Bedside Nurses: Champions of Antimicrobial Stewardship.
Microbial organisms include bacteria, viruses, fungi, and parasites. Antimicrobial medications are currently overused or misused, which has resulted in multidrug resistance. Hospitalized patients in the intensive care unit have the highest risk for infections leading to poor outcomes and require successful treatment options. Inappropriate prescription of antimicrobials places patients and the community at risk for more resistant infections in the future. To prevent misapplication of these important medications, interdisciplinary antimicrobial stewardship programs promote appropriate and safe antimicrobial medication use. Members of these programs are called to be good stewards of antimicrobial medications, incorporating the scope of practice and knowledge of each specialty and the evidence from the literature to develop strategies and protocols for safe and effective antimicrobial medication use. Nurse involvement in antimicrobial stewardship programs is inadequate, limiting the programs' potential. Support for increased direct-care nurse participation in antimicrobial stewardship programs is key to improve program targets and patient outcomes. This article calls for increased nursing awareness of the importance of antimicrobial stewardship programs in clinical practice and greater direct-care nurse involvement in these programs.


Individual and system influences on waiting time for substance abuse treatment.
Waiting time is a contemporary reality of many drug abuse treatment programs, resulting in substantial problems for substance users and society. Individual and system factors that influence waiting time are diverse and may vary at different points in the treatment continuum. This study assessed waiting time preceding clinical assessment at a centralized intake unit and during the period after the assessment but before treatment entry. The present study included 577 substance abusers who were enrolled in a large clinical trial of two brief treatment interventions in a midsize metropolitan area in Ohio. Bivariate analyses identified individual and system factors that influenced preassessment and postassessment waiting time, as well as total wait to treatment services. Multivariate analyses demonstrated that longer wait time for an assessment is influenced by being court referred, less belief in having a substance abuse problem, and less desire for change. A shorter wait to actually enter treatment is predicted by having a case manager, being more ready for treatment, and having less severe employment and alcohol problems. The different influences present during the two waiting periods suggest that assessment and treatment programs need to implement system changes and entry enhancement interventions that are specific to the needs of substance abusers at each waiting period.


Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study.
To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment. In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 ± 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards. In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95% CI 1.04-2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20-3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03-1.86], P-trend = 0.02), t-18:1 (1.32 [1.00-1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05-1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained. Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.


Role of ERM (ezrin-radixin-moesin) proteins in T lymphocyte polarization, immune synapse formation and in T cell receptor-mediated signaling.
Following antigen recognition, T lymphocytes undergo strong actin cytoskeletal rearrangements. These play a crucial role in the molecular reorganization at the contact site between the T lymphocyte and the antigen presenting cell, termed the immunological synapse. Moreover, they are necessary for T cell activation that leads to cytokine secretion, T cell proliferation and effector function. Little is known on how membrane and signaling molecules interact with the actin cytoskeleton during these processes. Here we review the function of the ERM family of membrane-microfilament linkers, making emphasis on the role of these proteins in T lymphocyte physiology. We discuss how ERM proteins are involved in membrane reorganization during T lymphocyte polarization and immune synapse formation, and how these proteins may contribute to T cell receptor-mediated intracellular signaling that leads to T cell activation.


NF1 inactivation in adult acute myelogenous leukemia.
This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix single nucleotide polymorphism 6.0 array-based genomic profiling. Through fine mapping of microdeletions on 17q, we derived a minimal deleted region of approximately 0.9-Mb length that harbors 11 known genes; this region includes Neurofibromin 1 (NF1). Sequence analysis of all NF1 coding exons in the 11 AML cases with NF1 copy number changes identified acquired truncating frameshift mutations in two patients. These NF1 mutations were already present in the hematopoetic stem cell compartment. Subsequent expression analysis of NF1 mRNA in the entire AML cohort using fluorescence-activated cell sorting sorted blasts as a source of RNA identified six patients (one with a NF1 mutation) with absent NF1 expression. The NF1 null states were associated with increased Ras-bound GTP, and short hairpin RNA-mediated NF1 suppression in primary AML blasts with wild-type NF1 facilitated colony formation in methylcellulose. Primary AML blasts without functional NF1, unlike blasts with functional NF1, displayed sensitivity to rapamycin-induced apoptosis, thus identifying a dependence on mammalian target of rapamycin (mTOR) signaling for survival. Finally, colony formation in methylcellulose ex vivo of NF1 null CD34+/CD38- cells sorted from AML bone marrow samples was inhibited by low-dose rapamycin. NF1 null states are present in 7 of 95 (7%) of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mammalian target of rapamycin-directed therapeutics.


Cross-domain person reidentification using domain adaptation ranking SVMs.
This paper addresses a new person reidentification problem without label information of persons under nonoverlapping target cameras. Given the matched (positive) and unmatched (negative) image pairs from source domain cameras, as well as unmatched (negative) and unlabeled image pairs from target domain cameras, we propose an adaptive ranking support vector machines (AdaRSVMs) method for reidentification under target domain cameras without person labels. To overcome the problems introduced due to the absence of matched (positive) image pairs in the target domain, we relax the discriminative constraint to a necessary condition only relying on the positive mean in the target domain. To estimate the target positive mean, we make use of all the available data from source and target domains as well as constraints in person reidentification. Inspired by adaptive learning methods, a new discriminative model with high confidence in target positive mean and low confidence in target negative image pairs is developed by refining the distance model learnt from the source domain. Experimental results show that the proposed AdaRSVM outperforms existing supervised or unsupervised, learning or non-learning reidentification methods without using label information in target cameras. Moreover, our method achieves better reidentification performance than existing domain adaptation methods derived under equal conditional probability assumption.


Spillover event of recombinant Lagovirus europaeus/GI.2 into the Iberian hare (Lepus granatensis) in Spain.
Viruses that affect lagomorphs have decades of reported history of spillover events. One of these viruses is the causative agent of the so-called rabbit or 'lagomorph' haemorrhagic disease (e.g. Lagovirus europaeus/GI.1 and L. europaeus/GI.2). In particular, L. europaeus/GI.2 has shown a great capacity to recombine with existing lagoviruses. In fact, it has replaced the former GI.1 genotype in the wild, and recently, an increase on spillover events has been detected among several lagomorph species including European and North American species of hares. In this study, we report for the first time the infection of a wild Iberian hare with GI.2 (RHDV2/b), potential shedding and associated histopathological alterations. We identify the recombinant GI.4P-GI.2 as causative of the infection and discuss plausible causes regarding the origin of the spillover event and its potential consequences for the Iberian hare wild populations, which is an endemic species of the Iberian Peninsula as well as an important game and prey species for many predators, including endangered species.


[Hypophyseal GnRH receptors. A minireview (author's transl)].
The preliminary step in the involvement of gonadoliberin (GnRH) in the cellular mechanism for the secretion of the gonadotropic hormones LH and FSH, consists of a reversible binding of GnRH with specific site on plasma membranes of the pituitary gland. The parameters of this interaction have been determined in vitro with the aid of biologically active preparations of synthetic GnRH labelled with [3H] or [125I], and homogenates or preparations of plasma membranes, from the pituitary glands, of rat, sheep or beef. According to several authors, one or two types of sites are involved in GnRH-receptor binding. At 0-4 degrees C, the equilibrium association constants of the high affinity sites vary from 0.77 X 10(8) M-1 to 2.33 X 10(10) M-1. At 37 degrees C, we have obtained a value of 1.1 X 10(8) M-1 for this constant. Low affinity binding sites have been found in pituitaries and in other tissues; according to CLAYTON (1979), they may be structurally bound to enzymes which degrade GnRH. Other authors feel that a correlation may exist between the biological activity of agonistic analogues of GnRH and their capacity for binding to high affinity sites. Modulation of the binding of GnRH to low and high affinity sites by steroids and/or peptidases has been considered. The existence of intracellular receptors and internalisation of the GnRH-receptor complex have also been reported.


Effects of Active Video Games on Energy Expenditure in Adults: A Systematic Literature Review.
The objective of this study was to estimate the mean difference in energy expenditure (EE) in healthy adults between playing active video games (AVGs) compared with traditional video games (TVGs) or rest. A systematic search was conducted on Ovid MEDLINE, Web of Knowledge, and Academic Search Premier between 1998 and April 2012 for relevant keywords, yielding 15 studies. EE and heart rate (HR) data were extracted, and random effects meta-analysis was performed. EE during AVG play was 1.81 (95% CI, 1.29-2.34; I² = 94.2%) kcal/kg/hr higher, or about 108 kcal higher per hour for a 60-kg person, compared with TVG play. Mean HR was 21 (95% CI, 13.7-28.3; I² = 93.4%) beats higher per minute during AVG play compared with TVG play. There was wide variation in the EE and HR estimates across studies because different games were evaluated. Overall metabolic equivalent associated with AVG play was 2.62 (95% CI, 2.25-3.00; I² = 99.2%), equivalent to a light activity level. Most studies had low risk of bias due to proper study design and use of indirect calorimetry to measure EE. AVGs may be used to replace sedentary screen time (eg, television watching or TVG play) with light activity in healthy adults.


Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor.
Aminoacyl-tRNA synthetases (AARSs) catalyze an early step in protein synthesis, but also regulate diverse physiological processes in animal cells. These include angiogenesis, and human threonyl-tRNA synthetase (TARS) represents a potent pro-angiogenic AARS. Angiogenesis stimulation can be blocked by the macrolide antibiotic borrelidin (BN), which exhibits a broad spectrum toxicity that has discouraged deeper investigation. Recently, a less toxic variant (BC194) was identified that potently inhibits angiogenesis. Employing biochemical, cell biological, and biophysical approaches, we demonstrate that the toxicity of BN and its derivatives is linked to its competition with the threonine substrate at the molecular level, which stimulates amino acid starvation and apoptosis. By separating toxicity from the inhibition of angiogenesis, a direct role for TARS in vascular development in the zebrafish could be demonstrated. Bioengineered natural products are thus useful tools in unmasking the cryptic functions of conventional enzymes in the regulation of complex processes in higher metazoans.


Health-service use in women with binge eating disorders.
To compare health-care utilization between participants who met DSM-IV criteria for binge eating disorder (BED) and those engaged in recurrent binge eating (RBE) and to evaluate whether objective binge eating (OBE) days, a key measurement for diagnosing BED, predicted health-care costs. We obtained utilization and cost data from electronic medical records to augment patient reported data for 100 adult female members of a large health maintenance organization who were enrolled in a randomized clinical trial to treat binge eating. Total costs did not differ between the BED and RBE groups (β = -0.117, z = -0.48, p = .629), nor did the number of OBE days predict total costs (β = -0.017, z = -1.01, p = .313). Findings suggest that the medical impairment, as assessed through health care costs, caused by BED may not be greater than impairment caused by RBE. The current threshold number of two OBE days/week as a criterion for BED may need to be reconsidered.


Prenatal Opioid Exposure and Intermittent Hypoxemia in Preterm Infants: A Retrospective Assessment.
Intermittent hypoxemia (IH) is defined as episodic drops in oxygen saturation (SpO2). Preterm infants are at increased risk for IH due to their immature respiratory control/apnea of prematurity. The clinical relevance of IH is a relatively new observation with rising evidence linking IH to neonatal morbidities and long-term impairment. Hence, assessing factors that influence IH in preterm infants is imperative. Given the epidemic of opioid misuse in the USA, there is an urgent need to understand the impact of prenatal opioid exposure on neonatal outcomes. Hence, we wanted to assess the relationship between isolated prenatal opioid exposure and IH in preterm infants. In order to accurately calculate IH, SpO2 data were prospectively collected using high-resolution pulse oximeters during the first 8 weeks of life in preterm infants less than 30 weeks gestational age. Data related to prenatal opioid misuse were retrospectively collected from medical charts. Infants with tobacco or poly-drug exposure were excluded. The primary outcome measure is percent time spent with SpO2 below 80% (%time-SpO2 < 80). The secondary outcome measure is the number of severe IH events/week with SpO2 less than 80% (IH-SpO2 < 80). A total of 82 infants with isolated opioid exposure (n = 14) or who were unexposed (n = 68) were included. There were no significant differences in baseline characteristics between opioid exposed and unexposed groups. There was a statistically significant increase of 0.23 (95% CI: 0.03, 0.43, p = 0.03) in mean of the square root of %time-SpO2 < 80. The number of IH-SpO2 < 80 events was higher in the opioid exposed group (mean difference = 2.95, 95% CI: -0.35, 6.25, p-value = 0.08), although statistical significance was not quite attained. This study shows that preterm infants prenatally exposed to opioids have increased IH measures compared to unexposed infants. Interestingly, the increased IH in the opioid exposed group persists beyond the immediate postnatal period.


The role of mobilisation and delivery processes on contrasting dissolved nitrogen and phosphorus exports in groundwater fed catchments.
Diffuse transfer of nitrogen (N) and phosphorus (P) in agricultural catchments is controlled by the mobilisation of sources and their delivery to receiving waters. While plot scale experiments have focused on mobilisation processes, many catchment scale studies have hitherto concentrated on the controls of dominant flow pathways on nutrient delivery. To place mobilisation and delivery at a catchment scale, this study investigated their relative influence on contrasting nitrate-N and soluble P concentrations and N:P ratios in two shallow groundwater fed catchments with different land use (grassland and arable) on the Atlantic seaboard of Europe. Detailed datasets of N and P inputs, concentrations in shallow groundwater and concentrations in receiving streams were analysed over a five year period (October 2010-September 2015). Results showed that nitrate-N and soluble P concentrations in shallow groundwater give a good indication of stream concentrations, which suggests a dominant control of mobilisation processes on stream exports. Near-stream attenuation of nitrate-N (-30%), likely through denitrification and dilution, and enrichment in soluble P (+100%), through soil-groundwater interactions, were similar in both catchments. The soil, climate and land use controls on mobilisation were also investigated. Results showed that grassland tended to limit nitrate-N leaching as compared to arable land, but grassland could also contribute to increased P solubilisation. In the context of land use change in these groundwater fed systems, the risk of pollution swapping between N and P must be carefully considered, particularly for interactions of land use with soil chemistry and climate.


Polarimetric high-resolution confocal scanning laser ophthalmoscope.
A polarimetric high-resolution confocal scanning laser ophthalmoscope has been developed. The system incorporates a fixed linear polarizer in the illumination path and a rotatory quarter-wave plate and another fixed linear polarizer in the registration path. Retinal areas that are smaller than those provided by commercial instruments can be imaged. Series of four fundus images for independent polarization states in the second pass were recorded for different eyes and retinal locations and the spatially resolved Stokes vectors calculated. From those images, the contrast across retinal blood vessels was maximized and the corresponding image was reconstructed. In terms of polarization, the analysis of small retinal areas might prove to be useful in the improvement of retinal imaging and the enhancement of structural details in the early diagnosis of ocular pathologies.


Extension of the generalized multipole technique to three-dimensional anisotropic scatterers.
New expansions are derived for the simulation of three-dimensional anisotropic scatterers with the generalized multipole technique (GMT). This extension of the GMT makes possible the investigation of subtle phenomena such as the interaction of light with realistic crystals or magneto-optic materials.


In silico Identification of a Molecular Circadian System With Novel Features in the Crustacean Model Organism Parhyale hawaiensis.
The amphipod Parhyale hawaiensis is a model organism of growing importance in the fields of evolutionary development and regeneration. A small, hardy marine crustacean that breeds year-round with a short generation time, it has simple lab culture requirements and an extensive molecular toolkit including the ability to generate targeted genetic mutant lines. Here we identify canonical core and regulatory clock genes using genomic and transcriptomic resources as a first step in establishing this species as a model in the field of chronobiology. The molecular clock of P. hawaiensis lacks orthologs of the canonical circadian genes cryptochrome 1 and timeless, in common with the mammalian system but in contrast to many arthropods including Drosophila melanogaster. Furthermore the predicted CLOCK peptide is atypical and CRY2 shows an extended 5' region of unknown function. These results appear to be shared by two other amphipod species.


Characterization of Diaporthe australafricana and Diaporthe spp. Associated with Stem Canker of Blueberry in Chile.
Stem canker and dieback are important factors that limit the longevity and reduce the yield of blueberry (Vaccinium spp.) in Chile. In this study, species of Diaporthe associated with blueberry were isolated and identified. The internal transcribed spacer (ITS) regions of ribosomal DNA of 30 isolates and the translation elongation factor 1-α (EF1-α) of 14 isolates were sequenced, analyzed, and compared with their morphological and pathological characteristics. The molecular analysis of ITS sequences by alignment with those of ex-type strains deposited in GenBank and morphological characteristics allowed the identification of Diaporthe ambigua, D. australafricana, D. neotheicola, D. passiflorae, and Diaporthe sp. 1. However, morphology alone was insufficient to identify these species. The combined analysis of ITS and EF1-α gene sequences grouped the Chilean blueberry isolates in the same five groups obtained in the ITS analysis. Pathogenicity tests conducted with attached and detached blueberry shoots (<1 year old) and stems (1 to 2 years old) confirmed that isolates of these Diaporthe spp. were pathogenic. The symptoms were reproducible and consisted of necrotic reddish-brown cankers on blueberry shoots and stems. These isolates were capable of infecting blueberry fruit, causing a soft decay, suggesting that they were tissue nonspecific and were also pathogenic on shoots of apple, grapevine, and pear. D. australafricana was the most frequently isolated species and D. ambigua, D. australafricana, and D. passiflorae were highly virulent in shoots, stems, and fruit of blueberry. This study showed that at least four species of Diaporthe are primary pathogens, capable of causing stem canker symptoms on blueberry, and this is the first report of D. ambigua, D. neotheicola, and D. passiflorae attacking this host.


Changing strategies of lung biopsies in diffuse lung diseases: the impact of video-assisted thoracoscopy.
The aims of this report were: 1) to compare the strategy of bioptic approach in Italy during the last 4 yrs with a previous period; and 2) to compare efficacy and safety of video-assisted thorascopic lung biopsy (VTLB) versus OLB. We retrospectively evaluated: 1) the strategy of the bioptic approach in the Milan Sarcoid Clinic in the years 1992-1995 (201 patients) versus 1988-1991 (197 patients); and 2) data from 65 VTLB procedures in the years 1992-1995 versus 68 OLB procedures in the years 1988-1991 performed in patients with diffuse lung disease. It was found that the use of OLB (17-9%), mediastinoscopy (15-5%), and scalene node biopsy (20-7%) decreased, whereas transbronchial biopsy (TBB) increased (11-17%). VTLB biopsy is now performed in 17% of patients. VTLB compares favourably with OLB as there is less need for analgesia (7.5+/-7.5 versus 17.5+/-8.0 methadone mg i.m.: p<0.001), lower blood loss (61+/-58 versus 156+/-84 mL in the first postoperative day: p<0.001), and shorter postoperative stay (4.7+/-1.6 versus 5.7+/-1.4 days: p<0.001). Specimen adequacy (98.6 versus 985%) and diagnostic accuracy (86.1% VTLB, versus 92.6% OLB: p>0.05) were the same in the two groups. In conclusion, video-assisted thoracoscopic lung biopsy is replacing both mediastinoscopy and open lung biopsy. It is at present the best option when a surgical procedure is required for histological confirmation of diffuse lung disease.


Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy.
In the Guillain-Barré syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement-mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement-mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were trafficked to recycling endosomes and lysosomes. Consequently, complement-mediated cytotoxicity was attenuated. Importantly, we observed the same AGAb endocytosis and protection from cytotoxicity in live mouse nerve terminals. AGAb uptake was attenuated following membrane cholesterol depletion in vitro and ex vivo, indicating that this process may be dependent upon cholesterol-enriched microdomains. In contrast, we observed minimal AGAb uptake at nodes of Ranvier, and this structure thus remained vulnerable to complement-mediated injury. These results indicate that differential endocytic processing of AGAbs by different neuronal and glial membranes might be an important modulator of site-specific injury in acute AGAb-mediated Guillain-Barré syndrome subforms and their chronic counterparts.


A novel approach for incremental uncertainty rule generation from databases with missing values handling: application to dynamic medical databases.
Current approaches for mining association rules usually assume that the mining is performed in a static database, where the problem of missing attribute values does not practically exist. However, these assumptions are not preserved in some medical databases, like in a home care system. In this paper, a novel uncertainty rule algorithm is illustrated, namely URG-2 (Uncertainty Rule Generator), which addresses the problem of mining dynamic databases containing missing values. This algorithm requires only one pass from the initial dataset in order to generate the item set, while new metrics corresponding to the notion of Support and Confidence are used. URG-2 was evaluated over two medical databases, introducing randomly multiple missing values for each record's attribute (rate: 5-20% by 5% increments) in the initial dataset. Compared with the classical approach (records with missing values are ignored), the proposed algorithm was more robust in mining rules from datasets containing missing values. In all cases, the difference in preserving the initial rules ranged between 30% and 60% in favour of URG-2. Moreover, due to its incremental nature, URG-2 saved over 90% of the time required for thorough re-mining. Thus, the proposed algorithm can offer a preferable solution for mining in dynamic relational databases.


Use of Ruthenium-106 Brachytherapy for Iris Melanoma: The Scottish Experience.
To analyse long-term outcomes of ruthenium-106 (106Ru) plaque brachytherapy for the treatment of iris melanoma. We retrospectively reviewed medical records of 19 consecutive patients with pure iris melanoma treated with 106Ru plaque brachytherapy between 1998 and 2016 at the Scottish Ophthalmic Oncology Service, Glasgow. The iris melanoma was treated with a ruthenium plaque placed on the corneal surface to deliver a surface dose of 555 Gy. We analysed vision preservation, local tumour control, radiation-related complications, eye retention rates, symptomatic metastasis and melanoma-related mortality. The mean largest basal diameter of the lesions was 3.50±1.42 mm (range 1.6-6.5 mm), and the mean maximum height was 1.47±0.65 mm (range 0.7-2.8 mm). The tumour control and eye retention were 100% at a mean follow-up of 62 months (range 6-195 months). A 62% reduction in tumour height was observed on ultrasonography. Complications included cataract (68%), dry eye (47%), uveitis (37%) and scleral thinning (5%). At the final follow-up visit, the mean loss of Snellen visual acuity was 1.11±2.90 lines and vision of 6/9 or better was maintained in 53% of patients. None of the patients had evidence of symptomatic metastasis (non-imaged) or melanoma-related mortality. 106Ru plaque treatment for iris melanoma was highly effective a high tumour control, no tumour recurrences and a relatively a low complication rate.


Most unicompartmental knee replacement revisions could be avoided: a radiographic evaluation of revised Oxford knees in the National Joint Registry.
The purpose of this study was to understand why the revision rate of unicompartmental knee replacement (UKR) in the National Joint Registry (NJR) is so high. Using radiographs, the appropriateness of patient selection for primary surgery, surgical technique, and indications for revision were determined. In addition, the alignment of the radiographs was assessed. Oxford UKR registered with the NJR between 2006 and 2010 and subsequently revised were identified by the NJR. A blinded review was undertaken of pre-primary, post-primary, and pre-revision anteroposterior and lateral radiographs of a sample of 107 cases from multiple centres. The recommended indications were satisfied in 70%, with 29% not demonstrating bone-on-bone arthritis. Major technical errors, likely leading to revision, were seen in 6%. Pre-revision radiographs were malaligned and, therefore, difficult to interpret in 53%. No reason for revision was seen in 67%. Reasons for revision included lateral compartment arthritis (10%), tibial loosening (7%), bearing dislocation (7%), infection (6%), femoral loosening (3%), and peri-prosthetic fracture (2%, one femoral, one tibial). Only 20% of the revised UKR were implanted for the recommended indications, using appropriate surgical technique and had a mechanical problem necessitating revision. One-third of primary surgeries were undertaken in patients with early arthritis, which is contraindicated. Two-thirds were presumably revised for unexplained pain, which is not advised as it tends not to help the pain. This study suggests that variable and inappropriate indications for primary and revision surgery are responsible for the high rates of revision seen in registries. III, Therapeutic study.


Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial.
A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 μg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.


Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism.
The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.


Multilocus sequence analysis of diverse Streptococcus iniae isolates indicates an underlying genetic basis for phenotypic heterogeneity.
Streptococcus iniae is a Gram-positive, opportunistically zoonotic bacterium infective to a wide variety of farmed and wild fish species worldwide. Outbreaks in wild fish can have detrimental environmental and cultural impacts, and mortality events in aquaculture can result in significant economic losses. As an emerging or re-emerging pathogen of global significance, understanding the coalescing factors contributing to piscine streptococcosis is crucial for developing strategies to control infections. Intraspecific antigenic and genetic variability of S. iniae has made development of autogenous vaccines a challenge, particularly where the diversity of locally endemic S. iniae strains is unknown. This study genetically and phenotypically characterized 11 S. iniae isolates from diseased wild and farmed fish from North America, Central America, and the Caribbean. A multilocus sequence analysis (MLSA) scheme was developed to phylogenetically compare these isolates to 84 other strains of Streptococcus spp. relevant to aquaculture. MLSA generated phylogenies comparable to established genotyping methods, and isolates formed distinct clades related to phenotype and host species. The endothelial Oreochromis mossambicus bulbus arteriosus cell line and whole blood from rainbow trout Oncorhynchus mykiss, Nile tilapia Oreochromis niloticus, and white sturgeon Acipenser transmontanus were used to investigate the persistence and virulence of the 11 isolates using in vitro assays. In vivo challenges using an O. niloticus model were used to evaluate virulence by the intragastric route of infection. Isolates showed significant differences (p < 0.05) in virulence and persistence, with some correlation to genogroup, establishing a basis for further work uncovering genetic factors leading to increased pathogenicity.


Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome.
A Giardia outbreak was associated with development of post-infectious functional gastrointestinal disorders (PI-FGID) and chronic fatigue syndrome (PI-CFS). Markers of immune dysfunction have given conflicting results in CFS and FGID patient populations. The aim of this study was to evaluate a wide selection of markers of immune dysfunction in these two co-occurring post-infectious syndromes. 48 patients, reporting chronic fatigue in a questionnaire study, were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS (n=19) and idiopathic chronic fatigue (n=5) and Rome II criteria for FGIDs (n=54). 22 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. In peripheral blood we found significantly higher CD8 T-cell levels in PI-FGID, and significantly lower NK-cell levels in PI-CFS patients. Severity of abdominal and fatigue symptoms correlated negatively with NK-cell levels. A tendency towards lower T-cell CD26 expression in FGID was seen. Patients with PI-CFS and/or PI-FGID 5 years after Giardia lamblia infection showed alterations in NK-cell and CD8-cell populations suggesting a possible immunological abnormality in these conditions. We found no significant changes in other markers examined in this well-defined group of PI-CFS and PI-FGID elicited by a gastrointestinal infection. Controlling for co-morbid conditions is important in evaluation of CFS-biomarkers.


Barbell kinematics should not be used to estimate power output applied to the Barbell-and-body system center of mass during lower-body resistance exercise.
The aim of this study was to compare measures of power output applied to the center of mass of the barbell and body system (CM) obtained by multiplying ground reaction force (GRF) by (a) the velocity of the barbell; (b) the velocity of the CM derived from three-dimensional (3D) whole-body motion analysis, and (c) the velocity of the CM derived from GRF during lower-body resistance exercise. Ten resistance-trained men performed 3 maximal-effort single back squats with 60% 1 repetition maximum while GRF and whole-body motion were captured using synchronized Kistler force platforms and a Vicon Motus motion analysis system. Repeated measures analysis of variance of time-normalized kinematic and kinetic data obtained using the different methods showed that the barbell was displaced 13.4% (p < 0.05) more than the CM, the velocity of the barbell was 16.1% (p < 0.05) greater than the velocity of the CM, and power applied to the CM obtained by multiplying GRF by the velocity of the barbell was 18.7% (p < 0.05) greater than power applied to the CM obtained by multiplying the force applied to the CM by its resultant velocity. Further, the velocity of the barbell was significantly greater than the velocity of the trunk, upper leg, lower leg, and foot (p < 0.05), indicating that a failure to consider the kinematics of body segments during lower-body resistance exercise can lead to a significant overestimation of power applied to the CM. Strength and conditioning coaches and investigators are urged to obtain measures of power from the force applied to and the velocity of either the barbell (using inverse dynamics) or CM (GRF or 3D motion analysis). Failure to apply these suggestions could result in continued overestimation of CM power, compromising methodological integrity.


Prosody and language comprehension.
This review provides a summary of the most recent advances on the study of how prosody is used during language comprehension. Prosody is characterized as an abstract structure composed of discrete tonal elements aligned with the segmental composition of the sentence organized in constituents of increasing size, and this structure is influenced by the phonological, syntactic, and informational structures of the sentence. Here, we discuss evidence that listeners are affected by prosody when establishing those linguistic structures. Prosody has been shown to influence the segmentation of the utterance into syllables and words, and, in some cases, whether a syllable or word is judged to be present or not. The literature on how prosody informs the structural relationship between words and phrases is also discussed, contrasting views that assume a direct (albeit probabilistic) link between syntax and prosody with those that posit a complex interface between syntax and prosodic structure. Finally, the role of prosody in conveying important aspects pertaining to the sentence's information structure (i.e., which parts of the sentence's meaning are highlighted and brought forward to the discourse, which ones are presupposed and left in the background, which attitudes are being conveyed about the concepts or propositional content) has long been recognized. Current research focuses on which prosodic elements contribute to marking the dimensions (or semantic primitives) of the information structure.


Community gardens: lessons learned from California Healthy Cities and Communities.
Community gardens enhance nutrition and physical activity and promote the role of public health in improving quality of life. Opportunities to organize around other issues and build social capital also emerge through community gardens. California Healthy Cities and Communities (CHCC) promotes an inclusionary and systems approach to improving community health. CHCC has funded community-based nutrition and physical activity programs in several cities. Successful community gardens were developed by many cities incorporating local leadership and resources, volunteers and community partners, and skills-building opportunities for participants. Through community garden initiatives, cities have enacted policies for interim land and complimentary water use, improved access to produce, elevated public consciousness about public health, created culturally appropriate educational and training materials, and strengthened community building skills.


Presence of Mycobacterium avium Subspecies paratuberculosis Monitored Over Varying Temporal and Spatial Scales in River Catchments: Persistent Routes for Human Exposure.
Mycobacterium avium subspecies paratuberculosis (Map) was monitored by quantitative PCR over a range of temporal and spatial scales in the River Tywi catchment. This study shows the persistence of Map over a 10-year period with little change, which correlates with the recognised levels of Johne's disease in British herds over that period (aim 1). Map was quantified within the river at up to 108 cell equivalents L-1 and was shown to be consistently present when monitored over finer timescales (aim 4). Small wastewater treatment plants where the ingress of human-associated Map might be expected had no significant effect (aim 2). Map was found for the first time to be located in natural river foams providing another route for spread via aerosols (aim 5). This study provides evidence for the environmental continuum of Map from the grazing infected animal via rain driven runoff through field drains and streams into main rivers; with detection at a high frequency throughout the year. Should Map need to be monitored in the future, we recommend that weekly or monthly sampling from a fixed location on a river will capture an adequate representation of the flow dynamics of Map in a catchment (aim 3). The human exposure to Map during this process and its impact on human health remains unquantified.


Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group study.
The acute and late toxicities of synchronous carboplatin, etoposide, and radiation therapy were prospectively assessed in a group of patients with high-risk Merkel cell carcinoma of the skin. Forty patients from six different centers throughout Australia were entered into a Phase II study under the auspices of the Trans-Tasman Radiation Oncology Group. The trial was activated in 1996 and continues to accrue. Patients are eligible if they have disease localized to the primary site and nodes and are required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (area under curve [AUC] 4.5) and etoposide (80 mg/M(2) i.v.) were given on days 1-3 during weeks 1, 4, 7, and 10. The median age of the group was 67 years (43-78). The median duration of follow-up was 22 months (2-45). There were no treatment-related deaths. Grade 3 or 4 skin toxicity occurred in 63% of patients (95% CI 48, 78). The most serious acute effect was on neutrophils with Grade 3 or 4 (neutrophils < 1 x 10(9)/L), occurring in 60% (95% CI 45, 75) of cases. Complications from neutropenia (fever and sepsis) occurred in 16 patients (40% of cases). The median time for neutropenic complications was 27 days (9-35), and 10/16 (62%) cases of neutropenic fever occurred after the second cycle of chemotherapy. The probability of Grade 3 or 4 late effects on platelets (<50 x 10(9)/L) and hemoglobin (<8 g/dl) was 10% (95% CI 1, 20) and 6% (95% CI 2, 15), respectively. Of the 40 patients, 35 were able to complete 4 cycles of chemotherapy. There were no factors predictive for neutropenic toxicity at a p value < 0.05. The protocol has acceptable toxicity, and the treatment has been deliverable in a multi-institutional trial setting. Neutropenia is likely to occur with synchronous carboplatin/etoposide and radiation in this population of patients. The risk of a febrile neutropenia was greatest at the time of the second cycle of chemotherapy, when there was moist desquamation of skin or mucosal membranes that provided a portal for infection. This should be considered in the design of subsequent protocols with chemoradiotherapy.


A canine model of inherited myopia: familial aggregation of refractive error in labrador retrievers.
To determine whether the distribution of naturally occurring myopia in Labrador Retrievers has a genetic component. Pedigree records of a large canine family were analyzed. Pure Labrador Retrievers, 1 to 8 years of age, free of ocular disease, and available for testing were studied. Refractive error was measured by cycloplegic retinoscopy in both eyes. The family included mating loops, and so an expectation maximization (EM) algorithm (multivar program, MORGAN software; University of Washington, Seattle) was used to calculate log likelihoods of refractive error with environmental and additive genetic models. The fixed effects of coat color, sex, and litter size were also tested. In our sample of 116 dogs from this one family, the average spherical equivalent refraction (SER) was -0.41 D (range, -5.38 to +1.65 D, mean of both eyes, n = 116): 31% were myopic (SER <or= -0.50 D), 60% were emmetropic (SER = -0.49 to +0.99 D), and 9% were hyperopic (SER >or= +1.00 D). The significance of fixed and genetic effects was tested by comparing the full model (including genetic and all fixed effects) to models with one effect removed. Litter size and additive genetic effects were significant (P = 0.0013 and P = 0.000093, respectively), whereas sex and coat color were not. The overall variance in SER was accounted for approximately equally by additive genetic variance and residual/environmental variance. Narrow sense heritability of SER was 0.506. The distribution of refractive error within this family of Labrador Retrievers had a significant genetic component, but was also influenced by other factors (litter size, and undefined residual/environmental effects). The dog represents a unique model for the study of naturally occurring, heritable, high-prevalence, low-degree myopia.


Arctigenin Attenuates Tumor Metastasis Through Inhibiting Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma via Suppressing GSK3β-Dependent Wnt/β-Catenin Signaling Pathway In Vivo and In Vitro.
Arctigenin (ARG) has been reported to be a bioactive lignan from Arctium lappa exerting various activities including anti-cancer and immune-regulation. The present study aimed to investigate the anti-metastasis activity and mechanism of ARG against hepatocellular carcinoma in vitro and in vivo. The results showed that ARG exhibited a significant cytotoxicity on Hep G2 and SMMC 7721 cells (but not on normal liver cells LO2). In addition, the migration and invasion of Hep G2 and SMMC 7721 cells were also remarkably repressed. Furthermore, ARG attenuated Wnt/β-catenin signaling activation, resulting in the down-regulation of β-catenin target genes including c-Myc, cyclin D1, MMP-9, and ZO-1. Noticeably, ARG attenuated the activation of Wnt/β-catenin through a GSK3β-dependent pathway. Besides, we also found that ARG potentially inhibited epithelial-mesenchymal transition by up-regulating the epithelial and down-regulating the mesenchymal marker proteins. In vivo, intraperitoneal injection of ARG not only significantly inhibited the growth of subcutaneous transplanted tumor but also dramatically alleviated the tumor metastasis in liver. Our data demonstrated that ARG exerted anti-epithelial-mesenchymal transition and anti-metastasis activities against hepatocellular carcinoma, which might make it a candidate as a preventive agent for cancer metastasis.


Regional brain metabolism as the predictor of performance on the Trail Making Test in schizophrenia. A 18FDG PET covariation study.
With the aim to indicate the functional anatomical substrate of cognitive dysfunction in schizophrenia we evaluated the relationship between resting brain metabolism and performance on the Trail Making Test (TMT). As the prerequisite analysis we compared the performance in Part A and B of the TMT between schizophrenic patients and controls. Resting brain metabolism was investigated by (18)FDG positron emission tomography (PET) as the probe for the relative regional synaptic strength and density. (18)FDG PET data were analyzed by SPM99 with TMT A and B as the covariate (p< or =0.001). Schizophrenic patients (N=42) had worse performance in both TMT A and B compared to controls (N=42). In schizophrenic subjects (18)FDG PET did not predict the performance on Part A (psychomotor speed) but predicted that for Part B (set-shifting and flexibility) of the TMT. The (18)FDG uptake in the superior, middle and inferior frontal gyruses bilaterally was associated with better performance in the TMT B. The negative covariation between 18FDG uptake and time spent in the TMT B was detected in the temporal and parietal cortices, pre- and postcentral gyruses, precuneus limbic regions (anterior cingulate, uncus) and the pons. Our data indicate that hypometabolism in the frontal lobes and hypermetabolism in the temporo-parieto-limbic regions is the neurobiological basis for deficient TMT B performance in schizophrenia.


Use of chemical tracers in assessing the diet and foraging regions of eastern North Pacific killer whales.
Top predators in the marine environment integrate chemical signals acquired from their prey that reflect both the species consumed and the regions from which the prey were taken. These chemical tracers-stable isotope ratios of carbon and nitrogen; persistent organic pollutant (POP) concentrations, patterns and ratios; and fatty acid profiles-were measured in blubber biopsy samples from North Pacific killer whales (Orcinus orca) (n=84) and were used to provide further insight into their diet, particularly for the offshore group, about which little dietary information is available. The offshore killer whales were shown to consume prey species that were distinctly different from those of sympatric resident and transient killer whales. In addition, it was confirmed that the offshores forage as far south as California. Thus, these results provide evidence that the offshores belong to a third killer whale ecotype. Resident killer whale populations showed a gradient in stable isotope profiles from west (central Aleutians) to east (Gulf of Alaska) that, in part, can be attributed to a shift from off-shelf to continental shelf-based prey. Finally, stable isotope ratio results, supported by field observations, showed that the diet in spring and summer of eastern Aleutian Island transient killer whales is apparently not composed exclusively of Steller sea lions.


Do dynamic-based MR knee kinematics methods produce the same results as static methods?
MR-based methods provide low risk, noninvasive assessment of joint kinematics; however, these methods often use static positions or require many identical cycles of movement. The study objective was to compare the 3D kinematic results approximated from a series of sequential static poses of the knee with the 3D kinematic results obtained from continuous dynamic movement of the knee. To accomplish this objective, we compared kinematic data from a validated static MR method to a fast static MR method, and compared kinematic data from both static methods to a newly developed dynamic MR method. Ten normal volunteers were imaged using the three kinematic methods (dynamic, static standard, and static fast). Results showed that the two sets of static results were in agreement, indicating that the sequences (standard and fast) may be used interchangeably. Dynamic kinematic results were significantly different from both static results in eight of 11 kinematic parameters: patellar flexion, patellar tilt, patellar proximal translation, patellar lateral translation, patellar anterior translation, tibial abduction, tibial internal rotation, and tibial anterior translation. Three-dimensional MR kinematics measured from dynamic knee motion are often different from those measured in a static knee at several positions, indicating that dynamic-based kinematics provides information that is not obtainable from static scans.


Occupation and breast cancer risk among Shanghai women in a population-based cohort study.
A total of 74,942 female subjects were recruited in a population-based cohort study in Shanghai, China between 1997 and 2000. We examined the relationship between occupation and breast cancer risk. Cases were 586 women previously diagnosed with breast cancer at baseline and 438 women newly diagnosed with breast cancer during follow-up through December 2004. Eight controls were randomly selected for each case from cancer-free cohort members and frequency-matched to the cases by year of birth and age at diagnosis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer risk associated with occupations, adjusting for established breast cancer risk factors. In the prevalent breast cancer data analysis, increased risks of breast cancer were associated with technicians in engineering/agriculture/forestry (OR = 1.6, CI: 1.0-2.4), teaching personnel (OR = 1.5, CI:1.1-2.0), tailoring/sewing workers (OR = 1.6, CI:1.0-2.7), and examiners/measurers/testers (OR = 1.5, CI:1.1-2.1) among those who started the jobs at least 20 years ago. Among incident breast cancer cases, significantly increased risks were associated with medical/health care workers (OR = 1.4, CI:1.0-2.0), administrative clerical workers (OR = 1.5, CI:1.0-2.4), postal/telecommunication workers (OR = 2.2, CI:1.0-5.5), and odd-job workers (OR = 1.7, CI:1.1-2.8) among those who started the jobs at least 20 years ago. The excess risks were found in both prevalent and incident cases for postal/telecommunication workers and purchasing/marketing personnel, although ORs reached only marginal significance. This study suggests that white-collar professionals and several production occupations may be associated with an increased risk of breast cancer.


CCA-treated wood disposed in landfills and life-cycle trade-offs with waste-to-energy and MSW landfill disposal.
Chromated copper arsenate (CCA)-treated wood is a preservative treated wood construction product that grew in use in the 1970s for both residential and industrial applications. Although some countries have banned the use of the product for some applications, others have not, and the product continues to enter the waste stream from construction, demolition and remodeling projects. CCA-treated wood as a solid waste is managed in various ways throughout the world. In the US, CCA-treated wood is disposed primarily within landfills; however some of the wood is combusted in waste-to-energy (WTE) facilities. In other countries, the predominant disposal option for wood, sometimes including CCA-treated wood, is combustion for the production of energy. This paper presents an estimate of the quantity of CCA-treated wood entering the disposal stream in the US, as well as an examination of the trade-offs between landfilling and WTE combustion of CCA-treated wood through a life-cycle assessment and decision support tool (MSW DST). Based upon production statistics, the estimated life span and the phaseout of CCA-treated wood, recent disposal projections estimate the peak US disposal rate to occur in 2008, at 9.7 million m(3). CCA-treated wood, when disposed with construction and demolition (C&D) debris and municipal solid waste (MSW), has been found to increase arsenic and chromium concentrations in leachate. For this reason, and because MSW landfills are lined, MSW landfills have been recommended as a preferred disposal option over unlined C&D debris landfills. Between landfilling and WTE for the same mass of CCA-treated wood, WTE is more expensive (nearly twice the cost), but when operated in accordance with US Environmental Protection Agency (US EPA) regulations, it produces energy and does not emit fossil carbon emissions. If the wood is managed via WTE, less landfill area is required, which could be an influential trade-off in some countries. Although metals are concentrated in the ash in the WTE scenario, the MSW landfill scenario releases a greater amount of arsenic from leachate in a more dilute form. The WTE scenario releases more chromium from the ash on an annual basis. The WTE facility and subsequent ash disposal greatly concentrates the chromium, often oxidizing it to the more toxic and mobile Cr(VI) form. Elevated arsenic and chromium concentrations in the ash leachate may increase leachate management costs.


Clinical potential of cariprazine in the treatment of acute mania.
Cariprazine (RGH-188, trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexyl-amine hydrochloride), is a novel antipsychotic with dopamine D2 and D3 receptors antagonist-partial agonist properties. Cariprazine has also moderate affinity for serotonin 5-hydroxytryptophan (5-HT) 1A receptors, high affinity for 5-HT1B receptors with pure antagonism and low affinity for 5-HT2A receptors. Randomized, double blind, placebo controlled, flexible-dose (3-12 mg/day) studies have demonstrated cariprazine is effective in both schizophrenia and acute manic episodes associated with bipolar disorder. The incidence of serious adverse events in cariprazine arm was no different than in placebo arm in these studies. The most common adverse events were extrapyramidal symptoms, headache, akathisia, constipation, nausea, and dyspepsia which can be explained with cariprazine's partial dopamine agonism. Although cariprazine treatment was associated with a higher incidence of treatment-emergent adverse events, particularly akathisia and tremor, common side effects of marketed second generation antipsychotics such as weight gain, metabolic disturbances, prolactin increase or QTc prolongation were not associated with cariprazine, probably due to its moderate to low binding affinity for histamine H1 and 5-HT2C receptors. Animal studies show that cariprazine may have additional therapeutic benefit on impaired cognitive functioning with D3 receptor activity, however clinical data is still scarce. The aim of this article is to review the potential use of cariprazine for the treatment of acute manic episodes in the light of the preclinical and clinical trials reported to date.


Branching effect on the linear and nonlinear optical properties of styrylpyrimidines.
This contribution aims at investigating the branching effect on the steady state, time resolved fluorescence and two-photon absorption (2PA) properties of dimethylamino and diphenylamino substituted styrylpyrimidine derivatives, by means of a combined experimental and theoretical study. In contrast to classical branched molecules with a triphenylamine central core and electron accepting groups at the periphery, here, branched molecules with reverse topology and different symmetries are examined, namely a styrylpyrimidine group is used as the electron withdrawing core and dimethylamino or diphenylamino donors are incorporated at the periphery. Besides, compared to the great majority of existing branched systems, the herein studied molecules do not have C3 symmetry. For this reason, the region of the linear and non-linear optical spectra of the two and three branched chromophores is actually similar. Interestingly, while the one-photon absorption spectra of one-branched systems versus two- or three-branched ones are spectrally shifted, there is almost no spectral shift in the main 2PA spectral region. Meanwhile, there is still an enhancement of both linear and nonlinear optical responses. Overall, here we developed a strategy that enhances the 2PA response while maintaining the spectral position. Specifically, 2PA cross section values as high as 500 GM have been obtained for the diphenylamino A-(π-D)3 molecule in dichloromethane.


Prognostic Tools for Early Mortality in Hemorrhagic Stroke: Systematic Review and Meta-Analysis.
Several risk scores have been developed to predict mortality in intracerebral hemorrhage (ICH). We aimed to systematically determine the performance of published prognostic tools. We searched MEDLINE and EMBASE for prognostic models (published between 2004 and April 2014) used in predicting early mortality (<6 months) after ICH. We evaluated the discrimination performance of the tools through a random-effects meta-analysis of the area under the receiver operating characteristic curve (AUC) or c-statistic. We evaluated the following components of the study validity: study design, collection of prognostic variables, treatment pathways, and missing data. We identified 11 articles (involving 41,555 patients) reporting on the accuracy of 12 different tools for predicting mortality in ICH. Most studies were either retrospective or post-hoc analyses of prospectively collected data; all but one produced validation data. The Hemphill-ICH score had the largest number of validation cohorts (9 studies involving 3,819 patients) within our systematic review and showed good performance in 4 countries, with a pooled AUC of 0.80 [95% confidence interval (CI)=0.77-0.85]. We identified several modified versions of the Hemphill-ICH score, with the ICH-Grading Scale (GS) score appearing to be the most promising variant, with a pooled AUC across four studies of 0.87 (95% CI=0.84-0.90). Subgroup testing found statistically significant differences between the AUCs obtained in studies involving Hemphill-ICH and ICH-GS scores (p=0.01). Our meta-analysis evaluated the performance of 12 ICH prognostic tools and found greater supporting evidence for 2 models (Hemphill-ICH and ICH-GS), with generally good performance overall.


DermaKNet: Incorporating the Knowledge of Dermatologists to Convolutional Neural Networks for Skin Lesion Diagnosis.
Traditional approaches to automatic diagnosis of skin lesions consisted of classifiers working on sets of hand-crafted features, some of which modeled lesion aspects of special importance for dermatologists. Recently, the broad adoption of convolutional neural networks (CNNs) in most computer vision tasks has brought about a great leap forward in terms of performance. Nevertheless, with this performance leap, the CNN-based computer-aided diagnosis (CAD) systems have also brought a notable reduction of the useful insights provided by hand-crafted features. This paper presents DermaKNet, a CAD system based on CNNs that incorporates specific subsystems modeling properties of skin lesions that are of special interest to dermatologists aiming to improve the interpretability of its diagnosis. Our results prove that the incorporation of these subsystems not only improves the performance, but also enhances the diagnosis by providing more interpretable outputs.


Distribution of Giardia duodenalis assemblages A and B among children living in a remote indigenous community of the Northern Territory, Australia.
Giardiasis is a communicable gastrointestinal disease caused by Giardia duodenalis and two genetic assemblages, A and B, cause human infection. In remote Indigenous communities of Australia, giardiasis is highly prevalent among children but disease transmission is poorly understood. This study investigated the prevalence of Giardia and genetic subtypes contributing to human disease in a remote Indigenous community, in the Northern Territory of Australia. Eighty-seven faecal samples were collected from 74 children (<15 years) over an 18 month period, and the distribution of positive cases relative to participant age and gender were examined. Screening by microscopy and 18S rRNA PCR amplification showed 66.7% (58/87) of faecal samples were positive for Giardia. Both males and females were equally affected and high detection rates were obtained for participants aged 0-<5 years and 5-<10 years (66.0 and 60.0% respectively). For 58.6% of the positive samples, Giardia was only detected by 18S rRNA PCR. Approximately 75% of cases were assemblage B, and subassemblage analyses using terminal restriction fragment length polymorphism of the glutamate dehydrogenase gene demonstrated that a variety of genetic variants were present. The high proportion of positive cases that were not detectable by microscopy, and dominance of assemblage B cases highlights the need for further research in this community, to assess the contribution of Giardia to chronic gastrointestinal disease among children, and to understand conditions conductive to assemblage B transmission.


The antineoplastic bryostatins affect human basophils and mast cells differently.
Bryostatins, macrocyclic lactones from the marine bryozoan Bugula neritina, are potent antineoplastic agents and multi-potential stimulators of immune cells. We have examined the effects of bryostatins on mediator release from human basophilic leukocytes and human tissue mast cells. Bryostatins 1, 2, and 5 (10 to 3,000 nmol/L) induced histamine secretion from purified and unpurified peripheral blood basophils, whereas they caused no release of peptide-leukotriene C4 from these cells. The rate of histamine release caused by bryostatin 1 was slower than that caused by anti-IgE (t1/2 +/- SEM = 38.2 +/- 4.7 minutes v 8.9 +/- 0.2 minutes; P < .01), whereas the temperature dependence was similar (optimum release at 37 degrees C, approximately 30% less at 30 degrees C, and no release at 22 degrees C or 4 degrees C). The addition of increasing concentrations of extracellular Ca2+ to the medium caused histamine release in the presence of bryostatins. Subeffective concentrations of bryostatins and anti-IgE produced a synergistic effect on histamine release from basophils. Staurosporine, chelerythrine, and calphostin C (0.1 to 10 nmol/L), which are protein kinase C inhibitors, inhibited the histamine secretion activated by bryostatin 1 and tetradecanoylphorbol-acetate (TPA). Preincubation with granulocyte-monocyte colony-stimulating factor (GM-CSF; 1 and 5 nmol/L) and interleukin-3 (IL-3; 10 ng/mL) potentiated the activation of human basophils induced by bryostatin 1. Neither bryostatin 1 nor bryostatin 2 induced the release of histamine from mast cells isolated from human lung or skin tissues. However, brief (10 minutes) preincubation with bryostatin 1 (3 to 300 nmol/L) potently inhibited the histamine secretion induced by anti-IgE from skin or lung mast cells. Bryostatin 1 was a more potent (by approximately 30 times) inhibitor of IgE-mediated histamine release than was TPA. The heterogeneous effects exerted by bryostatins on human basophils and mast cells can be of interest for those designing therapeutic trials using these agents.


Exploring Selection Bias by Causal Frailty Models: The Magnitude Matters.
Counter-intuitive associations appear frequently in epidemiology, and these results are often debated. In particular, several scenarios are characterized by a general risk factor that appears protective in particular subpopulations, for example, individuals suffering from a specific disease. However, the associations are not necessarily representing causal effects. Selection bias due to conditioning on a collider may often be involved, and causal graphs are widely used to highlight such biases. These graphs, however, are qualitative, and they do not provide information on the real life relevance of a spurious association. Quantitative estimates of such associations can be obtained from simple statistical models. In this study, we present several paradoxical associations that occur in epidemiology, and we explore these associations in a causal, frailty framework. By using frailty models, we are able to put numbers on spurious effects that often are neglected in epidemiology. We discuss several counter-intuitive findings that have been reported in real life analyses, and we present calculations that may expand the understanding of these associations. In particular, we derive novel expressions to explain the magnitude of bias in index-event studies.


The Antigenic Determinant That Defines Thymic Nurse Cells Is Expressed by Thymic Epithelial Progenitor Cells.
Stromal thymic epithelial cells with the multicellular structure unique to thymic nurse cells (TNCs) express the pH91 antigen on their cell surfaces. The multicellular TNC-complexes develop through an intimate association between αβTCR+CD4+CD8+ thymocytes and pH91-expressing cortical epithelial cells. TNCs participate in MHC-restriction and exhibit epithelial cell progenitor characteristics. In this report, we show that as early as E11.5 stage of thymus development, the pH91 antigen is expressed in association with K8, K5, Foxn1 and p63. The expression of these epithelial progenitor markers along with the pH91 antigen persists throughout thymic development in the murine thymus. At E13.5, pH91+ cells express relatively low levels of MHC class II. After E17.5, the first multicellular TNC complexes are recognizable along with increased cell surface expression of MHC class II. Our data suggest that epithelial cells bearing the "progenitor phenotype" develop into the multicellular TNCs.


Hybrid Pharmacophore Design, Molecular Docking, Synthesis, and Biological Evaluation of Novel Aldimine-Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor.
A series of hybrid aldimine-type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4-triazole-3-thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex (PDB: 1SA0) revealed that derivatives with nitro and/or chloro or dimethylamino substitutes (4-nitro, 2-nitro, 3-nitro, 4-Cl-3-nitro, and 4-Me2 N) on the aldehyde ring were the best compounds with remarkable binding energies (-9.09, -9.07, -8.63, -8.11, and -8.07 kcal mol-1 , respectively) compared to colchicine (-8.12 kcal mol-1 ). These compounds were also showed remarkable binding energies from -10.66 to -9.79 and -10.12 to -8.95 kcal mol-1 on human (PDB: 1PD8) and Candida albicans (PDB: 3QLS) DHFR, respectively. The obtained results of cytotoxic activities against HT1080, HepG2, HT29, MCF-7, and A549 cancer cell lines indicated that 4-nitro and 2-nitro substituted compounds were the most effective agents by mean IC50 values of 11.84 ± 1.01 and 19.92 ± 1.36 μm, respectively. 4-Nitro substituted compound (5 μm) and 2-nitro substituted compound (30 μm) were able to strongly inhibit the tubulin polymerization compared to colchicine (5 μm) and 4-nitro substituted compound displayed IC50 values of 0.16 ± 0.01 μm compared to that of colchicine (0.19 ± 0.01 μm). This compound also showed the lowest MIC values on all tested microbial strains including three Gram-positive, four Gram-negative, and three yeast pathogens.


Improved brain delivery of AZT using a glycosyl phosphotriester prodrug.
The concentration of AZT in mice plasma and brain was measured using HPLC after an ingestion of 20 mg/kg of AZT or the molar equivalent of hexadecyl 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate 3. The results demonstrated the promising qualities of the prodrug 3 which gave AZT-5'-phosphate as the main metabolite: the total concentration of AZT derivatives detected in brain presented a peak of 156 nmol/g (5 nmol/g for AZT) at 1 h; the half-life was about 24 h (1 h for AZT) with an AUC of 4366 nmol h/g as compared to 4 nmol h/g for AZT. The lipophilic properties of 3 were confirmed by its in vitro transport of inside synaptosomes. The derivative 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate (2) provided also a good delivery of AZT to the central nervous system, with values intermediate between those of AZT and 3.


Profile of pancreatic tumors at a tertiary care center.
Pancreas, a relatively inaccessible organ, poses diagnostic difficulties with overlapping presentation among benign and malignant tumors. In the present study, pancreatic aspirates obtained by computed tomography (CT) guided procedures were used for cytodiagnosis. Our study aims at correlating clinical, cytological, biochemical, and histopathological results in obtaining a final diagnosis. A retrospective study of 2 years was done which included 32 cases of pancreatic tumors at a tertiary care center. Patient data were retrieved and analyzed. Twenty-seven of the 32 (84.37%) cases were malignant tumors. Age distribution in malignant tumors was predominantly seen in the fourth to eighth decade, whereas in benign, it ranged in the second to third decade. Thirteen out of the 32 (40.62%) cases reported were females, with male:female ratio of 1.46:1. The most common presenting symptom was abdominal pain followed by jaundice and vomiting. Three of the 32 cases had visceral metastasis at the time of diagnosis. CT-guided aspirates in most cases yielded diagnostic material. Cytological and histopathological results concurred except for three cases. Cancer Antigen 19-9 was worked up for 14 of 27 malignant cases, 11 of which showed grossly elevated values (700-7000), and three cases showed mildly elevated values (100-300). Three of the four benign cases worked up for CA 19-9 showed normal values. Among the mass forming lesions in pancreas, malignancy was more common compared to benign tumors. A multidisciplinary approach in the assessment and diagnosis of pancreatic tumors yields accurate results in spite of the limitations faced in obtaining adequate samples by needle aspirates.


Intraocular use of bevacizumab in India: An issue resolved?
Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), which has been approved for intravenous use in certain cancers. There is evidence of its efficacy and safety as an intravitreal drug compared with ranibizumab and aflibercept. We have, in our practice, found it to be a cost-effective treatment option for ocular diseases, which could save a large amount of public money used in various national health insurance systems. An alert issued by the Drug Controller General of India led to a virtual ban on its intraocular use in India. However, pro-active advocacy and leadership by national ophthalmological societies helped to resolve the issue quickly.


Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults.
Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-β-hydroxybutyrate (βHB) to similar concentrations within minutes, with βHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18-70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, three times a day for 28 days (a total of 2.1 L). Anthropomorphic measurements, plus fasting blood and urine analyses were made weekly. It was found that elevating blood βHB concentrations from 0.1 to 4.1 (±1.1) mM three times a day for 28 days had no effect on body weights or composition, fasting blood glucose, cholesterol, triglyceride or electrolyte concentrations, nor blood gases or kidney function, which were invariably normal. Mild nausea was reported following 6 of the 2,016 drinks consumed. We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.


Patient-specific prediction model for clinical and quality-of-life outcomes after lumbar spine surgery.
Patient demographics, comorbidities, and baseline quality of life (QOL) are major contributors to postoperative outcomes. The frequency and cost of lumbar spine surgery has been increasing, with controversy revolving around optimal management strategies and outcome predictors. The goal of this study was to generate predictive nomograms and a clinical calculator for postoperative clinical and QOL outcomes following lumbar spine surgery for degenerative disease. Patients undergoing lumbar spine surgery for degenerative disease at a single tertiary care institution between June 2009 and December 2012 were retrospectively reviewed. Nomograms and an online calculator were modeled based on patient demographics, comorbidities, presenting symptoms and duration of symptoms, indication for surgery, type and levels of surgery, and baseline preoperative QOL scores. Outcomes included postoperative emergency department (ED) visit or readmission within 30 days, reoperation within 90 days, and 1-year changes in the EuroQOL-5D (EQ-5D) score. Bootstrapping was used for internal validation. A total of 2996 lumbar surgeries were identified. Thirty-day ED visits were seen in 7%, 30-day readmission in 12%, 90-day reoperation in 3%, and improvement in EQ-5D at 1 year that exceeded the minimum clinically important difference in 56%. Concordance indices for the models predicting ED visits, readmission, reoperation, and dichotomous 1-year improvement in EQ-5D were 0.63, 0.66, 0.73, and 0.84, respectively. Important predictors of clinical outcomes included age, body mass index, Charlson Comorbidity Index, indication for surgery, preoperative duration of symptoms, and the type (and number of levels) of surgery. A web-based calculator was created, which can be accessed here: https://riskcalc.org/PatientsEligibleForLumbarSpineSurgery/. The prediction tools derived from this study constitute important adjuncts to clinical decision-making that can offer patients undergoing lumbar spine surgery realistic and personalized expectations of postoperative outcome. They may also aid physicians in surgical planning, referrals, and counseling to ultimately lead to improved patient experience and outcomes.


Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.
To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.


Virucidal effect of commercially available disinfectants on equine group A rotavirus.
Although many disinfectants are commercially available in the veterinary field, information on the virucidal effects of disinfectants against equine group A rotavirus (RVA) is limited. We evaluated the performance of commercially available disinfectants against equine RVA. Chlorine- and iodine-based disinfectants showed virucidal effects, but these were reduced by the presence of organic matter. Glutaraldehyde had a virucidal effect regardless of the presence of organic matter, but the effect was reduced by low temperature or short reaction time, or both. Benzalkonium chloride had the greatest virucidal effect among the three quaternary ammonium compounds examined, but its effect was reduced by the presence of organic matter or by low temperature or a short reaction time. These findings will be useful for preventing the spread of equine RVA infection.


Tanshinone IIA Attenuates Diabetic Peripheral Neuropathic Pain in Experimental Rats via Inhibiting Inflammation.
Diabetic peripheral neuropathic pain (DPNP) is a common and intractable complication of diabetes. Conventional therapies are always not ideal; development of novel drugs is still needed to achieve better pain relief. Recent evidences have demonstrated that inflammation is involved in the onset and maintenance of DPNP. The anti-inflammatory property of Tanshinone IIA (TIIA) makes it a promising candidate to block or alter the pain perception. This study was conducted to investigate whether TIIA could attenuate DPNP in streptozotocin- (STZ-) induced rats model and its potential mechanisms. TIIA was administered to STZ-induced diabetic rats at the dose of 40 mg/kg once a day for 3 weeks. The effects of TIIA on thermal hyperalgesia and mechanical allodynia were investigated using behavioral tests. The mRNA level and expression of interleukin- (IL-) 1β, interleukin- (IL-) 6, tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 10 in the fourth to sixth segments of the dorsal root ganglion (L4-6 DRG) were detected by quantitative real-time PCR (qPCR) and Western blot. TIIA treatment significantly attenuated mechanical allodynia and thermal hyperalgesia in diabetic rats. In addition, the expression of the proinflammatory cytokines IL-1β, IL-6, and TNF-α was inhibited, and the level of the anti-inflammatory cytokine IL-10 was increased by TIIA. This study demonstrated that TIIA has significant antiallodynic and antihyperalgesic effects in a rat model of STZ-induced DPNP, and the effect may be associated with its anti-inflammation property.


Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva.
One hundred and thirty-five patients with squamous carcinoma of the vulva were treated at UCLA and City of Hope Medical Centers between 1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and 7 stage IV. Twenty-one patients developed a local vulvar recurrence after primary radical resection. Ninety-one patients had a surgical tumor-free margin greater than or equal to 8 mm on tissue section and none had a local vulvar recurrence. Forty-four patients had a margin less than 8 mm; 21 had a local recurrence and 23 did not (P less than 0.0001). Of the 23 patients with a margin less than 8 mm who did not recur locally, 14 remained free of disease, and 9 had either advanced disease, declining health, or short follow-up. Depth of invasion is associated with local recurrence, with a 9.1-mm reference value correctly predicting outcome in 81.5% of cases. Increasing tumor thickness is associated with local recurrence, with a 10-mm reference value predictive of 90% non-recurrence and 33% recurrences. A pushing border pattern is less likely to recur than an infiltrative growth pattern. Lymph-vascular space invasion has a combined predictive accuracy of 81.5%. Increasing keratin and greater than 10 mitoses per 10 high-power fields correlate with local recurrence. Neither clinical tumor size nor coexisting benign vulvar pathology correlates with local recurrence. Fourteen of twenty-one patients with vulvar recurrence died of metastatic disease, four died of intercurrent disease, and three were alive at 32, 68, and 157 months, with 16 recurring in less than 1 year. Surgical margin is the most powerful predictor of local vulvar recurrence. Combining factors in a stepwise logistical regression does not significantly improve this predictive value. Accounting for specimen preparation and fixation, a 1-cm tumor-free surgical margin on the vulva results in a high rate of local control, whereas a margin less than 8 mm is associated with a 50% chance of recurrence.


jClust: a clustering and visualization toolbox.
jClust is a user-friendly application which provides access to a set of widely used clustering and clique finding algorithms. The toolbox allows a range of filtering procedures to be applied and is combined with an advanced implementation of the Medusa interactive visualization module. These implemented algorithms are k-Means, Affinity propagation, Bron-Kerbosch, MULIC, Restricted neighborhood search cluster algorithm, Markov clustering and Spectral clustering, while the supported filtering procedures are haircut, outside-inside, best neighbors and density control operations. The combination of a simple input file format, a set of clustering and filtering algorithms linked together with the visualization tool provides a powerful tool for data analysis and information extraction. http://jclust.embl.de/. Supplementary data are available at Bioinformatics online.


Retrobulbar dexmedetomidine in pediatric vitreoretinal surgery eliminates the need for intraoperative fentanyl and postoperative analgesia: A randomized controlled study.
This study evaluated the efficacy of retrobulbar ropivacaine plus dexmedetomidine compared with systemic fentanyl in pediatric vitreoretinal (VR) surgery. This prospective double-blind, randomized controlled study was performed in 60 children undergoing VR surgery, age from 2 to 7 years. After general anesthesia, the following procedure was administrated: (1) retrobulbar block with 0.5% ropivacaine plus dexmedetomidine 1 μg/kg (group RD, n = 20), (2) retrobulbar block with 0.5% ropivacaine (group RB, n = 20), and (3) control group with general anesthesia only (group F, n = 20). Hemodynamics, postoperative pain scores, anesthetics consumption (remifentanil, propofol, fentanyl), and emergence agitation were recorded. Respiratory depression was observed in 7 of the 20 patients in group F after the laryngeal mask airway was removed in the operating room, compared with none in groups RD and RB. All patients in group F required intraoperative rescue fentanyl (average intraoperative fentanyl consumption, 26.6 ± 12.6 μg per patient). Some rescue fentanyl was required in group RB (three patients required one dose of rescue fentanyl). Patients in group RD required none. Groups RD and RB reported lower pain scores than group F at 4 h postoperatively (RD group: P < 0.001; RB group: P =0.002); pain scores in group RD were lower than that in group F at 6 h postoperatively (P < 0.001). Retrobulbar dexmedetomidine as an adjuvant to ropivacaine is a safe and effective alternative to systemic fentanyl. This regimen provides better pain management, hemodynamic stability, and stress response suppression in pediatric VR surgery.


Fast transport of neurofilament protein along microtubules in squid axoplasm.
Using squid axoplasm as a model system, we have visualized the fast transport of non-filamentous neurofilament protein particles along axonal microtubules. This transport occurs at speeds of 0.5-1.0 microm/second and the majority of neurofilament particles stain with kinesin antibody. These observations demonstrate, for the first time, that fast (0.5-1.0 microm/second) transport of neurofilament proteins occurs along microtubules. In addition, our studies suggest that neurofilament protein can be transported as non-membrane bound, nonfilamentous subunits along axons, and that the transport is kinesin-dependent. Microtubule-based fast transport might therefore provide a mechanism for the distribution and turnover of neurofilament, and perhaps other cytoskeletal proteins, throughout neurons.


Diagnostic accuracy of screening electrocardiograms in long QT syndrome I.
Inherited long QT syndrome (LQTS) may present with syncope, seizures, and/or sudden death as a result of ventricular tachyarrhythmias. Identification of family members who are at risk because they harbor the genetic substrate for LQTS is critical. Presently, such identification relies on the 12-lead electrocardiogram (ECG). The purpose of this study was to evaluate the efficacy of the automated ECG as a screening tool for LQTS. Molecular testing of a proband and 22 additional family members for the KVLQT1 mutation and symptomatic status facilitated the classification of each family member into the following patient groups: noncarriers (13), asymptomatic carriers (5), and symptomatic carriers (5). Each individual had a standard 12-lead ECG from which the computer and manual (lead II) corrected QT interval were determined. In addition, we determined the accuracy of the computer ECG diagnostic interpretation for each patient group. With the use of a corrected QT interval of >/=460 ms as a diagnostic cutoff, the positive and negative predictive values for identifying at-risk individuals were 100%. Despite this, the computer-generated ECG diagnostic interpretation erroneously classified 6 of 23 family members. Moreover, half of the family members, proved to have the ion channel defect, received the diagnostic interpretation "normal ECG." Reliance on the computer-generated ECG diagnostic interpretation alone will fail to identify many at-risk family members. It is suggested that all first-degree relatives of an identified LQTS proband have a 12-lead ECG that is reviewed independently by a physician who is familiar with LQTS in an effort to improve screening for this potentially lethal syndrome.electrocardiogram, long QT syndrome, QT interval, sudden death.


Analytical solution describing pesticide volatilization from soil affected by a change in surface condition.
An analytical solution describing the fate and transport of pesticides applied to soils has been developed. Two pesticide application methods can be simulated: point-source applications, such as idealized shank or a hot-gas injection method, and a more realistic shank-source application method that includes a vertical pesticide distribution in the soil domain due to a soil fracture caused by a shank. The solutions allow determination of the volatilization rate and other information that could be important for understanding fumigant movement and in the development of regulatory permitting conditions. The solutions can be used to characterize differences in emissions relative to changes in the soil degradation rate, surface barrier conditions, application depth, and soil packing. In some cases, simple algebraic expressions are provided that can be used to obtain the total emissions and total soil degradation. The solutions provide a consistent methodology for determining the total emissions and can be used with other information, such as field and laboratory experimental data, to support the development of fumigant regulations. The uses of the models are illustrated by several examples.


Directly phase-modulation-mode-locked doubly-resonant optical parametric oscillator.
We present results on direct mode-locking of a doubly-resonant optical parametric oscillator (DRO) using an electro-optic phase modulator with low resonant frequency of 80 MHz as the single mode-locking element. Pumped by a cw laser at 532 nm and based on MgO:sPPLT as the nonlinear material, the DRO generates 533 ps pulses at 80 MHz and 471 ps pulses at 160 MHz. Stable train of mode-locked pulses is obtained at a modulation depth of 1.83 radians when the modulation frequency is precisely tuned and the cavity length is carefully adjusted. The effects of frequency detuning, modulation depth, input laser pump power, crystal temperature and position of modulator inside the cavity, on pulse duration and repetition rate have been studied. Operating at degeneracy, under mode-locked condition, the signal-idler spectrum exhibits a bandwidth of ~31 nm, and the spectrum has been investigated for different phase-matching temperatures. Mode-locked operation has been confirmed by second-harmonic-generation of the DRO output in a β-BaB₂O₄ crystal, where a 4 times enhancement in green power is observed compared to cw operation.


Monitoring of Nitrification in Chloraminated Drinking Water Distribution Systems With Microbiome Bioindicators Using Supervised Machine Learning.
Many drinking water utilities in the United States using chloramine as disinfectant treatment in their drinking water distribution systems (DWDS) have experienced nitrification episodes, which detrimentally impact the water quality. Identification of potential predictors of nitrification in DWDS may be used to optimize current nitrification monitoring plans and ultimately helps to safeguard drinking water and public health. In this study, we explored the water microbiome from a chloraminated DWDS simulator operated through successive operational schemes of stable and nitrification events and utilized the 16S rRNA gene dataset to generate high-resolution taxonomic profiles for bioindicator discovery. Analysis of the microbiome revealed both an enrichment and depletion of various bacterial populations associated with nitrification. A supervised machine learning approach (naïve Bayes classifier) trained with bioindicator profiles (membership and structure) were used to classify water samples. Performance of each model was examined using the area under the curve (AUC) from the receiver-operating characteristic (ROC) and precision-recall (PR) curves. The ROC- and PR-AUC gradually increased to 0.778 and 0.775 when genus-level membership (i.e., presence and absence) was used in the model and increased significantly using structure (i.e., distribution) dataset (AUCs = 1.000, p < 0.01). Community structure significantly improved the predictive ability of the model beyond that of membership only regardless of the type of data (sequence- or taxonomy-based model) we used to represent the microbiome. In comparison, an ATP-based model (bulk biomass) generated a lower AUCs of 0.477 and 0.553 (ROC and PR, respectively), which is equivalent to a random classification. A combination of eight bioindicators was able to correctly classify 85% of instances (nitrification or stable events) with an AUC of 0.825 (sensitivity: 0.729, specificity: 0.894) on a full-scale DWDS test set. Abiotic-based model using total Chlorine/NH2Cl and NH3 generated AUCs of 0.740 and 0.861 (ROC and PR, respectively), corresponding to a sensitivity of 0.250 and a specificity of 0.957. The AUCs increased to > 0.946 with the addition of NO2 - concentration, which is indicative of nitrification in the DWDS. This research provides evidence of the feasibility of using bioindicators to predict operational failures in the system (e.g., nitrification).