The influence of total knee arthroplasty design on kneeling kinematics: a prospective randomized clinical trial.
Modern total knee arthroplasty (TKA) prostheses are designed to restore near normal kinematics including high flexion. Kneeling is a high flexion, kinematically demanding activity after TKA. The debate about design choice has not yet been informed by six-degrees-of-freedom in vivo kinematics. This prospective randomized clinical trial compared kneeling kinematics in three TKA designs. In total, 68 patients were randomized to either a posterior stabilized (PS-FB), cruciate-retaining (CR-FB), or rotating platform (CR-RP) design. Of these patients, 64 completed a minimum one year follow-up. Patients completed full-flexion kneeling while being imaged using single-plane fluoroscopy. Kinematics were calculated by registering the 3D implant models onto 2D-dynamic fluoroscopic images and exported for analysis. CR-FB designs had significantly lower maximal flexion (mean 116° (SD 2.1°)) compared to CR-RP (123° (SD 1.6°)) and PS-FB (125° (SD 2.1°)). The PS-FB design displayed a more posteriorly positioned femur throughout flexion. Furthermore, the CR-RP femur was more externally rotated throughout kneeling. Finally, individual patient kinematics showed high degrees of variability within all designs. The increased maximal flexion found in the PS-FB and CR-RP designs were likely achieved in different ways. The PS-FB design uses a cam-post to hold the femur more posteriorly preventing posterior impingement. The external rotation within the CR-RP design was surprising and hasn't previously been reported. It is likely due to the polyethylene bearing being decoupled from flexion. The findings of this study provide insights into the function of different knee arthroplasty designs in the context during deep kneeling and provide clinicians with a more kinematically informed choice for implant selection and may allow improved management of patients' functional expectations. Cite this article: Bone Joint J 2021;103-B(1):105-112.


Abrogated inflammatory response promotes neurogenesis in a murine model of Japanese encephalitis.
Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline. Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE) and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used. This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors.


Cerebrospinal fluid and plasma dopamine-beta-hydroxylase activity in human hypertension.
Cerebrospinal fluid (CSF) and plasma dopamine-beta-hydroxylase (DBH) activity was measured in 22 normotensive (NT), 31 essential hypertensive (EH), and 11 renal hypertensive (RH) patients. Although no differences were observed in their plasma DBH, the mean CSF-DBH activity and specific activity of EH were significantly lower than those of NT and RH patients. Very low CSF-DBH (less than 0.15 units/ml of CFS or less than 0.5 units/mg of CSF protein) was found only in EH (26% of EH). Of the 31 EH patients, 19(60%) had CSF-DHB activities lower than 0.5 units/ml, whereas only 5 of 22 NT (23%) and no RH fell within this range. Nevertheless, 20% of EH, 55% of NT, and 40% of RH patients had CSF-DBH activities above the mean value for NT (less than 0.9 units/ml). NT subjects with very low plasma DBH (less than 50 units/ml) had CSF-DBH activities that fell within normal range. With the exception of these subjects, the specific activity of CSF-DBH was always lower than that of the plasma enzyme. The concentration of albumin, alpha 1, beta, and gamma globulins was measured in plasma and CSF obtained from the last five NT, four EH, and two RH patients. A positive linear relationship was obtained when the log of the plasma/CSF concentration ratio for these proteins was plotted against their molecular weight. Similar slopes and intercepts were obtained for these patients, suggesting that no major differences seem to exist in their blood-brain-barrier permeability to proteins. The results suggest that measurements of CSF-DBH could be of help in the differential diagnosis of human hypertension and in the neurochemical characterization of EH. If CSF-DBH reflects central noradrenergic activity, its reduction might indicate the existence of a central catecholaminergic defect in a subgroup of EH patients.


Toll Like Receptors in systemic sclerosis: An emerging target.
Pattern Recognition Receptors are critical receptors that elicit an immune response upon their activation that culminates in activation of NF-KB and cytokine secretion. Key among these receptors are the Toll-Like Receptors (TLRs). These evolutionary conserved receptors form a key part in the defence against various pathogens and comprise a key part of the innate immune system. Systemic sclerosis is an autoimmune disease in which a breach of tolerance has occurred and leads to fulminant autoimmunity, dysregulated cytokines, pro-fibrotic mediators and activation of fibroblasts leading to fibrosis via collagen deposition. It has become apparent in recent years that the innate immune system and specifically TLRs are important in disease pathogenesis; responding to internal ligands to initiate an innate immune response ultimately leading to release of a variety of factors that initiate and perpetuate fibrosis. This review will examine the recent evidence of TLR signalling in systemic sclerosis and the internal danger associated molecules that may mediate the fibrotic cascade. Evaluation of their contribution to disease in systemic sclerosis and possible therapeutic targeting will be discussed.


Racial Pride and Condom Use in Post-Incarcerated African-American Men Who Have Sex With Men and Women: Test of a Conceptual Model for the Men in Life Environments Intervention.
African-American men who have sex with men and women (MSMW) are among those most heavily impacted by HIV in the United States, and those who have histories of incarceration are at further risk of infection. The Men in Life Environments (MILE) HIV prevention intervention was developed to provide culturally appropriate skills-based education and support for African-American MSMW with recent histories of incarceration. The MILE's conceptual framework was informed by three theories: Theory of Reasoned Action and Planned Behavior, Critical Thinking and Cultural Affirmation Model, and Empowerment Theory. The theory-based framework posits that improving racial pride is crucial in building self-efficacy and intentions that in turn promote health-protective behaviors. Therefore, our study aimed to assess whether baseline associations between racial pride and condom use self-efficacy, intentions, and behaviors among African-American MSMW with histories of incarceration align with our conceptual model. We report data on 212 participants recruited from Los Angeles County Sheriff's Department Men's Central Jail and the local community. Using structural equation modeling, we tested two separate models: one with female sexual partners and one with male sexual partners, while stratifying by participant's HIV status. Only among HIV-negative participants was greater racial pride associated with less condomless intercourse with men. In this group, greater self-efficacy and intentions-but not racial pride-predicted less condomless intercourse with women. Our findings suggest that racial pride is an important factor to address in HIV prevention interventions for post-incarcerated African-American MSMW.


Circle of least confusion of a spherical reflector.
A simple, tractable equation is provided for determining the size and location of the circle of least confusion of a concave spherical reflector. This method is exact for the object at infinity and with wave effects neglected. Designers of large radius Arecibo-like telescopes, both radio and optical, with symmetrical, spherical primaries should find the method useful. The mathematical results are valid for apertures with an angle of incidence up to 45 degrees. Comparisons of the location of the disk of least confusion with longitudinal spherical aberration and the radius of the disk with transverse spherical aberration are presented.


The Human Salivary Microbiome Is Shaped by Shared Environment Rather than Genetics: Evidence from a Large Family of Closely Related Individuals.
The human microbiome is affected by multiple factors, including the environment and host genetics. In this study, we analyzed the salivary microbiomes of an extended family of Ashkenazi Jewish individuals living in several cities and investigated associations with both shared household and host genetic similarities. We found that environmental effects dominated over genetic effects. While there was weak evidence of geographical structuring at the level of cities, we observed a large and significant effect of shared household on microbiome composition, supporting the role of the immediate shared environment in dictating the presence or absence of taxa. This effect was also seen when including adults who had grown up in the same household but moved out prior to the time of sampling, suggesting that the establishment of the salivary microbiome earlier in life may affect its long-term composition. We found weak associations between host genetic relatedness and microbiome dissimilarity when using family pedigrees as proxies for genetic similarity. However, this association disappeared when using more-accurate measures of kinship based on genome-wide genetic markers, indicating that the environment rather than host genetics is the dominant factor affecting the composition of the salivary microbiome in closely related individuals. Our results support the concept that there is a consistent core microbiome conserved across global scales but that small-scale effects due to a shared living environment significantly affect microbial community composition.IMPORTANCE Previous research shows that the salivary microbiomes of relatives are more similar than those of nonrelatives, but it remains difficult to distinguish the effects of relatedness and shared household environment. Furthermore, pedigree measures may not accurately measure host genetic similarity. In this study, we include genetic relatedness based on genome-wide single nucleotide polymorphisms (SNPs) (rather than pedigree measures) and shared environment in the same analysis. We quantify the relative importance of these factors by studying the salivary microbiomes in members of a large extended Ashkenazi Jewish family living in different locations. We find that host genetics plays no significant role and that the dominant factor is the shared environment at the household level. We also find that this effect appears to persist in individuals who have moved out of the parental household, suggesting that aspects of salivary microbiome composition established during upbringing can persist over a time scale of years.


Mapping visual stimuli to perceptual decisions via sparse decoding of mesoscopic neural activity.
In this talk I will describe our work investigating sparse decoding of neural activity, given a realistic mapping of the visual scene to neuronal spike trains generated by a model of primary visual cortex (V1). We use a linear decoder which imposes sparsity via an L1 norm. The decoder can be viewed as a decoding neuron (linear summation followed by a sigmoidal nonlinearity) in which there are relatively few non-zero synaptic weights. We find: (1) the best decoding performance is for a representation that is sparse in both space and time, (2) decoding of a temporal code results in better performance than a rate code and is also a better fit to the psychophysical data, (3) the number of neurons required for decoding increases monotonically as signal-to-noise in the stimulus decreases, with as little as 1% of the neurons required for decoding at the highest signal-to-noise levels, and (4) sparse decoding results in a more accurate decoding of the stimulus and is a better fit to psychophysical performance than a distributed decoding, for example one imposed by an L2 norm. We conclude that sparse coding is well-justified from a decoding perspective in that it results in a minimum number of neurons and maximum accuracy when sparse representations can be decoded from the neural dynamics.


The relationship between urinary infection, cystoscopic appearance, and pathology of the bladder in man: II Squamous change in the bladder epithelium.
The occurrence of squamous change in the bladder epithelium was studied in bladder biopsies from patients with recurrent urinary infections or symptoms of cystitis and comparisons were made with sections taken at necropsy from control subjects. Two types of squamous change, termed ;vaginal' and ;cornified', are described. Vaginal change was frequent in females, and seemed to be a normal finding in them, but was not observed in males. It did not seem to be caused by urinary infection. Cornified change was also common in females and was found in one (infected) man. Like vaginal change it was most often found in sections from the trigone. Urinary infection may predispose to its formation but we were unable to prove this. Squamous change did not seem to cause symptoms, and could not usually be recognized at cystoscopy. The varieties described are so common that they are unlikely to be markedly precarcinomatous.


Genetic overlap and causality between substance use disorder and attention-deficit and hyperactivity disorder.
Substance use disorder (SUD) often co-occur at high prevalence with other psychiatric conditions. Among them, attention-deficit and hyperactivity disorder (ADHD) is present in almost one out of every four subjects with SUD and is associated with higher severity, more frequent polysubstance dependence and increased risk for other mental health problems in SUD patients. Despite studies suggesting a genetic basis in the co-occurrence of these two conditions, the genetic factors involved in the joint development of both disorders and the mechanisms mediating these causal relationships are still unknown. In this study, we tested whether the genetic liability to five SUD-related phenotypes share a common background in the general population and clinically diagnosed ADHD individuals from an in-house sample of 989 subjects and further explored the genetic overlap and the causal relationship between ADHD and SUD using pre-existing GWAS datasets. Our results confirm a common genetic background between ADHD and SUD and support the current literature on the causal effect of the liability to ADHD on the risk for SUD. We added novel findings on the effect of the liability of lifetime cannabis use on ADHD and found evidence of shared genetic background underlying SUD in general population and in ADHD, at least for lifetime cannabis use, alcohol dependence and smoking initiation. These findings are in agreement with the high comorbidity observed between ADHD and SUD and highlight the need to control for substance use in ADHD and to screen for ADHD comorbidity in all SUD patients to provide optimal clinical interventions.


Effect of Aspirin on Disability-free Survival in the Healthy Elderly.
Information on the use of aspirin to increase healthy independent life span in older persons is limited. Whether 5 years of daily low-dose aspirin therapy would extend disability-free life in healthy seniors is unclear. From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or physical disability. Participants were randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally. The primary end point was a composite of death, dementia, or persistent physical disability. Secondary end points reported in this article included the individual components of the primary end point and major hemorrhage. A total of 19,114 persons with a median age of 74 years were enrolled, of whom 9525 were randomly assigned to receive aspirin and 9589 to receive placebo. A total of 56.4% of the participants were women, 8.7% were nonwhite, and 11.0% reported previous regular aspirin use. The trial was terminated at a median of 4.7 years of follow-up after a determination was made that there would be no benefit with continued aspirin use with regard to the primary end point. The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 per 1000 person-years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). The rate of adherence to the assigned intervention was 62.1% in the aspirin group and 64.1% in the placebo group in the final year of trial participation. Differences between the aspirin group and the placebo group were not substantial with regard to the secondary individual end points of death from any cause (12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group), dementia, or persistent physical disability. The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).


Nanoparticles in sentinel lymph node assessment in breast cancer.
The modern management of the axilla in breast cancer relies on surgery for accurate staging of disease and identifying those patients at risk who would benefit from adjuvant chemotherapy. The introduction of sentinel lymph node biopsy has revolutionized axillary surgery, but still involves a surgical procedure with associated morbidity in many patients with no axillary involvement. Nanotechnology encompasses a broad spectrum of scientific specialities, of which nanomedicine is one. The potential use of dual-purpose nanoprobes could enable imaging the axilla simultaneous identification and treatment of metastatic disease. Whilst most applications of nanomedicine are still largely in the laboratory phase, some potential applications are currently undergoing clinical evaluation for translation from the bench to the bedside. This is an exciting new area of research where scientific research may become a reality.


Numerical simulation of tissue differentiation around loaded titanium implants in a bone chamber.
The application of a bone chamber provides a controlled environment for the study of tissue differentiation and bone adaptation. The influence of different mechanical and biological factors on the processes can be measured experimentally. The goal of the present work is to numerically model the process of peri-implant tissue differentiation inside a bone chamber, placed in a rabbit tibia. 2D and 3D models were created of the tissue inside the chamber. A number of loading conditions, corresponding to those applied in the rabbit experiments, were simulated. Fluid velocity and maximal distortional strain were considered as the stimuli that guide the differentiation process of mesenchymal cells into fibroblasts, chondrocytes and osteoblasts. Mesenchymal cells migrate through the chamber from the perforations in the chamber wall. This process is modelled by the diffusion equation. The predicted tissue phenotypes as well as the process of tissue ingrowth into the chamber show a qualitative agreement with the results of the rabbit experiments. Due to the limited number of animal experiments (four) and the observed inter-animal differences, no quantitative comparison could be made. These results however are a strong indication of the feasibility of the implemented theory to predict the mechano-regulation of the differentiation process inside the bone chamber.


The SERCA pump as a therapeutic target: making a "smart bomb" for prostate cancer.
Prostate cancer is uniformly fatal once it has spread outside of the prostate gland. Prostate cancers have a remarkably low proliferative rate, which may in part explain their relative unresponsiveness to conventional antiproliferative chemotherapy. New therapies for prostate cancer that activate proliferation independent cell death are therefore needed. The endoplasmic reticulum (ER) has emerged as an organelle that plays a major role in cell signaling pathways, cellular response to stress and cellular activation of apoptosis. In this review, the SERCA pump is identified as an ER protein whose normal function is required by all cells and represents a potential therapeutic target for cancer therapy. Sustained SERCA inhibition by agents such as thapsigargin results in activation of ER-stress response and simultaneous activation of apoptotic pathways within the ER and the mitochondria. Due to the SERCA pump's critical role in normal cellular metabolism, agents like thapsigargin directed toward inhibiting SERCA function would likely produce significant toxicity to normal cells and, therefore, must be selectively targeted to cancer sites. The cytotoxicity of thapsigargin can be attenuated, however by coupling to a targeting peptide to produce an inactive prodrug that is only activated by prostate cancer specific proteases such as the serine protease prostate-specific antigen (PSA). PSA-activated thapsigargin prodrugs have been characterized that are selectively toxic to PSA-producing prostate cancer cells in vitro and in vivo. These prodrugs are currently undergoing preclinical evaluation as potential targeted therapy for prostate cancer.


Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes.
Papillary microcarcinoma (PMC) of the thyroid generally follows a benign clinical course. However, treatment strategies remain controversial. According to our previous retrospective review of 178 patients with PMC who underwent surgery between 1976 and 1993, the most significant risk factors affecting cancer-specific survival were clinical symptoms at presentation due to invasion or metastasis. Distant metastasis and cancer-specific death were never seen postoperatively for 148 cases (83%) of asymptomatic PMC without clinically apparent (>or=1 cm) lymph node metastasis or recurrent nerve palsy. Based on these results, we identified three biologically different types of PMC that should be treated differently. Type I comprises incidentally detected PMC without any symptoms, which is harmless and the lowest-risk cancer. Conservative follow-up with ultrasonography every 6 or 12 months is feasible. Type II involves the early stage of the usual low-risk papillary carcinoma. This can be treated by lobectomy when increasing size is noted during conservative follow-up. Type III comprises clinically symptomatic PMC, representing a high-risk cancer. Immediate wider resection followed by radioiodine treatment and suppression of thyroid-stimulating hormone is recommended. Since 1995, we have been conducting a prospective clinical trial of nonsurgical observation for asymptomatic PMC. As of 2008, 230 of 244 candidates (94%) have decided to accept this policy, whereas 56 patients underwent surgery for symptomatic PMC between 1976 and 2006. Nonsurgical observation for a mean of 5 (range, 1-17) years for 300 lesions of asymptomatic PMC revealed that 22 (7%) had increased in size, 269 (90%) were unchanged, and 9 (3%) had decreased. No patients developed extrathyroidal invasion or distant metastasis. Three patients (1%) who developed apparent lymph node metastasis and nine patients (4%) in whom tumor increased in size eventually received surgery after 1-12 years of follow-up. No recurrences have been identified postoperatively. Conversely, 10-year cause-specific survival for symptomatic PMC was 80%. Multivariate analysis identified extrathyroidal invasion, large lymph node metastasis (>or=2 cm), and poorly differentiated component as significantly related to adverse outcomes. Nonsurgical observation seems to represent an attractive alternative to surgery for asymptomatic PMC. Almost 95% of asymptomatic PMC patients are type I, and another 5% are type II and can be treated with conservative surgery. A small number of PMCs with bulky lymph node metastasis or extrathyroidal invasion are high-risk type III and require aggressive treatment.


Deconvolution for multimode fiber imaging: modeling of spatially variant PSF.
Focusing light through a step-index multimode optical fiber (MMF) using wavefront control enables minimally-invasive endoscopy of biological tissue. The point spread function (PSF) of such an imaging system is spatially variant, and this variation limits compensation for blurring using most deconvolution algorithms as they require a uniform PSF. However, modeling the spatially variant PSF into a series of spatially invariant PSFs re-opens the possibility of deconvolution. To achieve this we developed svmPSF: an open-source Java-based framework compatible with ImageJ. The approach takes a series of point response measurements across the field-of-view (FOV) and applies principal component analysis to the measurements' co-variance matrix to generate a PSF model. By combining the svmPSF output with a modified Richardson-Lucy deconvolution algorithm, we were able to deblur and regularize fluorescence images of beads and live neurons acquired with a MMF, and thus effectively increasing the FOV.


The effects of cognitive behavior therapy on depression in older patients with cardiovascular risk.
This study examined the effect of a cognitive behavior therapy (CBT) therapy intervention designed to reduce depression in older patients with elevated cardiovascular disease (CVD) risk. Forty-eight depressed patients with elevated CVD were randomized to a 16-week individual CBT intervention (n = 23) or a wait-list control (WLC) group (n = 25). Pre- and post-treatment measures of depression were obtained during office visits, and measures of positive and negative affect were obtained during laboratory psychological stress testing and at five points during the day. At post-treatment, the CBT subjects were significantly less depressed than WLC subjects on the Hamilton Depression Inventory (F = 52.8, P<.001, ES = 1.85) and the Beck Depression Inventory (F = 17.1, P = <.001, ES = 0.85). Fifty-seven percent (13/23) of subjects in the CBT treatment were considered to be in remission (on the basis of a clinical interview) at post compared to only 4% (1/25) in the WLC (chi(2) = 9.0, P =.003). Treatment subjects reported significantly less stress on the Perceived Stress Scale (F = 23.2, P<.001). CBT significantly improved mean positive affect during the day (F = 12.7, P =.0001) but there were no significant differences in mean negative affect (F = 1.8, P =.19). CBT significantly reduced negative affect (F = 7.1, P =.01) during psychological stress testing but did not affect positive affect. CBT is an effective treatment for reducing depression and increasing positive affect in patients at risk for CVD, but the results vary by time of measurement and measurement setting.


Location matters: the endoplasmic reticulum and protein trafficking in dendrites.
Neurons are highly polarized, but the trafficking mechanisms that operate in these cells and the topological organization of their secretory organelles are still poorly understood. Particularly incipient is our knowledge of the role of the neuronal endoplasmic reticulum. Here we review the current understanding of the endoplasmic reticulum in neurons, its structure, composition, dendritic distribution and dynamics. We also focus on the trafficking of proteins through the dendritic endoplasmic reticulum, emphasizing the relevance of transport, retention, assembly of multi-subunit protein complexes and export. We additionally discuss the roles of the dendritic endoplasmic reticulum in synaptic plasticity.


Atrial Fibrillation: Current Evidence and Management Strategies During the Perioperative Period.
Atrial fibrillation (AF) is the most common arrhythmia in the perioperative period. Previously considered a benign and self-limited entity, recent data suggest that perioperative AF is associated with considerable morbidity and mortality and may predict long-term AF and stroke risk in some patients. Despite known risk factors, AF remains largely unpredictable, especially after noncardiac surgery. As a consequence, strategies to minimize perioperative risk are mostly supportive and include avoiding potential arrhythmogenic triggers and proactively treating patient- and surgery-related factors that might precipitate AF. In addition to managing AF itself, clinicians must also address the hemodynamic perturbations that result from AF to prevent end-organ dysfunction. This review will discuss current evidence with respect to causes, risk factors, and outcomes of patients with AF, and address current controversies in the perioperative setting.


miRTarVis: an interactive visual analysis tool for microRNA-mRNA expression profile data.
MicroRNAs (miRNA) are short nucleotides that down-regulate its target genes. Various miRNA target prediction algorithms have used sequence complementarity between miRNA and its targets. Recently, other algorithms tried to improve sequence-based miRNA target prediction by exploiting miRNA-mRNA expression profile data. Some web-based tools are also introduced to help researchers predict targets of miRNAs from miRNA-mRNA expression profile data. A demand for a miRNA-mRNA visual analysis tool that features novel miRNA prediction algorithms and more interactive visualization techniques exists. We designed and implemented miRTarVis, which is an interactive visual analysis tool that predicts targets of miRNAs from miRNA-mRNA expression profile data and visualizes the resulting miRNA-target interaction network. miRTarVis has intuitive interface design in accordance with the analysis procedure of load, filter, predict, and visualize. It predicts targets of miRNA by adopting Bayesian inference and MINE analyses, as well as conventional correlation and mutual information analyses. It visualizes a resulting miRNA-mRNA network in an interactive Treemap, as well as a conventional node-link diagram. miRTarVis is available at http://hcil.snu.ac.kr/~rati/miRTarVis/index.html. We reported findings from miRNA-mRNA expression profile data of asthma patients using miRTarVis in a case study. miRTarVis helps to predict and understand targets of miRNA from miRNA-mRNA expression profile data.


Negative Affect-Related Factors Have the Strongest Association with Prescription Opioid Misuse in a Cross-Sectional Cohort of Patients with Chronic Pain.
Increased opioid prescription to relieve pain among patients with chronic pain is associated with increased risk for misuse, potentially leading to substance use disorders and overdose death. We aimed to characterize the relative importance and identify the most significant of several potential risk factors for the severity of self-reported prescribed opioid misuse behaviors. A sample of 1,193 patients (mean age ± SD = 50.72 ± 14.97 years, 64.04% female) with various chronic pain conditions completed a multidimensional registry assessing four pain severity measures and 14 physical, mental, and social health status factors using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS). A validated PROMIS measure of medication misuse was completed by 692 patients who endorsed currently taking opioid medication. Patients taking opioid medications were compared across all measures with those who do not take opioid medications. Subsequently, a data-driven regression analysis was used to determine which measures best explained variability in severity of misuse. We hypothesized that negative affect-related factors, namely anxiety, anger, and/or depression, would be key predictors of misuse severity due to their crucial role in chronic pain and substance use disorders. Patients taking opioid medications had significantly greater impairment across most measures. Above and beyond demographic variables, the only and most significant predictors of prescribed opioid misuse severity were as follows: anxiety (β = 0.15, P = 0.01), anger (β = 0.13, P = 0.02), Pain Intensity-worst (β = 0.09, P = 0.02), and depression (β = 0.13, P = 0.04). Findings suggest that anxiety, anger, and depression are key factors associated with prescribed opioid misuse tendencies in patients with chronic pain and that they are potential targets for therapeutic intervention.


Visual search at isoluminance: evidence for enhanced color weighting in standard sub-set and preview-based visual search.
Isoluminant displays depend on responses from the parvocellular visual stream, known to code color information. We examined the influence of isoluminance on attentional guidance by color using two procedures: (i) color sub-set search (Egeth, Virzi, & Garbart, 1984) and (ii) preview search (Watson & Humphreys, 1997). We used displays that do not generate a sub-set search advantage with luminant stimuli. Despite this, a sub-set search advantage was present for small color groups with isoluminant displays. Under preview-search conditions, presenting items at isoluminance amplified the effects of a negative color carry-over from a preview display to a new target, but only when there was an extended preview duration. Both findings demonstrate that presenting items at isoluminance increases the influence of color on visual search. Collectively, the data are consistent with the notion of a flexible inhibitory mechanism that can change the weighting applied to visual features in search.


Antagonism between fine and coarse motion sensors depends on stimulus size and contrast.
The perceived direction of motion of a brief visual stimulus that contains fine features reverses if static coarser features are added to it. Here we show that the reversal in perceived direction disappears if the stimulus is reduced in size from 2.8 deg to 0.35 deg radius. We show that for a stimulus with 1.4 deg radius, the reversals occur when the ratio between the contrast of the fine features and of the coarser features is higher than 0.8 and lower than 4. For stimulus with 0.35 deg radius, the reversals never appear for any contrast ratio. We also show that if the stimulus is presented within an annular window with small radius, errors disappear but they return if the radius is increased to 2 deg. The errors in motion discrimination described here can be explained by a model of motion sensing in which the signals from fine-scale and coarse-scale sensors are subtracted from one another (I. Serrano-Pedraza, P. Goddard, & A. M. Derrington, 2007). The model produces errors in direction when the signals in the fine and coarse sensors are approximately balanced. The errors disappear when stimulus size is reduced because the reduction in size differentially reduces the response of the low spatial frequency motion sensors.


Crystal structure of a recombinant form of the maltodextrin-binding protein carrying an inserted sequence of a B-cell epitope from the preS2 region of hepatitis B virus.
We report the crystal structure of MalE-B133, a recombinant form of the maltodextrin-binding protein (MBP) of Escherichia coli carrying an inserted amino-acid sequence of a B-cell epitope from the preS2 region of the hepatitis B virus (HBV). The structure was determined by molecular replacement methods and refined to 2.7 A resolution. MalE-B133 is an insertion/deletion mutant of MBP in which residues from positions 134 to 142, an external alpha helix in the wild-type structure, are replaced by a foreign peptide segment of 19 amino acids. The inserted residues correspond to the preS2 sequence from positions 132 to 145 and five flanking residues that arise from the creation of restriction sites. The conformation of the recombinant protein, excluding the inserted segment, closely resembles that of wild-type MBP in the closed maltose-bound form. MalE-B133 was shown by previous studies to display certain immunogenic and antigenic properties of the hepatitis B surface antigen (HBsAg), which contains the preS2 region. The crystal structure reveals the conformation of the first nine epitope residues (preS2 positions 132 to 140) exposed on the surface of the molecule. The remaining five epitope residues (preS2 positions 141 to 145) are not visible in electron density maps. The path of the polypeptide chain in the visible portion of the insert differs from that of the deleted segment in the structure of wild-type MBP, displaying a helical conformation at positions 134 to 140 (preS2 sequence numbering). A tripeptide (Asp-Pro-Arg) at the N terminus of the helix forms a stable structural motif that may be implicated in the cross-reactivity of anti-HBsAg antibodies with the hybrid protein.


Calodium hepaticum (Trichuroidea: Capillariidae) Infection In Akodon azarae: First Description of Histopathological Lesions In Sigmodontinae.
Calodium hepaticum (Trichinellida: Capillaridae) is a parasitic nematode of mammals distributed worldwide. Although this parasite can infect the liver of a wide diversity of mammals (including humans), it is mostly associated with Muroidea hosts. Sigmodontinae rodents were recently recognized as important hosts of this parasite in Argentina, but the impact of this parasitism on these hosts has not been established. Here we report results of histopathological analyses of 40 livers of Akodon azarae infected with C. hepaticum. Lesions were classified into 4 categories: level 0, absence of lesions; level 1, with focal granulomatous hepatitis; level 2, presence of multifocal granulomatous hepatitis, fibrosis and focal necrosis with neutrophils, and level 3, absence of intact adult parasites, diffuse distribution, necrosis, and fibrosis. Most samples presented lesions of level 2 (55%), but all categories of lesions were found. This is the first study to describe the lesions caused by C. hepaticum in the liver of Sigmodontinae rodents, and the results suggest that infection by this parasite is costly to A. azarae populations.


Adolescent Loneliness and the Interaction between the Serotonin Transporter Gene (5-HTTLPR) and Parental Support: A Replication Study.
Gene-by-environment interaction (GxEs) studies have gained popularity over the last decade, but the robustness of such observed interactions has been questioned. The current study contributes to this debate by replicating the only study on the interaction between the serotonin transporter gene (5-HTTLPR) and perceived parental support on adolescents' peer-related loneliness. A total of 1,111 adolescents (51% boys) with an average age of 13.70 years (SD = 0.93) participated and three annual waves of data were collected. At baseline, adolescent-reported parental support and peer-related loneliness were assessed and genetic information was collected. Assessment of peer-related loneliness was repeated at Waves 2 and 3. Using a cohort-sequential design, a Latent Growth Curve Model was estimated. Overall, a slight increase of loneliness over time was found. However, the development of loneliness over time was found to be different for boys and girls: girls' levels of loneliness increased over time, whereas boys' levels of loneliness decreased. Parental support was inversely related to baseline levels of loneliness, but unrelated to change of loneliness over time. We were unable to replicate the main effect of 5-HTTLPR or the 5-HTTLPR x Support interaction effect. In the Discussion, we examine the implications of our non-replication.


Geographic variation in apparent competition between native and invasive Phragmites australis.
Apparent competition, the negative interaction between species mediated by shared natural enemies, is thought to play an important role in shaping the structure and dynamics of natural communities. However, its importance in driving species invasions, and whether the strength of this indirect interaction varies across the latitudinal range of the invasion, has not been fully explored. We performed replicated field experiments at four sites spanning 900 km along the Atlantic Coast of the United States to assess the presence and strength of apparent competition between sympatric native and invasive lineages of Phragmites australis. Four herbivore guilds were considered: stem-feeders, leaf-miners, leaf-chewers and aphids. We also tested the hypothesis that the strength of this interaction declines with increasing latitude. Within each site, native and invasive plants of P. australis were cross-transplanted between co-occurring native and invasive patches in the same marsh habitat and herbivore damage was evaluated at the end of the growing season. Apparent competition was evident for both lineages and involved all but the leaf-chewer guild. For native plants, total aphids per plant was 296% higher and the incidence of stem-feeding and leaf-mining herbivores was 34% and 221% higher, respectively, when transplanted into invasive than native patches. These data suggest that invasive P. australis has a negative effect on native P. australis via apparent competition. Averaged among herbivore types, the indirect effects of the invasive lineage on the native lineage was 57% higher than the reverse situation, suggesting that apparent competition was asymmetric. We also found that the strength of apparent competition acting against the native lineage was comparable to the benefits to the invasive lineage from enemy release (i.e., proportionately lower mean herbivory of the invasive relative to the native taxa). Finally, we found the first evidence that the strength of apparent competition acting against the native lineage (from stem-feeders only) decreased with increasing latitude. These results suggest that not only could apparent competition be of tantamount importance to enemy release in enhancing the establishment and spread of invasive taxa, but also that these indirect and direct herbivore effects could vary over the invasion range.


Fracture risk with intermittent high-dose oral glucocorticoid therapy.
To evaluate the risk of fracture in patients receiving intermittent therapy with high-dose oral glucocorticoids (GCs). The study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of "current" and "no exposure." The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation. Patients who intermittently received high-dose GCs (daily dose > or =15 mg) and had no or little previous exposure to GCs (cumulative exposure < or =1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who received a daily dose > or =30 mg and whose cumulative exposure was >5 gm, the relative risk (RR) of osteoporotic fracture was 3.63 (95% confidence interval [95% CI] 2.54-5.20), the RR of fracture of the hip/femur was 3.13 (95% CI 1.49-6.59), and the RR of vertebral fracture was 14.42 (95% CI 8.29-25.08). Intermittent use of high-dose oral GCs (daily dose > or =15 mg and cumulative exposure < or =1 gm) may result in a small increased risk of osteoporotic fracture. Conversely, patients who receive several courses of high-dose GCs (daily dose > or =15 mg and cumulative exposure >1 gm) have a substantially increased risk of fracture.


Success Rate of Repeat Endoscopic Third Ventriculostomy Procedure According to the Ventriculostomy Orifice Closure Patterns: A Single Institutional Series of 74 Patients.
To analyze the success rates of repeat endoscopic third ventriculostomy (re-ETV) procedure according to ventriculostomy orifice closure types in patients who have undergone a second neuroendoscopic surgery for non-communicating hydrocephalus. The study included 74 patients who underwent re-ETV procedure due to dysfunctional ventriculostomy orifice. Ventriculostomy closure patterns are classified into three types: Type-1 is defined as the complete closure of the orifice with non-transparent gliosis or scar tissue. Type-2 represents the closure or narrowing of the orifice by newly formed translucent membranes. Type-3 pattern is defined as the blockage of CSF flow due to newly formed reactive membranes in the basal cisterns, with an intact ventriculostomy orifice. The frequency of the ventriculostomy closure patterns was found as follows. Type-1: 17 cases (22.97%); Type-2: 30 cases (40.54%); and Type-3: 27 cases (36.48%). The success rate of the re-ETV procedure according to closure types was 23.52% in Type-1 cases, 46.66% in Type-2 cases, and 37.03% in Type-3 cases. A significantly higher rate of Type-1 closure pattern was observed in the myelomeningocele associated hydrocephalus cases (p < 0.01). In cases where ETV failure occurs, an endoscopic exploration with reopening of the ventriculostomy orifice is a preferable treatment option. Therefore, identifying patients who may benefit from the re-ETV procedure is essential. Type-1 closure pattern was observed to have a higher frequency in cases where hydrocephalus was associated with myelomeningocele, and the success rate of re-ETV seems to be lower in those cases.


Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents.
Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled with its known (and modest) toxicity, has allowed the traditional process of drug evaluation to be shortened. We review the rationale for a modified approach to evaluation and outline the key steps that will optimize development of this agent in breast cancer, including discussion of a Phase III adjuvant trial (NCIC MA.32) that has recently been initiated.


Methylphenidate as a reinforcer for rats: contingent delivery and intake escalation.
Methylphenidate (MPH) is one of the most widely prescribed drugs for treating attention-deficit hyperactivity disorder. Previous research suggested that MPH is a reinforcer for rats, but not all of the manipulations to show that lever pressing is controlled by the contingency to obtain MPH have been examined. In Experiment 1, responding for MPH on a progressive ratio (PR) schedule was assessed. Rats self-administered varying doses of MPH (0.056-1.0 mg/kg/infusion) on a PR schedule of reinforcement, and self-administered more MPH than saline, with maximal responding occurring at a unit dose of 0.56 mg/kg/infusion. Experiment 2 examined if there were differences in responding between contingent and noncontingent MPH (0.56 mg/kg/infusion) on a fixed ratio schedule of reinforcement. Results showed that rats responded for contingent MPH, and that responding was not maintained when MPH was delivered noncontingently. Experiment 3 examined self-administration of MPH (0.1 or 0.3 mg/kg/infusion) during long access (6 hr) compared to short access sessions (1 hr). Results showed that rats given long access to MPH showed an escalation of intake across sessions, with this escalation being more pronounced at the lower unit dose (0.1 mg/kg/infusion); in contrast, rats given short access to MPH did not show an increase in MPH self-administration across sessions at either MPH dose tested. Taken together, these results indicate that MPH is an effective intravenous reinforcer for rats and that, similar to other stimulants such as cocaine, amphetamine and methamphetamine, MPH is subject to abuse as reflected by dysregulated intake across repeated long access sessions.


Imaging of scar in patients with ventricular arrhythmias of right ventricular origin: cardiac magnetic resonance versus electroanatomic mapping.
Assessment of late gadolinium enhancement (LGE) at cardiac magnetic resonance is often used to detect scar in patients with arrhythmias of right ventricular (RV) origin. Recently, electroanatomic mapping (EAM) has been shown to reliably detect scars corresponding to different cardiomyopathic substrates. We compared LGE with EAM for the detection of scar in patients with arrhythmias of RV origin. Thirty-one patients with RV arrhythmias and biopsy-proven structural heart disease (18 ARVC and 13 myocarditis), and 5 with idiopathic RV outflow tract arrhythmias underwent LGE analysis and EAM with scar validation through EAM-guided endomyocardial biopsy. EAM scars were present in 23 (64%) patients (all with structural heart disease), whereas LGE was present only in 12 (33%). In 2 cases, EAM provided a false-positive diagnosis of a small scar in the basal perivalvular area. LGE correctly diagnosed EAM scar in 48% of patients, resulting in high positive (92%) but low negative (50%) predictive values. The distribution of LGE was significantly associated with the distribution of EAM scars (P < 0.001 in the free wall, P = 0.003 in the outflow tract, and P = 0.023 in the posterior/inferior wall). Presence of LGE reflected a higher extension of EAM scars (34.4 ± 16.5% vs 7.9 ± 10.1% of the RV area, P < 0.001). At receiver operating characteristic (ROC) analysis, an extension of scar ≥20% of the RV area was the best cut-off value to detect LGE (sensitivity 83%, specificity 92%). Of note, LGE missed 10 of 11 (91%) patients with EAM scars <20% of RV area. LGE is significantly less sensitive than EAM in identifying RV cardiomyopathic substrates. Absence of LGE does not rule out the presence of small scars, and EAM with biopsy should be considered to increase the diagnostic yield.


Homeopathic treatment of mild traumatic brain injury: A randomized, double-blind, placebo-controlled clinical trial.
Mild traumatic brain injury (MTBI) affects 750,000 persons in the United States annually. Five to fifteen percent have persistent dysfunction and disability. No effective, standard pharmacological treatment exists specifically for this problem. We designed a pilot research project to study the clinical effectiveness of homeopathic medicine in the treatment of persistent MTBI. A randomized, double-blind, placebo-controlled trial of 60 patients, with a four-month follow-up (N = 50), was conducted at Spaulding Rehabilitation Hospital (SRH). Patients with persistent MTBI (mean 2.93 years since injury, SD 3.1) were randomly assigned to receive a homeopathic medicine or placebo. The primary outcome measure was the subject-rated SRH-MBTI Functional Assessment, composed of three subtests: a Difficulty with Situations Scale (DSS), a Symptom Rating Scale (SRS), and a Participation in Daily Activities Scale (PDAS). The SRH Cognitive-Linguistic Test Battery was used as the secondary measure. Analysis of covariance demonstrated that the homeopathic treatment was the only significant or near-significant predictor of improvement on DSS subtests (P =.009; 95% CI -.895 to -.15), SRS (P =.058; 95% CI -.548 to.01) and the Ten Most Common Symptoms of MTBI (P =.027; 95% CI -.766 to -.048). These results indicate a significant improvement from the homeopathic treatment versus the control and translate into clinically significant outcomes. This study suggests that homeopathy may have a role in treating persistent MTBI. Our findings require large-scale, independent replication.


ICD coding changes and discontinuities in trends in cause-specific mortality in six European countries, 1950-99.
To evaluate how often coding changes between and within revisions of the International Classification of Diseases (ICD) complicate the description of long-term trends in cause-specific mortality. Data on cause-specific mortality between 1950 and 1999 for men and women aged 60 and older were obtained from Denmark, England and Wales, Finland, the Netherlands, Norway and Sweden. Data were obtained by five-year age groups. We constructed a concordance table using three-digit ICD codes. In addition we evaluated the occurrence of mortality discontinuities by visually inspecting cause-specific trends and country-specific background information. Evaluation was also based on quantification of the discontinuities using a Poisson regression model (including period splines). We compared the observed trends in cause-specific mortality with the trends after adjustment for the discontinuities caused by changes to coding. In 45 out of 416 (10.8 %) instances of ICD revisions to cause-specific mortality codes, significant discontinuities that were regarded as being due to ICD revisions remained. The revisions from ICD-6 and ICD-7 to ICD-8 and a wide range of causes of death, with the exception of the specific cancers, were especially affected. Incidental changes in coding rules were also important causes of discontinuities in trends in cause-specific mortality, especially in England and Wales, Finland and Sweden. Adjusting for these discontinuities can lead to significant changes in trends, although these primarily affect only limited periods of time. Despite using a carefully constructed concordance table based on three-digit ICD codes, mortality discontinuities arising as a result of coding changes (both between and within revisions) can lead to substantial changes in long-term trends in cause-specific mortality. Coding changes should therefore be evaluated by researchers and, where necessary, controlled for.


Abstract: A Comparison of the Factor Mixture Model and Taxometric Procedures.
Taxometric procedures and the Factor Mixture Model (FMM) have a complimentary set of strengths and weaknesses. Both approaches purport to detect evidence of a latent class structure. Taxometric procedures, popular in psychiatric and psychopathology literature, make no assumptions beyond those needed to compute means and covariances. However, Taxometric procedures assume that observed items are uncorrelated within a class or taxon. This assumption is violated when there are individual differences in the trait underlying the items (i.e., severity differences within class). FMMs can model within-class covariance structures ranging from local independence to multidimensional within-class factor models and permits the specification of more than two classes. FMMs typically rely on normality assumptions for within-class factors and error terms. FMMs are highly parameterized and susceptible to misspecifications of the within-class covariance structure. The current study compared the Taxometric procedures MAXEIG and the Base-Rate Classification Technique to the FMM in their respective abilities to (1) correctly detect the two-class structure in simulated data, and to (2) correctly assign subjects to classes. Two class data were simulated under conditions of balanced and imbalanced relative class size, high and low class separation, and 1-factor and 2-factor within-class covariance structures. For the 2-factor data, simple and cross-loaded factor loading structures, and positive and negative factor correlations were considered. For the FMM, both correct and incorrect within-class factor structures were fit to the data. FMMs generally outperformed Taxometric procedures in terms of both class detection and in assigning subjects to classes. Imbalanced relative class size (e.g., a small minority class and a large majority class) negatively impacted both FMM and Taxometric performance while low class separation was much more problematic for Taxometric procedures than the FMM. Comparisons of alterative FMMs based on information criteria generally resulted in correct model choice but deteriorated when small class separation was combined with imbalanced relative class size.


Statistical Methods for Identifying Sequence Motifs Affecting Point Mutations.
Mutation processes differ between types of point mutation, genomic locations, cells, and biological species. For some point mutations, specific neighboring bases are known to be mechanistically influential. Beyond these cases, numerous questions remain unresolved, including: what are the sequence motifs that affect point mutations? How large are the motifs? Are they strand symmetric? And, do they vary between samples? We present new log-linear models that allow explicit examination of these questions, along with sequence logo style visualization to enable identifying specific motifs. We demonstrate the performance of these methods by analyzing mutation processes in human germline and malignant melanoma. We recapitulate the known CpG effect, and identify novel motifs, including a highly significant motif associated with A[Formula: see text]G mutations. We show that major effects of neighbors on germline mutation lie within [Formula: see text] of the mutating base. Models are also presented for contrasting the entire mutation spectra (the distribution of the different point mutations). We show the spectra vary significantly between autosomes and X-chromosome, with a difference in T[Formula: see text]C transition dominating. Analyses of malignant melanoma confirmed reported characteristic features of this cancer, including statistically significant strand asymmetry, and markedly different neighboring influences. The methods we present are made freely available as a Python library https://bitbucket.org/pycogent3/mutationmotif.


Use of Mass Spectrometric Vapor Analysis To Improve Canine Explosive Detection Efficiency.
Canines remain the gold standard for explosives detection in many situations, and there is an ongoing desire for them to perform at the highest level. This goal requires canine training to be approached similarly to scientific sensor design. Developing a canine training regimen is made challenging by a lack of understanding of the canine's odor environment, which is dynamic and typically contains multiple odorants. Existing methodology assumes that the handler's intention is an adequate surrogate for actual knowledge of the odors cuing the canine, but canines are easily exposed to unintentional explosive odors through training material cross-contamination. A sensitive, real-time (∼1 s) vapor analysis mass spectrometer was developed to provide tools, techniques, and knowledge to better understand, train, and utilize canines. The instrument has a detection library of nine explosives and explosive-related materials consisting of 2,4-dinitrotoluene (2,4-DNT), 2,6-dinitrotoluene (2,6-DNT), 2,4,6-trinitrotoluene (TNT), nitroglycerin (NG), 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), pentaerythritol tetranitrate (PETN), triacetone triperoxide (TATP), hexamethylene triperoxide diamine (HMTD), and cyclohexanone, with detection limits in the parts-per-trillion to parts-per-quadrillion range by volume. The instrument can illustrate aspects of vapor plume dynamics, such as detecting plume filaments at a distance. The instrument was deployed to support canine training in the field, detecting cross-contamination among training materials, and developing an evaluation method based on the odor environment. Support for training material production and handling was provided by studying the dynamic headspace of a nonexplosive HMTD training aid that is in development. These results supported existing canine training and identified certain areas that may be improved.


Chemokines, chemokine receptors and allergy.
Chemokines are a group of cytokines that are responsible for the influx of blood cells, including T and B lymphocytes, monocytes, neutrophils, eosinophils and basophils, in allergic and other inflammatory conditions. They function as G protein-coupled chemotactic factors which also activate the cells with which they interact. Certain chemokines function within the afferent arm of the immune system, in which antigen is processed and antibody formation initiated, and others are active within the effector pathways of cellular immunity and late-phase allergic reactions. Th2 lymphocytes, which are critical for allergy, employ the CC chemokine receptors CCR4 and CCR8 with the ligands thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and I-309, respectively. The chemokine receptor CCR3 and ligands monocyte chemoattractant protein (MCP)-3, MCP-4, regulated upon activation normal T cell expressed and secreted (RANTES) and eotaxins I and II are of particular relevance for the recruitment and activation of eosinophils. Th1 reactions depend upon interferon gamma-induced CXC chemokines interferon- inducible protein (IP)-10, interferon-inducible T cell-alpha chemoattractant (iTAC) and monokine induced by interferon-gamma (MiG), which bind to chemokine receptor CXCR3.


Three Dimensional Finite Element Analysis of Distal Abutment Stresses of Removable Partial Dentures with Different Retainer Designs.
This finite element method study aimed to compare the amount of stress on an isolated mandibular second premolar in two conventional reciprocal parallel interface designs of removable partial dentures (RPDs) and the same RPD abutment tooth (not isolated). A Kennedy Class 1, modification 1 RPD framework was simulated on a 3D model of mandible with three different designs: an isolated tooth with a mesial rest, an isolated tooth with mesial and distal rests and an abutment with a mesial rest (which was not isolated); 26 N occlusal forces were exerted bilaterally on the first molar sites. Stress on the abutment teeth was analyzed using Cosmos Works 2009 Software. In all designs, the abutment tooth stress concentration was located in the buccal alveolar crest. In the first model, the von Mises stress distribution in the contact area of I-bar clasp and cervical portion of the tooth was 19 MPa and the maximum stress was 30 MPa. In the second model, the maximum von Mises stress distribution was 15 MPa in the cervical of the tooth. In the third model, the maximum von Mises stress was located in the cervical of the tooth and the distal proximal plate. We recommend using both mesial and distal rests on the distal abutment teeth of distal extension RPDs. The abutment of an extension base RPD, which is not isolated in presence of its neighboring more anterior tooth, may have a better biomechanical prognosis.


Microbial Small Talk: Volatiles in Fungal-Bacterial Interactions.
There is increasing evidence that volatile organic compounds (VOCs) play an important role in the interactions between fungi and bacteria, two major groups of soil inhabiting microorganisms. Yet, most of the research has been focused on effects of bacterial volatiles on suppression of plant pathogenic fungi whereas little is known about the responses of bacteria to fungal volatiles. In the current study we performed a metabolomics analysis of volatiles emitted by several fungal and oomycetal soil strains under different nutrient conditions and growth stages. The metabolomics analysis of the tested fungal and oomycetal strains revealed different volatile profiles dependent on the age of the strains and nutrient conditions. Furthermore, we screened the phenotypic responses of soil bacterial strains to volatiles emitted by fungi. Two bacteria, Collimonas pratensis Ter291 and Serratia plymuthica PRI-2C, showed significant changes in their motility, in particular to volatiles emitted by Fusarium culmorum. This fungus produced a unique volatile blend, including several terpenes. Four of these terpenes were selected for further tests to investigate if they influence bacterial motility. Indeed, these terpenes induced or reduced swimming and swarming motility of S. plymuthica PRI-2C and swarming motility of C. pratensis Ter291, partly in a concentration-dependent manner. Overall the results of this work revealed that bacteria are able to sense and respond to fungal volatiles giving further evidence to the suggested importance of volatiles as signaling molecules in fungal-bacterial interactions.


Evolution from a nodeless gap to d(x(2)-y(2))-wave in underdoped La(2-x)Sr(x)CuO4.
Using angle-resolved photoemission spectroscopy (ARPES), it is revealed that the low-energy electronic excitation spectra of highly underdoped superconducting and nonsuperconducting La(2-x)Sr(x)CuO(4) cuprates are gapped along the entire underlying Fermi surface at low temperatures. We show how the gap function evolves to a d(x(2)-y(2)) form with increasing temperature or doping, consistent with the vast majority of ARPES studies of cuprates. Our results provide essential information for uncovering the symmetry of the order parameter(s) in strongly underdoped cuprates, which is a prerequisite for understanding the pairing mechanism and how superconductivity emerges from a Mott insulator.


Evaluation of the Synergistic Effect of Tomatidine with Several Antibiotics against Standard and Clinical Isolates of Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli.
Antibiotic resistance is an important problem in antibiotic treatment of infections, particularly in hospitals. Tomatidine is a plant secondary metabolite with antimicrobial and antifungal effects. This study examined the possible synergistic effect tomatidine with several antibiotics against standard and clinical strains of Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli. After determining the minimum inhibitory concentrations (MICs) of antibiotics and tomatidine against the bacterial isolates using broth microdilution method, the synergistic effect between tomatidine and antibiotics was evaluated by checkerboard method and calculation of FIC indices. Tomatidine alone did not show any antimicrobial effect. However, it had synergistic effect with gentamicin and cefepime against standard and clinical isolates of S. aureus and P. aeruginosa, respectively. It also had synergistic effect with ampicillin and ciprofloxacin only against standard strains of E. faecalis and P. aeruginosa, respectively. In conclusion, tomatidine could be considered as a potential antibiotic potentiator for gentamicin, cefepime and ciprofloxacin, and ampicillin against Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus faecalis infections, respectively. However, the toxicological and pharmacological properties of tomatidine for use as a therapeutic agent remain to be determined.


Fast routing in road networks with transit nodes.
When you drive to somewhere far away, you will leave your current location via one of only a few important traffic junctions. Starting from this informal observation, we developed an algorithmic approach, transit node routing, that allows us to reduce quickest path queries in road networks to a small number of table lookups. For road maps of Western Europe and the United States, our best query times improved over the best previously published figures by two orders of magnitude. This is also more than one million times faster than the best known algorithm for general networks.


Promotion of couples' voluntary HIV counselling and testing in Lusaka, Zambia by influence network leaders and agents.
Hypothesising that couples' voluntary counselling and testing (CVCT) promotions can increase CVCT uptake, this study identified predictors of successful CVCT promotion in Lusaka, Zambia. Cohort study. Lusaka, Zambia. 68 influential network leaders (INLs) identified 320 agents (INAs) who delivered 29 119 CVCT invitations to heterosexual couples. The CVCT promotional model used INLs who identified INAs, who in turn conducted community-based promotion and distribution of CVCT invitations in two neighbourhoods over 18 months, with a mobile unit in one neighbourhood crossing over to the other mid-way through. The primary outcome of interest was couple testing (yes/no) after receipt of a CVCT invitation. INA, couple and invitation characteristics predictive of couples' testing were evaluated accounting for two-level clustering. INAs delivered invitations resulting in 1727 couples testing (6% success rate). In multivariate analyses, INA characteristics significantly predictive of CVCT uptake included promoting in community-based (adjusted OR (aOR)=1.3; 95% CI 1.0 to 1.8) or health (aOR=1.5; 95% CI 1.2 to 2.0) networks versus private networks; being employed in the sales/service industry (aOR=1.5; 95% CI 1.0 to 2.1) versus unskilled manual labour; owning a home (aOR=0.7; 95% CI 0.6 to 0.9) versus not; and having tested for HIV with a partner (aOR=1.4; 95% CI 1.1 to 1.7) or alone (aOR=1.3; 95% CI 1.0 to 1.6) versus never having tested. Cohabiting couples were more likely to test (aOR=1.4; 95% CI 1.2 to 1.6) than non-cohabiting couples. Context characteristics predictive of CVCT uptake included inviting couples (aOR=1.2; 95% CI 1.0 to 1.4) versus individuals; the woman (aOR=1.6; 95% CI 1.2 to 2.2) or couple (aOR=1.4; 95% CI 1.0 to 1.8) initiating contact versus the INA; the couple being socially acquainted with the INA (aOR=1.6; 95% CI 1.4 to 1.9) versus having just met; home invitation delivery (aOR=1.3; 95% CI 1.1 to 1.5) versus elsewhere; and easy invitation delivery (aOR=1.8; 95% CI 1.4 to 2.2) versus difficult as reported by the INA. This study demonstrated the ability of influential people to promote CVCT and identified agent, couple and context-level factors associated with CVCT uptake in Lusaka, Zambia. We encourage the development of CVCT promotions in other sub-Saharan African countries to support sustained CVCT dissemination.


Rates of epithelial ingrowth after LASIK for different excimer laser systems.
To investigate the incidence of epithelial ingrowth after laser in situ keratomileusis (LASIK) using the VISX 20/20B and VISX Star S3 laser systems. A chart review of patients who had undergone LASIK between April 1999 and December 2001 was performed. Patients having known risk factors for epithelial ingrowth were excluded from the study. Both eyes of patients who were operated with both laser systems were included in a paired analysis. The first operated eyes of the remaining patients were included in an unpaired analysis. The outcomes studied were epithelial ingrowth (a region of epithelial growth under the flap that was contiguous with the flap edge and extended at least 0.7 mm in the radial direction) and epithelial ingrowth requiring treatment (extending into the pupillary zone, causing reduced vision, causing nighttime glare, or inducing any melting of the flap edge). In the paired study, 11 (61.1%) of 18 eyes treated with the VISX 20/20B had epithelial ingrowth, and 7 (38.9%) eyes required treatment. None of the eyes treated with the VISX Star S3 had epithelial ingrowth. In the unpaired study, 39 (37.1%) of 105 eyes treated with the VISX 20/20B were noted to have epithelial ingrowth and 14 (13.3%) eyes required treatment. None of the eyes treated with the VISX Star S3 had epithelial ingrowth. The incidence of epithelial ingrowth was significantly different for the VISX 20/20B and the VISX Star S3 in both analyses (paired: P<.001, McNemar's test; unpaired: P<.001, Fisher's exact test). The laser system used in LASIK is a risk factor for the development of epithelial ingrowth.


Implementation of a Simplified Regional Citrate Anticoagulation Protocol for Post-Dilution Continuous Hemofiltration Using a Bicarbonate Buffered, Calcium Containing Replacement Solution.
Recent updates to the Nikkiso Aquarius continuous renal replacement therapy (CRRT) platform allowed us to develop a post-dilution protocol for regional citrate anticoagulation (RCA) using standard bicarbonate buffered, calcium containing replacement solution with acid citrate dextrose formula-A as a citrate source. Our objective was to demonstrate that the protocol was safe and effective. Prospective audit of consecutive patients receiving RCA for CRRT within intensive care unit, who were either contraindicated to heparin or had poor filter lifespan (<12 h for 2 consecutive filters) on heparin. We present the first 29 patients who used 98 filters. After excluding 'non-clot' filter loss, 50% had a duration of >27 h. Calcium supplementation was required for 30 (30%) filter circuits, in 17 of 29 (58%) patients. One patient discontinued the treatment due to metabolic alkalosis, but there were no adverse bleeding events. Post-dilution RCA system is effective and simple to use on the Aquarius platform and results in comparable filter life for patients relatively contraindicated to heparin.


Streptavidin-coated gold nanoparticles: critical role of oligonucleotides on stability and fractal aggregation.
Gold nanoparticles (AuNPs) exhibit unique properties that can be modulated through a tailored surface functionalization, enabling their targeted use in biochemical sensing and medical diagnostics. In particular, streptavidin-modified AuNPs are increasingly used for biosensing purposes. We report here a study of AuNPs surface-functionalized with streptavidin-biotinylated oligonucleotide, focussing on the role played by the oligonucleotide probes in the stabilization/destabilization of the functionalized nanoparticle dispersion. The behaviour of the modified AuNP dispersion as a consequence of the competitive displacement of the biotinylated oligonucleotide has been investigated and the critical role of displaced oligonucletides in triggering the quasi one-dimensional aggregation of nanoparticles is demonstrated for the first time. The thorough understanding of the fundamental properties of bioconjugated AuNPs is of great importance for the design of highly sensitive and reliable functionalized AuNP-based assays.


Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis.
The CA1 pyramidal neurons in the hippocampus are selectively vulnerable to transient ischemic damage. In experimental animals, the CA1 pyramidal neurons undergo cell death several days after brief forebrain ischemia. It remains, however, unknown whether this delayed neuronal death is necrosis or apoptosis. To investigate the degenerating processes of the CA1 pyramidal neurons in gerbil hippocampus after brief ischemia, lysosomal and nuclear alterations in the cells were examined using immunocytochemistry, in situ nick-end labeling, and Southern blotting. By light and electron microscopy, immunoreactivity for cathepsins B, H, and L, representative lysosomal cysteine proteinases, increased in the CA1 pyramidal neurons 3 d after ischemic insult, which showed cell shrinkage. By morphometric analysis, the volume density of cathepsin B-positive lysosomes markedly increased 3 d after ischemic insult, while that of autophagic vacuole-like structures also increased at this stage, suggesting that cathepsin B-immunopositive lysosomes increasing in the neurons after ischemic insult are mostly autolysosomes. Nuclei of the CA1 neurons were nick-end labeled by biotinylated dUTP mediated by terminal deoxytransferase 3 and 4 d after ischemic insult, but not in the prior stages. Simultaneously, dense chromatin masses appeared in nuclei of the neurons. By Southern blotting, laddering of DNA occurred only in CA1 hippocampal tissues obtained 4 d after ischemic insult. Confocal laser scanning microscopy demonstrated that the fragmented DNA in the CA1 pyramidal layer was phagocytosed by microglial cells. The results suggest that delayed death of the CA1 pyramidal neurons after brief ischemia is not necrotic but apoptotic.


Social and Health-Related Factors Associated with Enrollment in Medicare Advantage Plans in Older Adults.
We assessed the characteristics of older Mexican American enrollees in traditional fee-for-service (FFS) and Medicare Advantage (MA) plans and the factors associated with disenrollment from FFS and enrollment in MA plans. Longitudinal study linked with Medicare claims data. The Hispanic Established Populations for the Epidemiologic Study of the Elderly. Community-dwelling Mexican American older adults (N = 1455). We examined insurance status using the Medicare Beneficiary Summary File and estimated the association of sociodemographic and clinical factors with insurance plan switching. Among Mexican American older adults, FFS enrollees were more likely to be born in Mexico, speak Spanish, have lower levels of education, and have more disability than MA enrollees. Older adults with a larger number of limitations of instrumental activities of daily living (odds ratio [OR] = .50; 95% confidence interval [CI] = .26-.98) and more social support (OR = .70; 95% CI = .45-.98) were less likely to switch from FFS to MA compared with older adults with no limitations and less social support. Additionally, older adults living in counties with a greater number of MA plans were more likely to switch from FFS to MA (OR = 2.1; 95% CI = 1.45-3.16), compared with counties with a lower number of MA plans. In counties with a higher number of MA plans, older adults with more social support had lower odds of switching from FFS to MA (OR = .48; 95% CI = .28-.82) compared with older adults with less social support. Compared with those enrolled in MA, older Mexican American adults enrolled in Medicare FFS are more socioeconomically disadvantaged and more likely to demonstrate poor health status. Stronger social support and increased physical limitations were strongly associated with less frequent switching from FFS to MA plans. Additionally, increased availability of MA plans at the county level is a significant driver of enrollment in MA plans. J Am Geriatr Soc 68:313-320, 2020.


A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers.
Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.


The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS.
Through a combination of fluorescence microscopy and patch-clamp analysis we have identified a striking alteration in K(+) channel expression in terminally differentiated human CCR7(-)CD45RA(-) effector memory T lymphocytes (T(EM)). Following activation, T(EM) cells expressed significantly higher levels of the voltage-gated K(+) channel Kv1.3 and lower levels of the calcium-activated K(+) channel IKCa1 than naive and central memory T cells (T(CM)). Upon repeated in vitro antigenic stimulation, naive cells differentiated into Kv1.3(high)IKCa1(low) T(EM) cells, and the potent Kv1.3-blocking sea anemone Stichodactyla helianthus peptide (ShK) suppressed proliferation of T(EM) cells without affecting naive or T(CM) lymphocytes. Thus, the Kv1.3(high)IKCa1(low) phenotype is a functional marker of activated T(EM) lymphocytes. Activated myelin-reactive T cells from patients with MS exhibited the Kv1.3(high)IKCa1(low) T(EM) phenotype, suggesting that they have undergone repeated stimulation during the course of disease; these cells may contribute to disease pathogenesis due to their ability to home to inflamed tissues and exhibit immediate effector function. The Kv1.3(high)IKCa1(low) phenotype was not seen in glutamic acid decarboxylase, insulin-peptide or ovalbumin-specific and mitogen-activated T cells from MS patients, or in myelin-specific T cells from healthy controls. Selective targeting of Kv1.3 in T(EM) cells may therefore hold therapeutic promise for MS and other T cell-mediated autoimmune diseases.


Epidemiology of extended-spectrum β-lactamase-producing Enterobacterales in five US sites participating in the Emerging Infections Program, 2017.
The incidence of infections from extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E) is increasing in the United States. We describe the epidemiology of ESBL-E at 5 Emerging Infections Program (EIP) sites. During October-December 2017, we piloted active laboratory- and population-based (New York, New Mexico, Tennessee) or sentinel (Colorado, Georgia) ESBL-E surveillance. An incident case was the first isolation from normally sterile body sites or urine of Escherichia coli or Klebsiella pneumoniae/oxytoca resistant to ≥1 extended-spectrum cephalosporin and nonresistant to all carbapenems tested at a clinical laboratory from a surveillance area resident in a 30-day period. Demographic and clinical data were obtained from medical records. The Centers for Disease Control and Prevention (CDC) performed reference antimicrobial susceptibility testing and whole-genome sequencing on a convenience sample of case isolates. We identified 884 incident cases. The estimated annual incidence in sites conducting population-based surveillance was 199.7 per 100,000 population. Overall, 800 isolates (96%) were from urine, and 790 (89%) were E. coli. Also, 393 cases (47%) were community-associated. Among 136 isolates (15%) tested at the CDC, 122 (90%) met the surveillance definition phenotype; 114 (93%) of 122 were shown to be ESBL producers by clavulanate testing. In total, 111 (97%) of confirmed ESBL producers harbored a blaCTX-M gene. Among ESBL-producing E. coli isolates, 52 (54%) were ST131; 44% of these cases were community associated. The burden of ESBL-E was high across surveillance sites, with nearly half of cases acquired in the community. EIP has implemented ongoing ESBL-E surveillance to inform prevention efforts, particularly in the community and to watch for the emergence of new ESBL-E strains.


Dynamic changes in the subgingival microbiome and their potential for diagnosis and prognosis of periodontitis.
The human microbiome influences and reflects the health or disease state of the host. Periodontitis, a disease affecting about half of American adults, is associated with alterations in the subgingival microbiome of individual tooth sites. Although it can be treated, the disease can reoccur and may progress without symptoms. Without prognostic markers, follow-up examinations are required to assess reoccurrence and disease progression and to determine the need for additional treatments. To better identify and predict the disease progression, we aim to determine whether the subgingival microbiome can serve as a diagnosis and prognosis indicator. Using metagenomic shotgun sequencing, we characterized the dynamic changes in the subgingival microbiome in periodontitis patients before and after treatment at the same tooth sites. At the taxonomic composition level, the periodontitis-associated microorganisms were significantly shifted from highly correlated in the diseased state to poorly correlated after treatment, suggesting that coordinated interactions among the pathogenic microorganisms are essential to disease pathogenesis. At the functional level, we identified disease-associated pathways that were significantly altered in relative abundance in the two states. Furthermore, using the subgingival microbiome profile, we were able to classify the samples to their clinical states with an accuracy of 81.1%. Follow-up clinical examination of the sampled sites supported the predictive power of the microbiome profile on disease progression. Our study revealed the dynamic changes in the subgingival microbiome contributing to periodontitis and suggested potential clinical applications of monitoring the subgingival microbiome as an indicator in disease diagnosis and prognosis. Periodontitis is a common oral disease. Although it can be treated, the disease may reoccur without obvious symptoms. Current clinical examination parameters are useful in disease diagnosis but cannot adequately predict the outcome of individual tooth sites after treatment. A link between the subgingival microbiota and periodontitis was identified previously; however, it remains to be investigated whether the microbiome can serve as a diagnostic and prognostic indicator. In this study, for the first time, we characterized the subgingival microbiome of individual tooth sites before and after treatment using a large-scale metagenomic analysis. Our longitudinal study revealed changes in the microbiota in taxonomic composition, cooccurrence of subgingival microorganisms, and functional composition. Using the microbiome profiles, we were able to classify the clinical states of subgingival plaque samples with a high accuracy. Follow-up clinical examination of sampled sites indicates that the subgingival microbiome profile shows promise for the development of diagnostic and prognostic tools.


Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study.
Diagnosis of infantile thiamine deficiency disorders (TDD) is challenging due to the non-specific, highly variable clinical presentation, often leading to misdiagnosis. Our primary objective is to develop a case definition for thiamine responsive disorders (TRD) to determine among hospitalised infants and young children, which clinical features and risk factors identify those who respond positively to thiamine administration. This prospective study will enrol 662 children (aged 21 days to <18 months) seeking treatment for TDD symptoms. Children will be treated with intravenous or intramuscular thiamine (100 mg daily for a minimum of 3 days) alongside other interventions deemed appropriate. Baseline assessments, prior to thiamine administration, include a physical examination, echocardiogram and venous blood draw for the determination of thiamine biomarkers. Follow-up assessments include physical examinations (after 4, 8, 12, 24, 36, 48 and 72 hours), echocardiogram (after 24 and 48 hours) and one cranial ultrasound. During the hospital stay, maternal blood and breast-milk samples and diet, health, anthropometric and socio-demographic information will be collected for mother-child pairs. Using these data, a panel of expert paediatricians will determine TRD status for use as the dependent variable in logistic regression models. Models identifying predictors of TRD will be developed and validated for various scenarios. Clinical prediction model performance will be quantified by empirical area under the receiver operating characteristic curve, using resampling cross validation. A frequency-matched community-based cohort of mother-child pairs (n=265) will serve as comparison group for evaluation of potential risk factors for TRD. Ethical approval has been obtained from The National Ethics Committee for Health Research, Ministry of Health, Lao PDR and the Institutional Review Board of the University of California Davis. The results will be disseminated via scientific articles, presentations and workshops with representatives of the Ministry of Health. NCT03626337.


Antiviral drugs in current clinical use.
The current armamentarium for the chemotherapy of viral infections consists of 37 licensed antiviral drugs. For the treatment of human immunodeficiency virus (HIV) infections, 19 compounds have been formally approved: (i) the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; (ii) the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate; (iii) the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz; (iv) the protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir (combined with ritonavir at a 4/1 ratio) and atazanavir; and the viral entry inhibitor enfuvirtide. For the treatment of chronic hepatitis B virus (HBV) infections, lamivudine as well as adefovir dipivoxil have been approved. Among the anti-herpesvirus agents, acyclovir, valaciclovir, penciclovir (when applied topically), famciclovir, idoxuridine and trifluridine (both applied topically) as well as brivudin are used in the treatment of herpes simplex virus (HSV) and/or varicella-zoster virus (VZV) infections; and ganciclovir, valganciclovir, foscarnet, cidofovir and fomivirsen (the latter upon intravitreal injection) have proven useful in the treatment of cytomegalovirus (CMV) infections in immunosuppressed patients (i.e. AIDS patients with CMV retinitis). Following amantadine and rimantadine, the neuraminidase inhibitors zanamivir and oseltamivir have recently become available for the therapy (and prophylaxis) of influenza virus infections. Ribavirin has been used (topically, as aerosol) in the treatment of respiratory syncytial virus (RSV) infections, and the combination of ribavirin with (pegylated) interferon-alpha has received increased acceptance for the treatment of hepatitis C virus (HCV) infections.


The web and the structure of taxonomy.
An easily accessible taxonomic knowledge base is critically important for all biodiversity-related sciences. At present, taxonomic information is organized and regulated by a system of rules and conventions that date back to the introduction of binomial nomenclature by Linnaeus. The taxonomy of any particular group of organisms comprises the sum information in the taxonomic literature, supported by designated type specimens in major collections. In this article, the way modern means of disseminating information will change the practice of taxonomy, in particular the Internet, is explored. Basic taxonomic information, such as specimen-level data, location of types, and name catalogues are already available, at least for some groups, on the Web. Specialist taxonomic databases, key-construction programs, and other software useful for systematists are also increasingly available. There has also been a move towards Web-publishing of taxonomic hypotheses, though as yet this is not fully permitted by the Codes of Nomenclature. A further and more radical move would be to transfer taxonomy completely to the Web. A possible model of this is discussed, as well as a pilot project, the "CATE" initiative, which seeks to explore the advantages and disadvantages of such a move. It is argued that taxonomy needs to forge better links with its user-communities to maintain its funding base, and that an important part of this is making the products of its research more accessible through the Internet.


Removal of trace organics by MBR treatment: the role of molecular properties.
This study examined the relationship between specific molecular features of trace organic contaminants and their removal efficiencies by a laboratory scale membrane bioreactor (MBR). Removal efficiencies of 40 trace organic compounds were assessed under stable operating conditions. The reported results demonstrate an apparent correlation between chemical structures and the removal of trace organic contaminants by the laboratory scale MBR system. The removal of all 14 very hydrophobic (Log D > 3.2) trace organic compounds selected in this study was consistently high and was above 85%. The occurrence and types of electron withdrawing or donating functional groups appear to be important factors governing their removal by MBR treatment. In this study, all hydrophilic and moderately hydrophobic (Log D<3.2) compounds possessing strong electron withdrawing functional groups showed removal efficiency of less than 20%. In contrast, high removal efficiencies were observed with most compounds bearing electron donating functional groups such as hydroxyl and primary amine groups. A qualitative framework for the assessment of trace organic removal by MBR treatment was proposed to provide further insights into the removal mechanisms.


The effects of hands-free communication device systems: communication changes in hospital organizations.
To analyze the effects that hands-free communication device (HCD) systems have on healthcare organizations from multiple user perspectives. This exploratory qualitative study recruited 26 subjects from multiple departments in two research sites located in Portland, Oregon: an academic medical center and a community hospital. Interview and observation data were gathered January through March, 2007. Data were analyzed using a grounded theory approach. Because this study was exploratory, data were coded and patterns identified until overall themes 'emerged'. Five themes arose: (1) Communication access-the perception that HCD systems provide fast and efficient communication that supports workflow; (2) Control-social and technical considerations associated with use of an HCD system; (3) Training-processes that should be used to improve use of the HCD system; (4) Organizational change-changes to organizational design and behavior caused by HCD system implementation; and (5) Environment and infrastructure-HCD system use within the context of physical workspaces. HCD systems improve communication access but users experience challenges integrating the system into workflow. Effective HCD use depends on how well organizations train users, adapt to changes brought about by HCD systems, and integrate HCD systems into physical surroundings.


Predictive value of inferior fronto-occipital fasciculus (IFO) DTI-fiber tracking for determining the extent of resection for surgery of frontal and temporal gliomas preoperatively.
This work reports the analysis of the relationship between inferior fronto-occipital fasciculus (IFO), neoplastic lesions and surgical resection, in patients operated for gliomas located in the frontal, temporal and insular lobes of the dominant hemisphere. Aim of the study is evaluating the predictive value of inferior fronto-occipital fasciculus DTI-fiber tracking (FT) for determining the extent of resection preoperatively. We selected 38 cases affected by lesions located in the frontal, temporal and insular lobes of the dominant hemisphere, which were related to the trajectory of the IFO. For each patient preoperative and postoperative MR images and DTI-FT were loaded into the neuronavigation system and merged; volumetric scan analysis was used for establishing tumor location and topography, as well as the volume of the lesion and of the residual tumor. All preoperative fiber tracking datasets were evaluated and the position of the tract (IFO) compared to the tumor was recorded. Postoperative MR scans were then compared with DTI-FT, in order to evaluate the correspondence between the resection boundaries and the trajectory of the fiber tract. Amongst the cases in which the IFO was inside the lesion, we found only incomplete resections (5 subtotal and 6 partial resections), while considering the cases in which the IFO was located outside the tumor, it was possible to perform a relevant (total/subtotal) resection in 18 of them (78%). FT of the inferior frontal-occipital fasciculus predicts the possibility and the extent of the resection for a frontal, temporal and/or insular lesion of the dominant hemisphere.