SCORE2 Report 2: Study Design and Baseline Characteristics.
To describe the design and baseline characteristics of participants in the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2) and to compare with cohorts from other retinal vein occlusion trials. Phase III prospective, multicenter, randomized clinical trial designed to assess whether intravitreal bevacizumab is noninferior to intravitreal aflibercept for treatment of decreased vision attributable to macular edema associated with central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO). Total of 362 participants: 307 with CRVO and 55 with HRVO. Demographic and study eye characteristics are summarized and compared between CRVO and HRVO study participants. Baseline ophthalmic characteristics, including visual acuity and retinal thickness, and medical history characteristics, including hypertension, diabetes mellitus, and coronary artery disease. The mean age of participants was 69 years, 76% of participants were white, and 90% were non-Hispanic. There was a racial disparity with respect to disease type, with 38% of HRVO patients being black compared with 11% of CRVO patients (P value adjusted for multiple testing = 0.0001). This is similar to findings from the previous SCORE Study. Comorbidities included hypertension (77%), diabetes mellitus (31%), and coronary artery disease (15%). At baseline, mean visual acuity letter score was 50 (20/100) (range, 19-73 [20/400 to 20/40]), mean optical coherence tomography (OCT)-measured central subfield thickness was 678 μm (range, 300-1203 μm), and mean number of months from diagnosis of macular edema to randomization was 6 (range, 0-104 months). One hundred twenty (33%) SCORE2 participants had been treated previously with anti-vascular endothelial growth factor (anti-VEGF) therapy, with these participants having baseline visual acuity letter score and OCT-measured central subfield thickness similar to those without prior anti-VEGF treatment, but longer mean duration of macular edema before randomization (18 months vs. 1 month for those without prior anti-VEGF treatment; P < 0.0001). The SCORE2 cohort is a heterogeneous population, including both CRVO and HRVO eyes and both treatment-naïve eyes and eyes treated previously with anti-VEGF, which will allow study results to have broad applicability to CRVO and HRVO patients receiving treatment for macular edema. Similarities of the baseline characteristics of the SCORE2 population to other CRVO trial cohorts will allow meaningful comparisons of outcome results across trials.


Challenges to Providing Fetal Anomaly Testing in a Cross-Cultural Environment: Experiences of Practitioners Caring for Aboriginal Women.
Across Australia there are substantial disparities in uptake of antenatal testing for fetal anomalies, with very low uptake observed among Aboriginal women. The reasons behind these disparities are unclear, although poorer access to testing has been reported in some communities. We interviewed health care practitioners to explore the perceived barriers to providing fetal anomaly screening to Aboriginal women. In 2009 and 2010, in-depth interviews were undertaken with 59 practitioners in five urban and remote sites across the Northern Territory (NT) of Australia. Data were analyzed thematically. Maximum variation sampling, independent review of findings by multiple analysts, and participant feedback were undertaken to strengthen the validity of findings. Participants included midwives (47%), Aboriginal health practitioners (AHP) (32%), general practitioners (12%), and obstetricians (9%); almost all (95%) were female. Participants consistently reported difficulties counseling women. Explaining the concept of "risk" (of abnormalities and the screening test result) was identified as particularly challenging, because of a perceived lack of an equivalent concept in Aboriginal languages. While AHPs could assist with overcoming language barriers, they are underutilized. Participants also identified impediments to organizing testing including difficulties establishing gestational age, late presentation for care, and a lack of standardized information and training. The availability of fetal anomaly testing is challenged by communication difficulties, including a focus on culturally specific biomedical concepts, and organizational barriers to arranging testing. Developing educational activities that address the technical aspects of screening and communication skills will assist in improving access. These activities must include AHPs.


Association of 1p/19q Codeletion and Radiation Necrosis in Adult Cranial Gliomas After Proton or Photon Therapy.
To analyze the incidence of and risk factors for clinically significant radiation necrosis (cRN) in adult cranial oligodendrogliomas and astrocytomas treated with proton or photon therapy. Between 2007 and 2015, 160 patients with grade 2 or 3 oligodendrogliomas (with 1p/19q codeletion, n = 53) or astrocytomas (without 1p/19q codeletion, n = 107) were treated with proton (n = 37) or photon (n = 123) therapy. Clinically significant radiation necrosis (RN) was defined as symptomatic RN or asymptomatic RN that resulted in surgery or bevacizumab administration. The cumulative incidence was calculated using competing risks. Risk factors were identified using Cox proportional hazards. After a median follow-up period of 28.5 months, cRN developed in 18 patients (proton, 6; photon, 12). The 2-year cumulative incidence of cRN for proton and photon therapy was 18.7% (95% confidence interval [CI], 7.5%-33.8%) and 9.7% (95% CI, 5.1%-16%), respectively (P = .16). On multivariate analysis, risk factors for cRN included oligodendroglioma (hazard ratio [HR], 3.57; 95% CI, 1.38-9.25; P = .009) and higher prescription dose (in gray relative biological equivalents [GyRBE]) (HR, 1.30; 95% CI, 1.05-1.61; P = .015). The 2-year cumulative incidence of cRN in oligodendrogliomas and astrocytomas was 24.2% and 6.2%, respectively (P = .01). The relative volume (percentage) of brain receiving 60 GyRBE was a significant dosimetric predictor of cRN in oligodendrogliomas (HR, 1.11; 95% CI, 1.03-1.20; P = .005). The study showed that 1p/19q codeleted oligodendroglioma was a significant risk factor associated with cRN and the relative volume (percentage) of brain receiving 60 GyRBE was an important dosimetric predictor of cRN for oligodendroglioma patients. There is insufficient evidence at this time to conclude a significant difference in the incidence of cRN between proton and photon therapy.


Methane oxidation in contrasting soil types: responses to experimental warming with implication for landscape-integrated CH4 budget.
Arctic ecosystems are characterized by a wide range of soil moisture conditions and thermal regimes and contribute differently to the net methane (CH4 ) budget. Yet, it is unclear how climate change will affect the capacity of those systems to act as a net source or sink of CH4 . Here, we present results of in situ CH4 flux measurements made during the growing season 2014 on Disko Island (west Greenland) and quantify the contribution of contrasting soil and landscape types to the net CH4 budget and responses to summer warming. We compared gas flux measurements from a bare soil and a dry heath, at ambient conditions and increased air temperature, using open-top chambers (OTCs). Throughout the growing season, bare soil consumed 0.22 ± 0.03 g CH4 -C m-2 (8.1 ± 1.2 g CO2 -eq m-2 ) at ambient conditions, while the dry heath consumed 0.10 ± 0.02 g CH4 -C m-2 (3.9 ± 0.6 g CO2 -eq m-2 ). These uptake rates were subsequently scaled to the entire study area of 0.15 km2 , a landscape also consisting of wetlands with a seasonally integrated methane release of 0.10 ± 0.01 g CH4 -C m-2 (3.7 ± 1.2 g CO2 -eq m-2 ). The result was a net landscape sink of 12.71 kg CH4 -C (0.48 tonne CO2 -eq) during the growing season. A nonsignificant trend was noticed in seasonal CH4 uptake rates with experimental warming, corresponding to a 2% reduction at the bare soil, and 33% increase at the dry heath. This was due to the indirect effect of OTCs on soil moisture, which exerted the main control on CH4 fluxes. Overall, the net landscape sink of CH4 tended to increase by 20% with OTCs. Bare and dry tundra ecosystems should be considered in the net CH4 budget of the Arctic due to their potential role in counterbalancing CH4 emissions from wetlands - not the least when taking the future climatic scenarios of the Arctic into account.


Efficacy of amantadine treatment on symptoms and neurocognitive performance among adolescents following sports-related concussion.
To evaluate the efficacy of amantadine in the treatment of symptoms and neurocognitive performance in adolescents following sports-related concussion. A clinical sample of 25 male (n = 11) and female (n = 14) adolescent subjects with an age-, sex-, and concussion history-matched group of 25 male (n = 11) and female (n = 14) control subjects. Outpatient concussion clinic. Retrospective, case-control design. Treatment group consisted of patients treated with 100 mg of amantadine twice daily (200 mg total per day) following a period of rest. Matched controls were evaluated and treated conservatively without medication at the same concussion program prior to the start of the current amantadine protocol. Immediate Postconcussion Assessment and Cognitive Test computerized neurocognitive test battery and symptom report. Results support significantly greater improvements from pre- to posttest in reported symptoms, verbal memory, and reaction time performance for the amantadine group than the matched controls. There were no significant differences for visual memory or visual motor processing speed. This study provides empirical support for amantadine as an effective pharmacologic treatment of certain concussion-related cognitive deficits and symptoms in athletes with protracted recovery of more than 3 weeks.


Dynamic paternity allocation as a function of male plumage color in barn swallows.
Paternity in male animals can be influenced by their phenotypic signals of quality. Accordingly, the behavior underlying patterns of paternity should be flexible as signals of quality change. To evaluate the dynamics of paternity allocation, we analyzed paternity before and after manipulating plumage coloration, a known signal of quality, in male barn swallows Hirundo rustica. We found that, in successive breeding bouts, only males whose plumage color was experimentally enhanced received greater paternity from their social mates, demonstrating evidence for flexible and dynamic paternity allocation and the importance for males of maintaining signals of quality well after pair bond formation.


Muscle strength, mobility, quality of life and falls in patients on maintenance haemodialysis: A prospective study.
The aim is to explore (i) the relationship between quality of life and physical parameters (muscle strength and mobility) among people undergoing maintenance haemodialysis; (ii) changes in strength and mobility over time and predictors of changes; and (iii) whether strength and mobility were associated with falls. We recruited 51 maintenance haemodialysis patients to a prospective longitudinal study. Baseline quality of life was assessed using the SF-36 physical component summary and mental component summary scores. Muscle strength (ankle dorsiflexion strength measured with a hand-held dynamometer), mobility (short physical performance battery) and falls history were assessed at baseline, 12 and 36 months. Associations between variables at baseline were assessed with linear regression models. Changes in physical parameters were evaluated with paired t-tests and prediction of falls assessed by negative binominal regression. Fifty and 34 patients completed 12 and 36 month follow-ups, respectively. Baseline mobility but not muscle strength correlated with physical component summary (P = 0.01 and P = 0.23, respectively). Neither baseline mobility nor muscle strength correlated with mental component summary. At 12 months, muscle strength and mobility had significantly deteriorated (mean ankle dorsiflexion strength 11.0 lb (SD 1.5) from 14.0 lb (SD 2.2), P < 0.01; short physical performance battery 8.5 (SD 2.8) from 9.3 (SD 2.6), P < 0.01). Falls at 12 and 36 months were predicted by baseline mobility (P = 0.06 and P = 0.02, respectively) but not muscle strength. Physical parameters appear to be associated with meaningful patient outcomes and showed measurable deterioration over relatively short time frames. Interventions, with the potential to slow physical decline in people receiving maintenance dialysis, such as exercise programmes, warrant further investigation.


Music Listening in Classical Concerts: Theory, Literature Review, and Research Program.
Performing and listening to music occurs in specific situations, requiring specific media. Empirical research on music listening and appreciation, however, tends to overlook the effects these situations and media may have on the listening experience. This article uses the sociological concept of the frame to develop a theory of an aesthetic experience with music as the result of encountering sound/music in the context of a specific situation. By presenting a transdisciplinary sub-field of empirical (concert) studies, we unfold this theory for one such frame: the classical concert. After sketching out the underlying theoretical framework, a selective literature review is conducted to look for evidence on the general plausibility of the single elements of this emerging theory and to identify desiderata. We refer to common criticisms of the standard classical concert, and how new concert formats try to overcome alleged shortcomings and detrimental effects. Finally, an empirical research program is proposed, in which frames and frame components are experimentally manipulated and compared to establish their respective affordances and effects on the musical experience. Such a research program will provide empirical evidence to tackle a question that is still open to debate, i.e., whether the diversified world of modern-day music listening formats also holds a place for the classical concert - and if so, for what kind of classical concert.


Failed labor induction: toward an objective diagnosis.
To evaluate maternal and perinatal outcomes in women undergoing labor induction with an unfavorable cervix according to duration of oxytocin administration in the latent phase of labor after ruptured membranes. This was a secondary analysis of a randomized multicenter trial in which all cervical examinations from admission were recorded. nulliparas at or beyond 36 weeks of gestation undergoing induction with a cervix of 2 cm or less dilated and less than completely effaced. The latent phase of labor was defined as ending at a cervical dilation of 4 cm and effacement of at least 90%, or at a cervical dilation of 5 cm regardless of effacement. A total of 1,347 women were analyzed. The overall vaginal delivery rate was 63.2%. Most women had exited the latent phase after 6 hours of oxytocin and membrane rupture (n=939; 69.7%); only 5% remained in the latent phase after 12 hours. The longer the latent phase, the lower the vaginal delivery rate. Even so, 39.4% of the 71 women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Chorioamnionitis, endometritis, or both, and uterine atony were the only maternal adverse outcomes related to latent-phase duration: adjusted odds ratios (95% confidence intervals) of 1.12 (1.07, 1.17) and 1.13 (1.06, 1.19), respectively, for each additional hour. Neonatal outcomes were not related to latent-phase duration. Almost 40% of the women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Therefore, it is reasonable to avoid deeming labor induction a failure in the latent phase until oxytocin has been administered for at least 12 hours after membrane rupture. III.


The bear-hug test: a new and sensitive test for diagnosing a subscapularis tear.
It was our intent to devise a new clinical test that would more accurately diagnose subscapularis tears than the current clinical tests. This new test is called the bear-hug test. The purpose of this study was to assess the bear-hug test and compare it with the current tests of subscapularis function (lift-off, belly-press, and Napoleon tests). Between January 2004 and March 2004, 68 consecutive patients scheduled for an arthroscopic procedure were evaluated preoperatively; the preoperative clinical examination findings were then correlated with arthroscopic findings. Lift-off, belly-press, Napoleon, and bear-hug tests were included in the examination. Furthermore, for the belly-press and bear-hug tests, the strength was precisely quantified by means of an electronic digital tensiometer (Kern HBC). Diagnostic arthroscopy was the reference that determined the actual pathologic lesions. Subscapularis tears occurred with a prevalence rate of 29.4%. Of the subscapularis tears, 40% were not predicted by preoperative assessment by use of all of the tests. The bear-hug test was found to be the most sensitive test (60%) of all of those studied (belly-press test, 40%; Napoleon test, 25%; and lift-off test, 17.6%). In contrast, all 4 tests had a high specificity (lift-off test, 100%; Napoleon test, 97.9%; belly-press test, 97.9%; and bear-hug test, 91.7%). No statistically significant difference was found between the area under the receiver operating characteristic curve of the bear-hug test and that of the belly-press test in diagnosing a torn subscapularis. However, the areas under the receiver operating characteristic curve for both the bear-hug test and the belly-press test were significantly greater than those for the lift-off and Napoleon tests (P < .05). Positive bear-hug and belly-press tests suggest a tear of at least 30% of the subscapularis, whereas a positive Napoleon test indicates that greater than 50% of the subscapularis is torn. Furthermore, a positive lift-off test is not found until at least 75% of the subscapularis is torn. The bear-hug test optimizes the chance of detecting a tear of the upper part of the subscapularis tendon. Moreover, because the bear-hug test represents the most sensitive test, it can be considered to be the most likely clinical test to alert the surgeon to a possible subscapularis tear. Performing all of the subscapularis tests is useful in predicting the size of the tear. Level I, diagnostic study: testing of previously developed criteria in a series of consecutive patients with arthroscopy used as the criterion standard.


A Fuzzy Inference System for Closed-Loop Deep Brain Stimulation in Parkinson's Disease.
Parkinsons disease is a complex neurodegenerative disorder for which patients present many symptoms, tremor being the main one. In advanced stages of the disease, Deep Brain Stimulation is a generalized therapy which can significantly improve the motor symptoms. However despite its beneficial effects on treating the symptomatology, the technique can be improved. One of its main limitations is that the parameters are fixed, and the stimulation is provided uninterruptedly, not taking into account any fluctuation in the patients state. A closed-loop system which provides stimulation by demand would adjust the stimulation to the variations in the state of the patient, stimulating only when it is necessary. It would not only perform a more intelligent stimulation, capable of adapting to the changes in real time, but also extending the devices battery life, thereby avoiding surgical interventions. In this work we design a tool that learns to recognize the principal symptom of Parkinsons disease and particularly the tremor. The goal of the designed system is to detect the moments the patient is suffering from a tremor episode and consequently to decide whether stimulation is needed or not. For that, local field potentials were recorded in the subthalamic nucleus of ten Parkinsonian patients, who were diagnosed with tremor-dominant Parkinsons disease and who underwent surgery for the implantation of a neurostimulator. Electromyographic activity in the forearm was simultaneously recorded, and the relation between both signals was evaluated using two different synchronization measures. The results of evaluating the synchronization indexes on each moment represent the inputs to the designed system. Finally, a fuzzy inference system was applied with the goal of identifying tremor episodes. Results are favourable, reaching accuracies of higher 98.7% in 70% of the patients.


Using virtual reality to evaluate executive functioning among persons with schizophrenia: a validity study.
Persons with Schizophrenia experience difficulties with Executive Functioning (EF) that affect independence and participation in activities. Specifically, EF impacts performance in Instrumental Activities of Daily Living (IADL) that require flexible thinking and accommodation to complex environments. However, less is known how schizophrenia affects EF and individuals' performance in activities. IADL performance can be tested using a virtual reality (VR) environment that simulates real life activities. The purpose of this study was: 1) to examine the feasibility and validity of the Virtual Action Planning-Supermarket (VAP-S) to assess EF in persons with schizophrenia as compared to a standardized EF measure (the Behavioral Assessment of Dysexecutive Syndrome, BADS); 2) to compare performance of persons with schizophrenia and healthy controls in the VAP-S; 3) to assess the ability of the VAP-S to differentiate between different levels of EF within schizophrenia; 4) to explore the relationships between negative and positive symptoms and performance on the tests. Thirty persons with schizophrenia were matched with 30 healthy controls. Significant differences in performance between research and control groups were detected on the VAP-S and BADS, with the research group performing worse. Large variations in number of purchases within the VAP-S by the research group point to level of task completion thus secondary analysis was conducted. There was a significant negative correlation between level of the negative signs and overall performance on the BADS and on most measures of the VAP-S. Results of this study support the use the VAP-S to assess EF among persons with Schizophrenia.


The Development of a Sorghum Bran-Based Biorefining Process to Convert Sorghum Bran into Value Added Products.
Sorghum bran, a starch rich food processing waste, was investigated for the production of glucoamylase in submerged fungal fermentation using Aspergillus awamori. The fermentation parameters, such as cultivation time, substrate concentration, pH, temperature, nitrogen source, mineral source and the medium loading ratio were investigated. The glucoamylase activity was improved from 1.90 U/mL in an initial test, to 19.3 U/mL at 10% (w/v) substrate concentration, pH 6.0, medium loading ratio of 200 mL in 500 mL shaking flask, with the addition of 2.5 g/L yeast extract and essential minerals. Fermentation using 2 L bioreactors under the optimum conditions resulted in a glucoamylase activity of 23.5 U/mL at 72 h, while further increase in sorghum bran concentration to 12.5% (w/v) gave an improved gluco-amylase activity of 37.6 U/mL at 115 h. The crude glucoamylase solution was used for the enzymatic hydrolysis of the sorghum bran. A sorghum bran hydrolysis carried out at 200 rpm, 55 °C for 48 h at a substrate loading ratio of 80 g/L resulted in 11.7 g/L glucose, similar to the results obtained using commercial glucoamylase. Large-scale sorghum bran hydrolysis in 2 L bioreactors using crude glucoamylase solution resulted in a glucose concentration of 38.7 g/L from 200 g/L sorghum bran, corresponding to 94.1% of the theoretical hydrolysis yield.


Recent clinical evidence for the treatment of osteoarthritis: what we have learned.
Osteoarthritis (OA) is a chronic arthritis affecting growing numbers of the ageing population. Patients diagnosed with OA place a large burden on access to healthcare services, including primary care, prescription of analgesic drugs, physiotherapy and joint replacement surgery. Not all patients diagnosed with OA will require joint replacement surgery, and therefore avenues for non-surgical treatment for such patients need to be explored in many cases. In this review we discuss current concepts underlying the pathophysiology of OA. These form a basis to understanding the rationale for new and existing therapies based on recent evidence available from clinical studies and trials in OA. In particular, we discuss the evidence for use of pharmacological treatments, including NSAIDs (non-steroidal anti-inflammatory drugs), chondroitin sulphate and glucosamine, hyaluronan, potential disease-modifying drugs and other interventions such as weight reduction and physiotherapy. Finally, we discuss new developments from clinical evidence for surgical options, including ACL repair surgery and joint replacement surgery.


Effect of the walking speed to the lower limb joint angular displacements, joint moments and ground reaction forces during walking in water.
The purpose of this study was to compare the changes in ground reaction forces (GRF), joint angular displacements (JAD), joint moments (JM) and electromyographic (EMG) activities that occur during walking at various speeds in water and on land. Fifteen healthy adults participated in this study. In the water experiments, the water depth was adjusted so that body weight was reduced by 80%. A video-motion analysis system and waterproof force platform was used to obtain kinematics and kinetics data and to calculate the JMs. Results revealed that (1) the anterior-posterior GRF patterns differed between walking in water and walking on land, whereas the medio-lateral GRF patterns were similar, (2) the JAD patterns of the hip and ankle were similar between water- and land-walking, whereas the range of motion at the knee joint was lower in water than on land, (3) the JMs in all three joints were lower in water than on land throughout the stance phase, and (4) the hip joint extension moment and hip extensor muscle EMG activity were increased as walking speed increase during walking in water. Rehabilitative water-walking exercise could be designed to incorporate large-muscle activities, especially of the lower-limb extensor muscles, through full joint range of motion and minimization of joint moments.


Search for direct top squark pair production in events with a [Formula: see text] boson, [Formula: see text]-jets and missing transverse momentum in [Formula: see text] TeV [Formula: see text] collisions with the ATLAS detector.
A search is presented for direct top squark pair production using events with at least two leptons including a same-flavour opposite-sign pair with invariant mass consistent with the [Formula: see text] boson mass, jets tagged as originating from [Formula: see text]-quarks and missing transverse momentum. The analysis is performed with proton-proton collision data at [Formula: see text] collected with the ATLAS detector at the LHC in 2012 corresponding to an integrated luminosity of 20.3 fb[Formula: see text]. No excess beyond the Standard Model expectation is observed. Interpretations of the results are provided in models based on the direct pair production of the heavier top squark state ([Formula: see text]) followed by the decay to the lighter top squark state ([Formula: see text]) via [Formula: see text], and for [Formula: see text] pair production in natural gauge-mediated supersymmetry breaking scenarios where the neutralino ([Formula: see text]) is the next-to-lightest supersymmetric particle and decays producing a [Formula: see text] boson and a gravitino ([Formula: see text]) via the [Formula: see text] process.


Adenylate cyclase toxin promotes internalisation of integrins and raft components and decreases macrophage adhesion capacity.
Bordetella pertussis, the bacterium that causes whooping cough, secretes an adenylate cyclase toxin (ACT) that must be post-translationally palmitoylated in the bacterium cytosol to be active. The toxin targets phagocytes expressing the CD11b/CD18 integrin receptor. It delivers a catalytic adenylate cyclase domain into the target cell cytosol producing a rapid increase of intracellular cAMP concentration that suppresses bactericidal functions of the phagocyte. ACT also induces calcium fluxes into target cells. Biochemical, biophysical and cell biology approaches have been applied here to show evidence that ACT and integrin molecules, along with other raft components, are rapidly internalized by the macrophages in a toxin-induced calcium rise-dependent process. The toxin-triggered internalisation events occur through two different routes of entry, chlorpromazine-sensitive receptor-mediated endocytosis and clathrin-independent internalisation, maybe acting in parallel. ACT locates into raft-like domains, and is internalised, also in cells devoid of receptor. Altogether our results suggest that adenylate cyclase toxin, and maybe other homologous pathogenic toxins from the RTX (Repeats in Toxin) family to which ACT belongs, may be endowed with an intrinsic capacity to, directly and efficiently, insert into raft-like domains, promoting there its multiple activities. One direct consequence of the integrin removal from the cell surface of the macrophages is the hampering of their adhesion ability, a fundamental property in the immune response of the leukocytes that could be instrumental in the pathogenesis of Bordetella pertussis.


Psychotropic medication use among nursing home residents in Austria: a cross-sectional study.
The use of psychotropic medications and their adverse effects in frail elderly has been debated extensively. However, recent data from European studies show that these drugs are still frequently prescribed in nursing home residents. In Austria, prevalence data are lacking. We aimed to determine the prevalence of psychotropic medication prescription in Austrian nursing homes and to explore characteristics associated with their prescription. Cross-sectional study and association analysis in forty-eight out of 50 nursing homes with 1844 out of a total of 2005 residents in a defined urban-rural region in Austria. Prescribed medication was retrieved from residents' charts. Psychotropic medications were coded according to the Anatomical Therapeutic Chemical Classification 2005. Cluster-adjusted multiple logistic regression analysis was performed to investigate institutional and residents' characteristics associated with prescription. Residents' mean age was 81; 73% of residents were female. Mean cluster-adjusted prevalence of residents with at least one psychotropic medication was 74.6% (95% confidence interval, CI, 72.0-77.2). A total of 45.9% (95% CI 42.7-49.1) had at least one prescription of an antipsychotic medication. Two third of all antipsychotic medications were prescribed for bedtime use only. Anxiolytics were prescribed in 22.2% (95% CI 20.0-24.5), hypnotics in 13.3% (95% CI 11.3-15.4), and antidepressants in 36.8% (95% CI 34.1-39.6) of residents. None of the institutional characteristics and only few residents' characteristics were significantly associated with psychotropic medication prescription. Permanent restlessness was positively associated with psychotropic medication prescription (AOR 1.54, 95% CI 1.32-1.79) whereas cognitive impairment was inversely associated (AOR 0.70, 95% CI 0.56-0.88). Frequency of psychotropic medication prescription is high in Austrian nursing homes compared to recent published data from other countries. Interventions should aim at reduction and optimisation of prescriptions.


Relative health performance in BRICS over the past 20 years: the winners and losers.
To determine whether the health performance of Brazil, the Russian Federation, India, China and South Africa--the countries known as BRICS--has kept in step with their economic development. Reductions in age- and sex-specific mortality seen in each BRICS country between 1990 and 2011 were measured. These results were compared with those of the best-performing countries in the world and the best-performing countries with similar income levels. We estimated each country's progress in reducing mortality and compared changes in that country's mortality rates against other countries with similar mean incomes to examine changes in avoidable mortality. The relative health performance of the five study countries differed markedly over the study period. Brazil demonstrated fairly even improvement in relative health performance across the different age and sex subgroups that we assessed. India's improvement was more modest and more varied across the subgroups. South Africa and the Russian Federation exhibited large declines in health performance as well as large sex-specific inequalities in health. Although China's levels of avoidable mortality decreased in absolute terms, the level of improvement appeared low in the context of China's economic growth. When evaluating a country's health performance in terms of avoidable mortality, it is useful to compare that performance against the performance of other countries. Such comparison allows any country-specific improvements to be distinguished from general global improvements.


Timing of galectin-1 exposure differentially modulates Nipah virus entry and syncytium formation in endothelial cells.
Nipah virus (NiV) is a deadly emerging enveloped paramyxovirus that primarily targets human endothelial cells. Endothelial cells express the innate immune effector galectin-1 that we have previously shown can bind to specific N-glycans on the NiV envelope fusion glycoprotein (F). NiV-F mediates fusion of infected endothelial cells into syncytia, resulting in endothelial disruption and hemorrhage. Galectin-1 is an endogenous carbohydrate-binding protein that binds to specific glycans on NiV-F to reduce endothelial cell fusion, an effect that may reduce pathophysiologic sequelae of NiV infection. However, galectins play multiple roles in regulating host-pathogen interactions; for example, galectins can promote attachment of HIV to T cells and macrophages and attachment of HSV-1 to keratinocytes but can also inhibit influenza entry into airway epithelial cells. Using live Nipah virus, in the present study, we demonstrate that galectin-1 can enhance NiV attachment to and infection of primary human endothelial cells by bridging glycans on the viral envelope to host cell glycoproteins. In order to exhibit an enhancing effect, galectin-1 must be present during the initial phase of virus attachment; in contrast, addition of galectin-1 postinfection results in reduced production of progeny virus and syncytium formation. Thus, galectin-1 can have dual and opposing effects on NiV infection of human endothelial cells. While various roles for galectin family members in microbial-host interactions have been described, we report opposing effects of the same galectin family member on a specific virus, with the timing of exposure during the viral life cycle determining the outcome. Nipah virus is an emerging pathogen that targets endothelial cells lining blood vessels; the high mortality rate (up to 70%) in Nipah virus infections results from destruction of these cells and resulting catastrophic hemorrhage. Host factors that promote or prevent Nipah virus infection are not well understood. Endogenous human lectins, such as galectin-1, can function as pattern recognition receptors to reduce infection and initiate immune responses; however, lectins can also be exploited by microbes to enhance infection of host cells. We found that galectin-1, which is made by inflamed endothelial cells, can both promote Nipah virus infection of endothelial cells by "bridging" the virus to the cell, as well as reduce production of progeny virus and reduce endothelial cell fusion and damage, depending on timing of galectin-1 exposure. This is the first report of spatiotemporal opposing effects of a host lectin for a virus in one type of host cell.


Preparedness, Identification and Care of COVID-19 Cases by Front Line Health Workers in Selected Health Facilities in Mbale District Uganda: A Cross-Sectional Study.
The nature of work of Health care professionals exposes them to high risks of contracting COVID-19 and spreading it among themselves, to their patients and subsequently to the general community. Thus, it is essential that frontline health workers are equipped with both material and knowledge to enable them accurately suspect, detect, isolate, and manage COVID-19 cases. Findings have indicated a high prevalence of COVID-19 infections among front-line health workers. The Current Study assessed preparedness, identification, and care of COVID-19 Cases by frontline health workers in selected health facilities in Mbale District. Across sectional survey was used to collect quantitative data using Google forms, An online platform for data collection. Data was collected from 189 frontline health workers in both government and private Health facilities in Mbale District between April and August 2020. Data was analysed using Statistical Package for the Social Sciences (SPSS) version 20. The study found that a good proportion of frontline health workers can identify cases by symptom and case definitions as probable case 113/189(59.8%), suspected case 60/189(36%) and confirmed case 22/189 (11.6%). There were generally low levels of preparedness in terms of initial service care being offered with the highest being 53/189(28.2%) and 50/189(26.4%) for facilities that had places for isolation and those with intravenous fluids respectively and the least was being able to offer oxygen and Intensive Care Services at 43/189(22.0%) and 20/189(10.3%) respectively. There's a need to ensure a continuous supply of PPEs and IPC materials to health facilities. CPD programs are essential in equipping Health workers with up-to-date information on COVID-19 Case Management. Facilities should be supported to setup isolation facilities at all levels, both permanent and temporary. Provision of Face masks to health workers should be prioritised and hand washing facilities should be installed at every serving point.


Self-efficacy did not predict the outcome of the transition to adult care in adolescents with inflammatory bowel disease.
It can be difficult for adolescents with inflammatory bowel disease (IBD) to make the transition from paediatric to adult care. We studied the outcomes of this process and defined what constituted a successful transition. In 2008, 50 adolescents who attended our IBD transition clinic completed IBD-yourself, a self-efficacy questionnaire that we had previously developed and validated. We approached the subjects in 2014, two to six years after they transferred to adult care, and 35 agreed to take part in the current study. The outcome of transition was assessed by our newly developed Transition Yourself Score. In addition, the relationship between self-efficacy and the outcome of the transition was measured. The mean age of the patients was 21.8 years, and 69% suffered from Crohn's disease. The transition process was successful in 63% of cases, moderately successful in 31% and failed in 6%. A successful transition was associated with effective use of medication and clinical remission at the time of transfer, but could not be predicted by self-efficacy. The Transition Yourself Score will be validated in future studies. Nearly two-thirds (63%) of the adolescents who attended the IBD transition clinic had a successful transition to adult care.


Detection of Race-Specific Resistance Against Puccinia coronata f. sp. avenae in Brachypodium Species.
Oat crown rust caused by Puccinia coronata f. sp. avenae is the most destructive foliar disease of cultivated oat. Characterization of genetic factors controlling resistance responses to Puccinia coronata f. sp. avenae in nonhost species could provide new resources for developing disease protection strategies in oat. We examined symptom development and fungal colonization levels of a collection of Brachypodium distachyon and B. hybridum accessions infected with three North American P. coronata f. sp. avenae isolates. Our results demonstrated that colonization phenotypes are dependent on both host and pathogen genotypes, indicating a role for race-specific responses in these interactions. These responses were independent of the accumulation of reactive oxygen species. Expression analysis of several defense-related genes suggested that salicylic acid and ethylene-mediated signaling but not jasmonic acid are components of resistance reaction to P. coronata f. sp. avenae. Our findings provide the basis to conduct a genetic inheritance study to examine whether effector-triggered immunity contributes to nonhost resistance to P. coronata f. sp. avenae in Brachypodium spp.


Home-Based Telehealth Exercise Intervention in Early-On Survivors of Childhood Acute Lymphoblastic Leukemia: Feasibility Study.
Acute lymphoblastic leukemia is the most common type of pediatric cancer. Acute lymphoblastic leukemia causes an altered bone mineral homeostasis state, which can contribute to osteopenia, and bone fractures, most commonly vertebral fractures. With the increasing number of childhood cancer survivors, late adverse effects such as musculoskeletal comorbidities are often reported and are further influenced by inactive lifestyle habits. Physical activity has been shown to increase the mechanical workload of the bone, mitigating bone impairment in other cancer-specific populations. This interventional pilot study aims to investigate the use of telehealth to deliver a home-based exercise intervention for early-on survivors of bone marrow-related hematological malignancies and to assess its impact on survivors' musculoskeletal and functional health. We aimed to recruit a group of 12 early-on survivors of acute lymphoblastic leukemia, within 6 months to 5 years of treatment, to participate in and complete the proposed telehealth intervention with a parent. The 16-week intervention included 40 potential home-based physical activity interventions supervised by a kinesiologist through a telehealth internet platform, with monthly progression. Patients were recruited to the cohort if they were able to participate in the intervention during the first month (minimum 12 weeks of intervention). Evaluation before and after the intervention protocol highlighted differences in functional capacities and musculoskeletal health of patients using mechanography, peripheral quantitative computed tomography, 6-minute walk test, and grip force test. The recruitment rate for the intervention was low (12/57, 21% of contacted patients). Of 12 patients, 3 were excluded (1=relapse, 1=failure to meet technical requirements, and 1=abandoned). The 9 patients who completed the intervention (6 girls; mean age 10.93, SD 2.83 years; mean BMI 21.58, SD 6.55 kg/m2; mean time since treatment completion 36.67, SD 16.37 months) had a mean adherence of 89% and a completion rate of 75%. In addition, these patients showed functional improvements in lower limb muscle force and power as well as in the 6-minute walk test distance. Participants also showed improved bone health after the intervention on the following parameters: bone mineral content, stress-strain index, total and cortical cross-sectional area at the 14% site (P=.03, P=.01, P=.01, and P=.001, respectively) and 38% site of the tibia (P=.003, P=.04, P=.001, and P=.003, respectively). High adherence and participation rates suggest that telehealth is a feasible method to deliver exercise interventions to young early-on survivors of acute lymphoblastic leukemia. The proposed intervention seems promising in providing benefits to patients' functional performance and bone health, but a large-scale study is needed to confirm this assumption.


ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.
To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.


Shoulder stabilization by modified Latarjet-Patte procedure: results at a minimum 10 years' follow-up, and role in the prevention of osteoarthritis.
In 1995, our team modified the Latarjet-Patte procedure by associating "south-north" capsule retention with reinsertion to the edge of the glenoid cavity to the coracoid bone-block. The present minimum 10-year follow-up study tested the hypothesis that the rate of osteoarthritis could be reduced by the strictly extra-articular position of the bone-block and stability be enhanced by the associated Bankart effect. Between January 1995 and December 2001, 78 shoulders were stabilized using the modified Latarjet-Patte procedure in 76 patients with a mean age at surgery of 26.7 years; 89.7% could be followed up, 82.8% of whom also had radiographic follow-up. Fifty-nine were sports players, including 25 at competition level. Stability was assessed on a questionnaire, any dislocation or subluxation being counted as recurrence. At a mean 13 years' follow-up (range, 10-15 years), there had been no revision surgery. Mean Duplay score was 82.6, mean Subjective Shoulder Value 91.9% and the satisfaction rate 98.5%. The recurrence rate was 1.4% and 10 patients reported residual apprehension. The osteoarthritis rate was 8.5%. Seven bone-blocks projected, but only one was associated with osteoarthritis (stage 1) (non-significant). There were 4 non-unions and 9 lyses, without instability or pain. The modified procedure provided a low rate of recurrence and an incidence of osteoarthritis (8.5%) much lower than in any other published series with a minimum 10 years' follow-up. The strictly extra-capsular situation of the bone-block appeared as an important factor in limiting long-term osteoarthritis. Capsule reinsertion also seemed to alleviate the radiologic complications. IV, retrospective study.


Contact toxicity and repellency of the essential oil of Liriope muscari (DECN.) bailey against three insect tobacco storage pests.
In order to find and develop new botanical pesticides against tobacco storage pests, bioactivity screening was performed. The essential oil obtained from the aerial parts of Liriope muscari was investigated by GC/MS and GC/FID. A total of 14 components representing 96.12% of the oil were identified and the main compounds in the oil were found to be methyl eugenol (42.15%) and safrole (17.15%), followed by myristicin (14.18%) and 3,5-dimethoxytoluene (10.60%). After screening, the essential oil exhibit potential insecticidal activity. In the progress of assay, it showed that the essential oil exhibited potent contact toxicity against Tribolium castaneum, Lasioderma serricorne and Liposcelis bostrychophila adults, with LD50 values of 13.36, 11.28 µg/adult and 21.37 µg/cm2, respectively. The essential oil also exhibited strong repellency against the three stored product insects. At the same concentrations, the essential oil was more repellent to T. castaneum than to L. serricorne adults. The results indicate that the essential oil of Liriope muscari has potential to be developed into a natural insecticide or repellent for controlling insects in stored tobacco and traditional Chinese medicinal materials.


Proteomic analysis of the abomasal mucosal response following infection by the nematode, Haemonchus contortus, in genetically resistant and susceptible sheep.
Sheep have a variable ability to resist gastrointestinal nematode infection, but the key factors mediating this response are poorly defined. Here we report the first large-scale application of quantitative proteomic technologies to define proteins that are differentially abundant between sheep selectively bred to have an enhanced (resistant) or reduced (susceptible) ability to eliminate nematodes. Samples were collected from the abomasal mucosa three days after experimental challenge with the nematode, Haemonchus contortus. This timing reflects the initial interaction of host and parasite, and the tissue represents the immediate interface. We identified and quantified more than 4400 unique proteins, of which 158 proteins showed >1.5 fold difference between the resistant and susceptible sheep. Trefoil factor 2, a member of RAS oncogene family (RAP1A) and ring finger protein 126 were amongst the proteins found to be highly abundant in the abomasal surface of resistant sheep, whereas adenosine deaminase and the gastrokine-3 like precursor were found at higher levels in susceptible sheep. Construction of gut proteome interaction networks identified mitochondrial function and energetic partitioning as important components of an effective nematode eliminating response. The differentially abundant proteins may be useful targets for phenotypic tests that aim to identify sheep with an enhanced ability to resist nematode infection.


JAK and STAT members in channel catfish: Identification, phylogenetic analysis and expression profiling after Edwardsiella ictaluri infection.
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is one of the main pleiotropic cascades used to transmit information from extracellular receptors to the nucleus, which results in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, migration, apoptosis, and cell survival. Members of JAK family and STAT family have been extensively studied in different mammalian species because of their important roles in innate and adaptive immune responses. However, they have not been systematically studied among teleost fish species. In this study, five JAK family members and eight STAT family members were identified and characterized from channel catfish. Phylogenetic analysis was conducted to properly annotate these genes. Syntenic analysis was also conducted to establish orthology, and confirm the results from phylogenetic analysis. Compared to mammals, more members of the JAK and STAT family were identified in channel catfish genome. Expression of JAK and STAT family members was detected in healthy catfish tissues, but was induced in gill, liver, and intestine after bacterial challenge. Notably, the significant upregulation of STAT1b gene in catfish liver, gill and intestine after Edwardsiella ictaluri infection supported the notion that high STAT1 expression are involved in defense against pathogens. Collectively, the increased expression of JAK and STAT members in tested tissues suggested their crucial function in defending the host against pathogen invasion.


Revisiting the structure/function relationships of H/ACA(-like) RNAs: a unified model for Euryarchaea and Crenarchaea.
A structural and functional classification of H/ACA and H/ACA-like motifs is obtained from the analysis of the H/ACA guide RNAs which have been identified previously in the genomes of Euryarchaea (Pyrococcus) and Crenarchaea (Pyrobaculum). A unified structure/function model is proposed based on the common structural determinants shared by H/ACA and H/ACA-like motifs in both Euryarchaea and Crenarchaea. Using a computational approach, structural and energetic rules for the guide:target RNA-RNA interactions are derived from structural and functional data on the H/ACA RNP particles. H/ACA(-like) motifs found in Pyrococcus are evaluated through the classification and their biological relevance is discussed. Extra-ribosomal targets found in both Pyrococcus and Pyrobaculum might support the hypothesis of a gene regulation mediated by H/ACA(-like) guide RNAs in archaea.


Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate.
The purpose of this research was to report results on long-term administration of dichloroacetate in 36 children with congenital lactic acidosis who participated previously in a controlled trial of this drug. We conducted a randomized control trial, followed by an open-label study. Data were analyzed for each patient from the time they began treatment through May 2005. Subject exposure to dichloroacetate totaled 110.42 years. Median height and weight increased over time, but the standardized values declined slightly and remained below the first percentile. There were no significant changes in biochemical metabolic indices, except for a 2% rise in total protein and a 22% increase in 24-hour urinary oxalate. Both the basal and carbohydrate meal-induced rises in lactate were blunted by dichloroacetate. The median cerebrospinal fluid lactate also decreased over time. Conduction velocity decreased and distal latency increased in peroneal nerves. Mean 3-year survival for all of the subjects was 79%. Oral dichloroacetate is generally well tolerated in young children with congenital lactic acidosis. Although continued dichloroacetate exposure is associated with evidence of peripheral neuropathy, it cannot be determined whether this is attributable mainly to the drug or to progression of underlying disease.


Failure of three decision rules to predict the outcome of in-hospital cardiopulmonary resuscitation.
The objective of this study was to evaluate three decision-support tools (the Pre-Arrest Morbidity or PAM score, the Prognosis After Resuscitation or PAR score, and the Acute Physiology and Chronic Health Evaluation or APACHE III score) for their abilities to predict the outcomes of in-hospital cardiopulmonary resuscitation (CPR). The medical records of all 656 adult inpatients undergoing CPR during a two-to-three-year period in three large hospitals were retrospectively reviewed, and demographic and clinical variables were abstracted. Of 656 patients undergoing resuscitation, 248 (37.8%) survived the resuscitation attempt long enough to be stabilized (immediate survival), but only 35 (5.3%) survived to discharge. Only 11 patients had PAM scores higher than 8, none of whom survived to discharge; 131 patients had PAR scores above 8, of whom six survived to discharge. The PAR score and the APACHE III score had the greatest areas under the receiver operating characteristic curves (when predicting the outcome of survival to discharge), although no individual area for either outcome was greater than 0.6. None of the decision-support tools studied was able to effectively discriminate between survivors and non-survivors for the outcomes of immediate survival and survival to discharge following in-hospital CPR. This is consistent with previous work utilizing the APACHE II score, which did not identify a threshold above which patients did not benefit from CPR. The findings for the PAR score and the PAM score stand in contrast to previous studies that found them to be potentially useful decision rules. Further work is needed to develop a decision-support tool that better discriminates between survivors and non-survivors of in-hospital CPR.


Whole genome comparisons of serotype 4b and 1/2a strains of the food-borne pathogen Listeria monocytogenes reveal new insights into the core genome components of this species.
The genomes of three strains of Listeria monocytogenes that have been associated with food-borne illness in the USA were subjected to whole genome comparative analysis. A total of 51, 97 and 69 strain-specific genes were identified in L.monocytogenes strains F2365 (serotype 4b, cheese isolate), F6854 (serotype 1/2a, frankfurter isolate) and H7858 (serotype 4b, meat isolate), respectively. Eighty-three genes were restricted to serotype 1/2a and 51 to serotype 4b strains. These strain- and serotype-specific genes probably contribute to observed differences in pathogenicity, and the ability of the organisms to survive and grow in their respective environmental niches. The serotype 1/2a-specific genes include an operon that encodes the rhamnose biosynthetic pathway that is associated with teichoic acid biosynthesis, as well as operons for five glycosyl transferases and an adenine-specific DNA methyltransferase. A total of 8603 and 105 050 high quality single nucleotide polymorphisms (SNPs) were found on the draft genome sequences of strain H7858 and strain F6854, respectively, when compared with strain F2365. Whole genome comparative analyses revealed that the L.monocytogenes genomes are essentially syntenic, with the majority of genomic differences consisting of phage insertions, transposable elements and SNPs.


Baseline subjective memory complaints associate with increased risk of incident dementia: the PREADVISE trial.
Subjective memory complaints reflect patient-identified deficits in memory and have been linked to increased risk of future dementia in nondemented (including cognitively intact) older adults. To assess the risk of incident dementia during follow-up for participants in the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADVISE) study who reported memory complaints at baseline. Double-blind, placebo controlled 2×2 randomized controlled trial that transformed into an observational cohort following discontinuation of supplementation in the SELECT parent trial. PREADVISE participants were assessed at 130 local clinical study sites in the United States, Canada, and Puerto Rico during the controlled trial phase and were later followed by telephone from a centralized location during the observational phase. PREADVISE enrolled a total of 7,547 nondemented men over the age of 60; 4,271 consented to participation in the observational study. Participants were interviewed at baseline for memory complaints. The Memory Impairment Screen (MIS) was administered to each participant at the annual memory screening. Participants who failed the MIS also received a more detailed neurocognitive assessment: an expanded Consortium to Establish a Registry in Alzheimer's Disease (CERADe) neuropsychological battery was used during the RCT, and the modified Telephone Interview for Cognitive Status (TICS-m) was used during the observational study. Participants who failed the second screen were asked to have a memory work-up with a local physician and to share their medical records with PREADVISE. Subgroups of men who did not fail the MIS were also asked to complete the CERADe battery and TICS-m for validation purposes. Additional measures collected include self-reported medical history, medication use, and the AD8 Dementia Screening Test. After controlling for important risk factors for dementia, Cox proportional hazards regression revealed that men who reported memory changes at baseline had an 80% increase in the hazard of incident dementia compared to men who reported no SMC. Men who reported memory problems at baseline had almost a 6-fold increase in the hazard of incident dementia compared to men who reported no memory complaint. Memory complaints in nondemented older men predicted future dementia. Men who reported that the changes in their memory were a problem were especially at risk, and the presence of common comorbidities like diabetes, sleep apnea, and history of head injury further exacerbated this risk.


Er:YAG laser-roughened enamel promotes osteoblastic differentiation.
The aim of this study was to test whether Er:YAG laser-etched enamel of human teeth could act as a biologically active scaffold for tissue regeneration. Hydroxylapatite (HA) with rough surface created by acid etching treatment has been used as a scaffold for tissue engineering. However, whether tooth HA can be a scaffold for osteoblastic cell seeding is still unclear. Enamel samples from human teeth were pretreated with an Er:YAG laser to create a rough surface. Then the surface of the laser-treated enamel was examined using a surface roughness profilometer and a scanning electron microscope. In addition, static water contact angles of the Er:YAG laser-treated enamel samples were measured using goniometry. To observe the effects of cell behavior on an Er:YAG laser-roughened enamel surface, we cultured MG63 osteoblast-like cells on the surface-modified enamel samples. Alkaline phosphatase activity, a marker of cell proliferation and differentiation, was monitored and compared with that in untreated control and acid-etched enamel samples. Er:YAG laser treatment significantly improved the surface roughness of the enamel samples. Furthermore, MG63 osteoblast-like cells cultured on the Er:YAG laser-roughened enamel surface expressed more alkaline phosphatase activity and exhibited greater degrees of cellular differentiation than did cells that had been cultured on untreated enamel samples. These results demonstrate that Er:YAG laser-roughened enamel promotes osteoblastic differentiation. This finding suggests that Er:YAG laser-roughened enamel surfaces can potentially serve as a scaffold for tissue engineering.


Putting on the brakes: cyclic AMP as a multipronged controller of macrophage function.
Macrophages orchestrate innate immune responses in tissues by activating various proinflammatory signaling programs. A key mechanism for preventing inflammatory disease states that result from excessive activation of such programs is the generation of the second messenger cyclic adenosine monophosphate (cAMP) by ligation of certain guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The pleiotropic actions of this cyclic nucleotide on various inflammatory functions of macrophages are mediated by diverse molecular mechanisms, including the assembly of distinct multiprotein complexes. A better understanding of crosstalk between cAMP signaling and proinflammatory pathways in macrophages may provide a basis for improved immunomodulatory strategies.


Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc.
Neurotrophins are important regulators of growth and regeneration, and acutely, they can modulate the activity of voltage-gated ion channels. Previously we have shown that acute brain-derived neurotrophic factor (BDNF) activation of neurotrophin receptor tyrosine kinase B (TrkB) suppresses the Shaker voltage-gated potassium channel (Kv1.3) via phosphorylation of multiple tyrosine residues in the N and C terminal aspects of the channel protein. It is not known how adaptor proteins, which lack catalytic activity, but interact with members of the neurotrophic signaling pathway, might scaffold with ion channels or modulate channel activity. We report the co-localization of two adaptor proteins, neuronal Src homology and collagen (nShc) and growth factor receptor-binding protein 10 (Grb10), with Kv1.3 channel as demonstrated through immunocytochemical approaches in the olfactory bulb (OB) neural lamina. To further explore the specificity and functional ramification of adaptor/channel co-localization, we performed immunoprecipitation and Western analysis of channel, kinase, and adaptor transfected human embryonic kidney 293 cells (HEK 293). nShc formed a direct protein-protein interaction with Kv1.3 that was independent of BDNF-induced phosphorylation of Kv1.3, whereas Grb10 did not complex with Kv1.3 in HEK 293 cells. Both adaptors, however, co-immunoprecipitated with Kv1.3 in native OB. Grb10 was interestingly able to decrease the total expression of Kv1.3, particularly at the membrane surface, and subsequently eliminated the BDNF-induced phosphorylation of Kv1.3. To examine the possibility that the Src homology 2 (SH2) domains of Grb10 were directly binding to basally phosphorylated tyrosines in Kv1.3, we utilized point mutations to substitute multiple tyrosine residues with phenylalanine. Removal of the tyrosines 111-113 and 449 prevented Grb10 from decreasing Kv1.3 expression. In the absence of either adaptor protein, channel co-expression reciprocally down-regulated expression and tyrosine phosphorylation of TrkB kinase and related insulin receptor kinase. Finally, through patch-clamp electrophysiology, we found that the BDNF-induced current suppression of the channel was prevented by both nShc and Grb10. We report that adaptor protein alteration of kinase-induced Kv1.3 channel modulation is related to the degree of direct protein-protein association and that the channel itself can reciprocally modulate receptor-linked tyrosine kinase expression and activity.


Copper deficiency and excess in infancy: developing a research agenda.
Copper deficiency and excess have been recognized as potential health problems for infants and children worldwide. Clinical manifestations of copper deficiency and excess are well characterized but the precise sequence by which high copper intake interacts with genetic control systems, leading to liver damage in infants, is unknown. The possibility that genetic mutations or epigenetic factors related to the functional development of copper homeostasis, could make otherwise normal infants on normal copper intake more susceptible to copper toxicity has been an issue of concern. In January 2001 a group of pediatricians and researchers interested in this area met at Tegernsee, Bavaria, Germany, to reviewing the state of knowledge on the topic. They addressed six main issues: 1) The relevance of copper deficit and excess as health problems. 2) The appropriate biomarkers to identify and characterize copper status 3) The genetic variability in copper metabolism 4) The mechanisms of whole body copper homeostasis in early life and their changes with age 5) The development of experimental and animal models to address research questions on copper homeostasis in infants. 6) The safe upper and lower limits of copper intake/exposure from water and food. We present here the highlights of the discussions and the main conclusions of the meeting.


Nature beats nurture: a case study of the physiological fitness of free-living and laboratory-reared male Anopheles gambiae s.l.
Laboratory experimentation forms the basis for most of our knowledge of the biology of many organisms, in particular insects. However, the accuracy with which laboratory-derived estimates of insect life history and behaviour can predict their fitness and population dynamics in the wild is rarely validated. Such comparison is especially important in cases where laboratory-derived information is used to formulate and implement strategies for the genetic control of insects in nature. We have conducted a comparative study of the reproductive potential and life history of male Anopheles gambiae Gilies sensu lato mosquitoes from both standardized laboratory conditions and from natural field settings. We measured three indirect indicators of male mosquito fitness: energetic reserves, body size and survival, in a bid to determine whether the demographics and energetic limitations of wild males can be correctly predicted from their laboratory counterparts. Crucially, the body size and lipid reserves of wild males were substantially greater than those reared under standard laboratory conditions. We caution that the energetic limitations of insects as identified in the laboratory may underestimate their resilience in the wild, and discuss the implications of this phenomenon with respect to vector-borne disease control programmes based on genetic control of mosquitoes.


Yeast vacuolar proenzymes are sorted in the late Golgi complex and transported to the vacuole via a prevacuolar endosome-like compartment.
We are studying intercompartmental protein transport to the yeast lysosome-like vacuole with a reconstitution assay using permeabilized spheroplasts that measures, in an ATP and cytosol dependent reaction, vacuolar delivery and proteolytic maturation of the Golgi-modified precursor forms of vacuolar hydrolases like carboxypeptidase Y (CPY). To identify the potential donor compartment in this assay, we used subcellular fractionation procedures that have uncovered a novel membrane-enclosed prevacuolar transport intermediate. Differential centrifugation was used to separate permeabilized spheroplasts into 15K and 150K g membrane pellets. Centrifugation of these pellets to equilibrium on sucrose density gradients separated vacuolar and Golgi complex marker enzymes into light and dense fractions, respectively. When the Golgi-modified precursor form of CPY (p2CPY) was examined (after a 5-min pulse, 30-s chase), as much as 30-40% fractionated with an intermediate density between both the vacuole and the Golgi complex. Pulse-chase labeling and fractionation of membranes indicated that p2CPY in this gradient region had already passed through the Golgi complex, which kinetically ordered it between the Golgi and the vacuole. A mutant CPY protein that lacks a functional vacuolar sorting signal was detected in Golgi fractions but not in the intermediate compartment indicating that this corresponds to a post-sorting compartment. Based on the low transport efficiency of the mutant CPY protein in vitro (decreased by sevenfold), this intermediate organelle most likely represents the donor compartment in our reconstitution assay. This organelle is not likely to be a transport vesicle intermediate because EM analysis indicates enrichment of 250-400 nm compartments and internalization of surface-bound 35S-alpha-factor at 15 degrees C resulted in its apparent cofractionation with wild-type p2CPY, indicating an endosome-like compartment (Singer, B., and H. Reizman. 1990. J. Cell Biol. 110:1911-1922). Fractionation of p2CPY accumulated in the temperature sensitive vps15 mutant revealed that the vps15 transport block did not occur in the endosome-like compartment but rather in the late Golgi complex, presumably the site of CPY sorting. Therefore, as seen in mammalian cells, yeast CPY is sorted away from secretory proteins in the late Golgi and transits to the vacuole via a distinct endosome-like intermediate.


Body Mass Index and Weight Loss in Metastatic Colorectal Cancer in CALGB (Alliance)/SWOG 80405.
In nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity's influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored. We conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss during the 6 months prior to study entry. We also examined weight loss prior to enrollment as an independent predictor of patient outcome. All statistical tests were two-sided. Among 2323 patients with mCRC, there were no statistically significant associations between BMI and overall or progression-free survival (adjusted P trend = .12 and .40, respectively). Weight loss during the 6 months prior to study entry was associated with shorter overall and progression-free survival; compared with individuals with stable weight ±4.9%, individuals with weight loss greater than 15% experienced an adjusted hazard ratio of 1.52 for all-cause mortality (95% confidence interval [CI] = 1.26 to 1.84; P trend < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; P trend = .006). In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression.


Tumor antigen-independent and cell size variation-inclusive enrichment of viable circulating tumor cells.
Isolation of circulating tumor cells (CTCs) from blood provides a minimally-invasive alternative for basic understanding, diagnosis, and prognosis of metastatic cancer. The roles and clinical values of CTCs are under intensive investigation, yet most studies are limited by technical challenges in the comprehensive enrichment of intact and viable CTCs with minimal white blood cell (WBC) contamination. Here, we report a novel method based on contrast of cell magnetization in biocompatible ferrofluids (a colloidal magnetic nanoparticle suspension), termed as integrated ferrohydrodynamic cell separation (iFCS), that enriches CTCs in a tumor antigen-independent and cell size variation-inclusive manner, achieves a high throughput (12 mL h-1), high recovery rate (99.08% at down to ∼10 cells per mL spike ratio), and low WBC contamination (533 cells for every one milliliter blood processed) and is biocompatible. This method will enable large cohort research to define the clinical and diagnostic value of CTC subtypes.


Short-term simvastatin treatment has no effect on plasma cytokine response in a human in vivo model of low-grade inflammation.
Statins reduce plasma cholesterol, but clinical trials and in vitro studies indicate that they might also possess anti-inflammatory properties. The effect of simvastatin on circulating cytokines and leucocytes was evaluated in a human in vivo model of low-grade inflammation. Thirty young healthy male participants received an injection of the bacterial cell wall product endotoxin (0.06 ng/kg) to induce systemic inflammation. Participants were then randomized into a control and a simvastatin group. The simvastatin group received simvastatin 20 mg daily for 14 days. All participants returned after 14 days to receive a second endotoxin injection. Plasma concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1 receptor antagonist were measured by enzyme-linked immunosorbent assay (ELISA) before and hourly for 6 hours after endotoxin administration. Plasma cytokines as well as total leucocyte counts increased in all participants upon endotoxin challenge but were not affected by simvastatin treatment. Tolerance to endotoxin was observed in both groups after 14 days. Short-term treatment with simvastatin (20 mg/day) did not influence circulating cytokine levels during endotoxaemia in this human in vivo study.


Rising incidence of early-onset colorectal cancer in Australia over two decades: report and review.
The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.


Contaminated landslide runout deposits in rivers - Method for estimating long-term ecological risks.
The potential catastrophic event of a landslide bringing contaminants to surface waters has been highlighted in public media, but there are still few scientific studies analyzing the risk of landslides with contaminated soil. The aim of this study is to present a method to estimate the risk of potential long-term ecological effects on water bodies due to contaminated soil released into a river through a landslide. The study constitutes further development of previous work focusing on the instantaneous (short-term) release of contaminants and associated effects. Risk is here defined as the probability of surface water failing to comply with environmental quality standards (EQS). The transport model formulation is kept simple enough to allow for a probabilistic analysis as a first assessment of the impact on the river water quality from a landslide runout deposit containing contaminated soil. The model is applied at a contaminated site located adjacent to the Göta Älv River that discharges into the Gothenburg estuary, in southwest Sweden. The results from the case study show that a contaminated runout deposit will likely cause contamination levels above EQSs in the near area for a long time and that it will take several years for the deposit to erode, with the greatest erosion at the beginning when water velocities are their highest above the deposit. A contaminated landslide runout deposit will thus act as a source of contamination to the downstream water system until all the contaminated deposit has been eroded away and the contaminants have been transported from the deposit to the river, and further to the river mouth - diluted but not necessarily negligible. Therefore, it is important to prevent landslides of contaminated soil or waste, and if such events were to occur, to remove the contaminated runout deposit as soon as possible.


Frequent occurrence of cytomegalovirus retinitis during immune reconstitution warrants regular ophthalmic screening in high-risk pediatric allogeneic hematopoietic stem cell transplant recipients.
Although cytomegalovirus (CMV) retinitis (CMVR) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT), standard operating procedures for ophthalmic monitoring are variable. In particular, authors perceived a greater risk of CMVR after pediatric HSCT for inherited immunodeficiencies, in patients who often have pretransplantation viremia. This study was therefore performed to identify high-risk pediatric HSCT recipients who would benefit from regular ophthalmic monitoring. During a 5-year study period, we retrospectively analyzed findings in 56 of 304 consecutive HSCT recipients (age range, 0.5-197 months) in whom significant CMV viremia developed (CMV level at PCR, ≥4000 copies/mL). All HSCT recipients with significant CMV viremia underwent retinal examination weekly (inpatients) or every other week (outpatients), with examinations performed by a skilled ophthalmologist. CMVR developed in 13 (4%) of 304 HSCT recipients, 23% (13 of 56) of those with significant CMV viremia. Pretransplant viremia (odds ratio, 11.3; P < .01), acute (grade ≥2) graft-vs-host disease (odds ratio, 8.2; P < .02) and mismatched graft (odds ratio, 8; P < .02) were identified as independent risk factors. Compared with other invasive CMV diseases, CMVR was more often a late-onset disease, occurring at a median of 199 days after HSCT. At diagnosis, a significantly higher CD4 T-cell count (≥200/µL; P < .03) and a lower CMV load (P < .004) was observed in children with CMVR, compared with those in whom lung, gut, or liver CMV disease developed. We report an increased risk of CMVR in high-risk pediatric HSCT recipients. This form of CMV disease differs from other invasive CMV disease in its relationship to immune reconstitution and viral dynamics. We have studied the relationship between these variables and suggested a risk-stratified ophthalmic screening strategy.


A brief review of biomarkers for preventing and treating cardiovascular diseases.
Cardiovascular diseases are the most prominent circulation disorders around the world. Biomarkers are characteristic biological properties that can be objectively measured as an indicator to evaluate a variety of health or disease characteristics. Cardiac biomarkers are a valuable tool for assessing the pathogenesis and diagnosis of cardiovascular diseases. In this review, we will focus on the major biomarkers used in recent clinical research for the diagnosis of cardiovascular diseases, which include mean platelet volume, hyperhomocysteinemia, serum magnesium, microalbuminuria, and prolongation of QT interval and dispersion. We also highlight the key findings of clinical case report based studies presented in this issue of JCDR.


Optic nerve head quantification in idiopathic intracranial hypertension by spectral domain OCT.
To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH). Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans. Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP). Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumbar punctures and could therefore ease monitoring of treatment or disease progression.


Occult bacteraemia in children with fever without focus though previously vaccinated against pneumococcus.
Pneumococcal conjugate vaccines (PCV) have reduced the rate of occult bacteraemia in developed countries. However, reports on the incidence of occult bacteraemia in tropical regions are scarce. The aim of our study was to determine its frequency in children consulting for fever without focus in Colombia after introduction of the pneumococcal conjugate vaccines. We concluded that in tropical areas, testing for occult bacteraemia should be considered regardless of previous pneumococcal conjugate vaccination status.


Effects of Shoal Margin Collapses on the Morphodynamics of a Sandy Estuary.
Shoal margin collapses of several million cubic meters have occurred in the Western Scheldt estuary, the Netherlands, on average five times a year over the last decades. While these collapses involve significant volumes of material, their effect on the channel-shoal morphology is unknown. We hypothesize that collapses dynamicize the channel-shoal interactions, which could impact the ecological functioning, flood safety, and navigation in the estuary. The objective is to investigate how locations, probability, type, and volume of shoal margin collapse affect the channel-shoal dynamics. We implemented an empirically validated parameterization for shoal margin collapses and tested its effect on simulated estuary morphological development in a Delft3D schematization of the Western Scheldt. Three sets of scenarios were analyzed for near-field and far-field effects on flow pattern and channel-shoal morphology: (1) an observed shoal margin collapse of 2014, (2) initial large collapses on 10 locations, and (3) continuous collapses predicted by our novel probabilistic model over a time span of decades. Results show that a single shoal margin collapse only affects the local dynamics in the longitudinal flow direction and dampen out within a year for typical volumes, whereas larger disturbances that reach the seaward or landward sill at tidal channel junctions grow. The direction of the strongest tidally averaged flow determined the redistribution of the collapsed sediment. We conclude that adding the process of shoal margin collapses increases the channel-shoal interactions and that in intensively dredged estuaries shoal margins oversteepen, amplifying the number of collapses, but because of dredging the natural morphological response is interrupted.


Sleep Duration and Diet Quality Among Women Within 5 Years of Childbirth in the United States: A Cross-Sectional Study.
Objective Only 9 % of women with young children consume a high quality diet. The association between sleep duration and health may be U-shaped. We examined diet quality in relation to sleep duration among US women within 5 years of childbirth. Methods Data were from non-pregnant women aged 20-44 years within 5 years of childbirth who completed two 24-h dietary recalls (N = 896) in the National Health and Nutrition Examination Survey 2005-2012. Self-reported weekday/workday sleep duration was categorized as short (≤6 h), adequate (7-8 h), or long (≥9 h). The Healthy Eating Index (HEI-2010, range 0-100) estimated overall and components of diet quality. Multivariable-adjusted linear regression models estimated the association between sleep duration and diet quality, adjusting for age, race/ethnicity, and education. Results Thirty-four percent of women reported short, 57.1 % adequate, and 8.6 % long sleep duration. The average diet quality total score was 47.4 out of 100. Short sleep duration was not associated with diet quality. Long sleep duration was associated with lower quality diet (β = -4.3; 95 % CI -8.1 to -0.4), lower consumption of total fruit (β = -0.7; 95 % CI -1.3 to -0.1), whole fruit (β = -0.9; 95 % CI -1.6 to -0.2), and total protein (β = -0.7; 95 % CI -1.3 to -0.03), and higher consumption of empty calories (β = 2.2; 95 % CI -4.3 to -0.1). Conclusions for practice Future studies should examine the longitudinal association between sleep duration and diet quality among women following childbirth and whether interventions to improve sleep can enhance diet quality.


Nuclear medicine practice in Japan: a report of the seventh nationwide survey in 2012.
The Subcommittee on the Survey of Nuclear Medical Practice in Japan has performed a nationwide survey of nuclear medicine practice every 5 years since 1982 to survey contemporary nuclear medicine practice and its changes over the years. The subcommittee sent questionnaires, including the number and category of examinations as well as the kind and dose of the radiopharmaceuticals during the 30 days of June 2012, to all the nuclear medicine institutes. The total numbers for the year 2012 were then estimated. A total of 1,167 institutes responded to the survey, including the 14 in vitro assay institutes and 266 PET centers. The recovery rate was 92 %. The number of gamma cameras installed was 1,425 in total, with 9 % decrease in 5 years. Dual-head cameras and hybrid SPECT/CT scanners accounted for 84 and 10.5 %, respectively. The number of single-photon tracer studies in 2012 was 1.15 million which means decrease in 19 % in 5 years and 29 % in 10 years. All but cerebral perfusion study and sentinel lymphoscintigraphy have decreased. Bone scintigraphy was a leading examination (38.7 %), followed by cardiac studies (29.4 %) and cerebral perfusion study (18.5 %) in order. SPECT studies showed an increase from 42.3 to 47.2 %. PET centers have also increased from 212 to 295, as compared to the last survey. The 135 PET centers have installed one or two in-house cyclotrons. PET studies showed 25.5 % increase in 5 years, with oncology accounting for 96.3 %. (18)F-FDG accounted for 98.2 % (505,990 examinations). PET examinations using (11)C-methionine have been increasing, with 3,352 examinations in 2012. The number of new PET studies using (11)C-PIB PET was 695. (131)I-radioiodine targeted therapies showed an increase, including 3,644 patients (53.6 %) for thyroid cancer and 4,889 patients (17.9 %) for hyperthyroidism. Out-patient thyroid bed ablation therapy with 30 mCi of (131)I accounted for 21.0 % of cancer patients. The number of admission rooms decreased from 158 to 135 in 5 years. In vitro radioassays have been declining continuously since 1992, with the number of studies of 9.0 million in 2012. Single-photon examinations showed a continuous tendency toward a decline in the survey. In contrast, the number of hybrid SPECT/CT scanner examinations has increased. PET/CT study in the oncology field and radionuclide targeted therapy have steadily increased.


Dosimetric Implications of Computerised Tomography-Only versus Magnetic Resonance-Fusion Contouring in Stereotactic Body Radiotherapy for Prostate Cancer.
Background: Magnetic resonance (MR)-fusion contouring is the standard of care in prostate stereotactic body radiotherapy (SBRT) for target volume localisation. However, the planning computerised tomography (CT) scan continues to be used for dose calculation and treatment planning and verification. Discrepancies between the planning MR and CT scans may negate the benefits of MR-fusion contouring and it adds a significant resource burden. We aimed to determine whether CT-only contouring resulted in a dosimetric detriment compared with MR-fusion contouring in prostate SBRT planning. Methods: We retrospectively compared target volumes and SBRT plans for 20 patients treated clinically with MR-fusion contouring (standard of care) with those produced by re-contouring using CT data only. Dose was 36.25 Gy in 5 fractions. CT-only contouring was done on two occasions blind to MR data and reviewed by a separate observer. Primary outcome was the difference in rectal volume receiving 36 Gy or above. Results: Absolute target volumes were similar: 63.5 cc (SD ± 27.9) versus 63.2 (SD ± 26.5), Dice coefficient 0.86 (SD ± 0.04). Mean difference in apex superior-inferior position was 1.1 (SD ± 3.5; CI: −0.4–2.6). Small dosimetric differences in favour of CT-only contours were seen, with the mean rectal V36 Gy 0.3 cc (95% CI: 0.1–0.5) lower for CT-only contouring. Conclusions: Prostate SBRT can be successfully planned without MR-fusion contouring. Consideration can be given to omitting MR-fusion from the prostate SBRT workflow, provided reference to diagnostic MR imaging is available. Development of MR-only work flow is a key research priority to gain access to the anatomical fidelity of MR imaging.


Does the Order of Submaximal Lactate Threshold and Maximal Oxygen Uptake Testing Influence Test Outcomes?
The aim of this study was to investigate if the order of submaximal lactate threshold and maximal oxygen uptake testing would influence test outcomes. Twelve well-trained male cross-country skiers (mean age 19.6 years) performed two test sessions within a week in a within-subjects repeated measures with cross-over design study. A maximal oxygen uptake test (VO2max) followed by a lactate threshold (LT) test and vice versa, were performed. The test data included VO2, blood lactate (La-b), heart rate (HR), performance speed, Borg scale (RPE) at all stages and lactate accumulation throughout the whole test protocol including the breaks. No significant effect of testing order was found for: VO2max (74.23 vs. 73.91 mL∙min-1∙kg-1), maximal HR (190.7 vs. 189.9 bpm) and speed at LT during uphill running. Three out of four common definitions of LT resulted in the same La-b at the last two steps, 11 and 12 km/h respectively, in the two protocols. It is worth noting that VO2, HR and La-b were higher in the first two stages of the LT test when VO2max was tested first in the protocol. Well-trained cross-country skiers conclusively attained a similar VO2max and LT in both protocols, and the two tests did not seem to influence each other in terms of the degree of exhaustion that occurs in a single VO2max or an incremental LT test. However, when using a curvilinear function to define the LT, it is important to know that the VO2max test can influence levels of VO2, HR and La-b at the first two stages of the LT test.


New Practical Approaches to Chemotherapy-Induced Neuropathic Pain: Prevention, Assessment, and Treatment.
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most disabling and demoralizing problems that arise for cancer survivors. When investigating symptoms of numbness, tingling, or pain in the extremities, it is critical to determine whether the problem is neuropathic, somatic, or mixed. If the diagnosis is CIPN, it is important to weigh the potential benefits and harms of possible treatment options, and to devise an evidence-based multimodality treatment program. Such programs may include mixtures of opioid and nonopioid adjunctive medications, based on evidence from CIPN trials, and also extrapolation from trials in patients with other neuropathic pain syndromes-although such extrapolating must be done with caution, since other syndromes sometimes respond to agents that CIPN does not respond to. Other components of a successful program might include exercise; and possibly neuromodulation via acupuncture, spinal cord electrical stimulation, or neurocutaneous stimulation. There is good randomized trial evidence that most of the anticonvulsants and tricyclic antidepressants typically prescribed for neuropathic pain have little or no effect on CIPN, but there is some evidence of efficacy for duloxetine-however, clinical practice with regard to pharmacologic treatment of CIPN often does not reflect these data. We review here the recommendations of the American Society of Clinical Oncology, as well as some new and promising approaches to neuropathy, including new neuromodulation techniques.


Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation.
Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using an intrapulmonary tracheal transplant model of OB with the conditional Syk-knockout Syk(flox/flox) //rosa26-CreER(T2) mice and a Syk-selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk-knockout (Syk(del/del) ) mice or wild-type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Syk(del/del) and GSK2230413-treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk-expressing (Syk(flox/flox) ) and placebo control-treated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Syk(del/del) and GSK2230413-treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation.


Suppression of epithelial signal transducer and activator of transcription 1 activation by extracts of Aspergillus fumigatus.
Aspergillus fumigatus (AF) is often pathogenic in immune-deficient individuals and can cause life-threatening infections such as invasive aspergillosis. The pulmonary epithelial response to AF infection and the signaling pathways associated with it have not been completely studied. BEAS-2B cells or primary human bronchial epithelial cells were exposed to extracts of AF and challenged with IFN-β or the Toll-like receptor 3 agonist double-stranded RNA (dsRNA). Cytokine release (B-cell activating factor of the TNF family [BAFF], IFN-γ-induced protein-10 [IP-10], etc.) was assessed. AF extract was separated into low-molecular-weight (LMW) and high-molecular-weight (HMW) fractions using ultra 4 centrifugal force filters to characterize the activity. Real-time PCR was performed with a TaqMan method, and protein estimation was performed using ELISA techniques. Western blot was performed to assess phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-β and dsRNA induced messenger RNA (mRNA) expression of BAFF (350- and 452-fold, respectively [n = 3]) and IP-10 (1,081- and 3,044-fold, respectively [n = 3]) in BEAS-2B cells. When cells were pretreated with AF extract for 1 hour and then stimulated with IFN-β or dsRNA for 6 hours, induction of BAFF and IP-10 mRNA was strongly suppressed relative to levels produced by IFN-β and dsRNA alone. When compared with control, soluble BAFF and IP-10 protein levels were maximally suppressed in dsRNA-stimulated wells treated with 1:320 wt/vol AF extract (P < 0.005). Upon molecular size fractionation, a LMW fraction of AF extract had no measurable suppressive effect on IP-10 mRNA expression. However, a HMW fraction of the AF extract significantly suppressed IP-10 expression in BEAS-2B cells that were stimulated with dsRNA or IFN-β. When BEAS-2B cells were pretreated with AF extract and then stimulated with IFN-β, reduced levels of pSTAT1 were observed, with maximum suppression at 4 and 6 hours. Our results show that AF extracts suppressed expression of inflammatory cytokines in association with inhibition of the IFN-β signaling pathway and suppression of the formation of pSTAT1.