bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving the Safety Assessment of Chemicals and Drug Candidates by the Integration of Bioinformatics and Chemoinformatics Data
Authors: Steger‐Hartmann Thomas , Pognan Francois 
Published: January 2018

AbstractThe application of read‐across and in silico tools for regulatory decision‐making has been limited for pharmaceutical compounds to the assessment of genotoxic impurity. In contrast, the broad availability of toxicity data for industrial chemicals has triggered regulatory frameworks for read‐across (e.g. ECHA Read‐Across Assessment Framework), software tools and public databases for an automated process of gap filling in the context of safety assessment. This MiniReview provides an overview of the currently existing in silico and read‐across approaches for chemicals together with recent developments for pharmaceutical compounds in these areas. It also highlights the differences and commonalities in the in silico safety assessment of industrial chemicals and drug candidates. Whereas toxicity data collection and sharing is now common practice for chemicals falling under the European REACH regulation (Registration, Evaluation, Authorisation and Restriction of Chemicals), the biggest hurdle for establishing preclinical safety databases for pharmaceutical compounds is the unwillingness to share proprietary data and lack of published data sets. In a recent consortium approach, thirteen pharmaceutical companies, eleven academic partners and six small to medium size enterprises (SMEs) of the bioinformatics sector joined forces over the last 7 years within the European Innovative Medicines Initiative project eTOX (‘electronic toxicity’) to design and implement a strategy for leveraging these preclinical data for small molecules and sharing them across project partners. The eTOX database has evolved as the largest preclinical toxicity database for drugs and drug candidates and currently contains more than 1900 different chemical structures and more than 8000 in vivo toxicity study data sets. It can be foreseen that the development and application of such databases for drugs or drug candidates will in the future also cross‐fertilize the read‐across and the in silico assessment of industrial or consumer chemicals particularly as soon as human safety data from clinical trials are integrated too.
Post‐partum haemorrhage and tranexamic acid: a global issue
Authors: Hibbs Stephen P. , Roberts Ian , Shakur‐Still Haleema , Hunt Beverley J. 
Published: January 2018

SummaryPost‐partum haemorrhage (PPH) remains the major cause of maternal death worldwide, with the overwhelming majority of bleeding deaths occurring in low income countries. These bleeding deaths occur due to a complex network of biological and socioeconomic factors, including changes to haemostasis and fibrinolysis during pregnancy. Tranexamic acid (TxA) has been shown to reduce death in bleeding trauma patients safely and is effective in reducing bleeding in surgical patients, however its role in PPH has been less well established. We discuss the impact of the recently published World Maternal Antifibrinolytic (WOMAN) trial, which demonstrated a significant reduction in bleeding deaths (Risk ratio 0·81) in women with PPH who received intravenous TxA compared to those receiving placebo. There were no increases in post‐partum thrombotic rates in mothers or breast‐fed babies. This trial has shown that intravenous TxA can be used safely and effectively to treat PPH, and should be implemented widely to reduce death due to PPH. However, for the full benefit of TxA to be fully realised in resource‐constrained settings, the effectiveness of oral or topical administration and/or pre‐emptive dosing need to be investigated.
Treatment of relapsed/refractory acute myeloid leukaemia in adults
Authors: Rashidi Armin , Weisdorf Daniel J. , Bejanyan Nelli 
Published: January 2018

SummaryThe prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo‐HCT), both transplant‐related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti‐leukaemia potential of the immune system. Several small‐molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre‐clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low‐toxicity maintenance strategies. While cure of relapsed/refractory AML without allo‐HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer.
Comparing transfusion reaction risks for various plasma products – an analysis of 7 years of ISTARE haemovigilance data
Authors: Saadah Nicholas H. , van der Bom Johanna G. , Wiersum‐Osselton Johanna C. , Richardson Clive , Middelburg Rutger A. , Politis Constantina , Renaudier Philippe , Robillard Pierre , Schipperus Martin R. 
Published: January 2018

SummaryPlasma transfusions may result in transfusion reactions. We used the International Surveillance of Transfusion‐Associated Reactions and Events (ISTARE) database, containing yearly reported national annual aggregate data on transfusion reactions from participating countries, to investigate risks of plasma transfusion reactions and compare transfusion reaction risks for different plasma types. We calculated risks for plasma transfusion reactions and compared transfusion reaction risks between plasma types using random effects regression on repeated measures. The ISTARE database contains data from 23 countries, reporting units issued and/or transfused and transfusion reactions observed for some portion of 7 years (2006–2012). Interquartile ranges (IQRs) of plasma transfusion reaction risks were: allergic reactions (5·6–72·2 reactions/105 units transfused); febrile non‐haemolytic transfusion reactions (0–9·1); transfusion‐associated circulatory overload (0–1·9); transfusion related acute lung injury (TRALI) (0–1·2); and hypotensive reactions (0–0·6). Apheresis plasma was associated with more allergic reactions [odds ratio (OR) = 1·29 (95% confidence interval: 1·19–1·40)] and hypotensive reactions [OR = 2·17 (1·38–3·41)] than whole blood‐derived plasma. Pathogen‐inactivated plasma was associated with fewer transfusion reactions than untreated plasma.
Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients
Authors: Jurczyszyn Artur , Radocha Jakub , Davila Julio , Fiala Mark A. , Gozzetti Alessandro , Grząśko Norbert , Robak Paweł , Hus Iwona , Waszczuk‐Gajda Anna , Guzicka‐Kazimierczak Renata , Atilla Erden , Mele Giuseppe , Sawicki Waldemar , Jayabalan David S. , Charliński Grzegorz , Szabo Agoston G. , Hajek Roman , Delforge Michel , Kopacz Agnieszka , Fantl Dorotea , Waage Anders , Avivi Irit , Rodzaj Marek , Leleu Xavier , Richez Valentine , Knopińska‐Posłuszny Wanda , Masternak Anna , Yee Andrew J. , Barchnicka Agnieszka , Druzd‐Sitek Agnieszka , Guerrero‐Garcia Thomas , Liu Jieqi , Vesole David H. , Castillo Jorge J. 
Published: January 2018

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety‐eight patients were treated with novel agents, with an overall response rate of 78%. Fifty‐five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow‐up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P = 0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 109/l and peripheral blood plasma cell count ≥20 × 109/l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2–3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.
Profit‐Sharing and Wages: An Empirical Analysis Using French Data between 2000 and 2007
Authors: Delahaie Noélie , Duhautois Richard 
Published: January 2018

AbstractEconomic theory presents different arguments about how profit‐sharing may affect wages. First, profit‐sharing may substitute for the base wage. Second, profit‐sharing can be interpreted as an ‘efficiency wage’ that adds to the base wage and increases total compensation. The existing empirical literature has not determined which of these arguments is valid. This article attempts to address this issue for France between 2000 and 2007. Based on a difference‐in‐differences selection model, we show that bonuses in firms adopting profit‐sharing are too small to conclude whether it substitutes for or complements the base wage. While base wage levels are generally higher among profit‐sharing firms, changes in the base wage over this period are lower among firms that have had profit‐sharing for a number of years.
Nerve‐sparing radical cystectomy has a beneficial impact on urinary continence after orthotopic bladder substitution, which becomes even more apparent over time
Authors: Furrer Marc A. , Studer Urs E. , Gross Tobias , Burkhard Fiona C. , Thalmann George N. , Nguyen Daniel P. 
Published: January 2018

ObjectiveTo analyse urinary continence in long‐term survivors after radical cystectomy (RC) and orthotopic bladder substitution (OBS) according to attempted nerve‐sparing (NS) status.Patients and MethodsWe analysed 180 consecutive patients treated at our department between 1985 and 2007, who underwent RC with OBS, and survived ≥10 years after RC. We stratified patients by attempted NS status and evaluated continence outcomes using descriptive statistics and Cox proportional hazards regression models. A secondary analysis evaluated erectile function as a quality control for attempted NS.ResultsThe median (interquartile range [IQR]) age at RC was 62 (57−71) years. Of 180 patients, attempted NS status was none in 24 (13%), unilateral in 100 (56%), and bilateral in 56 (31%). After a median (IQR) follow‐up of 169 (147−210) months, 160 (89%) patients were continent during daytime and 124 (69%) during night‐time. In multivariable analysis, any degree of attempted NS was significantly associated with daytime continence (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.05–4.11; P = 0.04). Correspondingly, any attempted NS was significantly associated with night‐time continence (OR 2.51, 95% CI 1.08–5.85; P = 0.03). Recovery of erectile function at 5 years was also significantly associated with attempted NS (P < 0.001).ConclusionNerve‐sparing during RC and OBS was associated with better long‐term continence outcomes. This becomes more apparent as the patients age with their OBS. We advocate a NS RC whenever an OBS is considered.
Prevalence and longitudinal trends of food allergy during childhood and adolescence: Results of the Isle of Wight Birth Cohort study
Authors: Venkataraman D. , Erlewyn‐Lajeunesse M. , Kurukulaaratchy R. J. , Potter S. , Roberts G. , Matthews S. , Arshad S. H. 
Published: January 2018

SummaryBackgroundThe prevalence and time trends of food allergy change during childhood depending on the age of the child and the type of food.ObjectiveTo study prevalence and longitudinal trends in food allergy from birth to 18 years in an unselected birth cohort in the Isle of Wight.MethodInformation on food allergy was collected at ages 1, 2, 4, 10 and 18 years from the Isle of Wight Birth Cohort (n = 1456). Skin prick testing (SPT) was performed at the age of 1 and 2 years in symptomatic children. At 4, 10 and 18 years of age, participants were tested to a panel of food and aeroallergens. Food allergy was diagnosed based on the criteria: symptoms suggestive of a typical IgE‐mediated reaction and reaction <4 hours following exposure to a known food allergen. McNemar's test was used to determine significance of changes in prevalence over time.ResultsThe prevalence of food allergy remained relatively constant in early childhood (5.3%, 4.4% and 5.0% at 1, 2 and 4 years, respectively), with significant decline at 10 years (2.3%, P < .001 vs 4 years) followed by significant rise at 18 years (4%, P = .02 vs 10 years). Cow's milk (1.6%‐3.5%) and egg (1.1%‐1.4%) were the most common allergens in the first 10 years with peanut (1%) and tree nuts (0.5%) becoming more prevalent beyond 10 years. Fruit and wheat allergy were less common at 10 years, and shellfish and kiwi emerged during adolescence. The prevalence of food allergy plus positive SPT was 1.3%, 0.8%, 0.8%, 0.9% and 2.2% at 1, 2, 4, 10 and 18 years, respectively.ConclusionFood allergy is highly prevalent in infancy with partial resolution during late childhood. However, a number of children acquire new food allergy during adolescence resulting in a relatively higher prevalence at 18 years.
Characterization of ectopic lymphoid structures in different types of acute renal allograft rejection
Authors: de Leur K , Clahsen-van Groningen M C , van den Bosch T P P , de Graav G N , Hesselink D A , Samsom J N , Baan C C , Boer K 
Published: January 2018

Summary
We hypothesize that T cells such as interleukin (IL)-21+B cell lymphoma 6 (BCL6)+ T follicular helper cells can regulate B cell-mediated immunity within the allograft during acute T cell-mediated rejection; this process may feed chronic allograft rejection in the long term. To investigate this mechanism, we determined the presence and activation status of organized T and B cells in so-called ectopic lymphoid structures (ELSs) in different types of acute renal allograft rejection. Biopsies showing the following primary diagnosis were included: acute/active antibody-mediated rejection, C4d+ (a/aABMR), acute T cell-mediated rejection grade I (aTCMRI) and acute T cell-mediated rejection grade II (aTCMRII). Paraffin sections were stained for T cells (CD3 and CD4), B cells (CD20), follicular dendritic cells (FDCs, CD23), activated B cells (CD79A), immunoglobulin (Ig)D, cell proliferation (Ki67) and double immunofluorescent stainings for IL-21 and BCL6 were performed. Infiltrates of T cells were detected in all biopsies. In aTCMRI, B cells formed aggregates surrounded by T cells. In these aggregates, FDCs, IgD and Ki67 were detected, suggesting the presence of ELSs. In contrast, a/aABMR and aTCMRII showed diffuse infiltrates of T and B cells but no FDCs and IgD. IL-21 was present in all biopsies. However, co-localization with BCL6 was observed mainly in aTCMRI biopsies. In conclusion, ELSs with an activated phenotype are found predominantly in aTCMRI where T cells co-localize with B cells. These findings suggest a direct pathway of B cell alloactivation at the graft site during T cell mediated rejection.
First Nations parenting and child reunification: Identifying strengths, barriers, and community needs within the child welfare system
Authors: Toombs Elaine , Drawson Alexandra S. , Bobinski Tina , Dixon John , Mushquash Christopher J. 
Published: January 2018

AbstractFirst Nations communities are seeking to improve current service delivery models and create alternative evidence‐based strategies. A First Nations child welfare organization has prioritized further understanding of reunification and parenting, including identification of successes and barriers to reunification, and service needs within communities. These priorities were addressed with a community‐based participatory research model and guided by a Research Advisory. Results were analysed using a blend of grounded theory and thematic analysis techniques. Participants indicated that placing children with extended family or within home communities facilitate best child outcomes. These reunifications could be increased by promoting parental and community capacity. Successes identified within communities included available supports, such as those that increased empowerment and community capacity. Identified barriers within communities were the lack of culturally appropriate services, hesitancy to obtain available support due to fears of child welfare intervention, and mental health difficulties of community member.
Identification of a single MPV17 nonsense‐associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy
Authors: Meldau S. , De Lacy R.J. , Riordan G.T.M. , Goddard E.A. , Pillay K. , Fieggen K.J. , Marais A.D. , Van der Watt G.F. 
Published: January 2018

MPV17‐related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non‐consanguineous Black South African heritage.Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122‐1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536‐1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.
Lateral bone augmentation in narrow posterior mandibles, description of a novel approach, and analysis of results
Authors: Beitlitum Ilan , Sebaoun Alon , Nemcovsky Carlos E. , Slutzkey Shimshon 
Published: January 2018

AbstractBackgroundCombination of particulate grafts and collagen membranes is widely used for augmentation of bony defects for implant placement. Fixation of the barrier membrane may avoid complications due to unfavorable mechanical properties and poor stability leading to collapse of the augmented area.PurposeTo evaluate a new simplified method for resorbable collagen membrane fixation in lateral bone augmentation procedures in narrow posterior mandibles.Materials and MethodsThis retrospective study analyzed 16 procedures performed in 15 patients who followed lateral ridge augmentation procedures before implant placement in the posterior mandible. A particulate mineralized bone allograft was covered with a cross‐linked resorbable collagen barrier membrane, which was fixated with a single, nonresorbable pin. Complications were registered and results analyzed on pre and post op measurements on computerized tomographic scans. Descriptive statistical analysis and ANOVA with repeated measures were performed.ResultsNo complications were recorded. Average bone gain was 3.3 mm at implant platform level and 4.29 mm at 3 mm apically, both, statistically significant. All sites had sufficient bone width allowing implant placement. Thirty‐three implants placed in the augmented areas, integrated and survived for over a 2‐year follow‐up.ConclusionThe simplified membrane fixation procedure enables large horizontal bone gain with minimal complications while allowing adequate implant placement.
Divalproex sodium modulates nuclear localization of ataxin‐3 and prevents cellular toxicity caused by expanded ataxin‐3
Authors: Wang Zi‐Jian , Hanet Aoife , Weishäupl Daniel , Martins Inês M. , Sowa Anna S. , Riess Olaf , Schmidt Thorsten 
Published: January 2018

SummaryBackground & AimsSpinocerebellar ataxia type 3 (SCA3), also known as Machado‐Joseph disease (MJD), is an autosomal dominantly inherited neurodegenerative disorder and the most common form of SCA worldwide. It is caused by the expansion of a polyglutamine (polyQ) tract in the ataxin‐3 protein. Nuclear localization of the affected protein is a key event in the pathology of SCA3 via affecting nuclear organization, transcriptional dysfunction, and seeding aggregations, finally causing neurodegeneration and cell death. So far, there is no effective therapy to prevent or slow the progression of SCA3.MethodsIn this study, we explored the effect of divalproex sodium as an HDACi in SCA3 cell models and explored how divalproex sodium interferes with pathogenetic processes causing SCA3.ResultsWe found that divalproex sodium rescues the hypoacetylation levels of histone H3 and attenuates cellular cytotoxicity induced by expanded ataxin‐3 partly via preventing nuclear transport of ataxin‐3 (particularly heat shock‐dependent).ConclusionOur study provides novel insights into the mechanisms of action of divalproex sodium as a possible treatment for SCA3, beyond the known regulation of transcription.
Improving text relatedness by incorporating phrase relatedness with word relatedness
Authors: Rakib Rashadul Hasan , Islam Aminul , Milios Evangelos 
Published: January 2018

AbstractText is composed of words and phrases. In the bag‐of‐words model, phrases in text are split into words. This may discard the semantics of phrases, which, in turn, may give an inconsistent relatedness score between 2 texts. Our objective is to apply phrase relatedness in conjunction with word relatedness on the text relatedness task to improve text relatedness performance. We adopt 2 existing word relatedness measures based on Google n‐gram and Global Vectors for Word Representation, respectively, and incorporate them differently with an existing Google n‐gram–based phrase relatedness method to compute text relatedness. The combination of Google n‐gram–based word and phrase relatedness performs better than Google n‐gram–based word relatedness alone, by achieving the higher weighted mean of Pearson's r, ie, 0.639 and 0.619, respectively, on the 14 data sets from the series of Semantic Evaluation workshops SemEval‐2012, SemEval‐2013, and SemEval‐2015. Similarly, the combination of GloVe‐based word relatedness and Google n‐gram–based phrase relatedness performs better than GloVe‐based word relatedness alone, by achieving the higher weighted mean of Pearson's r, ie, 0.619 and 0.605, respectively, on the same 14 data sets. On the SemEval‐2012, SemEval‐2013, and SemEval‐2015 data sets, the text relatedness results obtained from the combination of Google n‐gram–based word and phrase relatedness ranked 24, 3, and 31 out of 89, 90, and 73 text relatedness systems, respectively.