The biological carbon pump in CMIP6 models: 21st century trends and uncertainties.

The biological carbon pump (BCP) stores ∼1,700 Pg C from the atmosphere in the ocean interior, but the magnitude and direction of future changes in carbon sequestration by the BCP are uncertain. We quantify global trends in export production, sinking organic carbon fluxes, and sequestered carbon in the latest Coupled Model Intercomparison Project Phase 6 (CMIP6) future projections, finding a consistent 19 to 48 Pg C increase in carbon sequestration over the 21st century for the SSP3-7.0 scenario, equivalent to 5 to 17% of the total increase of carbon in the ocean by 2100. This is in contrast to a global decrease in export production of -0.15 to -1.44 Pg C y-1. However, there is significant uncertainty in the modeled future fluxes of organic carbon to the deep ocean associated with a range of different processes resolved across models. We demonstrate that organic carbon fluxes at 1,000 m are a good predictor of long-term carbon sequestration and suggest this is an important metric of the BCP that should be prioritized in future model studies.

Two emerging phenotypes of atypical inclusion body myositis: illustrative cases.

OBJECTIVES: Sporadic inclusion body myositis (IBM) is the most common acquired myopathy in those aged above 50. It is classically heralded by weakness in the long finger flexors and quadriceps. The aim of this article is to describe five atypical cases of IBM, outlining two potential emerging clinical subsets of the disease. METHODS: We reviewed relevant clinical documentation and pertinent investigations for five patients with IBM. RESULTS: The first phenotype we describe is young-onset IBM in two patients who had symptoms since their early thirties. The literature supports that IBM can rarely present in this age range or younger. We describe a second phenotype in three middle-aged women who developed early bilateral facial weakness at presentation in tandem with dysphagia and bulbar impairment followed by respiratory failure requiring non-invasive ventilation (NIV). Within this group, two patients were noted to have macroglossia, another possible rare feature of IBM. CONCLUSIONS: Despite the classical phenotype described within the literature IBM can present in a heterogenous fashion. It is important to recognise IBM in younger patients and investigate for specific associations. The described pattern of facial diplegia, severe dysphagia, bulbar dysfunction and respiratory failure in female IBM patients requires further characterisation. Patients with this clinical pattern may require more complex and supportive management. Macroglossia is a potentially under recognised feature of IBM. The presence of macroglossia in IBM warrants further study, as its presence may lead to unnecessary investigations and delay diagnosis.

Distinct binding of cetirizine enantiomers to human serum albumin and the human histamine receptor H1.

Cetirizine, a major metabolite of hydroxyzine, became a marketed second-generation H1 antihistamine that is orally active and has a rapid onset of action, long duration of effects and a very good safety record at recommended doses. The approved drug is a racemic mixture of (S)-cetirizine and (R)-cetirizine, the latter being the levorotary enantiomer that also exists in the market as a third-generation, non-sedating and highly selective antihistamine. Both enantiomers bind tightly to the human histamine H1 receptor (hH1R) and behave as inverse agonists but the affinity and residence time of (R)-cetirizine are greater than those of (S)-cetirizine. In blood plasma, cetirizine exists in the zwitterionic form and more than 90% of the circulating drug is bound to human serum albumin (HSA), which acts as an inactive reservoir. Independent X-ray crystallographic work has solved the structure of the hH1R:doxepin complex and has identified two drug-binding sites for cetirizine on equine serum albumin (ESA). Given this background, we decided to model a membrane-embedded hH1R in complex with either (R)- or (S)-cetirizine and also the complexes of both ESA and HSA with these two enantiomeric drugs to analyze possible differences in binding modes between enantiomers and also among targets. The ensuing molecular dynamics simulations in explicit solvent and additional computational chemistry calculations provided structural and energetic information about all of these complexes that is normally beyond current experimental possibilities. Overall, we found very good agreement between our binding energy estimates and extant biochemical and pharmacological evidence. A much higher degree of solvent exposure in the cetirizine-binding site(s) of HSA and ESA relative to the more occluded orthosteric binding site in hH1R is translated into larger positional fluctuations and considerably lower affinities for these two nonspecific targets. Whereas it is demonstrated that the two known pockets in ESA provide enough stability for cetirizine binding, only one such site does so in HSA due to a number of amino acid replacements. At the histamine-binding site in hH1R, the distinct interactions established between the phenyl and chlorophenyl moieties of the two enantiomers with the amino acids lining up the pocket and between their free carboxylates and Lys179 in the second extracellular loop account for the improved pharmacological profile of (R)-cetirizine.

Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma.

BACKGROUND: Promoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. OBJECTIVES: This is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival. MATERIALS AND METHODS: DNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method. RESULTS: In the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS. CONCLUSIONS: Aberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice.

Accuracy of magnetic resonance enterography in the preoperative assessment of patients with Crohn's disease of the small bowel.

AIM: To assess the accuracy of magnetic resonance enterography in predicting the extension, location and characteristics of the small bowel segments affected by Crohn's disease. METHOD: This is a prospective study including a consecutive series of 38 patients with Crohn's disease of the small bowel who underwent surgery at a specialized colorectal unit of a tertiary hospital. Preoperative magnetic resonance enterography was performed in all patients, following a homogeneous protocol, within the 3 months prior to surgery. A thorough exploration of the small bowel was performed during the surgical procedure; calibration spheres were used according to the discretion of the surgeon. The accuracy of magnetic resonance enterography in detecting areas affected by Crohn's disease in the small bowel was assessed. The findings of magnetic resonance enterography were compared with surgical and pathological findings. RESULTS: Thirty-eight patients with 81 lesions were included in the study. During surgery, 12 lesions (14.8%) that were not described on magnetic resonance enterography were found. Seven of these were detected exclusively by the use of calibration spheres, passing unnoticed at surgical exploration. Magnetic resonance enterography had 90% accuracy in detecting the location of the stenosis (75.0% sensitivity, 95.7% specificity). Magnetic resonance enterography did not precisely diagnose the presence of an inflammatory phlegmon (accuracy 46.2%), but it was more accurate in detecting abscesses or fistulas (accuracy 89.9% and 98.6%, respectively). CONCLUSION: Magnetic resonance enterography is a useful tool in the preoperative assessment of patients with Crohn's disease. However, a thorough intra-operative exploration of the entire small bowel is still necessary.

Imported malaria in children in Madrid, Spain, 2007-2013.

BACKGROUND: The majority of malaria cases diagnosed in Europe in the last few years have occurred in people living in non-endemic areas travelling back to their home country to visit friends and relatives (VFRs). Children account for 15-20% of imported malaria, with known higher risk of severe disease. MATERIAL AND METHODS: A retrospective multicentre study was conducted in 24 hospitals in Madrid (Spain) including patients under 16 years diagnosed with malaria (2007-2013). RESULTS: A total of 149 episodes in 147 children were reported. Plasmodium falciparum was the species most commonly isolated. Twenty-five patients developed severe malaria and there was one death related to malaria. VFR accounted for 45.8% of our children. Only 17 VFRs had received prophylaxis, and 4 of them taken appropriately. They presented more frequently with fever (98% vs. 69%), a longer time with fever (55 vs. 26%), delay in diagnosis of more than three days (62 vs. 37%), and more thrombocytopenia (65 vs. 33%) than non-VFRs, and with significant differences (p<0.05). CONCLUSIONS: VFRs represent a large proportion of imported malaria cases in our study. They seldom took adequate prophylaxis, and delayed the visit to the physician, increasing the length of fever and subsequent delaying in diagnosis. Appropriate preventive measures, such as education and pre-travel advices should be taken in this population.

Human challenge trials in vaccine development: Strasbourg, September 29 - October 1, 2014.

An international workshop to discuss the role of Human Challenge Trials (HCT) in vaccine development was held in Strasbourg, France from 29 September to 1 October 2015. In addition to scientific presentations, several panel discussions focused on key questions and proposed recommendations, including the acknowledgement that HCT have proven to be useful tools to explore vaccine targets, identify immune correlates of protection, and evaluate clinical efficacy, and when appropriate they should be continued and encouraged. In some cases, a HCT may be the only feasible way to move forward with development of an investigational product. HCT must be strongly scientifically justified, because the need for a given investigational objective must be always balanced against the risks a HCT may pose, understanding that an infectious organism will be given to the study participants. It should be noted that numerous HCT have been successfully performed, safely and ethically, to the benefit of vaccine development and public health. This workshop report highlights the scientific presentations, discussions by the panelists and attendees, and twenty recommendations that emerged as considerations for future development of international guidance on the role of HCT in vaccine development and licensure.

Bent-core liquid crystalline cyanostilbenes: fluorescence switching and thermochromism.

Fluorescent bent-core molecules, bearing one or two cyanostilbene units in the lateral structure and different positions of the cyano group (α- or ß-isomers), are described with the aim of modulating the molecular packing and fluorescence properties. These compounds give rise to a variety of crystal polymorphs and bent-core liquid crystalline phases (SmCP, Colr and B6), offering the unique chance to study the fluorescence properties of the cyanostilbene structure in different phases. Experimental and computational studies elucidate geometrical and electronic properties of these bent-core structures but especially the fluorescence properties (spectral positions, quantum yields and decay curves), in a detailed comparison between diluted solutions, in dichloromethane (DCM) or poly(methylmethacrylate) (PMMA), and condensed phases. Quantum yields as high as 70% have been obtained in some diluted solutions (PMMA) and condensed phases. Remarkably, the quantum yield values depend on the position of the cyano group, being higher for ß- than for the α-isomers due to the higher radiative rates and lower non-radiative rates of the former. The photophysical characterization in the condensed phase focuses on RT studies with solid samples and different processing, and show that, upon aggregation, interactions between the cyanostilbene groups result in changes of the emission spectra and dynamics compared to the diluted systems in DCM and PMMA, giving rise to H-aggregations of varying strength. Furthermore, the compounds exhibit thermochromism, showing a green-yellow fluorescence in the pristine crystalline phase that changes to blue on heating to the liquid crystal phase.

[HEALTH INCIDENT MANAGEMENT MATERIAL]. / Gestión de incidencias de material sanitario. COMISIÓN DE RECURSOS MATERIALES. HOSPITAL CLÍNIC (BARCELONA).

INTRODUCTION: The problems encountered with medical device increase patient morbidity, affect safety professionals and in crease health spending. The Material Resources Committee a the Hospital Clinic of Barcelona decided to understand the im plications associated with these products through a system o incident reporting from October2011 to June2013. METHODOLOGY: A descriptive retrospective study. No probabi listic statements consecutive occurrences sampling. Variable studied: type of material, type and time resolution and degre, of impact. For statistical analysis SPSS version 20 software wa used. RESULTS: 103 incident statements of 68 items, of which 83.8% were medical supplies and 16.2% for non-health were collected. The medical supplies impacted more frequently and severely in patients compared to non-health (p = 0.026). According to the family of the material, the incidents were related: 30.9%, to "infusión"; 17.6 %, to "cover material"; 13.2 %, to "cures" and 11.8 %, to "ventilation". Families of infusion and ventilation items got more serious problems in patients (p = 0.001). Incidences sanitary items were resolved in an average of 18.0 ± 28.0 days and non-health at an average of 8 4 ± 6.6 days (p = 0.03). CONCLUSIONS: The medical equipment is the one with most incidents, severely impacting on patient safety. These incidents ar resolved over a long period of time that could be imoroved.

[NURSING DIAGNOSES AND MIGRATION: PHENOMENOLOGICAL STUDY FROM THE IMMIGRANT'S POINT OF VIEW]. / Diagnósticos de enfermería y migración. ESTUDIO FENOMENOLÓGICO DESDE LA VISIÓN DE LOS INMIGRANTES.

OBJECTIVE: The objective of this research is to identify nursing diagnosis NANDA which is predominant within the immigrant community, linked to the migratory process and part of the framework of the Outcome Present State Test (OPT) of Pesut and Herman's critical awareness. METHODOLOGY: Keeping in mind the objectives of this research, this approaches the quality-based paradigm and follows the proposals of phenomenology research. The study was carried out using an individual semi-structured interview of 30 immigrants. A categorization of the data has been applied in accordance with the domains of NANDA for the identification of nursing diagnosis and its analysis has been carried with computer support with Atlas-ti 6.0. RESULTS: Twenty three diagnoses were identified in nine out of thirteen taxonomy NANDA domains. Analysis of their interrelationships according to the OPT model were carried out and a clinical reasoning net was created. The main diagnoses achieved in our study was: Readiness for Enhanced Coping. CONCLUSIONS: NANDA taxonomy doesn't include the migratory process in the characteristics and related factors of this nursing diagnosis. We consider that nursing taxonomy should be reassessed in order to describe more in depth the specific responses derived from the migratory experience so it can lead to a high quality health care.

Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study.

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.

Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. RESULTS: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. CONCLUSIONS: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease.

The aim of this study was to assess a 12-min self-paced walking test in patients with McArdle disease. Twenty patients (44.7 ± 11 years; 11 female) performed the walking test where walking speed, distance walked, heart rate (HR) and perceived muscle pain (Borg CR10 scale) were measured. Median (interquartile range) distance walked was 890 m (470-935). From 1 to 6 min, median walking speed decreased (from 75.0 to 71.4 m∙min(-1)) while muscle pain and %HR reserve increased (from 0.3 to 3.0 and 37% to 48%, respectively). From 7 to 12 min, walking speed increased to 74.2 m∙min(-1), muscle pain decreased to 1.6 and %HR reserve remained between 45% and 48%. To make relative comparisons, HR and muscle pain were divided by walking speed and expressed as ratios. These ratios rose significantly between 1 and 6 min (HR:walking speed P = .001 and pain:walking speed P < .001) and similarly decreased between 6 and 11 min (P = .002 and P = .001, respectively). Peak ratios of HR:walking speed and pain:walking speed were inversely correlated to distance walked: rs (HR) = -.82 (P < .0001) and rs (pain) = -.55 (P = .012). Largest peak ratios were found in patients who walked < 650 m. A 12-min walking test can be used to assess exercise capacity and detect the second wind in McArdle disease.

Supramolecular architectures from bent-core dendritic molecules.

Control of the self-assembly of small molecules to generate architectures with diverse shapes and dimensions is a challenging research field. We report unprecedented results on the ability of ionic, bent dendritic molecules to aggregate in water. A range of analytical techniques (TEM, SEM, SAED, and XRD) provide evidence of the formation of rods, spheres, fibers, helical ribbons, or tubules from achiral molecules. The compact packing of the bent-core structures, which promotes the bent-core mesophases, also occurs in the presence of a poor solvent to provide products ranging from single objects to supramolecular gels. The subtle balance of molecule/solvent interactions and appropriate molecular designs also allows the transfer of molecular conformational chirality to morphological chirality in the overall superstructure. Functional motifs and controlled morphologies can be combined, thereby opening up new prospects for the generation of nanostructured materials through a bottom-up strategy.

Facilitation of macrofaunal assemblages in marinas by the habitat-forming invader Amathia verticillata (Bryozoa: Gymnolaemata) across a spatiotemporal scale.

Widespread habitat-forming invaders inhabiting marinas, such as the spaghetti bryozoan Amathia verticillata, allow exploring facilitation processes across spatiotemporal contexts. Here we investigate the role of this bryozoan as habitat for native and exotic macrofaunal assemblages across different ecoregions of Western Mediterranean and East Atlantic coasts, and a monthly variation over a year. While only 7 (all peracarid crustaceans) of the 54 associated species were NIS, they dominated macrofaunal assemblages in terms of abundance, raising the potential for invasional meltdown. NIS richness and community structure differed among marinas but not among ecoregions, highlighting the importance of marina singularities in modulating facilitation at spatial scale. Despite facilitation did not depend on bryozoan abundance fluctuations, it was affected by its deciduous pattern, peaking in summer and disappearing in late winter. Monitoring A. verticillata in marinas, especially in summer periods, may improve the detection and management of multiple associated NIS.

Development of liver fibrosis during aging: effects of caloric restriction.

Liver is the central metabolic organ of the body and diet is considered one of the main environmental factors that can impact on aging liver. In the elderly stage liver function is relatively well conserved although there are a variety of not well defined morphological changes related to liver fibrosis which is commonly associated with an inflammatory state. The aim of this paper is to study these alterations during the physiological process of aging in Wistar rats and also test if caloric restriction (CR) could ameliorate them. As fibrosis is associated to hepatic stellate cell (HSC) function we also analyzed these cells during aging. Livers from five groups of male Wistar rats (3-, 8-, 24-months old ad libitum and 8- and 24-months caloric restricted rats) were used in this study. Histological analysis, expression of genes implicated in liver fibrosis and the status of inflammatory step-pathways as p38 mitogen-activated protein kinase (p38-MAPK), c-Jun N-terminal kinase (JNK) and the nuclear factor kappa B (NFkB) isoforms, p50 and p65, in cytosolic and nuclear fractions were performed. During elderly, associated with morphological change of HSC, there is a progressive increase in collagen deposition due to an inhibition in collagen degradation. Higher expression of cytokines and the activation of inflammatory pathways are associated with aging. CR ameliorates these circumstances being more effective when it started in middle age. In conclusion elderly stage is associated to a mild fibrotic and inflammatory state in the liver which could be ameliorated after CR.

Fractures of the limbs: basic concepts for the emergency department.

Traumatic injuries of the limbs are very common and account for a large number of imaging examinations, especially in emergency departments. These injuries can often be resolved if they are recognized and treated appropriately. Their diagnosis requires a complete clinical assessment and the correct interpretation of the appropriate imaging tests. Radiologists play an important role, especially in diagnosing lesions that can go undetected. To this end, radiologists need to know the normal anatomy and its variants, the mechanisms of injury, and the indications for different imaging tests, among which plain-film X-rays are the main technique for the initial evaluation. This article aims to review the relevant characteristics of limb fractures in adults and of lesions that can be associated with these fractures, as well as how to describe them to ensure appropriate clinical management.

Flight heights obtained from GPS versus altimeters influence estimates of collision risk with offshore wind turbines in Lesser Black-backed Gulls Larus fuscus.

The risk posed by offshore wind farms to seabirds through collisions with turbine blades is greatly influenced by species-specific flight behaviour. Bird-borne telemetry devices may provide improved measurement of aspects of bird behaviour, notably individual and behaviour specific flight heights. However, use of data from devices that use the GPS or barometric altimeters in the gathering of flight height data is nevertheless constrained by a current lack of understanding of the error and calibration of these methods. Uncertainty remains regarding the degree to which errors associated with these methods can affect recorded flight heights, which may in turn have a significant influence on estimates of collision risk produced by Collision Risk Models (CRMs), which incorporate flight height distribution as an input. Using GPS/barometric altimeter tagged Lesser Black-backed Gulls Larus fuscus from two breeding colonies in the UK, we examine comparative flight heights produced by these devices, and their associated errors. We present a novel method of calibrating barometric altimeters using behaviour characterised from GPS data and open-source modelled atmospheric pressure. We examine the magnitude of difference between offshore flight heights produced from GPS and altimeters, comparing these measurements across sampling schedules, colonies, and years. We found flight heights produced from altimeter data to be significantly, although not consistently, higher than those produced from GPS data. This relationship was sustained across differing sampling schedules of five minutes and of 10 s, and between study colonies. We found the magnitude of difference between GPS and altimeter derived flight heights to also vary between individuals, potentially related to the robustness of calibration factors used. Collision estimates for theoretical wind farms were consequently significantly higher when using flight height distributions generated from barometric altimeters. Improving confidence in telemetry-obtained flight height distributions, which may then be applied to CRMs, requires sources of errors in these measurements to be identified. Our study improves knowledge of the calibration processes for flight height measurements based on telemetry data, with the aim of increasing confidence in their use in future assessments of collision risk and reducing the uncertainty over predicted mortality associated with wind farms.