One-lung ventilation with a bronchial blocker in thoracic patients.
Lung isolation is a technique used in a multitude of surgeries to ensure single-lung ventilation with collapse of the contralateral lung, as to achieve improved access and visualization of relevant anatomical structures. Despite being accepted and having favorable outcomes, bronchial blockers (BBs) are not to this day the main device of choice among anaesthesiologists. In this retrospective and descriptive study, we analyzed the safety and efficacy of a BB in all types of thoracic surgeries in our centre between 2015 and 2022, excluding patients with massive hemoptysis or empyema, or who had undergone a prior pneumonectomy. One hundred and thirty-four patients were intervened due to lung cancer (67.9%), respiratory disease (23.9%), and non-respiratory disease (8.2%) undergoing lung surgeries (65.7%), pleural and mediastinal surgeries (29.9%), chest wall surgeries (3.0%) and other surgeries (1.5%). In most cases, lung collapse was considered excellent (63.9%) or good (33.1%) with only 4 cases (3.0%) of poor lung collapse. More than 90% of patients did not present intraoperative or immediate postoperative complications. No statistically significant differences were found between lung collapse and the demographic, clinical or BB-related variables (p > 0.05). However, we found a significatively higher proportion of excellent lung collapses in VATS surgeries and lateral decubitus positioning, as well as a significatively less proportion of poor lung collapses (p < 0.05). Moreover, there was a significantly higher proportion of excellent lung collapses when the BB was placed in the left bronchus (p < 0.05). With these results, in our experience BBs constitute an effective alternative, capable of achieving pulmonary collapse in all kinds of thoracic procedures with satisfactory safety rates due to their minimal complications.


Lack of definition of mathematical terms in ecology: The case of the sigmoid class of functions in macro-ecology.
Defining mathematical terms and objects is a constant issue in ecology; often definitions are absent, erroneous, or imprecise. Through a bibliographic prospection, we show that this problem appears in macro-ecology (biogeography and community ecology) where the lack of definition for the sigmoid class of functions results in difficulties of interpretation and communication. In order to solve this problem and to help harmonize papers that use sigmoid functions in ecology, herein we propose a comprehensive definition of these mathematical objects. In addition, to facilitate their use, we classified the functions often used in the ecological literature, specifying the constraints on the parameters for the function to be defined and the curve shape to be sigmoidal. Finally, we interpreted the different properties of the functions induced by the definition through ecological hypotheses in order to support and explain the interest of such functions in ecology and more precisely in biogeography.


Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS.
The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA PTCHD1-AS is frequently disrupted in male subjects with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. To evaluate the functional consequences of PTCHD1 locus deletions, we generated induced pluripotent stem cells (iPSCs) from unaffected control subjects and 3 subjects with ASD with microdeletions affecting PTCHD1-AS/PTCHD1, PTCHD1-AS/DDX53, or PTCHD1-AS alone. Function of iPSC-derived cortical neurons was assessed using molecular approaches and electrophysiology. We also compiled novel and known genetic variants of the PTCHD1 locus to explore the roles of PTCHD1 and PTCHD1-AS in genetic risk for ASD and other neurodevelopmental disorders. Finally, genome editing was used to explore the functional consequences of deleting a single conserved exon of PTCHD1-AS. iPSC-derived neurons from subjects with ASD exhibited reduced miniature excitatory postsynaptic current frequency and N-methyl-D-aspartate receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupted exons of PTCHD1-AS. We also found a novel ASD-associated deletion of PTCHD1-AS exon 3 and showed that exon 3 loss altered PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished miniature excitatory postsynaptic current frequency, supporting a role for the long noncoding RNA in the etiology of ASD. Our genetic findings provide strong evidence that PTCHD1-AS deletions are risk factors for ASD, and human iPSC-derived neurons implicate these deletions in the neurophysiology of excitatory synapses and in ASD-associated synaptic impairment.


New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource.
Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host-pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions.


The developmental origins of ageing: study protocol for the Dutch famine birth cohort study on ageing.
Evidence from animal studies suggest that the rate of ageing may be influenced not only by genetic and lifestyle factors, but also by the prenatal environment. We have previously shown that people who were exposed to famine during early gestation performed worse on a selective attention task, which may be a first sign of cognitive decline, and were on average 3 years younger at the time of coronary artery disease diagnosis. Women in this group seem to die at a younger age. We hypothesise that an accelerated ageing process, set in motion by the poor prenatal environment, underlies these findings. The Dutch Famine Birth Cohort consists of 2414 men and women born in Amsterdam as term singletons around the time of the Dutch famine. In a subsample of 150 cohort members, who now are about 68 years of age, we are currently measuring cognitive decline and the incidence of white matter hyperintensities and cerebral microbleeds (through MRI), incidence of fractures, grip strength and physical performance, visual acuity and incidence of cataract operations. In this same subgroup, we will assess telomere length, oxidative stress and inflammatory status as potential underlying mechanisms. Furthermore, in the entire cohort, we will assess mortality as well as hospital admissions for age-related diseases up to the age of 68 years. The study was approved by the local medical ethics committee (Academic Medical Centre, University of Amsterdam) and is being carried out in agreement with the Declaration of Helsinki. All participants give written informed consent. Study findings will be widely disseminated to the scientific public as well as to the medical society and general public.


Malacoplakia of a cadaveric renal allograft: a case report.
A case of malacoplakia in a cadaveric renal allograft is presented. Infection and immunotherapy are presented as possible etiologic factors. The pathogenesis of malacoplakia is discussed with reference to histologic findings in this specific case. The suggestion is made that an altered macrophage response in this disease is the reason for this granulomatous lesion of the bladder.


Cytogenetic heteromorphisms: survey results and reporting practices of giemsa-band regions that we have pondered for years.
Cytogenetic heteromorphisms (normal variants) pose diagnostic dilemmas. Common Giemsa-band heteromorphisms are not described in the literature, although Giemsa-banding is the method most frequently used in cytogenetic laboratories. To summarize the responses from more than 200 cytogeneticists concerning the definition and reporting of cytogenetic heteromorphisms, to offer these responses as a reference for use in clinical interpretations, and to provide guidance for interpretation of newly defined molecular cytogenetic heteromorphisms. The Cytogenetics Resource Committee of the College of American Pathologists and the American College of Medical Genetics administered a proficiency testing survey in 1997 to 226 participant cytogenetic laboratories. Supplemental questions asked whether participants considered particular Giemsa-banded chromosomal features to be heteromorphisms and if these would be described in a cytogenetic clinical report. Responses were obtained from 99% of participants; 61% stated they would include selected heteromorphism data in a clinical report. More than 90% considered prominent short arms, large or double satellites, or increased stalk length on acrocentric chromosomes to be heteromorphisms; 24% to 36% stated that they would include these in a clinical report. Heterochromatic regions on chromosomes 1, 9, 16, and Y were considered heteromorphisms by 97% of participants, and 24% indicated they would report these findings. Pericentric inversions of chromosomes 1, 2, 3, 5, 9, 10, 16, and Y were considered heteromorphisms with more than 75% of respondents indicating they would report these findings. Responses were not unanimous, but a clear consensus is presented describing which Giemsa-band regions were considered heteromorphisms and which would be reported.


Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma.
Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.


Designing functionally graded materials with superior load-bearing properties.
Ceramic prostheses often fail from fracture and wear. We hypothesize that these failures may be substantially mitigated by an appropriate grading of elastic modulus at the ceramic surface. In this study, we elucidate the effect of elastic modulus profile on the flexural damage resistance of functionally graded materials (FGMs), providing theoretical guidelines for designing FGMs with superior load-bearing property. The Young's modulus of the graded structure is assumed to vary in a power-law relation with a scaling exponent n; this is in accordance with experimental observations from our laboratory and elsewhere. Based on the theory for bending of graded beams, we examine the effect of n value and bulk-to-surface modulus ratio (E(b)/E(s)) on stress distribution through the graded layer. Theory predicts that a low exponent (0.15<n<0.5), coupled with a relatively small modulus ratio (3<E(b)/E(s)<6), is most desirable for reducing the maximum stress and transferring it into the interior, while keeping the surface stress low. Experimentally, we demonstrate that elastically graded materials with various n values and E(b)/E(s) ratios can be fabricated by infiltrating alumina and zirconia with a low-modulus glass. Flexural tests show that graded alumina and zirconia with suitable values of these parameters exhibit superior load-bearing capacity, 20-50% higher than their homogeneous counterparts. Improving load-bearing capacity of ceramic materials could have broad impacts on biomedical, civil, structural, and an array of other engineering applications.


Bile acid and bile salt disrupt gastric mucosal barrier in the dog by different mechanisms.
The present study was undertaken to assess the mechanism by which protonated taurocholic acid disrupts the gastric mucosal barrier. By the criterion of lecithin solubilization, the critical micellar concentration of taurocholic acid (pH 1) was 4.5 mM, as opposed to 3.0 mM for sodium taurocholate (pH 7). In canine Heidenhain pouches, taurocholic acid significantly increased net forward diffusion of Na+ and backdiffusion of H+ at concentrations of 9, 4.5, and 3.5 mM, indicating that micelle formation was not required for disruption of the gastric mucosal barrier by this bile acid. Saturation of the 9 mM taurocholic acid solution with lecithin (and cholesterol) did not prevent disruption of the gastric mucosal barrier. At 9 mM, taurocholic acid was absorbed from the pouches at a mean rate of 1,150 +/- 115 nmol/min in contrast to an absorption rate of 225 +/- 10 nmol/min for sodium taurocholate at the same concentration. These findings indicate that, unlike ionized bile salts, disruption of the gastric mucosal barrier by taurocholic acid is mediated largely by uptake of bile acid by the gastric mucosa rather than dissolution of mucosal membrane lipids.


Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model.
Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.


Estimating copy numbers of alleles from population-scale high-throughput sequencing data.
With the recent development of microarray and high-throughput sequencing (HTS) technologies, a number of studies have revealed catalogs of copy number variants (CNVs) and their association with phenotypes and complex traits. In parallel, a number of approaches to predict CNV regions and genotypes are proposed for both microarray and HTS data. However, only a few approaches focus on haplotyping of CNV loci. We propose a novel approach to infer copy unit alleles and their numbers in each sample simultaneously from population-scale HTS data by variational Bayesian inference on a generative probabilistic model inspired by latent Dirichlet allocation, which is a well studied model for document classification problems. In simulation studies, we evaluated concordance between inferred and true copy unit alleles for lower-, middle-, and higher-copy number dataset, in which precision and recall were ≥ 0.9 for data with mean coverage ≥ 10× per copy unit. We also applied the approach to HTS data of 1123 samples at highly variable salivary amylase gene locus and a pseudogene locus, and confirmed consistency of the estimated alleles within samples belonging to a trio of CEPH/Utah pedigree 1463 with 11 offspring. Our proposed approach enables detailed analysis of copy number variations, such as association study between copy unit alleles and phenotypes or biological features including human diseases.


Freely available artificial intelligence for pelvic lymph node metastases in PSMA PET-CT that performs on par with nuclear medicine physicians.
The aim of this study was to develop and validate an artificial intelligence (AI)-based method using convolutional neural networks (CNNs) for the detection of pelvic lymph node metastases in scans obtained using [18F]PSMA-1007 positron emission tomography-computed tomography (PET-CT) from patients with high-risk prostate cancer. The second goal was to make the AI-based method available to other researchers. [18F]PSMA PET-CT scans were collected from 211 patients. Suspected pelvic lymph node metastases were marked by three independent readers. A CNN was developed and trained on a training and validation group of 161 of the patients. The performance of the AI method and the inter-observer agreement between the three readers were assessed in a separate test group of 50 patients. The sensitivity of the AI method for detecting pelvic lymph node metastases was 82%, and the corresponding sensitivity for the human readers was 77% on average. The average number of false positives was 1.8 per patient. A total of 5-17 false negative lesions in the whole cohort were found, depending on which reader was used as a reference. The method is available for researchers at www.recomia.org . This study shows that AI can obtain a sensitivity on par with that of physicians with a reasonable number of false positives. The difficulty in achieving high inter-observer sensitivity emphasizes the need for automated methods. On the road to qualifying AI tools for clinical use, independent validation is critical and allows performance to be assessed in studies from different hospitals. Therefore, we have made our AI tool freely available to other researchers.


Granulocyte aggregometry: a sensitive technique for the detection of C5a and complement activation.
We have previously shown that complement (C) activated plasma causes granulocyte (PMN) aggregation in vitro and that C5a is responsible. The C-induced aggregation of PMNs treated with cytochalasin-B (CB) is markedly enhanced and irreversible, and the magnitude of the response is proportional to the log (concentration of activated plasma), allowing use of this technique to detect C5a and hence C-activation. To compare the sensitivity of granulocyte aggregometry to that of more standard methods of detecting C-activation, we produced graded C-activation in vitro by treating fresh serum with varying amounts of zymosan. Aggregometry was the most sensitive index of C-activation, detecting C-activation, produced by 0.02 mg zymosan/ml of serum--1/10 that required to produce C-activation detectable by C3 immunoelectrophoresis (the next most sensitive technique). Granulocyte aggregometry may also be used to detect in vivo C-activation. We have found aggregating activity in plasmas from patients with systemic lupus erythematosus, immune vasculitis, transfusion reactions, and other conditions associated with in vivo C-activation, but not in the plasmas of normal subjects.


Fluorescence Investigations into Complex Coacervation between Polyvinylimidazole and Sodium Alginate.
Electrostatic interactions between the imidazole-based cationic homopolymer, polyvinylimidazole (PVIm), and anionic polysaccharide, sodium alginate, lead to the formation of colloidal aggregates known as complex coacervates in the pH range 4-6.5. PVIm was labeled with the fluorescent reporter pyrene to investigate the coacervation-induced changes in and around PVIm chains. While the pyrene-tagged PVIm had blue fluorescence in water, the coacervate phase exhibited an additional broad band around 492 nm (green) due to formation of pyrene excimers. Fluorescence spectroscopic investigations point toward aggregation of PVIm chains and desolvation upon coacervation. Highly anisotropic fluorescence emission indicates tight packing of the polymer chains in the coacervate. Confocal microscopy of fluorescein-labeled alginate and rhodamine-labeled PVIm shows coacervates as dense aggregates with uniform distribution of the polymers. Fluorescence spectroscopy offers sensitive and easy investigation into polyelectrolyte interactions.


An evaluation of stakeholder engagement in comparative effectiveness research: lessons learned from SWOG S1415CD.
Aim: Stakeholder engagement is central to comparative effectiveness research yet there are gaps in definitions of success. We used a framework developed by Lavallee et al. defining effective engagement criteria to evaluate stakeholder engagement during a pragmatic cluster-randomized trial. Methods: Semi-structured interviews were developed from the framework and completed to learn about members' experiences. Interviews were analyzed in a deductive approach for themes related to the effective engagement criteria. Results: Thirteen members participated and described: respect for ideas, time to achieve consensus, access to information and continuous feedback as areas of effective engagement. The primary criticism was lack of diversity. Discussion: Feedback was positive, particularly among themes of respect, trust and competence, and led to development of a list of best practices for engagement. The framework was successful for evaluating engagement. Conclusion: Standardized frameworks allow studies to formally evaluate their stakeholder engagement approach and develop best practices for future research.


Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists.
It is widely accepted that non-endogenous compounds that target CB(1) and/or CB(2) receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Delta(9)-tetrahydrocannabinol or nabilone, both CB(1)/CB(2) receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB(2)-selective agonists, peripherally restricted CB(1)/CB(2) receptor agonists and CB(1)/CB(2) antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB(1) and CB(2) receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB(1), non- CB(2) G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB(1) and/or CB(2) receptors.


Highly accurate CCSD(T) and DFT-SAPT stabilization energies of H-bonded and stacked structures of the uracil dimer.
The CCSD(T) interaction energies for the H-bonded and stacked structures of the uracil dimer are determined at the aug-cc-pVDZ and aug-cc-pVTZ levels. On the basis of these calculations we can construct the CCSD(T) interaction energies at the complete basis set (CBS) limit. The most accurate energies, based either on direct extrapolation of the CCSD(T) correlation energies obtained with the aug-cc-pVDZ and aug-cc-pVTZ basis sets or on the sum of extrapolated MP2 interaction energies (from aug-cc-pVTZ and aug-cc-pVQZ basis sets) and extrapolated DeltaCCSD(T) correction terms [difference between CCSD(T) and MP2 interaction energies] differ only slightly, which demonstrates the reliability and robustness of both techniques. The latter values, which represent new standards for the H-bonding and stacking structures of the uracil dimer, differ from the previously published data for the S22 set by a small amount. This suggests that interaction energies of the S22 set are generated with chemical accuracy. The most accurate CCSD(T)/CBS interaction energies are compared with interaction energies obtained from various computational procedures, namely the SCS-MP2 (SCS: spin-component-scaled), SCS(MI)-MP2 (MI: molecular interaction), MP3, dispersion-augmented DFT (DFT-D), M06-2X, and DFT-SAPT (SAPT: symmetry-adapted perturbation theory) methods. Among these techniques, the best results are obtained with the SCS(MI)-MP2 method. Remarkably good binding energies are also obtained with the DFT-SAPT method. Both DFT techniques tested yield similarly good interaction energies. The large magnitude of the stacking energy for the uracil dimer, compared to that of the benzene dimer, is explained by attractive electrostatic interactions present in the stacked uracil dimer. These interactions force both subsystems to approach each other and the dispersion energy benefits from a shorter intersystem separation.


Molecular polarizability in open ensemble simulations of aqueous nanoconfinements under electric field.
Molecular polarization at aqueous interfaces involves fast degrees of freedom that are often averaged-out in atomistic-modeling approaches. The resulting effective interactions depend on a specific environment, making explicit account of molecular polarizability particularly important in solutions with pronounced anisotropic perturbations, including solid/liquid interfaces and external fields. Our work concerns polarizability effects in nanoscale confinements under electric field, open to an unperturbed bulk environment. We model aqueous molecules and ions in hydrophobic pores using the Gaussian-charge-on-spring BK3-AH representation. This involves nontrivial methodology developments in expanded ensemble Monte Carlo simulations for open systems with long-ranged multibody interactions and necessitates further improvements for efficient modeling of polarizable ions. Structural differences between fixed-charge and polarizable models were captured in molecular dynamics simulations for a set of closed systems. Our open ensemble results with the BK3 model in neat-aqueous systems capture the ∼10% reduction of molecular dipoles within the surface layer near the hydrophobic pore walls in analogy to reported quantum mechanical calculations at water/vapor interfaces. The polarizability affects the interfacial dielectric behavior and weakens the electric-field dependence of water absorption at pragmatically relevant porosities. We observe moderate changes in thermodynamic properties and atom and charged-site spatial distributions; the Gaussian distribution of mobile charges on water and ions in the polarizable model shifts the density amplitudes and blurs the charge-layering effects associated with increased ion absorption. The use of polarizable force field indicates an enhanced response of interfacial ion distributions to applied electric field, a feature potentially important for in silico modeling of electric double layer capacitors.


Identification and characterization of the ZRT, IRT-like protein (ZIP) family genes reveal their involvement in growth and kojic acid production in Aspergillus oryzae.
The ZRT, IRT-like protein (ZIP) family exists in many species and plays an important role in many biological processes, but little is known about ZIP genes in Aspergillus oryzae. Here, 10 ZIP genes in A. oryzae were identified and these were classified into four groups based on phylogenetic analysis. The structures of these AoZip genes were determined, which indicated a great divergence of AoZip members from different groups. Synteny analysis revealed that AoZip7, AoZip8, and AoZip10 are conserved among Aspergillus species. We also found that the promoter regions of AoZip2, AoZip7, AoZip8, and AoZip10 contain multiple conserved response elements. Expression analysis revealed that AoZips exhibited different expression patterns in response to different metal treatments. Moreover, overexpression and RNA-interference (RNAi) of AoZip2 led to a decrease in mycelium growth diameter and inhibited conidia formation. AoZip2 overexpression and RNAi strains showed distinct sensitivity to severely Zn/Mn-depleted stress. In addition, kojic acid production was markedly lower in AoZip2 overexpression and RNAi strains than in the control strains, and the expression of kojA, kojR, and kojT was down-regulated in AoZip2 overexpression and RNAi strains. This study provides new insights into our understanding of ZIP genes and lays a foundation for further investigation of their roles in Aspergillus oryzae.


Modelling opportunity: An examination of quadratic effects of adolescent Venezuelan substance use.
Numerous studies have found a linear relationship between an exposure opportunity and age of first drug use. This study further tests this relationship by exploring whether a quadratic exposure opportunity best fits the data on age of first use and whether gender moderates this relationship. That is, is there a peak age in which the transition to use occurs for male compared to female adolescents? A sample of 1716 adolescents from 14 public and private schools, representative of two school districts in Caracas, Venezuela, was examined using a zero-inflated Poisson modelling approach to test for quadratic effects. A series of models were tested for each set of substances (alcohol, tobacco and other drugs) to assess whether a quadratic model has better predictive ability than linear models and to test whether gender moderates the quadratic relationship. After controlling for common covariates, the quadratic models for alcohol indicated the peak age of transition from an exposure opportunity to use was 10-years of age in this Venezuelan sample. Gender did not moderate these models suggesting an important move toward gender equality in substance use. Focused efforts on preventing exposure to alcohol use during these windows of rapid transition is likely to have the greatest impact on delaying age of onset, which will reduce the overall prevalence of alcohol related problems among adolescents.


Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine.
Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.


15-Deoxy-{delta}12,14-prostaglandin j2 inhibits interleukin-1{beta}-induced nuclear factor-{kappa}b in human amnion and myometrial cells: mechanisms and implications.
Proinflammatory cytokines and prostaglandins play key roles in term and preterm human labor. The expression of the prostaglandin synthetic enzyme cyclooxygenase (COX)-2 and cytokines IL-1beta and IL-8 increases within the uterus at the time of labor, and each is regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). In addition to its role in driving inflammation, COX-2 may also synthesize 15-deoxy-Delta (12, 14)-prostaglandin J(2) (15d-PGJ(2)), an antiinflammatory cyclopentenone prostaglandin (cyPG), which acts in some cells as an agonist of peroxisome proliferator-activated receptors (PPARs). We found that PPARalpha and -gamma proteins are expressed in both amnion epithelial and myometrial cells, but synthetic PPAR agonists could not inhibit NF-kappaB activity or COX-2 expression. 15d-PGJ(2) inhibited NF-kappaB activity and COX-2 expression in both cell types. This was unaffected by a PPAR antagonist and could be mimicked by the cyPG PGA(1) but not 9,10-dihydro-15d-PGJ(2) in which the cyclopentenone ring is disrupted. This shows that, in amnion and myometrium, inhibition of NF-kappaB activity and COX-2 expression by 15d-PGJ(2) is independent of PPARs and requires the cyclopentenone ring. We further show that 15d-PGJ(2) acts at multiple levels in the NF-kappaB pathway: blocking inhibitor of kappaBalpha degradation by repressing inhibitor of kappaB kinase activation and the 26S proteasome and also repressing NF-kappaB DNA binding and phosphorylation. Our data suggest that PPARs are unlikely to play a role in the regulation of either NF-kappaB or COX-2 in human amnion and myometrium. Targeting of NF-kappaB is a potential therapeutic strategy in preterm labor. PPAR agonists are unlikely to be effective in this context, but cyPGs may have potential.


Decreasing donor site morbidity after groin vascularized lymph node transfer with lessons learned from a 12-year experience and review of the literature.
Donor site morbidity related to vascularized lymph node transfer (VLNT) remains a cause of worry among surgeons. As such, our study explores donor site morbidity after VLNT with or without concomitant deep inferior epigastric artery perforator (DIEP) flap breast reconstruction. Furthermore, we evaluate our surgical approach to ascertain whether it reduces the morbidity rate. A retrospective chart review of donor site complications and surgical techniques was performed from 2006 to 2018. The patients' medical histories and demographic data were analyzed for risk factors. Patients were contacted by telephone for a long-term follow-up questionnaire. A literature review was implemented to evaluate the reported donor site complications and surgical strategies in literature. Complications were evaluated with and without concomitant autologous breast reconstruction (DIEP flap). Eighty-nine patients were included in our case series. Sixty-five cases (73%) were combined with DIEP flap breast reconstruction. Seroma rate diminished from 60% in the first 39 cases to 18% in the last five years (50 cases) (p < 0,001). Lymphedema of the afferent lower limb is described in the literature but did not occur in our series. Seroma formation is the most common donor site morbidity after groin VLNT flap harvest, particularly when combined with DIEP flap breast reconstruction. This paper contains the largest reported series of combined VLNT + DIEP flaps and describes surgical strategies on how to decrease seroma formation and avoid iatrogenic lymphedema of the lower limb.


Kangaroo care in a neonatal context: parents' experiences of information and communication of nurse-parents.
Kangaroo Care (KC) is an evidence-based nursing practice with many benefits for infants and parents. The purpose of this study was to describe parents' experience of information and communication mediated by staff nurses before and during KC at neonatal wards. A qualitative study with semi-structured interviews was performed. The sample consisted of 20 parents. THE RESULTS SHOW THAT THE INFORMATION AND COMMUNICATION WERE EXPERIENCED AS BOTH OPTIMAL AND SUBOPTIMAL INCLUDING FOLLOWING CATEGORIES: initially conflicting emotions in relation to KC, participation and confidence in KC is evolving, strengthening preparation and context is decisive as well as parental sense and caution. The overall theme was that good preparation will contribute to a positive experience of KC. The conclusion is that most of the parents had positive experiences of KC. The information and communication from the staff nurses encouraged and motivated the parents to practice KC, in a sense that it was a natural way to get to know the infant, when the staff nurses were well versed in the method and coherent and supportive. Conflicting emotions emerged when staff nurses practised KC as a routine without deeper knowledge and skills of the method and its advantages as well as without sensitivity to parents' vulnerable situation.


CK2 is responsible for phosphorylation of human La protein serine-366 and can modulate rpL37 5'-terminal oligopyrimidine mRNA metabolism.
La protein binds precursors to 5S rRNA, tRNAs, and other transcripts that contain 3' UUU-OH and also promotes their maturation in the nucleus. Separate from this function, human La has been shown to positively modulate the translation of mRNAs that contain complex 5' regulatory motifs that direct internal initiation of translation. Nonphosphorylated La (npLa) inhibits pre-tRNA processing, while phosphorylation of human La serine-366 (S(366)) promotes pre-tRNA processing. npLa was found specifically associated with a class of mRNAs that have unusually short 5' untranslated regions comprised of terminal oligopyrimidine (5'TOP) tracts and that encode ribosomal proteins and translation elongation factors. Although La S(366) represents a CK2 phosphorylation site, there was no evidence that CK2 phosphorylates it in vivo. We used the CK2-specific inhibitor, 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), and antisense-mediated knockdown to demonstrate that CK2 is responsible for La S(366) phosphorylation in vivo. Hypophosphorylation was not associated with significant change in total La levels or proteolytic cleavage. Quantitative reverse transcription-PCR revealed increased association of the 5'TOP-mRNA encoding ribosomal protein L37 (rpL37) with La after TBB treatment. Transfection revealed more rpL37 mRNA associated with nonphosphorylatable La A(366) than with La S(366), concomitant with La A(366)-specific shift of a fraction of L37 mRNA off polysomes. The data indicate that CK2 phosphorylates La S(366) in vivo, that this limits 5'TOP mRNA binding, and that increasing npLa leads to greater association with potentially negative effects on TOP mRNA translation. Consistent with data that indicate that phosphorylation reverses negative effects of npLa on tRNA production, the present data suggest that CK2 phosphorylation of La can affect production of the translational machinery.


Health care utilization of chronic inebriates.
Chronic inebriates often use emergency services, including the emergency department (ED), because they lack other resources or access to primary care. Because of their complicated medical needs, which are often exacerbated by acute intoxication and related illness or injury, a relatively small number of acutely intoxicated chronic inebriates can stretch ED resources and contribute to ED over-crowding. In order to address this, as well as overutilization of other county services, three county programs were developed (ethnic- and gender-specific supportive housing; intensive street case management) to reduce emergency resource utilization while still providing a safe environment. This study determined the effectiveness of these programs. The authors hypothesized that program enrollment would reduce medical and detoxification (detox) expenditures for this patient population. Pre- and postprogram comparisons were made on the number of detox and medical visits, insured days, and charges. Data were retrieved (with patients' written informed consent) from hospital and health plan billings and county databases. Descriptive statistics compared groups pre and post enrollment. Least-squares regression predicted total and non-inpatient medical charges. Complete data were available for 92 of 122 patients (mean age = 47 years; 60% Native American; 93% male); seven had severe illnesses or injuries, skewing the mean. However, there were significant overall reductions in the median numbers of yearly detox visits (10 to 1) and medical visits (11 to 8), and in median medical charges ($5,436 to $2,770) and total health care charges ($9,297 to $5,218). The median number of days insured increased (284 to 353). By regression analysis, injury was the most important preprogram predictor of medical charges; illness drives charges post-entry. Alcohol-related visits added to the model before entry but disappeared post-entry. These programs reduced health care use for most patients. However, serious medical illness or injury in a small number of patients contributed heavily to resource utilization.


[How are interstitial lung diseases diagnosed in Germany? Results of the scientific registry for the exploration of interstitial lung diseases ("Fibrosis registry") of the WATL].
From 1995 to 1999 we evaluated questionnaires sent by pulmonologists and departments of pulmonology in order to register interstitial lung diseases. On the whole 1142 patients (579 males, 563 females, mean age 51.1 +/- 15.3 years, sarcoidosis, n = 511, extrinsic allergic alveolitis, n = 145, idiopathic pulmonary fibrosis, n = 308, bronchiolitis obliterans organizing pneumonia (BOOP), n = 93, others, n = 85) were recorded in the registry. With reference to the mean age sarcoidosis occurred most frequently in the fourth decade and idiopathic pulmonary fibrosis in the sixth decade. In all these diseases bronchoscopy with bronchoalveolar lavage and transbronchial biopsy was predominantly used for further diagnosis. It was striking that high-resolution computed tomography of the thorax was still rarely used when diagnosing these diseases. Apart from the group with BOOP the number of non-smokers in men and women was decisively higher than the average of the population of Germany.


Comparing venlafaxine extended release and fluoxetine for preventing the recurrence of major depression: results from the PREVENT study.
This secondary analysis from the Prevention of Recurrent Episodes of Depression with Venlafaxine Extended Release (ER) for Two Years (PREVENT) study compared the efficacy of venlafaxine ER and fluoxetine for the prevention of recurrence in patients with a history of recurrent major depressive disorder (MDD). Patients received double-blind treatment with venlafaxine ER (75-300 mg/d) or fluoxetine (20-60 mg/d) for 10 weeks (acute phase). Responders (17-item Hamilton Rating Scale for Depression [HAM-D(17)] score ≤ 12 and ≥ 50% reduction from baseline) continued on the same treatment during the 6-month continuation phase. At the start of the first and second 12-month maintenance phases, venlafaxine ER responders were randomly assigned to receive venlafaxine ER or placebo, whereas patients receiving fluoxetine continued to receive fluoxetine throughout both maintenance phases. The primary outcome was time to recurrence (HAM-D(17) > 12, reduction in HAM-D(17) score ≤ 50% from acute baseline, and meeting DSM-IV criteria for a diagnosis of MDD), which was assessed using Kaplan-Meier estimates. Using the primary definition of recurrence, the estimated probability of not experiencing a recurrence was 71.9% for venlafaxine ER (n = 160) and 55.8% for fluoxetine (n = 99) across 24 months of maintenance treatment. For this primary analysis, the overall effect of venlafaxine ER treatment was not statistically significant (p = 0.399) compared with fluoxetine; however, a significant treatment-by-time interaction was observed (p = 0.034). No significant between-group differences were observed with any of the secondary efficacy variables. Venlafaxine ER and fluoxetine were similarly well tolerated across 2 years of maintenance-phase therapy.


Lipid metabolism and intake behavior of dairy cows: effects of intravenous lipid and beta-adrenergic supplementation.
The goal of this experiment was to determine whether modulation of beta 2-adrenoceptors influenced DMI of lactating dairy cows. Because stimulation of these receptors induces mobilization of body fat stores, the effect of such stimulation on feed intake was compared with the effect of an intravenous administration of lipid nutrients. Four treatments were infused intravenously over a 4-h period: 1) a beta 2-agonist (clenbuterol), 2) a beta-blocker (propranolol), 3) triglyceride emulsion (lipids), or 4) saline. Two trials were carried out for the same four cows to compare the effects of two expected lipolytic situations. Trial 1 used cows at 60 DIM treated with infusions from 0300 to 0700 h, and trial 2 used cows at 92 DIM treated with infusions from 0800 to 1200 h. Each trial was composed of three consecutive replications of a 4 x 4 balanced Latin square design with 2-d periods. A complete diet (70% maize silage and 30% concentrate) was offered for ad libitum intake. In both trials, clenbuterol reduced DMI on the day of infusion (-7.9 and -11.2% for trials 1 and 2, respectively) and on the following day (-5.1 and -6.3% in trials 1 and 2, respectively). This decrease occurred some time after the end of infusion. Intravenous lipid supplementation reduced DMI during infusion in both trials and during the entire day in trial 2. Both clenbuterol and lipids increased plasma NEFA only during infusion. Propranolol had no effect on DMI or basal lipolysis. The data demonstrated that stimulating beta 2-adrenoceptors reduced DMI but in a manner different from that of lipid energy supplementation.


The selective impairment of the perception of first-order motion by unilateral cortical brain damage.
First-order (Fourier) motion consists of stable spatiotemporal luminance variations. Second-order (non-Fourier) motion consists instead of spatiotemporal modulation of contrast, flicker, or spatial frequency. In spite of extensive psychophysical and computational analysis of the nature and relationship of these two types of motion, it remains unclear whether they are detected by the same mechanism or whether separate mechanisms are involved. Here we report the selective impairment of first-order motion, on a range of local and global motion tasks, in the contralateral visual hemifield of a patient with unilateral brain damage centered on putative visual areas V2 and V3 in the medial part of the occipital lobe. His perception of second-order motion was unimpaired. As his disorder is the obverse of that reported after damage in the vicinity of human visual area MT (V5), the results support models of motion processing in which first- and second-order motion are, at least in part, computed separately at the extrastriate cortical level.


Lexical organization and competition in first and second languages: computational and neural mechanisms.
How does a child rapidly acquire and develop a structured mental organization for the vast number of words in the first years of life? How does a bilingual individual deal with the even more complicated task of learning and organizing two lexicons? It is only until recently have we started to examine the lexicon as a dynamical system with regard to its acquisition, representation, and organization. In this article, I outline a proposal based on our research that takes the dynamical approach to the lexicon, and I discuss how this proposal can be applied to account for lexical organization, structural representation, and competition within and between languages. In particular, I provide computational evidence based on the DevLex model, a self-organizing neural network model, and neuroimaging evidence based on functional magnetic resonance imaging (fMRI) studies, to illustrate how children and adults learn and represent the lexicon in their first and second languages. In the computational research, our goal has been to identify, through linguistically and developmentally realistic models, detailed cognitive mechanisms underlying the dynamic self-organizing processes in monolingual and bilingual lexical development; in the neuroimaging research, our goal has been to identify the neural substrates that subserve lexical organization and competition in the monolingual and the bilingual brain. In both cases, our findings lead to a better understanding of the interactive dynamics involved in the acquisition and representation of one or multiple languages.


Spatial prediction and validation of zoonotic hazard through micro-habitat properties: where does Puumala hantavirus hole - up?
To predict the risk of infectious diseases originating in wildlife, it is important to identify habitats that allow the co-occurrence of pathogens and their hosts. Puumala hantavirus (PUUV) is a directly-transmitted RNA virus that causes hemorrhagic fever in humans, and is carried and transmitted by the bank vole (Myodes glareolus). In northern Sweden, bank voles undergo 3-4 year population cycles, during which their spatial distribution varies greatly. We used boosted regression trees; a technique inspired by machine learning, on a 10 - year time-series (fall 2003-2013) to develop a spatial predictive model assessing seasonal PUUV hazard using micro-habitat variables in a landscape heavily modified by forestry. We validated the models in an independent study area approx. 200 km away by predicting seasonal presence of infected bank voles in a five-year-period (2007-2010 and 2015). The distribution of PUUV-infected voles varied seasonally and inter-annually. In spring, micro-habitat variables related to cover and food availability in forests predicted both bank vole and infected bank vole presence. In fall, the presence of PUUV-infected voles was generally restricted to spruce forests where cover was abundant, despite the broad landscape distribution of bank voles in general. We hypothesize that the discrepancy in distribution between infected and uninfected hosts in fall, was related to higher survival of PUUV and/or PUUV-infected voles in the environment, especially where cover is plentiful. Moist and mesic old spruce forests, with abundant cover such as large holes and bilberry shrubs, also providing food, were most likely to harbor infected bank voles. The models developed using long-term and spatially extensive data can be extrapolated to other areas in northern Fennoscandia. To predict the hazard of directly transmitted zoonoses in areas with unknown risk status, models based on micro-habitat variables and developed through machine learning techniques in well-studied systems, could be used.


[Level of evidence for therapeutic drug monitoring of vancomycin].
Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).


Safety and immunogenicity observations pooled from eight clinical trials of recombinant human thrombin.
We evaluated safety and immunogenicity observations pooled from 8 clinical trials of recombinant human thrombin (rThrombin), an active topical hemostatic agent. Recombinant thrombin was applied with an absorbable gelatin sponge or spray applicator during a surgical procedure (day 1). Adverse events and laboratory parameters were monitored until study end (day 29). Immunogenicity was evaluated after study completion on plasma samples collected at baseline and on day 29. Studies included 583 rThrombin-treated patients (median age, 59 years; 54% men). Surgical procedures included: spinal, 33% of patients; hepatic resection, 14%; peripheral arterial bypass, 23%; arteriovenous graft formation for hemodialysis access, 18%; and skin graft after burn wound excision, 12%. Adverse events reported for >or= 10% patients included incision site pain, procedural pain, nausea, constipation, pyrexia, anemia, insomnia, vomiting, and pruritus. Five of 552 patients developed antibodies to rThrombin (0.9%; 95% CI, 0.3 to 2.1; day 29); antibodies did not neutralize the biologic activity of native human thrombin. At baseline, 12 patients had pre-existing, antibodies recognizing rThrombin (12 of 552; 2.2%; 95% CI, 1.1 to 3.8); these patients had no previous exposure to rThrombin and their antibody titer did not increase >or= 1.0 unit (>or= 10-fold) at day 29. Results from 8 clinical trials collectively demonstrated that rThrombin is well tolerated in numerous surgical settings when used as a topical adjunct to hemostasis. Adverse events and changes in laboratory parameters were consistent with commonly reported postoperative events. Less than 1% of patients developed antibodies to rThrombin; the antibodies did not neutralize native human thrombin.


Large-scale single-neuron speech sound encoding across the depth of human cortex.
Understanding the neural basis of speech perception requires that we study the human brain both at the scale of the fundamental computational unit of neurons and in their organization across the depth of cortex. Here we used high-density Neuropixels arrays1-3 to record from 685 neurons across cortical layers at nine sites in a high-level auditory region that is critical for speech, the superior temporal gyrus4,5, while participants listened to spoken sentences. Single neurons encoded a wide range of speech sound cues, including features of consonants and vowels, relative vocal pitch, onsets, amplitude envelope and sequence statistics. Neurons at each cross-laminar recording exhibited dominant tuning to a primary speech feature while also containing a substantial proportion of neurons that encoded other features contributing to heterogeneous selectivity. Spatially, neurons at similar cortical depths tended to encode similar speech features. Activity across all cortical layers was predictive of high-frequency field potentials (electrocorticography), providing a neuronal origin for macroelectrode recordings from the cortical surface. Together, these results establish single-neuron tuning across the cortical laminae as an important dimension of speech encoding in human superior temporal gyrus.


High-throughput electrochemical sensing platform for screening nanomaterial-biomembrane interactions.
A high-throughput, automated screening platform has been developed for the assessment of biological membrane damage caused by nanomaterials. Membrane damage is detected using the technique of analyzing capacitance-current peak changes obtained through rapid cyclic voltammetry measurements of a phospholipid self-assembled monolayer formed on a mercury film deposited onto a microfabricated platinum electrode after the interaction of a biomembrane-active species. To significantly improve wider usability of the screening technique, a compact, high-throughput screening platform was designed, integrating the monolayer-supporting microfabricated electrode into a microfluidic flow cell, with bespoke pumps used for precise, automated control of fluid flow. Chlorpromazine, a tricyclic antidepressant, and a citrate-coated 50 nm diameter gold nanomaterial (AuNM) were screened to successfully demonstrate the platform's viability for high-throughput screening. Chlorpromazine and the AuNM showed interactions with a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) monolayer at concentrations in excess of 1 µmol dm-3. Biological validity of the electrochemically measured interaction of chlorpromazine with DOPC monolayers was confirmed through quantitative comparisons with HepG2 and A549 cytotoxicity assays. The platform also demonstrated desirable performance for high-throughput screening, with membrane interactions detected in <6 min per assay. Automation contributed to this significantly by reducing the required operating skill level when using the technique and minimizing fluid consumption.


Simultaneous intraoperative detection of methicillin-resistant Staphylococcus and pan-bacterial infection during revision surgery: use of simple DNA release by ultrasonication and real-time polymerase chain reaction.
Periprosthetic infection is one of the most serious complications of arthroplasty, and low-grade infections are particularly difficult to diagnose with use of conventional culture methods. Real-time polymerase chain reaction is a potentially viable way to overcome this detection problem as it is a more rapid and sensitive technique. In the current study, we used intraoperative polymerase chain reaction identification combined with a simple DNA-release method with ultrasonication to diagnose periprosthetic infections during revision surgery. Thirty revision arthroplasty procedures were included in this prospective study. Surgical specimens were obtained intraoperatively, treated with ultrasonication, and then analyzed with real-time polymerase chain reaction. Methicillin-resistant Staphylococcus-specific polymerase chain reaction and 16S rRNA gene universal polymerase chain reaction were performed simultaneously to facilitate both specific and broad-range detection. Specimens obtained from the same sites were also analyzed with microbiologic culture and histopathological evaluation. The specific polymerase chain reaction revealed methicillin-resistant Staphylococcus infection in specimens from six of the thirty operations analyzed in the present study, and the 16S rRNA gene universal polymerase chain reaction analysis was positive for specimens from thirteen operations. Conventional cultures revealed six methicillin-resistant Staphylococcus infections, two Staphylococcus aureus infections, one infection with another Staphylococcus species, and two Streptococcus infections. The sensitivity of the polymerase chain reaction method was 0.87 and the specificity was 0.8 when compared with the combined results of microbiologic culture and histopathological evaluation. The ultrasonication method that we developed for accelerated DNA sample preparation as a replacement for conventional extraction made possible the potential intraoperative identification of periprosthetic infection during revision surgery. The simultaneous detection of methicillin-resistant Staphylococcus and broad-range bacterial infections would be invaluable for the informed selection of antibiotics and also for the formulation of the subsequent treatment strategy (a one-stage or two-stage revision) for the patient.


Mechanisms of aggregation in an ant-tended treehopper: Attraction to mutualists is balanced by conspecific competition.
Understanding the spatial structure of populations and communities has been a dominant focus of ecological research, and spatial structure is increasingly seen as critical for understanding population dynamics. Habitat (or host) preference is a proximate mechanism that can generate aggregation or overdispersion, lending insight into the ultimate consequences of observed spatial distributions. Publilia concava is a univoltine phloem-feeding insect that forms mutualistic associations with ants, which consume honeydew and protect treehoppers from predation. Treehopper adults and nymphs are aggregated at the scale of goldenrod plant stems, and previous studies have suggested that this aggregation is an adaptive response that increases feeding performance or maximizes benefits of ant-tending. Previous studies have also shown experimentally that individual treehoppers preferentially oviposit on plants with ants present, but a complimentary hypothesis that treehoppers prefer to oviposit near conspecifics (e.g., to take advantage of density-dependent ant attraction) remains untested. We show that, as expected, the probability of treehopper oviposition increases with ant-presence and relative ant abundance. However, we also find that treehopper oviposition decreases with increasing treehopper density. Thus our results are inconsistent with the hypothesis that treehopper aggregation is a socially cooperative strategy to attract ants; we suggest that aggregation is a form of conflict and an unavoidable by-product of individual responses to ant-tending levels.


Antiinfective properties of human milk.
The unfavorable effects of neonatal immunodeficiency are limited by some naturally occurring compensatory mechanisms, such as the introduction of protective and immunological components of human milk in the infant. Breast-feeding maintains the maternal-fetal immunological link after birth, may favor the transmission of immunocompetence from the mother to her infant, and is considered an important contributory factor to the neonatal immune defense system during a delicate and crucial period for immune development. Several studies have reported that breast-feeding, because of the antimicrobial activity against several viruses, bacteria, and protozoa, may reduce the incidence of infection in infants. The protection from infections may be ensured either passively by factors with antiinfective, hormonal, enzymatic, trophic, and bioactive activity present in breast milk, or through a modulator effect on the neonatal immune system exerted by cells, cytokines, and other immune agents in human milk.


Virtue versus ethical obligations: working for system-wide change.
Clinical ethics issues most often focus on the individual encounter or relationship between a specific doctor and patient. This is an appropriate focus, since this dynamic defines the normal course of health care delivery and it is within this relationship that most ethical dilemmas arise. Once a provider has discharged his or her ethical duties to a particular patient, further efforts toward assisting that patient or toward social policy affecting health care in general are virtuous but are not ethical mandates. Issues of distributive justice in health care allocation and reimbursement are examples of policy issues that impact persons who may not be patients in one's practice but who may benefit from the actions of the dental profession. Many times, as in the case presented, the dentist's awareness of such issues of distributive injustice may arise from an individual patient encounter. In the process of attempting to secure justice for a particular patient, the dentist may become aware of the broader social context of the problem. This awareness calls upon dentists, just as it calls upon other health care providers, to become involved via their professional organization and to work for distributive justice. While individual values may mediate the duty to advocate for many social issues, professional values that are oriented toward improving the health and well-being of all in a society require organized health care professions to advance these causes.


Transcriptome analysis of thermogenic Arum concinnatum reveals the molecular components of floral scent production.
Several plant species can generate enough heat to increase their internal floral temperature above ambient temperature. Among thermogenic plants, Arum concinnatum shows the highest respiration activity during thermogenesis. However, an overall understanding of the genes related to plant thermogenesis has not yet been achieved. In this study, we performed de novo transcriptome analysis of flower organs in A. concinnatum. The de novo transcriptome assembly represented, in total, 158,490 non-redundant transcripts, and 53,315 of those showed significant homology with known genes. To explore genes associated with thermogenesis, we filtered 1266 transcripts that showed a significant correlation between expression pattern and the temperature trend of each sample. We confirmed five putative alternative oxidase transcripts were included in filtered transcripts as expected. An enrichment analysis of the Gene Ontology terms for the filtered transcripts suggested over-representation of genes involved in 1-deoxy-D-xylulose-5-phosphate synthase (DXS) activity. The expression profiles of DXS transcripts in the methyl-D-erythritol 4-phosphate (MEP) pathway were significantly correlated with thermogenic levels. Our results suggest that the MEP pathway is the main biosynthesis route for producing scent monoterpenes. To our knowledge, this is the first report describing the candidate pathway and the key enzyme for floral scent production in thermogenic plants.


Numerical modeling of transverse mode competition in strongly pumped multimode fiber lasers and amplifiers.
A model based on propagation-rate equations with consideration of transverse gain distribution is built up to describe the transverse mode competition in strongly pumped multimode fiber lasers and amplifiers. An approximate practical numerical algorithm by multilayer method is presented. Based on the model and the numerical algorithm, the behaviors of multitransverse mode competition are demonstrated and individual transverse modes power distributions of output are simulated numerically for both fiber lasers and amplifiers under various conditions.


Relative inactivation by Staphylococcus aureus of eight cephalosporin antibiotics.
These studies extend the recent observation that cefazolin is inactivated to a greater extent than cephaloridine by some strains of penicillinase-producing Staphylococcus aureus, whereas cephalothin undergoes little if any inactivation. In Mueller-Hinton broth (inoculum, 3 x 10(6)) 100 recently isolated strains had minimal inhibitory concentrations (MICs) </= 2 mug/ml for cephalothin and cephaloridine, whereas in Trypticase soy broth (TSB) 50% had MICs > 2 mug/ml and 10% (designated "resistant" strains) were >8 mug/ml for cephaloridine but remained </=2 mug/ml for cephalothin. A large inoculum (3 x 10(7)) of strains with high MICs in TSB almost completely inactivated 50 mug of cefazolin per ml in 6 h, with progressively less inactivation, in the following order, of cephaloridine, cephalexin, cephradine, cephapirin, and cefamandole; cefoxitin and cephalothin underwent little if any inactivation. The greater inactivation in TSB than in Mueller-Hinton broth appeared to be due to a greater production of beta-lactamases by each colony-forming unit, since the inoculum size in the two broths was not significantly different. In contrast, "susceptible" strains (MICs </= 2 mug/ml in both broths) inactivated cephaloridine more than cefazolin, and equal amounts of powdered bacterial extracts confirmed the fact that qualitatively different beta-lactamases were produced by the susceptible and resistant strains. Disk diffusion tests were unreliable in separating the two groups of staphylococci. The clinical significance of inactivation by strains with high MICs is not known but, unless susceptibility can be clearly established, cephalothin appears preferable for severe staphylococcal infections, since it undergoes little if any inactivation by any strains of staphylococci.


The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care.
The 2011 Canadian Cardiovascular Society Heart Failure (HF) Guidelines Focused Update reviews the recently published clinical trials that will potentially impact on management. Also reviewed is the less studied but clinically important area of sleep apnea. Finally, patients with advanced HF represent a group of patients who pose major difficulties to clinicians. Advanced HF therefore is examined from the perspectives of HF complicated by renal failure, the role of palliative care, and the role of mechanical circulatory support (MCS). All of these topics are reviewed from a perspective of practical applications. Important new studies have demonstrated in less symptomatic HF patients that cardiac resynchronization therapy will be of benefit. As well, aldosterone receptor antagonists can be used with benefit in less symptomatic HF patients. The important role of palliative care and the need to address end-of-life issues in advanced HF are emphasized. Physicians need to be aware of the possibility of sleep apnea complicating the course of HF and the role of a sleep study for the proper assessment and management of the conditon. Patients with either acute severe or chronic advanced HF with otherwise good life expectancy should be referred to a cardiac centre capable of providing MCS. Furthermore, patients awaiting heart transplantation who deteriorate or are otherwise not likely to survive until a donor organ is found should be referred for MCS.


Factors associated with emergency department useamong veteran psychiatric patients.
Frequent utilization of emergency department (ED) services contributes substantially to the cost of healthcare nationally and is often driven by psychiatric factors. Using national-level data from the Veterans Health Administration (VHA), the present study examined patient-level factors associated with ED use among veteran psychiatric patients. Veterans who had at least one ED visit with a psychiatric diagnosis in fiscal years 2011-2012 (n = 226,122) were identified in VHA administrative records. Andersen's behavioral model of healthcare utilization was used to identify need, enabling, and predisposing factors associated with frequency of ED use (primary outcome) in multivariate regression models. Greater ED use was primarily linked with need (psychotic, anxiety, personality, substance use, and bipolar disorders) and enabling (detoxification-related service utilization and homelessness) factors. Chronic medical conditions, receipt of an opioid prescription, and predisposing factors (e.g., younger age) were also linked to greater ED use; however, the effect sizes for these factors were markedly lower than those of most psychiatric and psychosocial factors. The findings suggest that intensive case management programs aimed reducing frequent ED use among psychiatric patients may require greater emphasis on homelessness and other psychosocial deficits that are common among these patients, and future research should explore cost-effective approaches to implementing these programs.


Massive colonic diverticular hemorrhage in a transplant patient.
An infrequent colonic complication, massive diverticular hemorrhage, occurred in a high-risk renal transplant recipient. Arteriographic location of the bleeding site, colotomy and arterial ligation were used to successfully control the hemorrhage and gave a satisfactory longterm result.


Collision Avoidance With Multiple Walkers: Sequential or Simultaneous Interactions?
Collision avoidance between multiple walkers, such as pedestrians in a crowd, is based on a reciprocal coupling between the walkers with a continuous loop between perception and action. Such interpersonal coordination has previously been studied in the case of dyadic locomotor interactions. However, when walking through a crowd of people, collision avoidance is not restricted to dyadic interactions. We examined how dyadic avoidance (1 vs. 1) compared to triadic avoidance (1 vs. 2). Additionally, we examined how the dynamics of a passable gap between two walkers affected locomotor interactions. To this end, we manipulated the starting formation of two walkers that formed a potentially pass-able gap for the other walker. We analyzed the interactions in terms of the evolution over time of the Minimal Predicted Distance and the Dynamics of the Gap, which both provide information about what action is afforded (i.e., passing in front/behind and the pass-ability of the gap). Results showed that some triadic interactions invited for sequential interactions, resulting in avoidance strategies comparable with dyadic interactions. However, some formations resulted in simultaneous interactions where the dynamics of the pass-ability of the gap revealed that the coordination strategy emerged over time through the bi-directional interactions between all walkers. Future work should address which circumstances invite for simultaneous and which for sequential interactions between multiple walkers. This study contributed toward understanding how collision is avoided between multiple walkers at the level of the local interactions.


Feasibility and usability of experience sampling methodology for capturing everyday experiences of individuals with autism spectrum disorders.
Understanding experiences from the perspective of adults with autism spectrum disorders (ASD), in the myriad of circumstances in which they find themselves every day, is crucial for developing client-centered interventions. However, capturing these experiences can be difficult. To investigate the feasibility and usability of experience sampling method (ESM), an ecological momentary assessment, for studying individuals with ASD. Four participants (2 males) with Asperger's syndrome or high functioning autism aged 16-32 years carried an iPod touch or iPhone with a pre-installed ESM survey exploring the situation and their perceived internal experiences. Participants were asked to respond to the survey 7 times daily, at random times generated by the device, for 7 days. A high signal response rate (mean = 71%) and a short average time required for survey completion (mean = 1 min 42 s) supported feasibility of the ESM for use in research with individuals with ASD. Participants reported that the questions were straightforward and that survey completion interfered very little with everyday activities, supporting acceptability of the method. Results of a split-week analysis revealed consistency of experiences; correlations among experiences that are linked logically provided evidence of the internal logic of data gathered using the ESM. Through graphic analysis, we illustrated the usability of ESM for capturing the influence of everyday contexts on internal experiences/perceptions. The ESM holds promise for examining the impact of social context on the everyday experiences of individuals with ASD.


Renal graft outcome in autosomal dominant medullary cystic kidney disease type 1.
Medullary cystic kidney disease (MCKD) is an inherited interstitial nephritis, leading to end-stage renal disease (ESRD) between the fourth and seventh decade of life. MCKD shares clinical and morphological features with nephronophthisis, although advances in molecular genetics have distinguished these 2 entities. Data regarding graft survival after kidney transplantation in MCKD patients are extremely limited. The aim of this study was to compare renal graft survival in transplanted MCKD1 and non-MCKD1 patients, to discover whether renal transplantation can be considered as an acceptable treatment for MCKD. Thirty-three transplanted patients with MCKD1 and 33 controls (transplanted due to other causes) were included in the study. Graft losses were considered censored for death. Graft survival was evaluated with the Kaplan-Meier method, and comparisons between groups were made by log-rank test. Cox regression analysis was used to estimate the effect of several variables on graft survival, and the chi-square test was used to compare groups of categorical data. The 1-year cumulative graft survival rate for the MCKD1 group was 97%, while at 5 and 10 years it was 94% and 86%, respectively. For the control group, the respective values at years 1, 5 and 10 were 97%, 97% and 90%. Comparisons of graft survival rates between the 2 groups revealed no significant differences. Renal graft survival of transplanted MCKD1 patients was not shown to be inferior in comparison with that for patients undergoing transplants due to other causes. Therefore, it may represent a treatment of choice in MCKD1 patients with ESRD.


Membrane fission by protein crowding.
Membrane fission, which facilitates compartmentalization of biological processes into discrete, membrane-bound volumes, is essential for cellular life. Proteins with specific structural features including constricting rings, helical scaffolds, and hydrophobic membrane insertions are thought to be the primary drivers of fission. In contrast, here we report a mechanism of fission that is independent of protein structure-steric pressure among membrane-bound proteins. In particular, random collisions among crowded proteins generate substantial pressure, which if unbalanced on the opposite membrane surface can dramatically increase membrane curvature, leading to fission. Using the endocytic protein epsin1 N-terminal homology domain (ENTH), previously thought to drive fission by hydrophobic insertion, our results show that membrane coverage correlates equally with fission regardless of the hydrophobicity of insertions. Specifically, combining FRET-based measurements of membrane coverage with multiple, independent measurements of membrane vesiculation revealed that fission became spontaneous as steric pressure increased. Further, fission efficiency remained equally potent when helices were replaced by synthetic membrane-binding motifs. These data challenge the view that hydrophobic insertions drive membrane fission, suggesting instead that the role of insertions is to anchor proteins strongly to membrane surfaces, amplifying steric pressure. In line with these conclusions, even green fluorescent protein (GFP) was able to drive fission efficiently when bound to the membrane at high coverage. Our conclusions are further strengthened by the finding that intrinsically disordered proteins, which have large hydrodynamic radii yet lack a defined structure, drove fission with substantially greater potency than smaller, structured proteins.


A tighter generalization bound for reservoir computing.
While reservoir computing (RC) has demonstrated astonishing performance in many practical scenarios, the understanding of its capability for generalization on previously unseen data is limited. To address this issue, we propose a novel generalization bound for RC based on the empirical Rademacher complexity under the probably approximately correct learning framework. Note that the generalization bound for the RC is derived in terms of the model hyperparameters. For this reason, it can explore the dependencies of the generalization bound for RC on its hyperparameters. Compared with the existing generalization bound, our generalization bound for RC is tighter, which is verified by numerical experiments. Furthermore, we study the generalization bound for the RC corresponding to different reservoir graphs, including directed acyclic graph (DAG) and Erdős-R e´nyi undirected random graph (ER graph). Specifically, the generalization bound for the RC whose reservoir graph is designated as a DAG can be refined by leveraging the structural property (i.e., the longest path length) of the DAG. Finally, both theoretical and experimental findings confirm that the generalization bound for the RC of a DAG is lower and less sensitive to the model hyperparameters than that for the RC of an ER graph.


[Mortality from pleural mesothelioma in the province of Barcelona].
Pleural mesothelioma is a tumor of low incidence whose relation with the exposure to asbestos has been widely demonstrated. This exposure is generally occupational, but may also be domestic and there is the possibility of environmental exposure. By death certifications all the cases of death by pleural mesothelioma residing in the province of Barcelona from 1983-1990 have been identified. The rates of direct or indirect mortality (standardized by age and sex) (cause of standard mortality) for all the municipalities of the province with some case of mesothelioma over the period studied were calculated. The geographic localization of the companies using asbestos in the province of Barcelona has been obtained, being classified into 6 groups according to the productive subsector to which they belong. The rate of mortality per 100,000 inhabitants from 1983-1990 was 0.83 for males and 0.47 for females. The calculation of the cause of standard mortality for the municipalities of the province has shown an statistically significant increase in the risk of pleural mesothelioma for El Prat de Llobregat (ratio of standard mortality: 355.1) and Cerdanyola (ratio of standard mortality 313.9) where the companies producing fibrocement are located. Part of the cases of pleural mesothelioma in the province of Barcelona may not be due to direct occupational exposure; thus there may be important domestic and/or environmental exposure.


Feasibility of RetinoQuest: e-health application to facilitate and improve additional care for retinoblastoma survivors.
The current study aimed to evaluate the feasibility of RetinoQuest in clinical practice, from survivors and healthcare professionals' (HCPs) point of view. RetinoQuest is a touch screen computer program to monitor health-related quality of life (HRQoL) of retinoblastoma survivors via patient-reported outcome measures (PROMs) targeting children (4-10 years) as evaluated by their parents (proxy measures), adolescents (11-18 years), and adults. Feasibility was evaluated by the actual time taken to complete the PROMs, acceptability of the time as perceived by the users, the content of PROMs in RetinoQuest, and overall satisfaction with RetinoQuest. Ninety-six survivors participated: 41 parents of children, 38 adolescents, and 17 adults. Mean time to complete the evaluation form was 7.8 min (median 6.7, range 2.4-24.5), and 90% of the users stated that the time needed to complete PROMs in RetinoQuest was acceptable. The majority of users reported that it was important to answer the questions (88% of the parents, 66% of the adolescents, and 76% of the adult survivors) and that all important issues were covered, e.g., no missing questions (78, 84, and 76%, respectively). Satisfaction rate was high, 7.8 according to parents, 8.1 according to adolescents, and 7.7 for adults. RetinoQuest is a feasible e-health application to monitor HRQoL in retinoblastoma survivors in clinical practice. This tool allows for open and structured communication which can lead to early detection of psychosocial impacts on quality of life and referral of the retinoblastoma survivors.


Educational Electronic Health Records at the University of Victoria: Challenges, Recommendations and Lessons Learned.
There has been an acknowledged need for the integration of health technologies such as the electronic health record system (EHR) into health professional education. At the University of Victoria we have been experimenting with different models, architectures and applications of educational EHRs in the context of training health informatics, medical, and nursing students who will ultimately use this technology in their daily practice upon graduation. Our initial work involved the development of a Web-based portal that contained a number of open source EHRs and is described in this paper. In addition to the technical side, considerations around pedagogy and how best to integrate such technology into the classroom and educational experience are discussed. Finally, challenges and lessons learned from our decade of work in this area are discussed.


Myogenic and melanotic differentiated medulloblastoma: case report.
Medulloblastoma is the most common malignant tumor of childhood and usually arises from the cerebellar vermis. Several histological types of medulloblastoma have been described. Myogenic and melanotic differentiated medulloblastoma are seldom seen. We present a case diagnosed as myogenic medulloblastoma with focal areas of melanotic differentiation. A 4-year-old boy was admitted due to headache, nausea and vomiting for a month. MRI revealed a heterogeneous enhanced posterior fossa tumor rising from the fourth ventricle. He was operated and pathological examination of the specimen revealed myogenic medulloblastoma with myogenic and melanotic differentiation. According to our knowledge there are six cases reported in the literature so far. Oncogenic factors in medulloblastoma development are controversial. Presence of multiple differentiation patterns supports a pluripotent origin for these tumors.


Bulk-like and Interfacial Water Dynamics in Nafion Fuel Cell Membranes Investigated with Ultrafast Nonlinear IR Spectroscopy.
The water confined in the hydrophilic domains of Nafion fuel cell membranes is central to its primary function of ion transport. Water dynamics are intimately linked to proton transfer and are sensitive to the structural features and length scales of confinement. Here, ultrafast polarization-selective pump-probe and two-dimensional infrared vibrational echo (2D IR) experiments were performed on fully hydrated Nafion membranes with sodium counterions to explicate the water dynamics. Like aerosol-OT reverse micelles (AOT RMs), the water dynamics in Nafion are attributed to bulk-like core water in the central region of the hydrophilic domains and much slower interfacial water. Population and orientational dynamics of water in Nafion are slowed by polymer confinement. Comparison of the observed dynamics to those of AOT RMs helps identify local interactions between water and sulfonate anions at the interface and among water molecules in the core. This comparison also demonstrates that the well-known spherical cluster morphology of Nafion is not appropriate. Spectral diffusion of the interfacial water, which arises from structural dynamics, was obtained from the 2D IR experiments taking the core water to have dynamics similar to bulk water. Like the orientational dynamics, spectral diffusion was found to be much slower at the interface compared to bulk water. Together, the dynamics indicate slow reorganization of weakly hydrogen-bonded water molecules at the interface of Nafion. These results provide insights into proton transport mechanisms in fuel cell membranes, and more generally, water dynamics near the interface of confining systems.


Common risk factor approach to address socioeconomic inequality in the oral health of preschool children--a prospective cohort study.
Dental caries remains the most prevalent chronic condition in children and a major contributor to poor general health. There is ample evidence of a skewed distribution of oral health, with a small proportion of children in the population bearing the majority of the burden of the disease. This minority group is comprised disproportionately of socioeconomically disadvantaged children. An in-depth longitudinal study is needed to better understand the determinants of child oral health, in order to support effective evidence-based policies and interventions in improving child oral health. The aim of the Study of Mothers' and Infants' Life Events Affecting Oral Health (SMILE) project is to identify and evaluate the relative importance and timing of critical factors that shape the oral health of young children and then to seek to evaluate those factors in their inter-relationship with socioeconomic influences. This investigation will apply an observational prospective study design to a cohort of socioeconomically-diverse South Australian newborns and their mothers, intensively following these dyads as the children grow to toddler age. Mothers of newborn children will be invited to participate in the study in the early post-partum period. At enrolment, data will be collected on parental socioeconomic status, mothers' general and dental health conditions, details of the pregnancy, infant feeding practice and parental health behaviours and practices. Data on diet and feeding practices, oral health behaviours and practices, and dental visiting patterns will be collected at 3, 6, 12 and 24 months of age. When children turn 24-30 months, the children and their mothers/primary care givers will be invited to an oral examination to record oral health status. Anthropometric assessment will also be conducted. This prospective cohort study will examine a wide range of determinants influencing child oral health and related general conditions such as overweight. It will lead to the evaluation of the inter-relationship among main influences and their relative effect on child oral health. The study findings will provide high level evidence of pathways through which socio-environmental factors impact child oral health. It will also provide an opportunity to examine the relationship between oral health and childhood overweight.


Stimulated Raman scattering in a potassium titanyl phosphate crystal: simultaneous self-sum frequency mixing and self-frequency doubling.
A potassium titanyl phosphate crystal is used to achieve efficient stimulated Raman scattering conversion with simultaneous self-sum frequency mixing and self-frequency doubling. Inside a diode-pumped Nd:YAG Q-switched laser cavity, 1.03 W of 1129-nm second Stokes average output power and 0.25 W of 548-nm sum-frequency average power are simultaneously generated with a diode input power of 10 W at a pulse repetition rate of 10 kHz.


The Reinforcing Effects of Nicotine in Humans and Nonhuman Primates: A Review of Intravenous Self-Administration Evidence and Future Directions for Research.
Cigarette smoking is largely driven by the reinforcing properties of nicotine. Intravenous (IV) self-administration procedures are the gold standard for investigating the reinforcing effects of psychoactive drugs. The goal of this review was to examine the results of published investigations of the reinforcing effects of nicotine measured using IV self-administration procedures in humans and nonhuman primates. The body of literature using nonhuman primate subjects indicates nicotine functions as a positive reinforcer when available for self-administration via IV catheters. However, it can also be difficult to establish IV nicotine self-administration in nonhuman primates and sometimes supplemental strategies have been required (e.g., priming injections or food deprivation) before subjects acquire the behavior. Although the body of literature using human subjects is limited, the evidence indicates nicotine functions as a reinforcer via the IV route of administration in adult cigarette smokers. Rates of nicotine self-injection can be variable across subjects and responding is sometimes inconsistent across sessions in both humans and nonhuman primates. The Family Smoking Prevention and Tobacco Control Act, enacted in 2009, gave the Food and Drug Administration regulatory authority over the manufacture, marketing, and distribution of tobacco products. Research examining the threshold reinforcing doses for initiation and maintenance of nicotine self-administration, comparisons of the reinforcing effects of nicotine in adolescent versus adult subjects, investigations of gender differences in the reinforcing effects of nicotine, and studies of the abuse liability of non-nicotine tobacco product constituents and their ability to alter the reinforcing effects of nicotine will inform potential tobacco regulatory actions.


Safety and tolerability of varenicline tartrate (Champix(®)/Chantix(®)) for smoking cessation in HIV-infected subjects: a pilot open-label study.
The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix(®), Pfizer, Saint-Laurent, QC, Canada or Chantix(®), Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p = 0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9-12 was 42% (95% confidence interval [CI]: 26-58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline.


Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma.
The contribution of mutations in regulatory regions to tumorigenesis has been the subject of many recent studies. We propose a new framework for integrative analysis of genome-wide sequencing data by considering diverse genetic information. This approach is applied to study follicular lymphoma (FL), a disease for which little is known about the contribution of regulatory gene mutations. Results from a test FL cohort revealed three novel highly recurrent regulatory mutation blocks near important genes implicated in FL, BCL6 and BCL2. Similar findings were detected in a validation FL cohort. We also found transcription factors (TF) whose binding may be disturbed by these mutations in FL: disruption of FOX TF family near the BCL6 promoter may result in reduced BCL6 expression, which then increases BCL2 expression over that caused by BCL2 gene translocation. Knockdown experiments of two TF hits (FOXD2 or FOXD3) were performed in human B lymphocytes verifying that they modulate BCL6/BCL2 according to the computationally predicted effects of the SNVs on TF binding. Overall, our proposed integrative analysis facilitates non-coding driver identification and the new findings may enhance the understanding of FL.


Medical Tourism Abroad: A new challenge to Oman's health system - Al Dakhilya region experience.
This study aimed to understand why people seek medical advice abroad given the trouble and expense this entails. The types of medical problems for which treatment abroad was sought, preferred destinations and satisfaction with the treatment were explored. A secondary aim was to give feedback to stakeholders in the health care system on how to handle this issue and meet the needs of the community. 45 patients who had recently travelled abroad for treatment were asked to complete a questionnaire or were interviewed by telephone. 40 questionnaires were received. 68% of the respondents were male. Orthopaedic diseases were the most common conditions leading patients to seek treatment abroad. Thailand was the most popular destination followed by India (50% and 30% respectively). 85% of respondents went abroad for treatment only, 10% for treatment and tourism and 2.5% were healthy, but travelled abroad for a checkup. Interestingly, 15% of the participants went abroad without first seeking medical care locally. Out of those initially treated in Oman, 38.2% had no specific diagnosis and 38.2% had received treatment, but it was not effective. 73% of respondents obtained information on treatment abroad from a friend. The Internet and medical tourism offices were the least used sources of information. 15% of the patients experienced complications after their treatment abroad. Various facts about medical treatment abroad need to be disseminated to the public. This will necessitate greater effort in public health promotion and education.