bluuebunny/crossref_metadata_2025 huggingface dataset:
Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center's 10‐year experience
Authors: Girardet A. , Ishmukhametova A. , Willems M. , Coubes C. , Hamamah S. , Anahory T. , Des Georges M. , Claustres M.
Published: April 2014

This study provides an overview of 10 years of experience of preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in our center. Owing to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR) mutations in south of France, we have set up a powerful universal test based on haplotyping eight short tandem repeats (STR) markers together with the major mutation p.Phe508del. Of 142 couples requesting PGD for CF, 76 have been so far enrolled in the genetic work‐up, and 53 had 114 PGD cycles performed. Twenty‐nine cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper‐ or hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or with a single CF‐causing mutation) were transferable. Twenty‐eight clinical pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in the group of seven couples with one member affected with CF, and 38.3% in the group of couples whose both members are carriers of a CF‐causing mutation [including six couples with congenital bilateral absence of the vas deferens (CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was recorded. Our test is applicable to 98% of couples at risk of transmitting CF.
Will your article be found? Authors choose a confusing variety of words to describe dental survival analyses
Authors: Layton Danielle M. , Clarke Michael
Published: April 2014

Objectives

Identify the words and phrases that authors used to describe time‐to‐event outcomes of dental treatments in patients.

Materials and methods

A systematic handsearch of 50 dental journals with the highest Citation Index for 2008 identified articles reporting dental treatment with time‐to‐event statistics (included “case” articles, n = 95), without time‐to‐event statistics (active “control” articles, n = 91), and all other articles (passive “control” articles n = 6796). The included and active controls were read, identifying 43 English words across the title, aim and abstract, indicating that outcomes were studied over time. Once identified, these words were sought within the 6796 passive controls. Words were divided into six groups. Differences in use of words were analyzed with Pearson's chi‐square across these six groups, and the three locations (title, aim, and abstract).

Results

In the abstracts, included articles used group 1 (statistical technique) and group 2 (statistical terms) more frequently than the active and passive controls (group 1: 35%, 2%, 0.37%, P < 0.001 and group 2: 31%, 1%, 0.06%, P < 0.001). The included and active controls used group 3 (quasi‐statistical) equally, but significantly more often than the passive controls (82%, 78%, 3.21%, P < 0.001). In the aims, use of target words was similar for included and active controls, but less frequent for groups 1–4 in the passive controls (P < 0.001). In the title, group 2 (statistical techniques) and groups 3–5 (outcomes) were similar for included and active controls, but groups 2 and 3 were less frequent in the passive controls (P < 0.001). Significantly more included articles used group 6 words (stating the study duration) (54%, 30%, P = 0.001).

Conclusion

All included articles used time‐to‐event analyses, but two‐thirds did not include words to highlight this in the abstract. There is great variation in the words authors used to describe dental time‐to‐event outcomes. Electronic identification of such articles would be inconsistent, with low sensitivity and specificity. Authors should improve the reporting quality. Journals should allow sufficient space in abstracts to summarize research, and not impose unrealistic word limits. Readers should be mindful of these problems when searching for relevant articles. Additional research is required in this field.
Effectiveness of the Healthy Skin Clinic – a randomized clinical trial of nurse‐led patient counselling in hand eczema
Authors: Mollerup Annette , Veien Niels K. , Johansen Jeanne D.
Published: April 2014

Background

Hand eczema is a common disease, and continuous preventive skin protection and skin care must be adopted to prevent a chronic course. Hand eczema is not a uniform disease, and counselling must therefore be individually tailored.

Objectives

To evaluate the effectiveness of a nurse‐led counselling programme, the Healthy Skin Clinic, emphasizing the patient's self‐management, resources, and risks.

Patients and methods

Patients (n = 306) referred for diagnostic work‐up and treatment of hand eczema were randomized and allocated either to the programme or to usual care. The primary outcome was clinical disease severity at follow‐up. Secondary outcomes were quality of life, burden of disease, skin protective behaviours, and self‐reported medication adherence.

Results

Patients in the intervention group had greater reductions in clinical severity and reported more beneficial behavioural changes at follow‐up than those in the usual‐care group. This was especially true of patients who were treated solely with topical corticosteroids and who had a primarily exogenous aetiology of hand eczema. However, the effect was very dependent on baseline disease severity. No differences in quality of life or burden of disease were found between the two groups.

Conclusion

A tailored nurse‐led programme of skin protection counselling may be recommended as an essential part of hand eczema treatment.
The effects of thoracic surgery operations on quality of life: a multicenter study
Authors: Öz Gürhan , Solak Okan , Metin Muzaffer , Esme Hıdır , Sayar Adnan
Published: April 2014

Objective

Some treatment modalities may cause losses in patients' life comfort because of the treatment process. Our aim is to determine the effects of thoracic surgery operations on patients' quality of life.

Materials and Methods

This is a multicenter and prospective study. A hundred patients, who had undergone posterolateral thoracotomy (PLT) and/or lateral thoracotomy (LT), were included in the study. A quality of life questionnaire (SF‐36) was used to determine the changes in life comfort. SF‐36 was performed before the operation, on the first month, third month, sixth month and twelfth month after the operation.

Results

Seventy‐two percent (n = 72) of the patients were male. PLT was performed in 66% (n = 66) of the patients, and LT was performed in 34% (n = 34) of the patients. The types of resections in patients were pneumonectomy in four patients, lobectomy in 59 patients and wedge resection in 11 patients. No resection was performed in 26 patients. Thoracotomy caused deteriorations in physical function (PF), physical role (RP), bodily pain (BP), health, vitality and social function scores. The deteriorations observed in the third month improved in the sixth and twelfth months. The PF, RP, BP and MH scores of the patients with lung resection were much more worsened compared with the patients who did not undergo lung resection.

Conclusion

Thoracic surgery operations caused substantial dissatisfaction in life comfort especially in the third month postoperatively. The worsening in physical function, physical role, pain and mental health is much more in patients with resection compared with the patients who did not undergo resection.
Pulmonary involvement in patients with Behçet's disease: report of 15 cases
Authors: Zhang Xiaolei , Dai Huaping , Ma Zhanhong , Yang Yuanhua , Liu Yan
Published: April 2014

Background and Objectives

Behçet's disease (BD) is a multisystem vasculitis, and pulmonary involvement in BD can have complex clinical manifestations. We aimed to analyze the clinical and radiological features, as well as the outcomes, of BD patients with pulmonary manifestation.

Method

We retrospectively reviewed the medical records of 106 patients with BD diagnosed in our institute between January 2000 and January 2013. Patients with pulmonary vascular or parenchymal abnormalities on chest radiography, thorax computed tomography, magnetic resonance imaging or pulmonary scintigraphy were included in this study.

Results

Fifteen patients (14%) were identified to have pulmonary involvement. Pulmonary artery aneurysms (PAA) was observed in six patients, and all of them had concomitant thrombi, attenuation or occlusion of PAs, and five of them also had radiographic parenchymal changes. Three patients had solely pulmonary artery thrombus (PAT) without PAA. For the six patients with isolated radiographic parenchyma changes, pulmonary infiltration resolved with immunosuppressant therapy in four subjects; the lesion remained unchanged in one subject with radiographic interstitial changes, and acid‐fast bacilli were found in the remaining subject. Patients with PAA or PAT had more frequency of hemoptysis and extra‐pulmonary vascular lesions compared with isolated parenchymal involvement. Radiographic parenchyma changes are nonspecific, with ill‐defined ground‐glass opacity being the most common pulmonary radiographic parenchymal changes. Patients with isolated parenchymal changes had better prognosis than those with PAA or PAT.

Conclusions

BD with pulmonary involvement can have a wide spectrum of abnormal clinical and radiographic manifestations, and multiple pulmonary lesions can exit in the same patient.
IL‐32 was involved in cigarette smoke‐induced pulmonary inflammation in COPD
Authors: Rong Yao , Xiang Xu‐dong , Li Ya‐min , Peng Zhen‐yu , Li Jin‐xiu
Published: April 2014

Purpose

Previous study has proven the overexpression of interleukin 32 (IL‐32) in lungs with chronic obstructive pulmonary disease (COPD). But the soluble IL‐32 levels and the role of IL‐32 in smokers and COPD are still unclear.

Methods

In this study, we enrolled 133 subjects who were divided into three groups: nonsmokers, control smokers and smokers with COPD. We detected the IL‐32 levels in serum and induced sputum of all subjects. The pulmonary function, PaO2 and smoking exposure index were also collected. Moreover, macrophages were isolated and stimulated by cigarette smoke extraction (CSE). A special siRNA was used to suppress the IL‐32 expression.

Results

There was no significant difference in IL‐32 serum levels among the three groups. The IL‐32 levels of induced sputum in COPD patients were markedly higher than control smokers and nonsmokers. The IL‐32 levels in induced sputum of COPD patients were negatively correlated with forced expiratory volume (FEV1)/forced vital capacity and FEV1%. Moreover, a low concentration CSE could stimulate IL‐32 expression and promote the release of several inflammatory factors (such as IL‐6 and tumor necrosis factor‐α). A special siRNA could significantly suppress the release of these inflammatory factors.

Conclusions

This study revealed the critical role of IL‐32 in pulmonary inflammation of COPD and smoker‐associated diseases.
GARDENIA JASMINOIDES: A Traditional Chinese Dye Plant Becomes A Garden Ornamental in Europe
Authors: Jarvis Charles E. , DuVal Ashley , Crane Peter R.
Published: April 2014

Gardenia jasminoides J. Ellis, a plant native to southern China, was introduced into Britain in the mid‐18th century in its sterile double‐flowered form. It quickly became a horticultural sensation because of its large white jasmine‐like flowers and scent. At first, understanding the taxonomic placement of the species was inhibited by the lack of fertile flowers, but eventually the species was understood to be very different from a true jasmine. Interest in this plant in the mid‐18th century was not confined to its use as an ornamental, but also focused on the potential use of its seeds as the source of a yellow‐scarlet dye.
775. ANEMONE PULSATILLA
Authors: Fay Michael F. , Barlow Sarah E.
Published: April 2014

Anemone pulsatilla, the pasque flower, is described and illustrated. Details of its distribution, relationships and studies on conservation requirements in England are presented. Cultivation and propagation are discussed.
780. TETRADIUM DANIELLII
Authors: Upson Tim
Published: April 2014

The genus Tetradium Lour. is discussed with special reference to taxa in cultivation and the most widely planted species, Tetradium daniellii, (commonly called Euodia daniellii (Benn.) Hemsl. or E. hupehensis Dode) which is the subject of this plate. Its variation, synonymy, history and cultivation are reviewed.
781. ALONSOA AURICULATA
Authors: Duncan Graham
Published: April 2014

The Peruvian and Bolivian perennial Alonsoa auriculata Diels has potential for temperate gardens, and in cold climates as a half hardy summer bedding plant and pot subject for the temperate conservatory and cool greenhouse. A description and details of its history, taxonomy and cultivation are provided, with general notes on the genus.
Trends in public opinion on alcohol issues during a period of increasing access to alcohol: Ontario, Canada, 1996–2011
Authors: Ialomiteanu Anca R. , Giesbrecht Norman , Adlaf Edward M. , Wettlaufer Ashley
Published: April 2014

Introduction and Aims

The aim of our paper is to present trend data concerning public opinion on alcohol policy in the Canadian province of Ontario over a 16‐year period (1996–2011), to assess if the level of support for alcohol control policies changed over this period and if any changes in public support for alcohol policy parallel real changes in alcohol distribution in Ontario.

Design and Methods

Selected policy‐related items from 10 probability surveys of Ontario adults were analysed by means of logistic regression.

Results

A significant decline was found for attitudes supporting restricting corner stores sales and government control of liquor stores. A weaker decline was seen for attitudes towards reducing the number of places to buy alcohol. However, an increasing trend for attitudes favouring the status quo or greater control through taxes and hours of sale was found. There was no significant trend for attitudes towards maintaining the current level or reducing the number of liquor or beer stores. While there was some variation in trends in support by demographic characteristics and drinking level, not one sector stood out.

Discussion and Conclusions

A gradual erosion of support is evident and concurrent with gradual increase in access to alcohol in Ontario during the time‐period under study. The decline in support for alcohol control measures seems to be a general rather than a focused development. It appears that this was largely due to a shift in a greater percentage supporting the status quo, not a move towards increasing access to alcohol.
Will a novel semi‐quantitative scale for classification of structural brain MRI improve patient care and research in children with cerebral palsy?
Authors: Izbudak Izlem , Poretti Andrea , Lequin Maarten
Published: April 2014

This commentary is on the original article by Fiori et al. on pages 839–845 of this issue.
Dose‐finding results in an adaptive, seamless, randomized trial of once‐weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD‐5)
Authors: Skrivanek Z. , Gaydos B. L. , Chien J. Y. , Geiger M. J. , Heathman M. A. , Berry S. , Anderson J. H. , Forst T. , Milicevic Z. , Berry D.
Published: April 2014

Aims

AWARD‐5 was an adaptive, seamless, double‐blind study comparing dulaglutide, a once‐weekly glucagon‐like peptide‐1 (GLP‐1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose‐finding portion whose results are presented here.

Methods

Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected.

Results

Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks −0.63 (−0.98 to −0.20)%. Dulaglutide 2.0 mg showed the greatest placebo‐adjusted mean change in weight [−1.99 (−2.88 to −1.20) kg] and in PR [0.78 (‐2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo‐adjusted mean change in DBP [−0.62 (−3.40 to 2.30) mmHg].

Conclusions

The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial.
Global gradients of avian longevity support the classic evolutionary theory of ageing
Authors: Valcu M. , Dale J. , Griesser M. , Nakagawa S. , Kempenaers B.
Published: April 2014

Senescence, the process of physiological deterioration associated with growing old, is a shared characteristic of a wide range of animals. Yet, lifespan varies dramatically among species. To explain this variation, the evolutionary theory of ageing has been proposed more than 50 yr ago. Although the theory has been tested experimentally and through comparative analyses, there remains debate whether its fundamental prediction is empirically supported. Here, we use a comprehensive database on avian life history traits to test the evolutionary theory of ageing at a global scale. We show that pronounced geographical gradients of maximum longevity exist, that they are predicted by measures of predator diversity and only partly depend on correlated life‐history traits. The results are consistent with species‐level analyses and can be replicated across bio‐geographical regions. Our analyses suggest that stochastic predation is an important driver of the evolution of lifespan, at least in birds.
Remeasuring man
Authors: Weisberg Michael
Published: April 2014

Samuel George Morton (1799–1851) was the most highly regarded American scientist of the early and middle 19th century. Thanks largely to Stephen Jay Gould's book The Mismeasure of Man, Morton's cranial capacity measurements of different races is now held up as a prime example of and cautionary tale against scientific racism. A team of anthropologists recently reevaluated Morton's work and argued that it was Gould, not Morton, who was biased in his analysis. This article is a reexamination of the Morton and Gould controversy. It argues that most of Gould's arguments against Morton are sound. Although Gould made some errors and overstated his case in a number of places, he provided prima facia evidence, as yet unrefuted, that Morton did indeed mismeasure his skulls in ways that conformed to 19th century racial biases. Gould's critique of Morton ought to remain as an illustration of implicit bias in science.
Fruiting and sporulation of Thekopsora and Chrysomyxa cone rusts in Picea cones and Prunus leaves
Authors: Kaitera J. , Hiltunen R. , Kauppila T. , Pitkäranta M. , Hantula J.
Published: April 2014

Natural fruiting and sporulation of cone rusts were investigated in cones of Picea spp. and leaves of Prunus spp. in a botanical garden in northern Finland in 2007–2012. Thekopsora areolata was the most frequent cone rust in Picea abies cones, where it colonizes the host tissues and hinders normal seed development. Aecia of T. areolata were also common in cones of Picea engelmannii and occasionally in cones of P. glauca. Aecia of T. areolata sporulated in cones that were at least one year old. Chrysomyxa pirolata, another pathogenic cone rust, fruited and sporulated annually but infrequently in current‐year cones of P. abies. The spruce needle rust, Chrysomyxa ledi, fruited and sporulated commonly in current‐year cone scales of P. abies, P. omorika and P. glauca, while P. rubens, P. mariana and P. pungens appeared to be resistant during the study period. Chrysomyxa ledi did not affect seed development in infected cones. Uredinia of T. areolata frequently occurred on leaves of 41 Finnish and Russian cultivars, varieties or subspecies of Prunus padus L. ssp. badus and ssp. borealis and Pr. virginiana both in the botanical garden and in the field, while 13 exotic Prunus spp. lacked rust fruitbodies. All the Pr. padus cultivars were highly susceptible to T. areolata, thus, spreading the rust efficiently to surroundings. This is the first report of aecia of T. areolata in cones of P. engelmannii and P. glauca, and those of C. ledi in cones of P. omorika and P. glauca. Molecular identification confirmed the presence of T. areolata and C. pirolata on all hosts, and all samples of C. ledi belonged to the C. ledi‐rhododendri complex.
Seedling emergence and summer survival after direct seeding for woodland restoration on old fields in south‐western Australia
Authors: Hallett Lauren M. , Standish Rachel J. , Jonson Justin , Hobbs Richard J.
Published: April 2014

Restoration opportunities provided by an emerging carbon market have largely focused on large‐scale woodland restoration projects. Gondwana Link is one such project operating in a 1000‐km corridor in south‐western Australia. We identified environmental factors affecting the success of woody‐species restoration at a dry‐woodland Gondwana Link site, Peniup, by relating the emergence and survival of 1522 seedlings to abiotic and biotic variables, including soil conditions and weed cover. We found soil conditions were highly variable across the site and, together with the dry Mediterranean‐climate summer, affected seedling emergence and summer survival. Seedling emergence was higher in sandy soils, but summer survival was higher in clay soils. Most of the seedlings that emerged and survived the summer were in either the Fabales or Myrtaceae family. We concluded that attempts to analyse restoration outcomes that do not consider how the influence of primary abiotic and biotic factors changes over time may mask the mechanisms driving seedling establishment.
Analysis of stress fractures associated with lameness inThoroughbred flat racehorses training on different track surfaces undergoing nuclear scintigraphic examination
Authors: MacKinnon M. C. , Bonder D. , Boston R. C. , Ross M. W.
Published: April 2014

Reasons for performing study

There is limited information regarding the impact of training track surface on the occurrence of stress fractures.

Objectives

To evaluate the impact of training track surface on the proportion of long bone and pelvic stress fractures associated with lameness inThoroughbred horses in flat race training undergoing nuclear scintigraphic examination.

Study design

Retrospective study.

Methods

Scintigraphic examinations ofThoroughbred flat racehorses were evaluated from 2 hospitals (hospital A [TorontoEquineHospital], 2003–2009, and hospital B [GeorgeD.WidenerHospital forLargeAnimals,School ofVeterinaryMedicine,University ofPennsylvania], 1994–2006). Horses admitted to hospital A trained at a single track, at which the main training surface changed from dirt to synthetic on 27August 2006. Two distinct populations existed at hospital B: horses that trained on dirt (numerous trainers) and those that trained on turf (single trainer). All scintigraphic images were evaluated by a blinded reviewer. Fisher's exact test and logistic regression were used when appropriate, and significance was set at P<0.05.

Results

When reviewing 528 scintigraphic examinations from hospital A (257 dirt and 271 synthetic, numerous trainers), there was a greater proportion of stress fractures detected in scintigraphic examinations from horses training on a synthetic surface (31.7%) in comparison to scintigraphic examinations from horses training on a dirt surface (23.0%) at an earlier point in time (P = 0.03). There was a greater proportion of hindlimb/pelvic and tibial stress fractures diagnosed in horses from the synthetic surface‐trained group than from the dirt‐trained group at hospital A (P<0.04 and P = 0.03, respectively).

Conclusions

This study provides evidence that training surface may affect the proportion of stress fractures diagnosed, but other factors, such as training philosophy, appear to be important. Future prospective investigations to fully elucidate the relationship between training track surface and the proportion of stress fractures and other nonfatal musculoskeletal injuries are warranted.
Defining critical residues for substrate binding to 1‐deoxy‐d‐xylulose 5‐phosphate synthase – active site substitutions stabilize the predecarboxylation intermediate C2α‐lactylthiamin diphosphate
Authors: Brammer Basta Leighanne A. , Patel Hetalben , Kakalis Lazaros , Jordan Frank , Freel Meyers Caren L.
Published: April 2014

1‐Deoxy‐d‐xylulose 5‐phosphate (DXP) synthase catalyzes the formation of DXP from pyruvate and d‐glyceraldehyde 3‐phosphate (GraP) in a thiamin diphosphate‐dependent manner, and is the first step in the essential pathway to isoprenoids in human pathogens. Understanding the mechanism of this unique enzyme is critical for developing new anti‐infective agents that selectively target isoprenoid biosynthesis. The present study used mutagenesis and a combination of protein fluorescence, CD and kinetics experiments to investigate the roles of Arg420, Arg478 and Tyr392 in substrate binding and catalysis. The results support a random sequential, preferred order mechanism, and predict that Arg420 and Arg478 are involved in binding of the acceptor substrate, GraP. d‐Glyceraldehyde, an alternative acceptor substrate lacking the phosphoryl group predicted to interact with Arg420 and Arg478, also accelerates decarboxylation of the predecarboxylation intermediate C2α‐lactylthiamin diphosphate (LThDP) on DXP synthase, indicating that this binding interaction is not absolutely required, and that the hydroxyaldehyde sufficiently triggers decarboxylation. Unexpectedly, Tyr392 contributes to GraP affinity, and is not required for LThDP formation or its GraP‐promoted decarboxylation. Time‐resolved CD spectroscopy and NMR experiments indicate that LThDP is significantly stabilized on R420A and Y392F variants as compared with wild‐type DXP synthase in the absence of acceptor substrate, but these substitutions do not appear to affect the rate of GraP‐promoted LThDP decarboxylation in the presence of high levels of GraP, and LThDP formation remains the rate‐limiting step. These results suggest a role of these residues in promoting GraP binding, which in turn facilitates decarboxylation, and also highlight interesting differences between DXP synthase and other thiamin diphosphate‐dependent enzymes.
Optimizing carbon storage and biodiversity protection in tropical agricultural landscapes
Authors: Gilroy James J. , Woodcock Paul , Edwards Felicity A. , Wheeler Charlotte , Medina Uribe Claudia A. , Haugaasen Torbjørn , Edwards David P.
Published: April 2014

With the rapidly expanding ecological footprint of agriculture, the design of farmed landscapes will play an increasingly important role for both carbon storage and biodiversity protection. Carbon and biodiversity can be enhanced by integrating natural habitats into agricultural lands, but a key question is whether benefits are maximized by including many small features throughout the landscape (‘land‐sharing’ agriculture) or a few large contiguous blocks alongside intensive farmland (‘land‐sparing’ agriculture). In this study, we are the first to integrate carbon storage alongside multi‐taxa biodiversity assessments to compare land‐sparing and land‐sharing frameworks. We do so by sampling carbon stocks and biodiversity (birds and dung beetles) in landscapes containing agriculture and forest within the Colombian Chocó‐Andes, a zone of high global conservation priority. We show that woodland fragments embedded within a matrix of cattle pasture hold less carbon per unit area than contiguous primary or advanced secondary forests (>15 years). Farmland sites also support less diverse bird and dung beetle communities than contiguous forests, even when farmland retains high levels of woodland habitat cover. Landscape simulations based on these data suggest that land‐sparing strategies would be more beneficial for both carbon storage and biodiversity than land‐sharing strategies across a range of production levels. Biodiversity benefits of land‐sparing are predicted to be similar whether spared lands protect primary or advanced secondary forests, owing to the close similarity of bird and dung beetle communities between the two forest classes. Land‐sparing schemes that encourage the protection and regeneration of natural forest blocks thus provide a synergy between carbon and biodiversity conservation, and represent a promising strategy for reducing the negative impacts of agriculture on tropical ecosystems. However, further studies examining a wider range of ecosystem services will be necessary to fully understand the links between land‐allocation strategies and long‐term ecosystem service provision.
Nitrogen and phosphorus additions impact arbuscular mycorrhizal abundance and molecular diversity in a tropical montane forest
Authors: Camenzind Tessa , Hempel Stefan , Homeier Jürgen , Horn Sebastian , Velescu Andre , Wilcke Wolfgang , Rillig Matthias C.
Published: April 2014

Increased nitrogen (N) depositions expected in the future endanger the diversity and stability of ecosystems primarily limited by N, but also often co‐limited by other nutrients like phosphorus (P). In this context a nutrient manipulation experiment (NUMEX) was set up in a tropical montane rainforest in southern Ecuador, an area identified as biodiversity hotspot. We examined impacts of elevated N and P availability on arbuscular mycorrhizal fungi (AMF), a group of obligate biotrophic plant symbionts with an important role in soil nutrient cycles. We tested the hypothesis that increased nutrient availability will reduce AMF abundance, reduce species richness and shift the AMF community toward lineages previously shown to be favored by fertilized conditions. NUMEX was designed as a full factorial randomized block design. Soil cores were taken after 2 years of nutrient additions in plots located at 2000 m above sea level. Roots were extracted and intraradical AMF abundance determined microscopically; the AMF community was analyzed by 454‐pyrosequencing targeting the large subunit rDNA. We identified 74 operational taxonomic units (OTUs) with a large proportion of Diversisporales. N additions provoked a significant decrease in intraradical abundance, whereas AMF richness was reduced significantly by N and P additions, with the strongest effect in the combined treatment (39% fewer OTUs), mainly influencing rare species. We identified a differential effect on phylogenetic groups, with Diversisporales richness mainly reduced by N additions in contrast to Glomerales highly significantly affected solely by P. Regarding AMF community structure, we observed a compositional shift when analyzing presence/absence data following P additions. In conclusion, N and P additions in this ecosystem affect AMF abundance, but especially AMF species richness; these changes might influence plant community composition and productivity and by that various ecosystem processes.
Asynchrony of taxonomic, functional and phylogenetic diversity in birds
Authors: Monnet Anne‐Christine , Jiguet Frédéric , Meynard Christine N. , Mouillot David , Mouquet Nicolas , Thuiller Wilfried , Devictor Vincent
Published: April 2014

Aim

We assessed the temporal trends of taxonomic, functional and phylogenetic diversities in the French avifauna over the last two decades. Additionally, we investigated whether and how this multifaceted approach to biodiversity dynamics can reveal an increasing similarity of local assemblages in terms of species, traits and/or lineages.

Location

France.

Methods

We analysed a large‐scale dataset that recorded annual changes in the abundance of 116 breeding birds in France between 1989 and 2012. We decomposed and analysed the spatio‐temporal dynamics of taxonomic, phylogenetic and functional diversities and each of their α‐, β‐ and γ‐components. We also calculated the trend in the mean specialization of bird communities to track the relative success of specialist versus generalist species within communities during the same period.

Results

We found large variation within and among the temporal trends of each biodiversity facet. On average, we found a marked increase in species and phylogenetic diversity over the period considered, but no particular trend was found for functional diversity. Conversely, changes in β‐diversities for the three facets were characterized by independent and nonlinear trends. We also found a general increase in the local occurrence and abundance of generalist species within local communities.

Main conclusions

These results highlight a relative asynchrony of the different biodiversity facets occurring at large spatial scales. We show why a multifaceted approach to biodiversity dynamics is needed to better describe and understand changes in community composition in macroecology and conservation biogeography.
A global 1‐km consensus land‐cover product for biodiversity and ecosystem modelling
Authors: Tuanmu Mao‐Ning , Jetz Walter
Published: April 2014

Aim

For many applications in biodiversity and ecology, existing remote sensing‐derived land‐cover products have limitations due to among‐product inconsistency and their typically non‐continuous nature. Here we aim to help address these shortcomings by generating a 1‐km resolution global product that provides scale‐integrated and accuracy‐weighted consensus land‐cover information on an approximately continuous scale.

Location

Global.

Methods

Using a generalized classification scheme and an accuracy‐based integration approach, we integrated four global land‐cover products. We evaluated the performance of this product compared with inputs for estimating subpixel 30‐m resolution land cover. We also compared the accuracy of deductive and inductive species distribution models built with the different products for modelling the continental distributions of six avian habitat specialists.

Results

Our product offers accuracy‐weighted consensus information on the prevalence of 12 land‐cover classes within every nominal 1‐km pixel across the globe (except for Antarctica). Compared with the four base products, it better captures the land‐cover information contained in the fine‐grain validation data for all classes combined and for most individual classes. It also has the highest sensitivity and overall accuracy for detecting the presence of every fine‐grain land‐cover class. Both deductive and inductive models built with the consensus dataset have the highest or second highest accuracy for modelling bird species distributions.

Main conclusions

Our consensus product integrates the four base products and successfully maximizes accuracy and reduces errors of omission. Specifically, the consensus product reduces limitations caused by misclassifications, false absence rates and the categorical format of existing land‐cover products. Consequently, it surpasses single base products in the ability to capture subpixel land‐cover information and the utility for modelling species distributions. Both the presented methodology and the consensus product have multiple applications in biodiversity research and for understanding and modelling of global terrestrial ecosystems.
Medical co‐morbidities and practice
Authors: Kulkarni R. , Mauser‐Bunschoten E. P. , Stedman C. , Street A.
Published: April 2014

All‐oral treatments of hepatitis C (HCV) have been trialled in patients with hereditary bleeding disorders and found to be effective. Further refinements of dosing and duration are being established. Importantly for patient acceptability these regimens are interferon‐free. Cohort studies in older patients with haemophilia direct the need for attention to weight control, exercice, assessment of cardiovascular risk, especially hypertension and detection of osteoporosis. Where patients live a long way from a comprehensive care centre, telemedicine connections can engage centre experts with the patient and his/her local practitioners in devising and monitoring care plans
Inhibitors – cellular aspects and novel approaches for tolerance
Authors: Scott D. W.
Published: April 2014

The immune response against therapeutic clotting factors VIII and IX (FVIII and FIX) is a major adverse event that can effectively thwart their effectiveness in correcting bleeding disorders. Thus, a significant number of haemophilia patients form antibodies, called inhibitors, which neutralize the procoagulant functions of therapeutic cofactors FVIII (haemophilia A) or FIX (haemophilia B). Understanding the cellular and molecular aspects of inhibitor formation is critical to designing tolerogenic therapies for clinical use. This review will focus on the basis of the immune response to FVIII, in particular, and will discuss emerging efforts to not only reduce immunogenicity but also to prevent and/or reverse inhibitor formation.
Genetic testing in bleeding disorders
Authors: de Brasi C. , El‐Maarri O. , Perry D. J. , Oldenburg J. , Pezeshkpoor B. , Goodeve A.
Published: April 2014

The aim of molecular genetic analysis in families with haemophilia is to identify the causative mutation in an affected male as this provides valuable information for the patient and his relatives. For the patient, mutation identification may highlight inhibitor development risk or discrepancy between different factor VIII assays. For female relatives, knowledge of the familial mutation can facilitate carrier status determination and prenatal diagnosis. Recent advances in understanding mutations responsible for haemophilia and methods for their detection are presented. For reporting of such mutations, participation in external quality assessment ensures that essential patient and mutation details are routinely included and that pertinent information is incorporated in the interpretation.
Current status of haemophilia gene therapy
Authors: High K. H. , Nathwani A. , Spencer T. , Lillicrap D.
Published: April 2014

After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno‐associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV‐mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector‐mediated gene transfer is discussed. While AAV‐mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future.
Inhibitors – genetic and environmental factors
Authors: Lillicrap D. , Fijnvandraat K. , Santagostino E.
Published: April 2014

It is known that a large number of both genetic and environmental factors contribute to the risk of inhibitor development, but underlying pathogenetic mechanisms are still under investigation. The clinical research on inhibitors towards factor VIII (FVIII) is challenged by the fact that this is an infrequent event occurring in a rare disease. Therefore, it is widely accepted that complementary studies involving animal models can provide important insights into the pathogenesis and treatment of this complication. In this respect, mouse models have been studied for clues to FVIII immunogenicity, natural history of immunity and for different approaches to primary and secondary tolerance induction. In the clinical setting, the type of FVIII product used and the occurrence of product switching are considered important factors which may have an influence on inhibitor development. The evaluation of data currently available in the literature does not prove unequivocally that a difference in the immunogenicity exists between particular FVIII products (e.g. recombinant vs. plasma‐derived, full length vs. B‐domainless). In addition, national products switches have occurred and, in this context, switching was not associated with an enhanced inhibitor risk. In contrast with severe haemophilia A, patients with moderate and mild haemophilia A receive FVIII treatment infrequently for bleeds or surgery. In this condition the inhibitor risk is low but remains present lifelong, requiring continuous vigilance, particularly after intensive FVIII exposure.
Novel products for haemostasis
Authors: Shima M. , Hermans C. , de Moerloose P.
Published: April 2014

The primary major issue in haemophilia treatment remains the development of inhibitors. Recently two novel bypassing products have been developed. First, a humanized bispecific antibody against FIXa and FX, termed hBS23, was produced utilizing these two molecules placed into a spatially appropriate position to mimic FVIIIa, and recently this mimetic activity and the pharmacokinetics of the original antibody were improved by engineering the charge properties of the variable region within the immunoglobulin. Using the new antibody, termed ACE910, a phase 1 study in 64 Japanese and Caucasian healthy adults was performed and data from this trial suggested that the product had medically acceptable safety and tolerability profiles. The other new bypassing agent is named MC710, and consists of a mixture of plasma‐derived FVIIa and FX. Preclinical studies using in vitro and in vivo haemophilia B inhibitor monkey models indicated that the haemostatic effects of FVIIa and FX were enhanced by simultaneous administration. Results from phase I and II clinical studies suggested that MC710 had equal or greater pharmacokinetic (PK), pharmacodynamic (PD), efficacy and safety profiles than conventional bypassing agents in the treatment of joint bleeding in haemophilia patients with inhibitors. Another significant current issue in this context is the increased medical cost of conventional treatment due to the higher consumption of concentrates. Biosimilar products may offer advantages in these circumstances and may offer a less expensive alternative. Regulatory issues, however, together with acceptability of biosimilar materials and reimbursement policies as well as supply and demand incentives remain to be considered. Rare bleeding disorders (RBDs) have attracted less attention from the pharmaceutical industry than haemophilia or von Willebrand disease due to the limited number of patients involved. Many cases of this type have been treated, therefore, using fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs) which carry serious risks of infections, allergic reactions and fluid overload. Several specific plasma‐derived or recombinant products including fibrinogen, FVIIa, FXI and FXIII have now become available, however, and a phase III clinical study of recombinant FXIIIa has recently been completed demonstrating safety and efficacy of substances of this nature.
Joint WFH‐ISTH session: issues in clinical trial design
Authors: Peyvandi F. , Farrugia A. , Iorio A. , Key N. S. , Srivastava A.
Published: April 2014

Haemophilia therapy is experiencing an unprecedented expansion in the number and novelty of clotting factor concentrates. Every product must be licensed by regulatory authorities, primarily on the basis of its safety and efficacy profiles. The low prevalence of haemophilia, and other inherited bleeding disorders, presents a significant challenge to patient recruitment for preauthorization clinical trials, especially given the low frequency of inhibitory antibodies, the major adverse event related to clotting factor exposure. Other challenges include a lack of harmonization between the major regulatory authorities in certain key areas, the selection of laboratory monitoring methodologies and the difficulty in obtaining high‐quality phase IV safety data following authorization. These aspects will be reviewed in this session, which will also highlight the roles played by the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis in the promotion of these discussions.
With blood in the joint – what happens next? Could activation of a pro‐inflammatory signalling axis leading to iRhom2/TNFα‐convertase‐dependent release of TNFα contribute to haemophilic arthropathy?
Authors: Haxaire C. , Blobel C. P.
Published: April 2014

One of the main complications of haemophilia A is haemophilic arthropathy (HA), a debilitating disease with a significant negative impact on motility and quality of life. Despite major advances in the treatment of haemophilia A, many patients still suffer from HA. We wish to develop new treatments for HA, but must first better understand its causes. Our laboratory studies molecular scissors that release the pro‐inflammatory cytokine tumour necrosis factor alpha (TNFα) from cells. TNFα is considered the ‘fire alarm’ of the body – it helps to fight infections, but can also cause diseases such as inflammatory arthritis. We know that the molecular scissors, called TNFα convertase (TACE), and its newly discovered regulator termed iRhom2 can be rapidly activated by small amounts of cytokines, growth factors, and pro‐inflammatory mediators present in the blood. We hypothesize that the rapid activation of TACE could help explain one of the unsolved mysteries regarding the development of HA, which is how even small amounts of blood can provoke a persistent inflammatory response. We propose that once blood enters the joint, iRhom2 and TACE are activated to release TNFα and that this could promote the development of HA in a similar manner to that in which it promotes rheumatoid arthritis (RA). We are currently using immune cells stimulated with blood degradation products, and mouse models of HA, to test this hypothesis. If successful, our study could provide the rationale for testing anti‐TNF antibodies, which are already used to treat RA, for the treatment of HA. In addition, they might uncover iRhom2 and TACE as attractive new candidate targets for the treatment of HA.
Monitoring of modified factor VIII and IX products
Authors: Kitchen S. , Gray E. , Mertens K.
Published: April 2014

The dawning era of novel recombinant factor VIII and factor IX concentrates, many of which have been bioengineered to achieve prolonged activity, brings with it the need to consider the most appropriate clinical laboratory approaches for potency assignment, as well as the measurement of postinfusion levels. This session will highlight the known limitations and inconsistencies between existing assay methodologies with respect to currently available products, and discuss some of the early data with respect to the novel agents.