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ObjectivesTo describe and quantify the dengue-related knowledge, attitudes and practices of residents in an urban shantytown in Lima, Peru.Design/settingA cross-sectional survey of adults between 18 and 80 years living in approximately 120 blocks in Oasis, an urban shantytown situated in the low-to-middle income district of Villa El Salvador in Southern Lima. The survey was adapted from an existing survey previously used in Iquitos, Peru, and included questions relating to knowledge of dengue symptoms, transmission, prevention and current mosquito control practices.ParticipantsA total of 240 surveys were completed with 80% of respondents being female and approximately 50% of all respondents describing themselves as housewives.ResultsAlthough 97.9% of respondents had heard of dengue, only 6.2% of people knew someone who had experienced the disease. Approximately half (54.2%) of the respondents knew dengue was transmitted by mosquitoes and 51.7% were able to identify fever and one other correct symptom of dengue. Female sex was significantly associated with greater symptom knowledge (OR 2.22, 95% CI 1.08 to 4.72) and prevention knowledge (OR 2.12, 95% CI 1.06 to 4.21). Past or current higher education attendance was significantly associated with symptom knowledge (OR 2.56, 95% CI 1.25 to 5.44) and transmission knowledge (OR 3.46, 95% CI 1.69 to 7.57). Knowledge of dengue was not significantly associated with carrying out practices to control mosquitoes (OR 1.76, 95% CI 0.87 to 3.54).ConclusionsThis population demonstrated baseline dengue knowledge. However, this was incomplete and substantially less when compared with endemic areas. Given the sporadic nature of dengue transmission in Lima, it is not surprising that knowledge of the disease was not associated with carrying out practices to reduce mosquitoes. However, as dengue transmission in Lima is likely to increase, understanding how best to improve public knowledge of the disease and how to translate this into appropriate community action will be a key public health consideration.

Background:Follow-up cohorts (observational studies) were initiated consecutively or simultaneously to the development of randomised controlled trials (RCTs) in JIA patients(1,2). They help to identify many complications observed only in clinical practice related to off label use, coadministration of treatments, drug misuse, and occurrence of rare or unexpected event. In addition, observational studies include a higher number of patients with a longer duration of follow-up compared to randomised trials. Hence, they have a higher power to capture the occurrence of serious adverse events (SAE) in daily clinical practice3.Objectives:To estimate the incidence of serious adverse events (SAEs) including serious infections, malignancies, and death in patients with juvenile idiopathic arthritis (JIA) treated with biological agents (BAs) in daily clinical practice, using meta-analysis techniques.Methods:We systematically searched, up to May 2019, Medline and Embase databases for observational studies performed in JIA disease under BAs treatment. Outcomes were SAEs, serious infections, malignancies and all-cause mortality. Complementary, the incidence of SAEs in randomised controlled trials (RCTs) with withdrawal and parallel designs was performed by meta-analysis.Results:A total of 31 observational studies were included (6811 patients totalizing 17530 patients-years [PY] of follow-up). The incidence rate of SAEs was similar in observational cohorts and withdrawal RCTs (4.46 events per 100 PY, 95% CI 2.85- 6.38, I2= 95%) and 3.71 events per 100 PY (95%CI 0.0-13.34), I2= 56%, respectively). The incidence of SAE was lower in parallel RCT. The incidence rate of serious infections, malignancies and death in observational cohorts was estimated at 0.74 events per 100 PY (95%CI 0.32-1.30, I2=83%), 0.10 events per 100 PY (95% CI 0.06-0.16, I2=0%) and 0.09 events per 100 PY (95% CI 0.05-0.14, I2=0%), respectively. Infections were the known cause of death in 8 of the 14 deaths. In meta-regression and subgroup analysis, variation of serious infections rates were partially explained by follow-up time (R2= 30.3%, p= 0.0008), JIA categories (all JIA versus polyarticular versus systemic JIA categories, p= 0.001) and cohort quality (Newcastle-Ottawa score ≥ to 6 versus ≤ to 5 stars, p= 0.0025).Conclusion:Our results suggest that the incidence rate of SAEs related to BAs in JIA disease is similar to those observed in randomised withdrawal trials. The overall incidence remained low. However, unsatisfactory description of SAEs prevents analysis of hospitalisation causes. Infection and, to a lesser extent, cancer and death, explain only part of burden of BAs.References:[1]Berard RA, Laxer RM. Learning the hard way: clinical trials in juvenile idiopathic arthritis. Ann Rheum Dis. 2018;77(1):1–2.[2]Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva Е, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. 2018 27;20(1):285.[3]Monti S, Grosso V, Todoerti M, Caporali R. Randomized controlled trials and real-world data: differences and similarities to untangle literature data. Rheumatol Oxf Engl. 2018 01;57(57 Suppl 7):vii54–Disclosure of Interests:None declared

We report the detection of two exoplanets and a further tentative candidate around the M-dwarf stars Gl96 and Gl617A, based on radial velocity measurements obtained with the SOPHIE spectrograph at the Observatoire de Haute-Provence. Both stars were observed in the context of the SOPHIE exoplanet consortium's dedicated M-dwarf subprogramme, which aims to detect exoplanets around nearby M-dwarf stars through a systematic survey. For Gl96, we present the discovery of a new exoplanet at 73.9 d with a minimum mass of 19.66 earth masses. Gl96 b has an eccentricity of 0.44, placing it among the most eccentric planets orbiting M stars. For Gl617A we independently confirm a recently reported exoplanet at 86.7 d with a minimum mass of 31.29 earth masses. Both Gl96 b and Gl617A b are potentially within the habitable zone, though Gl96 b's high eccentricity may take it too close to the star at periapsis., 22 pages, 23 figures

Background Survival of biological therapies (BT) may be considered as an indicator of efficacy and safety of the drug. BT survival have been studied mainly in adult’s patients, whereas only few studies have been focused on paediatric population to date. Objectives To analyse and compare BT survival in adults and juvenile onset arthritis patients from BIOBADAGUAY registry. Methods Patients with a chronic inflammatory arthritis enrolled in the Paraguayan-Uruguayan biological register (BIOBADAGUAY) between2015 and 2017 where included. For this study, patients were divided in two groups: 1. Adults with anychronic inflammatory arthritis and 2. Patients with juvenile idiopathic arthritis (JIA). To compare the groups according to BT, only the first biotherapy was considered. Survival analysis was performed using Kaplan-Meier estimators and proportional hazard regression model. First we analysed global BT survival in both groups; secondly we compare BT survival between groups. Results From 778 BTs(etanercept n=184, adalimumab n=440, rituximab n=44, infliximab n=27, tocilizumab n=75, and others n=8), 556 where identify as first line BTs. Of these, only adalimumab and etanercept were included in the study due to sufficient number prescriptions in both groups for the analysis. We found a mean survival times for adults of 289 (±20.7 SD) weeks for etanercept and 287 (±8.6 SD) weeks for adalimumab. In JIA patients the mean survival were 243 (±26.0 SD) and 216 (±24.0 SD) weeks for etanercept and adalimumab respectively When comparing survival between groups, we found that JIA presented more discontinuation of BT when compare with adult patients (p=4.4 × 10–4, HR=0.51 [95%CI, 0.35–0.73]). Similar results were observed when analysing only etanercept (p=3.92 × 10–2; HR=0.50 [95% CI, 0.26–0.97]) or adalimumab (p=1.20 × 10–3; HR=0.48 [95% CI, 0.30–0.75])treatments. Then we analysed withdrawn motive in JIA patients, and found that remission was the principal reason of discontinuation in this group of patients. Finally, we stratified survival analysis by discontinuation according to adverse events, and found that JIA group presented a lower risk of discontinuation due to adverse events than adults (p=1.96 × 10–1; HR=2.18 [95% CI, 0.67–7.07]). Conclusions In our study we have analysed mean BT survival between adults and JIA at the BIOBADAGUAY registry. When we compared both groups of patients it was observed that JIA patients presented more BT discontinuation but due to remission. Disclosure of Interest None declared

Background The biological agents (BAs) have revolutionized the care and have improved the prognosis of juvenile idiopathic arthritis (JIA). Effectiveness and short-term tolerance was well established in randomized clinical trials (RCTs), initially in JIA. However, there is an insufficient evidence for the long-term tolerance 1 . The serious adverse events (SAEs) include infections, malignancies and drug induced auto-immune diseases (e.g. uveitis). Objectives To assess the benefit/risk balance of BAs assessed by RCTs vs placebo or vs standard treatment in JIA, using meta-analysis (MA) technique. Methods All RCTs in JIA comparing BAs to placebo or standard treatment (e.g. methotrexate) published between 1950 and February 2016 were eligible. Data source: Cochrane, Medline, ClinicalTrial.gov register. The ILAR classification for JIA 2 was used and the clinical efficacy of treatment was measured by the ACR pediatric score 3 . Efficacy was analyzed considering the design of study. Effectiveness (ACRpedi30) was estimated as the measure of the benefit of the BAs and SAEs as a measure of risk by random effect models. The benefit/risk balance was analyzed using the net efficacy adjusted for risk (NEAR) 4 . An OR >1 indicates that the treatment has a beneficial effect and OR Results We included 20 RCTs conducted in JIA encompassing 1533 children. The disease duration, at the inclusion of RCTs, varies between 2 and 6 years for most studies. The maintenance of the therapeutic effect was estimated in the studies using withdrawal design in 6 studies. The maintenance of clinical response showed a large heterogeneity. Sub-groups analyses showed that the heterogeneity is marked in the systemic JIA 5 . The global NEAR OR was in favor of BAs in parallel (OR 3.83, CI 1.49–9.82) and withdrawal (OR 2.75, CI 1.51–5.01) trials. The efficacy of BAs in JIA was superior to the placebo in parallel (OR 5.46, CI 2.26–13.21) and withdrawal (OR 3.52, CI 2.15–5.77) trials. In RCTs (parallel and withdrawal design), SAEs did not differ between BAs and control (OR 1.18, CI 0.73–1.9). No death occurred at follow-up. Conclusions This is the first MA assessing all BAs used in all JIA categories combined. This MA in patients with JIA shows that the benefit/risk ratio of BAs in JIA is favorable. References Klotsche, J. et al. Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA). Ann. Rheum. Dis. 75, 855–861 (2016). Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 31, 390–392 (2004). Consolaro, A. et al. Optimisation of disease assessments in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 32, S-126–130 (2014). Boada, J. N. et al. Net efficacy adjusted for risk (NEAR): a simple procedure for measuring risk:benefit balance. PloS One 3, e3580 (2008). Tarp, S. et al. Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials. Rheumatol. Oxf. Engl. 55, 669–679 (2016). Disclosure of Interest None declared

Lycopodium clavatum or locally known as “lumot” is one of the many plants used in the traditional system of medicine here in the Philippines. It has been known that this plant was used for body pains and “facial wipes” recognizing its anti-aging potential by the Obo community in Lake Sebu, South Cotabato. However, there is a lack of sufficient data on its phytochemical components and medicinal properties. Thus, this study is conducted to determine the secondary metabolites present and its antioxidant property of the decoction and ethanolic extracts of Lycopodium clavatum Linn. Free radical scavenging activity of Lycopodium clavatum Linn. was determined by in vitro 2, 2-diphenyl-1-picrylhydrazyl (DPPH) method. Antioxidant activities were observed which may be due to the presence of alkaloids, steroids, and flavonoids in both decoction and ethanolic extracts.

Transformers are very expensive apparatuses and are vital to make the whole power system run normally. The failures in such apparatuses could leave them out of service, causing severe economic losses. The life of a transformer can be effectively determined by the life of the insulating paper. In the present work, we show an alternative diagnostic technique to determine the ageing condition of transformer paper by the use of FTIR spectroscopy and an empirical model. This method has the advantage of using a microsample that could be extracted from the transformer on-site. The proposed technique offers an approximation quantitative evaluation of the degree of polymerization of dielectric papers and could be used for transformer diagnosis and remaining life estimation.

SummaryThe diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/ genotypic association was estimated in 96.5 % of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

To investigate motor cortical map patterns in children with diplegic and hemiplegic cerebral palsy (CP), and the relationships between motor cortical geometry and motor function in CP.Transcranial magnetic stimulation (TMS) was used to map motor cortical representations of the first dorsal interosseus (FDI) and tibialis anterior (TA) muscles in 13 children with CP (age 9-16 years, 6 males.) The Gross Motor Function Measure (GMFM) and Melbourne upper extremity function were used to quantify motor ability.In the hemiplegic participants (N = 7), the affected (right) FDI cortical representation was mapped on the ipsilateral (N = 4), contralateral (N = 2), or bilateral (N = 1) cortex. Participants with diplegia (N = 6) showed either bilateral (N = 2) or contralateral (N = 4) cortical hand maps. The FDI and TA motor map center-of-gravity mediolateral location ranged from 2-8 cm and 3-6 cm from the midline, respectively. Among diplegics, more lateral FDI representation locations were associated with lower Melbourne scores, i.e. worse hand motor function (Spearman's rho = -0.841, p = 0.036).Abnormalities in TMS-derived motor maps cut across the clinical classifications of hemiplegic and diplegic CP. The lateralization of the upper and lower extremity motor representation demonstrates reorganization after insults to the affected hemispheres of both diplegic and hemiplegic children.The current study is a step towards defining the relationship between changes in motor maps and functional impairments in CP. These results suggest the need for further work to develop improved classification schemes that integrate clinical, radiologic, and neurophysiologic measures in CP.

The MHC class I chain-related protein A (MICA) is an inducible molecule almost not expressed by normal cells but strongly up-regulated in tumor cells. MICA-expressing cells are recognized by natural killer (NK) cells, CD8+ aßTCR and ?dTCR T lymphocytes through the NKG2D receptor. Engagement of NKG2D by MICA triggers IFN-? secretion and cytotoxicity against malignant cells. Although most solid tumors express MICA and this molecule is a target during immune surveillance against tumors, it has been observed that high grade tumors from different histotypes express low amounts of cell surface MICA due to a metalloprotease- induced shedding. Also, melanomas develop after a complex process of neotransformation of normal melanocytes. However, the expression of MICA in premalignant stages (primary human quiescent melanocytic nevi) remains unknown. Here, we assessed expression of MICA by flow cytometry using cell suspensions from 15 primary nevi isolated from 11 patients. When collected material was abundant, cell lysates were prepared and MICA expression was also analyzed by Western blot. We observed that MICA was undetectable in the 15 primary nevi (intradermic, junction, mixed, lentigo and congenital samples) as well as in normal skin, benign lesions (seborrheic keratosis), premalignant lesions (actinic keratosis) and benign basocellular cancer. Conversely, a primary recently diagnosed melanoma showed intense cell surface MICA. We conclude that the onset of MICA expression is a tightly regulated process that occurs after melanocytes trespass the stage of malignant transformation. Thus, analysis of MICA expression in tissue sections of skin samples may constitute a useful marker to differentiate between benign and malignant nevi.MHC class I chain-related protein A (MICA) es una molécula casi ausente en células normales pero sobre-expresada por células tumorales, que promueve el reconocimiento por células citotóxicas naturales (natural killer o NK) y por linfocitos T CD8+ aß y ?d a través del receptor NKG2D, lo que dispara la secreción de IFN-? y la citotoxicidad contra las células malignas. Aunque la mayoría de los tumores sólidos expresan MICA y esta molécula constituye un blanco durante la inmunovigilancia contra tumores, tumores de alto grado expresan bajos niveles de MICA en superficie celular debido al clivaje inducido por metaloproteasas. Asimismo, los melanomas se desarrollan luego de la neotransformación maligna de melanocitos. Sin embargo, se desconoce la expresión de MICA en estadios premalignos (nevos melanocíticos). En este trabajo analizamos la expresión de MICA en 19 nevos primarios de 11 pacientes mediante citometría de flujo. Cuando el material fue suficiente, también analizamos la expresión de MICA por Western blot. En ninguno de los 15 nevos primarios (intradérmicos, junction, mixtos, lentigo y congénitos) ni en muestras de piel normal, lesiones benignas (queratosis seborreica), premalignas (queratosis actínica) y cáncer benigno basocelular, detectamos expresión de MICA. Contrariamente, un melanoma primario de diagnóstico reciente mostró intensa expresión de MICA en superficie celular. Nuestros resultados indican que el inicio de la expresión de MICA ocurre una vez que la célula ha traspasado el estadio de transformación maligna, por lo que el análisis de su expresión en secciones de piel podría constituir un marcador útil para diferenciar nevos benignos de melanomas malignos.

Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine(®) , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL(-1) per IU kg(-1) at baseline and 1.23 ± 0.34 IU dL(-1) per IU kg(-1) 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine(®) were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine(®) showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.

The correct diagnosis and classification of von Willebrand disease (VWD) is difficult because of the variability of its clinical expression and limitations of laboratory methods. However, correctly diagnosing VWD is important for therapy and genetic counselling. A survey related to the referred VWD patients in Spain revealed local diagnostic problems in at least one third of the cases of VWD. Consequently, a Spanish multicenter study was carried out in which a cohort of 556 patients from 330 families was analyzed centrally. VWD was confirmed in 480 patients. Next generation sequencing (NGS) of the whole coding von Willebrand factor gene ( VWF ) was carried out in all recruited patients, compared with the phenotype, and a final diagnosis was established. A total of 238 different VWF mutations were found: 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 467 were found to have a VWF mutation/s. A good phenotype/genotype association was estimated in 94.6% of the cases. One hundred and eighty patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred and sixteen patients presented with mutations that had previously been associated with an increased VWF clearance. Ristocetin induced platelet agglutination (RIPA) unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 74 patients. A local/central disagreement over diagnosis occurred in 42.3% of the whole cohort. The NGS study facilitated an appropriate classification in 60 of them. Based on these results, a proposal for a change in the VWD diagnostic paradigm, suggesting the inclusion of the analysis of VWF at the initial diagnostic process, has been made. An extension of this project to include 400 new VWD patients has begun. A diagnostic strategy has been developed, and a Spanish consensus guideline for optimal treatment of VWD was developed in Spain. Desmopressin (DDAVP) is the treatment of choice in responsive VWD patients. VWF concentrates (VWF/FVIII) are used in individuals unresponsive to DDAVP, when DDAVP is contraindicated, or in VWD types 2B and 3, and for long term management needs (e.g., post major surgery).

Background Intrathecal baclofen (ITB) is an effective treatment of spasticity in patients with cerebral palsy. However, several recent reports have raised concerns that the treatment may be associated with a rapid progression of scoliosis. The objective of this study was to further examine the effect of ITB treatment on the progression of scoliosis in patients with cerebral palsy. Methods Spastic cerebral palsy patients who were ITB candidates were followed radiographically. Baseline Cobb angles of the primary curve were measured during the period of ITB pump insertion and at the most recent follow-up visit. Each patient was matched with a control patient by the diagnosis of cerebral palsy, age, sex, topographic involvement, and initial Cobb angle. The mean rate of change in Cobb angle was compared between ITB and control patients using paired t test. A multiple linear regression model was used to examine the difference, controlling for age, sex, topographic involvement, and initial Cobb angle. Results Fifty ITB patients and 50 controls were included in the analysis. There was no statistically significant difference between the mean change in Cobb angle in ITB patients (6.6 degrees per year) compared with the matched control patients (5.0 degrees per year, P = 0.39). The results from the multiple regression analysis also failed to show a statistically significant difference (0.92 degrees per year difference between ITB patients and controls, P = 0.56). Conclusions The progression of scoliosis in cerebral palsy patients with ITB treatment is not significantly different from those without ITB treatment. The findings suggest that patients receiving ITB experience a natural progression of scoliosis similar to the natural history reported in the literature. Level of evidence Level III.

Hemophilia A is an X-linked recessive disorder caused by a lack or decrease of factor VIII activity. Its socio-economic impact is high given its high bleeding expression and treatment cost. Our aim was to establish the mutation of each patient to improve family management. A total of 116 unrelated families with severe and moderate hemophilia A were involved. Non-carriers of intron 22 and intron 1 rearrangements were included in F8 gene screening. Intron 1 and 22 inversion frequencies were 3% and 52.5% respectively. Putative mutations were identified in all the families; 38 were new. The cumulative inhibitor incidence was 22%. Approximately half the families carry non-recurrent mutations, which were unique in around one third. Harmful effects for mutations predicting null alleles are expected. Missense mutation consequences are not easily predictable, despite the help of some bio-informatics tools.

The incidence of inhibitors in haemophilia A is 21-33%. The development of inhibitors to factor VIII (FVIII) is one of the most serious complications in haemophilia therapy and is an important challenge in haemophilia care. The main short-term objective of the treatment of haemophilic patients with inhibitors is to control bleeding episodes, and the long-term one is to eradicate the inhibitor by means of immune tolerance induction (ITI). The choice of treatment for bleeding in inhibitor patients is dictated by the current inhibitor titre, the severity of the bleed and the previous anamnesic response to FVIII. In low responder inhibitor patients the best treatment is large doses of concentrates of FVIII to attain haemostatic levels of the factor infused. The same approach can also be considered in high responders who have a temporarily low inhibitor level and major haemorrhage. High responders patients with high inhibitors titre or with minor haemorrhage must be treated with bypassing agents, such as FEIBA (factor VIII inhibitor bypassing activity) or recombinant activated FVII (rVIIa); there is no agreement which of both agents should be chosen in the different clinical situations. Only in patients waiting to start ITI treatment the rFVIIa use is clearly recommended, in order to avoide an anamnesic responce. In case of failure with this agents, extracorporeal immunoadsortion may be considered. All haemophiliac children who develop an inhibitor should be considered for ITI. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda units/mL (BU ml(-1)) where possible. Starting the treatment when inhibitor titre is below 10 BU ml(-1) is the strongest predictor of success. However, there are many other points to clarify: recommended FVIII doses in the ITI; if the results can be affected by concomitant infections during ITI; if there are any differences using plasma derived or recombinant concentrates, even more if the plasma-derived concentrate contains large amounts von willebrand factor or not; age of starting the ITI and the delay in beginning it; if using immunosupresors can help in the treatment of patients with a bad prognosis; and when the treatment must be left in patients without a clear failure.

When a disease affects only a few individuals in each country (ultra-orphan disease), it can be very hard to establish the costs of illness (COI) and the cost-effectiveness (CE) of treatments (ultra-orphan drugs). Conventional methods for COI and CE of drugs for common conditions do not apply, and additional factors need to be considered. As expensive medications (biologicals) show promising results, it becomes crucial to have detailed information on as many patients as possible.

High-precision radial velocity surveys explore the population of low-mass exoplanets orbiting bright stars. This allows accurately deriving their orbital parameters such as their occurrence rate and the statistical distribution of their properties. Based on this, models of planetary formation and evolution can be constrained. The SOPHIE spectrograph has been continuously improved in past years, and thanks to an appropriate correction of systematic instrumental drift, it is now reaching 2 m/s precision in radial velocity measurements on all timescales. As part of a dedicated radial velocity survey devoted to search for low-mass planets around a sample of 190 bright solar-type stars in the northern hemisphere, we report the detection of a warm Neptune with a minimum mass of 16.1 +- 2.7 Mearth orbiting the solar analog HD164595 in 40 +- 0.24 days . We also revised the parameters of the multiplanetary system around HD190360. We discuss this new detection in the context of the upcoming space mission CHEOPS, which is devoted to a transit search of bright stars harboring known exoplanets., Comment: 11 pages, 9 figures

In this work, a flow analysis procedure for the determination of copper, chromium, iron and lead in lubricating oils using flame AAS as detection technique is described. The flow manifold was designed to implement the multicommutation approach and it comprised three 3-way solenoid valves controlled by a personal computer. The flow system presented allowed to process the oil samples to determine wear metals without any prior preparation. Aiming to assess accuracy the results were compared with those obtained by manual procedure using flame AAS. Applying the joint-confidence ellipse test, no significant difference at the 95% confidence level was observed. Other profitable features such as a sample throughput of 50 determinations per hour; relative standard deviations (n = 5) below 2% for Cu, and below 8% for Cr, Fe and Pb; and linear responses in the range 0–40 ppm (w/w) (Cu, Fe) and 0–15 ppm (w/w) (Cr, Pb) were also achieved.

La biopsia del ganglio centinela en el carcinoma de mama fue descrita por A. Giuliano en el ano 1994. En la actualidad, la mayor parte de los expertos en Patologia Mamaria reconocen que la biopsia del ganglio centinela permite la estadificacion axilar con un minimo porcentaje de falsos negativos, y practicamente sin morbilidad. A pesar de las cuestiones discutidas tanto en el seno de la Reunion Nacional de Consenso sobre Ganglio Centinela y Cancer de mama organizada por la Seccion de Patologia Mamaria de la Asociacion Espanola de Cirujanos en octubre de 2000 como en la organizada por la Sociedad Espanola de Oncologia Quirurgica (SEOQ, miembro de la FESEO) en este mismo periodo, no todos los investigadores estan de acuerdo en ciertos puntos controvertidos, tanto en cuanto a la tecnica como en relacion con las indicaciones. En este articulo se discuten ciertos temas controvertidos como: la necesidad de una curva de aprendizaje clasica antes de la incorporacion de la tecnica del ganglio centinela a la clinica rutinaria, metodos de localizacion del ganglio centinela, consideraciones tecnicas en la puncion del radiotrazador, procedimientos diagnosticos que optimizan el resultado de la biopsia del ganglio centinela, biopsia del ganglio centinela despues de neoadyuvancia, biopsia del ganglio centinela en la mastectomia profilactica, biopsia de la cadena mamaria interna, estudio intraoperatorio del ganglio centinela y micrometastasis del ganglio centinela.

The effect of using a compatibilizer, such as maleic anhydride grafted polyethylene (PEgMA), on the flame retardancy and mechanical (tensile) properties of HDPE nanocomposites with silane modified Mg(OH)2 was studied. The silane modification of Mg(OH)2 was confirmed by FTIR. Filler dispersion was characterized by scanning electron microscopy in transmission mode (STEM) and the effect of filler on mechanical properties was also evaluated. The flame retardant properties were evaluated by flammability tests (Underwriters Laboratory – UL-94) and cone calorimeter. The mechanism by which the use of PEgMA compatibilizer improves the flame retardancy of HDPE/Mg(OH)2 was studied. Through the simultaneous TGAIR analysis, it was found that when using PEgMA, the flame retardant properties of HDPE/Mg(OH)2 are modified, due to the generation of volatile compounds in the thermal decomposition.

Summary Switching between different therapeutic FVIII concentrate types has been postulated as a possible cause of inhibitor development in patient with haemophilia A. In this single-centre, retrospective study, the incidence, titre and duration of inhibitor development in multitransfused patients, defined as patients with more than 150 exposure days (ED), were analysed from January 1970 to December 2007 in relation to ED and the number of switches between different products. Inhibitor titre was assessed by Bethesda assay (before 1998) or Nijmegen assay (after 1998). Medical records of 167 patients were screened, of which 97 patients met the inclusion criteria. Fourteen products of plasmatic origin (different purities) and five recombinant (three generations) were used. Nine patients (9%) developed inhibitors, all transient, low-titre (1.41 ± 0.54 BU) after 323 ± 287 ED in average. Seventeen patients had no product switches of which four patients (23%) developed inhibitors (97 ED in average), whereas 13 patients (77%) did not (ED: 230). Fifty patients switched between plasmatic products only (median: 10 changes) of which five patients (10%) developed inhibitors (ED: 503), whereas 45 patients did not (ED: 932). Five patients switched between recombinant products only (seven changes) of which no patient developed inhibitors (748 ED). Twenty-five patients switched between plasmatic and recombinant products (13 changes) of which no patient developed inhibitors (ED: 1654). No statistically significant differences between patient groups were observed. Neither the number of different FVIII products administered nor the switching of products influenced the incidence of inhibitor in multitransfused patients.

Performance-induced pain in musicians can be a debilitating and career-threatening problem. However, solutions such as early intervention and prevention have been shown to be efficacious. In addition to clinical examinations, an objective measurement of pain while playing would be a valuable assessment tool in monitoring a performer’s pain complaint, as subjective observations are often difficult to obtain and interpret. Computerized infrared imaging (CII) is an objective and noninvasive test that records cutaneous temperature. A close interrelationship between pain fibers and cutaneous temperature exists. To examine the use of CII in evaluating musicians with performance-induced pain, the authors report a case study of a professional clarinetist seen with complaints of right-sided performance-induced pain. Infrared images obtained before, during, and after playing indicated changes in asymmetry that correlated with his pain complaints. This case report introduces CII as an effective objective assessment tool for evaluating musicians with performance-induced pain.

A new method for the determination of silicon in Portland cement, based on the generation of volatile species without sample pre-treatment, is proposed. The method reduces operational complexity and time without loss of precision and with similar accuracy as the current methods. It employs microwave-assisted (domestic microwave oven) digestion to produce volatile silicon fluorides by reaction of the sample with a fluorinated salt (CaF 2 ) in the presence of H 2 SO 4 (98% w/w), using a Teflon® (PFA) reactor. The volatile fluorides are flushed out by a dry nitrogen stream and collected in 0.3 mol l −1 NaOH solution where they dissolve. Silicon is determined in this solution by flame atomic absorption spectrometry (FAAS). The recoveries are between 98 and 102%, and the precision is better than 2.5% relative standard deviation (R.S.D).

This paper describes a Microsoft Word 97 macro designed for restriction endonuclease analysis. Selected DNA fragments in the active Word document can be analyzed through a dynamic dialog box that formats the enzyme restriction lists for further analysis. The results can be obtained in a new Word document with the name of the enzymes, number of cuts and positions. This macro has several advantages: the results can be printed in a format suitable for record keeping, no additional programs are required and it is simple to use.

Summary. Measuring von Willebrand factor (VWF)activity is essential for the diagnosis of von Willebranddisease (VWD). The VWF activity is usually assessedbased on measurement of the ristocetin cofactor (VWF:RCo). However, that test is technically challenging andhas high intra- and inter-assay variabilities. A newautomated chemiluminescent immunoassay VWFactivity has recently become commercially available(HemosIL AcuStar von Willebrand Factor RistocetinCofactor Activity). The main objective of this study wasto evaluate this new method and to compare it with theVWF:RCo assay as the reference method. We studied91 samples, 18 healthy volunteers samples and 73samples from patients (VWF:RCo level

In situanionic homo- and copolymerization of caprolactam (CL) and laurolactam (LL) with sodium montmorillonite clay (NaMMT) was carried out using two different initiators, sodium caprolactamate (CLNa) and caprolactam magnesium bromide (CLMgBr). Degree of conversion and final molecular weight were used to assess the advancement and efficiency of the polymerization reaction and X-ray diffraction and electron microscopy were used to evaluate the sodium montmorillonite clay intercalation/exfoliation. The use of CLNa as initiator produced a higher conversion degree and molecular weight than the use of CLMgBr. Through DSC, it was observed that CLNa and CLMgBr tended to produce random and block copolymer structures, respectively, and either random or block, this eventually has an effect on the clay dispersion within the polymer matrix. In all cases, increasing the LL content produced a decrease in the conversion degree and in the molecular weight of the resulting polymer.

Some 17 alpha-alkylated androgens used as anabolic agents, such as stanozolol (ST) and danazol (DA), have specific effects on the liver that are not exerted by testosterone. This gives rise to the possibility that a steroid-binding protein, other than the androgen receptor, could modulate the intracellular actions of these agents. Male rat liver microsomes contain a homogeneous population of [3H]dexamethasone ([3H]DEX)-binding sites which we have denominated low affinity glucocorticoid-binding sites (LAGS). Because glucocorticoids, progestagens, and the synthetic estrogen ethynyl estradiol compete with [3H]DEX for binding to the LAGS, we aimed to study the possible interactions between androgens and the LAGS. To investigate whether several androgens had the capability of interacting with the LAGS, we performed competition experiments. The LAGS had no affinity for testosterone or methyltrienolone (R1881). However, some 17 alpha-alkylated androgens (DA (IC50, 116 nM)STfluoxymesteronemestalinemethandriolmethandrostenolonemethyltestosterone) were able to compete with [3H]DEX binding to liver microsomes. ST and DA were potent inhibitors of [3H]DEX binding to liver microsomes. They decreased both the affinity and the number of [3H]DEX-binding sites, increased the dissociation rate of [3H]DEX from the LAGS, and provoked a time- and dose-dependent inactivation of the [3H]DEX-binding site. These results strongly suggest that ST and DA exert a negative allosteric modulation on [3H]DEX binding to the LAGS. The in vivo administration of ST (but not other androgens) to male rats provoked a time- and dose-dependent decrease in the LAGS level. Full recovery of the LAGS concentration required at least 8 h and was blocked by protein synthesis inhibitors. Such results suggest that ST irreversibly inactivates the [3H]DEX-binding site in vivo as it does in vitro. Taken together, these observations are indicative of an irreversible interaction between some 17 alpha-alkylated androgens and the LAGS both in vitro and in vivo and suggest that ST may be an important pharmacological tool that can be used in the elucidation of the molecular structure of the LAGS. These results also mean that the LAGS are a steroid-binding entity able to distinguish between natural androgens and 17 alpha-alkylated testosterone derivatives used as anabolic agents.

The purpose of this study is to report the short-term outcome of intrathecal baclofen therapy on the function of individuals with diplegic cerebral palsy (CP) and the health-related quality of life (HRQL) of their caregivers. Eight pediatric patients with spastic diplegia were treated with ITB following failed oral spasticity management and were followed for a minimum of 2 years. Physical and functional outcomes were assessed using Ashworth Scores (AS), Physician Rating Scale (PRS), and a subset of the Functional Independence Measure for children (WeeFIM). HRQL was assessed using SF-36, CES-D short form, Impact on Family Scale, Life Orientation Test, Rand Social Support Scale, and Social Desirability Scale. At final follow-up, AS was significantly reduced (all p ⩽ 0.03). The PRS scale showed statistically significant improvement in four out of six subscales: median gait pattern (p = 0.05), median hind foot strike (p = 0.03), median knee position (p = 0.03) and median hind foot gait (p = 0.05). The WeeFIM score improved significantly with a mean increase of 32% (p = 0.03). ITB therapy significantly reduced spasticity and improved the function of these eight children with diplegic CP. HRQL of the parents or the caregivers remained stable despite the surgical intervention and follow-up visits required for pump refills.

To assess the significance and the impact of focal FDG uptake in the colon in oncology patients without known colorectal carcinoma.A retrospective study was undertaken on 2,220 (18)F-FDG PET/CT studies carried out consecutively in the Nuclear Medicine Department in our hospital from 2 December 2008 to 31 May 2010. Inclusion criteria were patients with abnormal (18)F-FDG uptake in colorectal area that could not be explained (or not previously known) by their clinical histories. Patients previously diagnosed with colorectal carcinoma were excluded. A total of 86 patients (57 male, average age 63.4, range 46-85) were finally included. Colonoscopy with biopsy was established as a reference test. The impact of these findings on the diagnostic-therapeutic management in these patients was evaluated.A colonoscopy was performed in 54 of the 86 patients, this examination not having been done up-to-date in the remaining 32 patients. Biopsy was obtained in 43 lesions of the 54 patient in whom a colonoscopy was performed. Colon disease was detected in 49 of these 54 patients, obtaining 54 FDG incidental foci which corresponded to 10 previously unsuspected primary colorectal carcinoma, 3 metastases, 27 adenomatous polyps with different degrees of dysplasia and 14 inflammatory processes. In the remaining 5 patients, the colonoscopy was normal. PET/CT modified the diagnostic and treatment management in most of the patients (49/54, that is 91%).These results confirm the need to determine the cause of abnormal (18)F-FDG colorectal uptakes in the PET/CT studies by using colonoscopy and biopsy. This approach allows for the detection and early treatment of malignant and premalignant lesions.

Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine(®) , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL(-1) per IU kg(-1) at baseline and 1.23 ± 0.34 IU dL(-1) per IU kg(-1) 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine(®) were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine(®) showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.

Patients with spastic quadriplegia secondary to cerebral palsy manifest with severe spasticity and often with neuromuscular scoliosis. In order to optimize treatment and minimize morbidity in selected cases, the authors present a surgical option concurrently addressing these problems. This study reviews one case and describes the surgical technique in detail where intrathecal baclofen pump implantation and posterior spinal fusion are concomitantly performed to manage spasticity and scoliosis, respectively.

Optimal replacement treatment in haemophilia B patients requires a good understanding of the pharmacokinetics of factor IX (FIX). The aim of this study was to compare the pharmacokinetic profile of Factor IX Grifols, a highly purified human FIX concentrate with two specific pathogen inactivation/removal steps, to that of available FIX preparations. The study was an open, non-randomized trial including 25 male subjects older than 12 years of age with severe haemophilia B. Pharmacokinetic profile of the FIX preparation regularly used by the subjects was determined as control. Pharmacokinetic profile of Factor IX Grifols was determined twice, one 7-15 days after control assessment and second after a 6 months period had elapsed. Results showed that all products had peak plasma levels of FIX:C within 30 min. Mean recovery was 1.3 +/- 0.3 IU dL(-1) per IU kg(-1) for Factor IX Grifols and 1.0 +/- 0.3 IU dL(-1) per IU kg(-1) for control products (P < 0.001). The mean terminal half-life (t(1/2)) for Factor IX Grifols was 26.7 h and 26.8 h for control product. Pharmacokinetic parameters after 6 months of treatment with Factor IX Grifols did not statistically differ from the parameters obtained with the first infusion. There were no adverse events related to Factor IX Grifols for the duration of the study. In conclusion, Factor IX Grifols has adequated pharmacokinetic properties comparable to the control plasma-derived FIX and these parameters remain stable after 6 months of treatment. Factor IX Grifols can be an effective and safe plasma-derived FIX concentrate for replacement therapy in haemophilia B patients.