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The new inhibitors of the signaling pathway of androgens changed the treatment paradigm of metastatic castration-resistant prostate cancer (MCRPC). To analyse the effectiveness and safety of enzalutamide (ENZ) in the treatment of males with MCRPC. Retrospective analysis of all patients with MCRPC treated with ENZ since its introduction, in February/2015, in Hospital Centre of Cova da Beira, to April/2016. The adverse effects were classified according to the Common Terminology Criteria for Adverse Events v4.03. A total of 11 patients were treated during the studied period. Four patients had MCRPC progressing after abiraterone acetate plus prednisolone. The mean age of patients at the beginning of treatment with ENZ was 74 (64-74) years. The mean follow-up with ENZ was 6.7 (2-15) months, with a compliance rate to this drug of 98.9%. Of the patients who started treatment with ENZ, 2 died during treatment and 3 discontinued the treatment: 1 due to grade 2 adverse events and 2 due radiological and clinical/biochemical progression. The most significant reported side effects (grade 1 and 2), attributable to ENZ, were fatigue, weight loss and thrombocytopenia. The prostate-specific antigen (PSA) response rate (>50% decline in PSA level from baseline) was 54.5%. The mean overall survival was 11.4 months (CI95%: 8.1-14.6; median not reached). The median radiological and clinical/biochemical free-progression survival was 10 months (CI95%: 0.5-19.5). The treatment with ENZ has been effective in our study and with a high tolerability, according to the relatively low number of dropouts due to adverse effects and high compliance rate.

ObjectiveTo assess the association between histological chorioamnionitis without maternal clinical symptoms and neurodevelopmental disabilities at age 5 years in children born very preterm.Design French national prospective population-based cohort study, EPIPAGE-2 (Etude épidémiologique sur les petits âges gestationnels).SettingAll births from 22 to 34 weeks of gestational age in France in 2011 were eligible.PopulationInfants born alive between 24+0 and 31+6 weeks following preterm labour (PTL) or preterm premature rupture of membranes (PPROMs).ExposureHistological chorioamnionitis without maternal clinical symptoms, also called isolated histological chorioamnionitis, was defined as the presence of neutrophils in the chorionic plate, excluding clinical chorioamnionitis.Main outcome measuresNeurodevelopmental disabilities, a composite outcome including cerebral palsy, developmental coordination disorders, sensory impairment, developmental cognitive deficiencies or behavioural difficulties. These assessments were comprehensive, standardised and conducted by trained neuropsychologists and paediatricians at age 5 years.ResultsAmong 1296 children alive at 5 years of age, 486 (36.3%) were born in a context of isolated histological chorioamnionitis. Overall, 47% vs 33.6% of children exposed and not exposed to isolated histological chorioamnionitis had mild neurodevelopmental disabilities, and 13.8% vs 13.3% had moderate-to-severe neurodevelopmental disabilities. After multiple imputation and multivariable analysis, isolated histological chorioamnionitis was found not to be associated with the occurrence of mild or moderate-to-severe neurodevelopmental disabilities (adjusted OR: 1.0, 95% CI: 0.7 to 1.4 and 0.9, 0.6 to 1.2).ConclusionWe did not find any association between isolated histological chorioamnionitis and neurodevelopmental disabilities at age 5 years in children born very preterm after PTL or PPROM.

ObjectiveTo compare mortality and rates of significant neurosensory impairment (sNSI) at 18–36 months’ corrected age in infants born extremely preterm across three international cohorts.DesignRetrospective analysis of prospectively collected neonatal and follow-up data.SettingThree population-based observational cohort studies: the Australian and New Zealand Neonatal Network (ANZNN), the Canadian Neonatal and Follow-up Networks (CNN/CNFUN) and the French cohort Etude (Epidémiologique sur les Petits Ages Gestationnels: EPIPAGE-2).PatientsExtremely preterm neonates of <28 weeks’ gestation in year 2011.Main outcome measuresPrimary outcome was composite of mortality or sNSI defined by cerebral palsy with no independent walking, disabling hearing loss and bilateral blindness.ResultsOverall, 3055 infants (ANZNN n=960, CNN/CNFUN n=1019, EPIPAGE-2 n=1076) were included in the study. Primary composite outcome rates were 21.3%, 20.6% and 28.4%; mortality rates were 18.7%, 17.4% and 26.3%; and rates of sNSI among survivors were 4.3%, 5.3% and 3.3% for ANZNN, CNN/CNFUN and EPIPAGE-2, respectively. Adjusted for gestational age and multiple births, EPIPAGE-2 had higher odds of composite outcome compared with ANZNN (OR 1.71, 95% CI 1.38 to 2.13) and CNN/CNFUN (OR 1.72, 95% CI 1.39 to 2.12). EPIPAGE-2 did have a trend of lower odds of sNDI but far short of compensating for the significant increase in mortality odds. These differences may be related to variations in perinatal approach and practices (and not to differences in infants’ baseline characteristics).ConclusionsComposite outcome of mortality or sNSI for extremely preterm infants differed across high-income countries with similar baseline characteristics and access to healthcare.

BackgroundA potential complication of chemotherapy is vesicant cytotoxic extravasation, such as anthracyclines, which may affect the quality of life of patients. Therefore, fast acting and active treatment is essential.PurposeThe aim of this study was to develop an algorithm for management of anthracycline extravasation, which contains management measures, antidote and treatments that should be supplied.Material and methodsA literature review was performed, by research and analysis of guidelines and articles obtained from PubMed from January 2000 to September/2015, using the terms ‘cytotoxic extravasation’ and ‘extravasation treatment’.ResultsThe first action is to stop anthracycline infusion immediately, not remove the cannula, disconnect the infusion, and with a new syringe aspirate as much of the infusate as possible. The medical staff on service are then notified and the extravasated drug is identified. Thereafter, the extravasation area is marked and photographed and the cannula is removed. Ice packs, to promote local cooling of the extravasation site, should be applied to the affected area for 20 min with minimal pressure. Pharmacological measures involve intravenous infusion of dexrazoxane, for 1–2 h, into a large vein of an area other than the one affected by the extravasation. Cooling procedures should have been removed from the area at least 15 min before dexrazoxane administration in order to allow sufficient blood flow. Treatment should be given once daily for 3 consecutive days. The first infusion should be initiated as soon as possible, within the first 6 h after the accident. Treatment day 2 and day 3 should start at the same time (±3 h) as day 1. Analgesia should be provided if required. The follow-up and long term management is central. According to the clinical trials and case studies available, correct administration of dexrazoxane prevented skin necrosis and ulceration in up to 98% of patients.ConclusionThe development of algorithms for management of chemotherapy extravasation, which allow a quick and effective intervention, is essential. The developed algorithm is a valuable tool for all hospital services that prepare and administer anthracyclines, contributing to a quick and effective response to episodes of extravasation.References and/or AcknowledgementsInt J Clin Pract 2013;67:244–9No conflict of interest.

BackgroundBeing responsible for the management of the investigational medicinal products (IMPs), pharmacists should create a descriptive standard operational procedure (SOP) to ensure the management of IMPs. Pharmacists should also implement good practices that promote therapeutic compliance to minimise the occurrence of errors and enhance the information available to the patient.PurposeTo describe the activity of a clinical trial service in a hospital pharmacy since 2006.Material and methodsRecords of all clinical trials that took place in the hospital since 2006 were reviewed with evaluation of recently implemented methodologies.ResultsPharmacists created methodologies to keep accurate and up to date records to provide a full audit trail from reception until destruction of an IMP. They had written a clinical trial SOP and created four specific forms for each clinical trial: clinical trial summary; clinical trial diary; IMP stock control; and IMP accountability. To ensure the correct use and compliance of medication, four self-adhesive labels and leaflets with IMP information were developed. The growth of this service is evident in all pharmaceutical activities, with a maximum of IMP dispensing (150) and the number of ongoing patients (63) in August 2016. The maximum of IMP receipts (42) was dated to 2015, and there were 7 site selection visits which resulted in an increase in the number of initiation and monitoring visits. IMP dispensing is the activity that represents the largest number of pharmaceutical activities. The clinical trials were mainly phase III (78%), in haematology (30%) and cardiology (26%), with anticoagulant and antihypertensive drugs. In August 2016, the pharmacy took part in 11 clinical trials of 6 sponsors with 5 clinical services.ConclusionThe clinical trial service began in pharmacy in 2006 and methodologies were created over time to ensure a full audit trail of IMP management. Strategies were also implemented to ensure compliance with therapy, which has proved fundamental. This service has continuously grown, particularly since 2014 due to an increase in the number of clinical trials and the number of recruited patients which has brought challenges to our service that will continue to grow over time.No conflict of interest

The culture within which electricians operated in early Victorian England is discussed. These electricians' work constituted the norm for electrical science during this period.

Friction and wear reduction by diamond-like carbon (DLC) in automotive applications can be affected by zinc-dialkyldithiophosphate (ZDDP), which is widely used in engine oils. Our experiments show that DLC’s tribological behaviour in ZDDP-additivated oils can be optimised by tailoring its stiffness, surface nano-topography and hydrogen content. An optimal combination of ultralow friction and negligible wear is achieved using hydrogen-free tetrahedral amorphous carbon (ta-C) with moderate hardness. Softer coatings exhibit similarly low wear and thin ZDDP-derived patchy tribofilms but higher friction. Conversely, harder ta-Cs undergo severe wear and sub-surface sulphur contamination. Contact-mechanics and quantum-chemical simulations reveal that shear combined with the high local contact pressure caused by the contact stiffness and average surface slope of hard ta-Cs favour ZDDP fragmentation and sulphur release. In absence of hydrogen, this is followed by local surface cold welding and sub-surface mechanical mixing of sulphur resulting in a decrease of yield stress and wear. Wear reduction in diamond-like carbon interacting with ZDDP-additivated oils is essential for current automotive applications. Here, the authors present an atomic-scale study revealing that this can be achieved by tailoring diamond-like carbon’s stiffness, surface nano-topography, and hydrogen content.

Ocean alkalinity enhancement (OAE) is a method that can remove carbon dioxide (CO 2 ) from the atmosphere and counteract ocean acidification through the dissolution of alkaline minerals. Currently, critical knowledge gaps exist regarding the dissolution of different minerals suitable for OAE in natural seawater. Of particular importance is to understand how much alkaline mineral can be dissolved before secondary precipitation of calcium carbonate (CaCO 3 ) occurs, since secondary CaCO 3 precipitation reduces the atmospheric CO 2 uptake potential of OAE. Using two types of mineral proposed for OAE, quick lime (CaO) and hydrated lime (Ca(OH) 2 ), we show that both ( <63   µ m of diameter) dissolved in seawater within a few hours. No CaCO 3 precipitation occurred at a saturation state ( ΩA ) of ∼5 , but CaCO 3 precipitation in the form of aragonite occurred above an ΩA value of 7. This limit is lower than expected for typical pseudo-homogeneous precipitation, i.e. in the presence of colloids and organic matter. Secondary precipitation at low ΩA ( ∼  7) was the result of heterogeneous precipitation onto mineral surfaces, most likely onto the added CaO and Ca(OH) 2 particles. Most importantly, runaway CaCO 3 precipitation was observed, a condition where significantly more total alkalinity (TA) was removed than initially added. Such runaway precipitation could reduce the OAE CO 2 uptake efficiency from ∼  0.8 mol of CO 2 per mole of added TA down to 0.1 mol of CO 2 per mole of TA. Runaway precipitation appears to be avoidable by dilution below the critical ΩA threshold of 5, ideally within hours of the mineral additions to minimise initial CaCO 3 precipitation. Finally, OAE simulations suggest that for the same ΩA threshold, the amount of TA that can be added to seawater would be more than 3 times higher at 5  ∘ C than at 30  ∘ C. The maximum TA addition could also be increased by equilibrating the seawater to atmospheric CO 2 levels (i.e. to a p CO 2 of ∼  416  µ atm) during addition. This would allow for more TA to be added in seawater without inducing CaCO 3 precipitation, using OAE at its CO 2 removal potential.

Ocean Alkalinity Enhancement (OAE) is a carbon dioxide removal strategy that aims to chemically sequester atmospheric CO2 in the ocean while potentially alleviating localized effects of ocean acidification. Depending on the implementation approach, OAE can considerably alter seawater carbonate chemistry, resulting in temporarily reduced CO2 partial pressure (pCO2) and elevated pH before re-equilibration with the atmosphere or mixing with unperturbed waters. To investigate the effects of OAE on biogeochemical processes and organisms under close-to-natural conditions, a large-scale mesocosm experiment was conducted in a temperate fjord ecosystem near Bergen, Norway, during late spring. A non-CO2-equilibrated OAE approach was chosen, simulating OAE with calcium- and silicate-based minerals. A gradient of five OAE levels was achieved by increasing total alkalinity (TA) by 0–600 µmol kg−1. The added TA remained relatively stable over the 47 d experiment and measured CO2 gas exchange rates reached up to −15 mmol C m−2 d−1. We estimated that full equilibration (95 %) by air-sea gas exchange for a ΔTA of 600 µmol kg−1 would take ∼1050 d. Furthermore, various mineral-type and/or pCO2 / pH effects were found. Coccolithophore calcification followed an optimum curve response along the pCO2 gradient, consistent with findings from single-species laboratory cultures. In contrast, in-situ net community production (NCP) was higher in the silicate-based treatments, but was not modified by changes in pCO2. Zooplankton respiration, estimated from in-situ NCP and in-vitro NCP incubations, was lower for the silicate-based treatments and negatively correlated with pCO2. These complex findings suggest both direct and indirect effects of mineral type and OAE level and provide a valuable foundation for designing future OAE field trials. For a safe application of OAE, non-equilibrated alkalinity additions must balance efficiency and environmental impact.

Two-dimensional materials with high charge carrier mobility and tunable band gaps have attracted intense research effort for their potential use in nanoelectronics. Two-dimensional π-conjugated polymers constitute a promising subclass because the band structure can be manipulated by varying the molecular building blocks while preserving key features such as Dirac cones and high charge mobility. The major barriers to the application of two-dimensional π-conjugated polymers have been the small domain size and high defect density attained in the syntheses explored so far. Here, we demonstrate the fabrication of mesoscale ordered two-dimensional π-conjugated polymer kagome lattices with semiconducting properties, Dirac cone structures and flat bands on Au(111). This material has been obtained by combining a rigid azatriangulene precursor and a hot dosing approach, which favours molecular diffusion and eliminates voids in the network. These results open opportunities for the synthesis of two-dimensional π-conjugated polymer Dirac cone materials and their integration into devices. Optimized Ullmann coupling reaction of heterotriangulene precursors allows the synthesis of two-dimensional π-conjugated polymers with ordered domains larger than 100 × 100 nm 2 showing both Dirac cones and flat bands in their electronic structure.