bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired polysaccharide responsiveness without agammaglobulinaemia in three patients with hypomorphic mutations in Bruton Tyrosine Kinase—No detection by newborn screening for primary immunodeficiencies
Authors: Krüger Renate , Baumann Ulrich , Borte Stephan , Kölsch Uwe , Lorenz Myriam Ricarda , Keller Baerbel , Harder Ina , Warnatz Klaus , Ehl Stephan , Schwarz Klaus , Wahn Volker , von Bernuth Horst 
Published: August 2019

AbstractHypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B‐cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa‐deleting‐recombination‐excision circles (KRECs) reliably identifies classical X‐linked agammaglobulinaemia (XLA) patients with profound B‐cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B‐cell lymphopenia with residual B‐cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B‐cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B‐cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.
Transposable elements contribute to dynamic genome content in maize
Authors: Anderson Sarah N. , Stitzer Michelle C. , Brohammer Alex B. , Zhou Peng , Noshay Jaclyn M. , O'Connor Christine H. , Hirsch Cory D. , Ross‐Ibarra Jeffrey , Hirsch Candice N. , Springer Nathan M. 
Published: August 2019

SummaryTransposable elements (TEs) are ubiquitous components of eukaryotic genomes and can create variation in genome organization and content. Most maize genomes are composed ofTEs. We developed an approach to define shared and variableTEinsertions across genome assemblies and applied this method to four maize genomes (B73, W22, Mo17 andPH207) with uniform structural annotations ofTEs. Among these genomes we identified approximately 400 000TEs that are polymorphic, encompassing 1.6 Gb of variableTEsequence. These polymorphicTEs include a combination of recent transposition events as well as deletions of olderTEs. There are examples of polymorphicTEs within each of the superfamilies ofTEs and they are found distributed across the genome, including in regions of recent shared ancestry among individuals. There are many examples of polymorphicTEs within or near maize genes. In addition, there are 2380 gene annotations in the B73 genome that are located within variableTEs, providing evidence for the role ofTEs in contributing to the substantial differences in annotated gene content among these genotypes.TEs are highly variable in our survey of four temperate maize genomes, highlighting the major contribution ofTEs in driving variation in genome organization and gene content.Open Research BadgesThis article has earned an Open Data Badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available athttps://github.com/SNAnderson/maizeTE_variation;https://mcstitzer.github.io/maize_TEs.
Association between restriction policies and rate of alcohol-related harm in Australian Aboriginal and Torres Strait Islander communities: a systematic review protocol
Authors: Hines Sonia , Carey Timothy A. , Martin Kathleen , Cibich Mikaela 
Published: August 2019

ABSTRACT

Objective:
This review aims to examine the association between alcohol restriction policies and rates of alcohol-related harms in Australian Aboriginal and Torres Strait Islander communities.

Introduction:
A number of different strategies have been used to reduce the harms and costs associated with excessive alcohol consumption in Aboriginal and Torres Strait Islander communities. These strategies, implemented at federal and state government levels, as well as by individual communities, have aimed to promote reduced alcohol consumption or prohibit consumption entirely. Strategies to address the problems associated with alcohol misuse can be categorized into three types: harm, demand and supply reduction.

Inclusion criteria:
This review will consider any kind of quantitative research study that includes Australian Aboriginal and Torres Strait Islander peoples living in communities subject to alcohol control policies due to the imposition of alcohol management plans or other alcohol restriction policies. Included studies will measure physical alcohol-related harms. The secondary outcome of interest will be rates of alcohol consumption measured as alcohol sales per person or as self-reported consumption. Studies published in English from 1998 will be included.

Methods:
The proposed systematic review will be conducted in accordance with the JBI methodology for systematic reviews of etiology and risk. Published and unpublished studies will be sourced from multiple databases and resources. Two independent reviewers will screen, appraise and extract data from studies meeting the inclusion criteria. Data synthesis will be conducted and a Summary of Findings will be constructed.
Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study
Authors: Gale Richard P , Pearce Ian , Eter Nicole , Ghanchi Faruque , Holz Frank G , Schmitz-Valckenberg Steffen , Balaskas Konstantinos , Burton Ben J L , Downes Susan M , Eleftheriadis Haralabos , George Sheena , Gilmour David , Hamilton Robin , Lotery Andrew J , Patel Nishal , Prakash Priya , Santiago Cynthia , Thomas Saju , Varma Deepali , Walters Gavin , Williams Michael , Wolf Armin , Zakri Rosina H , Igwe Franklin , Ayan Filis 
Published: August 2019

Background/AimsProspective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity.MethodsSAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed.ResultsOne hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of −30.75 µm (95% CI −59.50,–20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0–≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified.ConclusionSwitching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.
Pharmacy-based sexual health services: a systematic review of experiences and attitudes of pharmacy users and pharmacy staff
Authors: Gauly Julia , Ross Jonathan , Hall Isobel , Soda Irekanmi , Atherton Helen 
Published: August 2019

BackgroundPharmacies are increasingly providing services related to contraception and STIs. Identifying pharmacy staff’ and users’ experiences and attitudes relating to sexual health services is critical to understand users’ needs and examining how pharmacy staff can most effectively contribute to patient-centred care. This systematic review aimed to examine pharmacy staff and pharmacy users’ experiences and attitudes towards the delivery of a large range of sexual health services.MethodsSeven electronic databases and the reference lists of all included studies were searched in September 2018. Studies giving insight into pharmacy users’ and pharmacy staff’s experiences and attitudes towards the delivery of services related to contraception and STIs were included. The Mixed Methods Appraisal Tool was used to assess the quality of included studies and a narrative synthesis applied to analyse evidence.ResultsNineteen studies were included. Eleven studies looked at pharmacy staff, four at users and four at both groups. Users found services accessible and convenient and staff found service provision feasible. However, several barriers to service delivery were identified including lack of privacy for delivering services, lack of trained staff available to provide services and subjective judgements being made on who should be provided or offered a service.DiscussionBarriers to service delivery need to be addressed to allow pharmacies to deliver their full potential. Future research on pharmacy-based gonorrhoea and syphilis screening, and hepatitis B vaccination is needed.PROSPERO registration numberCRD42018106807.
Cost saving of switching to equivalent inhalers and its effect on health outcomes
Authors: Bloom Chloe I , Douglas Ian , Olney Jack , D'Ancona Grainne , Smeeth Liam , Quint Jennifer K 
Published: August 2019

BackgroundSwitching inhalers to cheaper equivalent products is often advocated as a necessary cost saving measure, yet the impact on patient’s health and healthcare utilisation has not been measured.MethodsWe identified asthma and chronic obstructive pulmonary disease (COPD) patients from UK primary care electronic healthcare records between 2000 and 2016. A self-controlled case series was used to estimate incidence rate ratios (IRR); comparing outcome rates during the risk period, 3 months after the exposure (financially motivated switch), and control periods (preswitch and postrisk period). Four outcomes were assessed: disease exacerbation, general practitioner consultation, non-specific respiratory events and adverse-medication events. Medication possession ratio (MPR) was calculated to assess adherence. 2017 National Health Service indicative prices were used to estimate cost differences per equivalent dose.ResultsWe identified a cohort of 569 901 asthma and 171 231 COPD regular inhaler users, 2% and 6% had been switched, respectively. Inhaler switches between a brand-to-generic inhaler, and all other switches (brand-to-brand, generic-to-generic, generic-to-brand), were associated with reduced exacerbations (brand-to-generic: IRR=0.75, 95% CI 0.64 to 0.88; all other: IRR=0.79, 95% CI 0.71 to 0.88). Gender, age, therapeutic class, inhaler device and inhaler-technique checks did not significantly modify this association (p<0.05). The rate of consultations, respiratory-events and adverse-medication events did not change significantly (consultations: IRR=1.00, 95% CI 0.99 to 1.01; respiratory-events: IRR=0.96, 95% CI 0.95 to 0.97; adverse-medication-events: IRR=1.05, 95% CI 0.96 to 1.15). Adherence significantly increased post-switch (median MPR: pre-switch=54%, post-switch=62%; p<0.001). Switching patients, in the cohort of regular inhaler users, to the cheapest equivalent inhaler, could have saved around £6 million annually.ConclusionSwitching to an equivalent inhaler in patients with asthma or COPD appeared safe and did not negatively affect patient’s health or healthcare utilisation.
Review of the British Thoracic Society Winter Meeting 2018, 5–7 December 2018, London, UK
Authors: Goodwin Amanda T , Singanayagam Aran , Jenkins Gisli 
Published: August 2019

IntroductionThe Winter Meeting of the British Thoracic Society (BTS) is a platform for the latest clinical and scientific research in respiratory medicine. This review summarises some key symposia and presentations from the BTS Winter Meeting 2018.MethodsKey symposia and research presentations from the BTS Winter Meeting 2018 were attended and reviewed by the authors.ResultsThe seminal messages from the latest clinical and scientific research covering a range of respiratory diseases, including asthma, interstitial lung disease, infection, cystic fibrosis, pulmonary vascular disease, pleural disease and occupational lung disease were summarised in this review.DiscussionThe BTS Winter Meeting 2018 brought the very best of respiratory research to an audience of scientists, physicians, nurses and allied health professionals. The Winter Meeting continues to be a highlight of the UK respiratory research calendar, and we look forward to the next meeting in December 2019.
Values of rational functions in small subgroups of finite fields and the identity testing problem from powers
Authors: Mérai László 
Published: August 2019

Motivated by some algorithmic problems, we give lower bounds on the size of the multiplicative groups containing rational function images of low-dimensional affine subspaces of a finite field [Formula: see text] considered as a linear space over a subfield [Formula: see text]. We apply this to the recently introduced algorithmic problem of identity testing of “hidden” polynomials [Formula: see text] and [Formula: see text] over a high degree extension of a finite field, given oracle access to [Formula: see text] and [Formula: see text].
Long-term Effects of Moderate versus High Durations of Aerobic Exercise on Biomarkers of Breast Cancer Risk: Follow-up to a Randomized Controlled Trial
Authors: Friedenreich Christine M. , Wang Qinggang , Yasui Yutaka , Stanczyk Frank Z. , Duha Aalo , Brenner Darren R. , Courneya Kerry S. 
Published: August 2019

Abstract

Background:
The optimal lifestyle for breast cancer prevention over the long term is unclear. We aimed to determine whether or not the amount of exercise prescribed in a year-long exercise intervention influences breast cancer biomarker levels 1 year later.

Methods:
We conducted a 24-month follow-up study (2012–2014) to the Breast Cancer and Exercise Trial in Alberta (BETA), a 12-month, two-armed (1:1), two-center randomized controlled trial of exercise in 400 cancer-free, postmenopausal women. The exercise prescription was moderate–vigorous aerobic exercise, 5 days/week (3 days/week supervised) for 30 minutes/session (MODERATE) or 60 minutes/session (HIGH). Participants were asked not to change their usual diet. We used linear mixed models to compare biomarker concentrations (C-reactive protein, insulin, glucose, HOMA-IR, estrone, sex hormone binding globulin, total estradiol, and free estradiol) over time (0, 12, and 24 months) by group (MODERATE, HIGH), using group–time interactions.

Results:
After 12 months of no intervention, 24-month fasting blood samples were available for 84.0% and 82.5% of MODERATE and HIGH groups, respectively (n = 333/400). We found no evidence that 0 to 24– or 12 to 24–month biomarker changes differed significantly between randomized groups (HIGH:MODERATE ratio of mean biomarker change ranged from 0.97 to 1.06, P values &gt;0.05 for all). We found more favorable biomarker profiles among participants who experienced greater than the median fat loss during the trial.

Conclusions:
Prescribing aerobic exercise for 300 versus 150 minutes/week for 12 months to inactive, postmenopausal women had no effects on longer-term biomarkers.

Impact:
Exercise may lead to larger improvements in breast cancer biomarkers after intervention among women who also experience fat loss with exercise.
Abemaciclib Is Effective Against Pancreatic Cancer Cells and Synergizes with HuR and YAP1 Inhibition
Authors: Dhir Teena , Schultz Christopher W. , Jain Aditi , Brown Samantha Z. , Haber Alex , Goetz Austin , Xi Chunhua , Su Gloria H. , Xu Liang , Posey James , Jiang Wei , Yeo Charles J. , Golan Talia , Pishvaian Michael J. , Brody Jonathan R. 
Published: August 2019

Abstract

Mutation or promoter hypermethylation of CDKN2A is found in over 90% of pancreatic ductal adenocarcinomas (PDAC) and leads to loss of function of cell-cycle inhibitors p16 (INK4A) and p14 (ARF) resulting in unchecked proliferation. The CDK4/6 inhibitor, abemaciclib, has nanomolar IC50s in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell-cycle arrest, apoptosis, and the senescent phenotype detected with β-galactosidase staining and relevant mRNA elevations. Daily abemaciclib treatments in mouse PDAC xenograft studies were safe and demonstrated a 3.2-fold decrease in tumor volume compared with no treatment (P &lt; 0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a prosurvival mRNA stability factor that regulates cyclin D1, and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional coactivator important for CDK6 and cyclin D1, were both synergistic with abemaciclib. Accordingly, siRNA oligonucleotides targeted against HuR, YAP1, and their common target cyclin D1, validated the synergy studies. In addition, we have seen increased sensitivity to abemaciclib in a PDAC cell line that harbors a loss of the ELAVL1 gene via CRISP-Cas9 technology. As an in vitro model for resistance, we investigated the effects of long-term abemaciclib exposure. PDAC cells chronically cultured with abemaciclib displayed a reduction in cellular growth rates (GR) and coresistance to gemcitabine and 5-fluorouracil (5-FU), but not to HuR or YAP1 inhibitors as compared with no treatment controls. We believe that our data provide compelling preclinical evidence for an abemaciclib combination–based clinical trial in patients with PDAC.

Implications:
Our data suggest that abemaciclib may be therapeutically relevant for the treatment in PDAC, especially as part of a combination regimen inhibiting YAP1 or HuR.
As crianças, a educação e os sonhos adultos em tempos de autismo
Authors: Lajonquière Leandro De 
Published: August 2019

O imaginário pedagógico contemporâneo estrutura-se em torno de um personagem chamado autista. Trata-se de um ser ficcional que não deve ser confundido com nenhuma criança autista em particular. Isso permite afirmar que vivemos em tempos de autismo que entranham um empobrecimento da vida cotidiana com as crianças de carne e osso. Embora não se possa afirmar o caráter patogênico desse empobrecimento educativo à maneira de um vírus ou conforme o raciocínio determinista clássico “causa-efeito”, propomos pensar o imaginário atual como uma espécie de caldo de cultivo no interior do qual cada criança confronta-se com o desafio de conquistar por si e para si um lugar de sujeito de palavra numa história mais ou menos aberta para o futuro. A criança bem pode virar vítima de um mal-entendido educativo e assim vir a ficar em certa medida à deriva no mundo. Talvez, pois isso não pode ser sabido, mais de uma criança autista esteja a testemunhar de semelhante infortúnio.
Secular Trends in Procedural Stroke or Death Risks of Stenting Versus Endarterectomy for Symptomatic Carotid Stenosis
Authors: Müller Mandy D. , von Felten Stefanie , Algra Ale , Becquemin Jean-Pierre , Bulbulia Richard , Calvet David , Eckstein Hans-Henning , Fraedrich Gustav , Halliday Alison , Hendrikse Jeroen , Howard George , Gregson John , Jansen Olav , Brown Martin M. , Mas Jean-Louis , Brott Thomas G. , Ringleb Peter A. , Bonati Leo H. ,   for the Carotid Stenosis Trialists’ Collaboration
Published: August 2019

Background:
Over the past decades, stroke risk associated with carotid disease has decreased, reflecting improvements in medical therapy and a more rigorous control of vascular risk factors. It is less clear whether the procedural risk of carotid revascularization has declined over time.

Methods:
We analyzed temporal changes in procedural risks among 4597 patients with symptomatic carotid stenosis treated with carotid artery stenting (n=2326) or carotid endarterectomy (n=2271) in 4 randomized trials between 2000 and 2008, using generalized linear mixed-effects models with a random intercept for each source trial. Models were additionally adjusted for age and other baseline characteristics predicting treatment risk. The primary outcome event was any procedural stroke or death, occurring during or within 30 days after revascularization.

Results:

The procedural stroke or death risk decreased significantly over time in all patients (unadjusted odds ratio per year, 0.91; 95% CI, 0.85–0.97;
P
=0.006). This effect was driven by a decrease in the carotid endarterectomy group (unadjusted odds ratio per year, 0.82; 95% CI, 0.73–0.92;
P
=0.003), whereas no significant decrease was found after carotid artery stenting (unadjusted odds ratio, 0.96; 95% CI, 0.88–1.04;
P
=0.33). Carotid endarterectomy patients had a lower procedural stroke or death risk compared with carotid artery stenting patients, and the difference significantly increased over time (interaction
P
=0.031). After adjustment for baseline characteristics, the results remained essentially the same.

Conclusions:
The risk of stroke or death associated with carotid endarterectomy for symptomatic carotid stenosis decreased over an 8-year period, independent of clinical predictors of procedural risk. No corresponding reduction in procedural risk was seen in patients treated with stenting.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
;
http://www.isrctn.com
. Unique identifier: NCT00190398 (EVA-3S), NCT00004732 (CREST), ISRCTN57874028 (SPACE), and ISRCTN25337470 (ICSS).