleep.


Observers fail to detect that behavior is the control of perception: A computer demonstration of unintended writing.
Perceptual control theory (PCT) approaches the behavior of living systems as though it were a phenomenon of control and systematically assesses the variables that the individual controls using the test for the controlled variable (TCV). PCT may be supported by the minority because the majority of behavior scientists, like most people, can miss the phenomenon of control as it is occurring. An earlier paper reported three studies of a behavior that was known to be a process of control because it had been explicitly instructed. In each case, most observers did not detect the control. Our novel extension of this study used live observation of "actors" and "observers." We tested in pairs 164 participants randomly allocated to each role. The actors completed a two-dimensional compensatory tracking task. To keep a dot at the center of a circle, the movements of a computer mouse needed to vary as the inverse of a disturbance pattern that was an inverted form of the word "hello" in script. The trace of their mouse movements was displayed on the screen-writing the word "hello". As predicted, most observers missed the phenomenon of control; they inferred that the actor's instruction had been to write "hello", rather than to control the dot. In contrast, the actors reported that they had been keeping the dot in the circle and were unaware of having written the word. The TCV analyzes behavior by consistently identifying the controlled variable without relying on heuristic methods used by researchers that can be inaccurate. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Hamilton acute pain service safety study: using root cause analysis to reduce the incidence of adverse events.
Although intravenous patient-controlled analgesia opioids and epidural analgesia offer improved analgesia for postoperative patients treated on an acute pain service, these modalities also expose patients to some risk of serious morbidity and even mortality. Root cause analysis, a process for identifying the causal factor(s) that underlie an adverse event, has the potential to identify and address system issues and thereby decrease the chance of recurrence of these complications. This study was designed to compare the incidence of adverse events on an acute pain service in three hospitals, before and after the introduction of a formal root cause analysis process. The "before" cohort included all patients with pain from February 2002 to July 2007. The "after" cohort included all patients with pain from January 2009 to December 2009. A total of 35,384 patients were tracked over the 7 yr of this study. The after cohort showed significant reductions in the overall event rate (1.47 vs. 2.35% or 1 in 68 vs. 1 in 42, the rate of respiratory depression (0.41 vs. 0.71%), the rate of severe hypotension (0.78 vs. 1.34%), and the rate of patient-controlled analgesia pump programming errors (0.0 vs. 0.08%). Associated with these results, the incidence of severe pain increased from 6.5 to 10.5%. To achieve these results, 26 unique recommendations were made of which 23 being completed, 1 in progress, and 2 not completed. Formal root cause analysis was associated with an improvement in the safety of patients on a pain service. The process was effective in giving credibility to recommendations, but addressing all the action plans proved difficult with available resources.