bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Estimation of Time-Dependent Attributable Fraction from Population-Based Case-Control Studies
Authors: Zhao Wei , Chen Ying Qing , Hsu Li 
Published: January 2017

Summary
Population attributable fraction (PAF) is widely used to quantify the disease burden associated with a modifiable exposure in a population. It has been extended to a time-varying measure that provides additional information on when and how the exposure's impact varies over time for cohort studies. However, there is no estimation procedure for PAF using data that are collected from population-based case-control studies, which, because of time and cost efficiency, are commonly used for studying genetic and environmental risk factors of disease incidences. In this article, we show that time-varying PAF is identifiable from a case-control study and develop a novel estimator of PAF. Our estimator combines odds ratio estimates from logistic regression models and density estimates of the risk factor distribution conditional on failure times in cases from a kernel smoother. The proposed estimator is shown to be consistent and asymptotically normal with asymptotic variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimator performs well in finite sample sizes. Finally, the method is illustrated by a population-based case-control study of colorectal cancer.
A Generalized Levene's Scale Test for Variance Heterogeneity in the Presence of Sample Correlation and Group Uncertainty
Authors: Soave David , Sun Lei 
Published: January 2017

Summary
We generalize Levene's test for variance (scale) heterogeneity between k groups for more complex data, when there are sample correlation and group membership uncertainty. Following a two-stage regression framework, we show that least absolute deviation regression must be used in the stage 1 analysis to ensure a correct asymptotic distribution of the generalized scale (gS) test statistic. We then show that the proposed gS test is independent of the generalized location test, under the joint null hypothesis of no mean and no variance heterogeneity. Consequently, we generalize the recently proposed joint location-scale (gJLS) test, valuable in settings where there is an interaction effect but one interacting variable is not available. We evaluate the proposed method via an extensive simulation study and two genetic association application studies.
Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype
Authors: Mann David M.A. , Snowden Julie S. 
Published: January 2017

AbstractFrontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non‐fluent aphasia (PNFA); three principal histologies, involving tau, TDP‐43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP‐43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter‐relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP‐43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP‐43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein – the product of MAPT – is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP‐43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP‐43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.
High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies
Authors: McLachlan S M , Aliesky H A , Banuelos B , Lesage S , Collin R , Rapoport B 
Published: January 2017

Summary
The thyrotrophin receptor (TSHR) A-subunit is the autoantigen targeted by pathogenic autoantibodies that cause Graves' hyperthyroidism, a common autoimmune disease in humans. Previously, we reported that pathogenic TSHR antibodies develop spontaneously in thyroiditis-susceptible non-obese diabetic (NOD).H2h4 mice bearing a human TSHR A-subunit transgene, which is expressed at low levels in both the thyroid and thymus (Lo-expressor transgene). The present study tested recent evidence that high intrathymic TSHR expression protects against the development of pathogenic TSHR antibodies in humans. By successive back-crossing, we transferred to the NOD.H2h4 background a human TSHR A-subunit transgene expressed at high levels in the thyroid and thymus (Hi-expressor transgene). In the sixth back-cross generation (&gt; 98% NOD.H2h4 genome), only transgenic offspring produced spontaneously immunoglobulin (Ig)G class non-pathogenic human TSHR A-subunit antibodies. In contrast, both transgenic and non-transgenic offspring developed antibodies to thyroglobulin and thyroid peroxidase. However, non-pathogenic human TSHR antibody levels in Hi-expressor offspring were lower than in Lo-expressor transgenic mice. Moreover, pathogenic TSHR antibodies, detected by inhibition of TSH binding to the TSHR, only developed in back-cross offspring bearing the Lo-expressor, but not the Hi-expressor, transgene. High versus low expression human TSHR A-subunit in the NOD.H2h4 thymus was not explained by the transgene locations, namely chromosome 2 (127–147 Mb; Hi-expressor) and chromosome 1 (22.9–39.3 Mb; low expressor). Nevertheless, using thyroiditis-prone NOD.H2h4 mice and two transgenic lines, our data support the association from human studies that low intrathymic TSHR expression is associated with susceptibility to developing pathogenic TSHR antibodies, while high intrathymic TSHR expression is protective.
Accounting for Life‐History Strategies and Timescales in Marine Restoration
Authors: Montero‐Serra Ignasi , Garrabou Joaquim , Doak Daniel F. , Figuerola Laura , Hereu Bernat , Ledoux Jean‐Baptiste , Linares Cristina 
Published: January 2017

AbstractUnderstanding the drivers of restoration success is a central issue for marine conservation. Here, we explore the role of life‐history strategies of sessile marine species in shaping restoration outcomes and their associated timescales. A transplantation experiment for the extremely slow‐growing and threatened octocoralCorallium rubrumwas highly successful over a relatively short term due to high survival and reproductive potential of the transplanted colonies. However, demographic projections predict that from 30 to 40 years may be required for fully functionalC. rubrumpopulations to develop. More broadly, a comprehensive meta‐analysis revealed a negative correlation between survival after transplanting and growth rates among sessile species. As a result, simulated dynamics for a range of marine sessile invertebrates predict that longer recovery times are positively associated with survival rates. These results demonstrate a tradeoff between initial transplantation efforts and the speed of recovery. Transplantation of slow‐growing species will tend to require lower initial effort due to higher survival after transplanting, but the period required to fully recover habitat complexity will tend to be far longer. This study highlights the important role of life history as a driver of marine restoration outcomes and shows how demographic knowledge and modeling tools can help managers to anticipate the dynamics and timescales of restored populations.
Clinical and histopathological features of cutaneous nontuberculous mycobacterial infection: a review of 13 cases
Authors: Li Jing Jing , Beresford Rohan , Fyfe Janet , Henderson Christopher 
Published: January 2017

BackgroundThe incidence of cutaneous nontuberculous mycobacterial (NTM) infection has increased in recent decades because of widespread use of immunosuppressive therapy and better detection methods. The histopathology of cutaneous NTM infection is not pathognomic and the organisms are slow and difficult to culture, making diagnosis challenging.MethodsWe reviewed the clinical and histopathological features of 13 cases of cutaneous NTM infection, and performed panmycobacterial polymerase chain reaction (PCR) on the paraffin blocks.ResultsThe immunocompetent patients presented with localized lesions on the extremities, whereas the immunocompromised patients presented with disseminated cutaneous lesions. The histopathology in immunocompetent patients was characterized by pseudoepitheliomatous epidermal hyperplasia, intraepithelial abscesses, transepidermal elimination and dermal granulomatous inflammation accompanied by necrosis and suppuration. The immunocompromised patients showed suppurative inflammation with little granuloma formation and numerous acid‐fast bacilli. Paraffin block PCR was positive in 4 of 13 cases (31%), whereas culture was positive in 11 of 13 cases (85%).ConclusionThe aforementioned histological features should help in diagnosing cutaneous NTM infection when combined with clinical and microbiological correlation. In our study, we did not find paraffin block PCR to be superior to conventional culture in detecting cutaneous NTM infection.
Are winter and breeding bird communities able to track rapid climate change? Lessons from the high North
Authors: Santangeli Andrea , Lehikoinen Aleksi 
Published: January 2017

AbstractAimClimate change is a major threat to biodiversity and a major factor underlying observed shifts in species distribution, abundance and phenology. Research effort on climate change impacts on species has often been based on single‐species studies focused on a single season, typically the breeding season, of species life cycles. We test how well winter and breeding bird communities are able to track climate change.LocationFinland.MethodsWe use a dataset consisting of bird counts from the winter and the breeding period spanning over four decades and a 1000 km latitudinal gradient across Finland, Northern Europe. We use the bird count data in combination with a species‐specific average temperature index to derive a functional index, the Community Temperature Index (CTI), which provides a measure of the relative temperature average of a community.ResultsWe show that the CTI of the winter bird community (CTIw) in Finland has increased significantly over the past four decades, but not as fast as the average winter temperature. Across Finland, CTIw decreased towards the north and the east of the country and increased with increasing temperature. Further, we show that change in CTI through time (from 1970s–1980s to 2000–2014) was similar between the winter and the breeding communities.Main conclusionsOverall, our results suggest that while the winter and breeding bird communities are, to a certain level, tracking increasing temperatures, the magnitude of temperature change is multiple times greater than the magnitude of community shifts. This is particularly true for the winter birds that are facing the most rapid temperature shifts. Our findings shed light on the importance of assessing and eventually addressing the effects of rapid climate warming beyond the breeding season of species life cycles.
The use of range size to assess risks to biodiversity from stochastic threats
Authors: Murray Nicholas J. , Keith David A. , Bland Lucie M. , Nicholson Emily , Regan Tracey J. , Rodríguez Jon Paul , Bedward Michael 
Published: January 2017

AbstractAimStochastic threats such as disease outbreak, pollution events, fire, tsunami and drought can cause rapid species extinction and ecosystem collapse. The ability of a species or ecosystem to persist after a stochastic threat is strongly related to the extent and spatial pattern of its geographical distribution. Consequently, protocols for assessing risks to biodiversity typically include geographic range size criteria for assessing risks from stochastic threats. However, owing in part to the rarity of such events in nature, the metrics for assessing risk categories have never been tested. In this study, we investigate the performance of alternative range size metrics, including the two most widely used, extent of occurrence (EOO) and area of occupancy (AOO), as predictors of ecosystem collapse in landscapes subject to stochastic threats.MethodsWe developed a spatially explicit stochastic simulation model to investigate the impacts of four threat types on a dataset of 1350 simulated geographic distributions of varying pattern and size. We empirically estimated collapse probability in response to each threat type and evaluated the ability of a set of spatial predictors to predict risk.ResultsThe probability of ecosystem collapse increased rapidly as range size declined. While AOO and EOO were the most important predictors of collapse risk for the three spatially explicit threats included in our model (circle, swipe and cluster), core area, patch density and mean patch size were better predictors for edge effect threats.Main conclusionsOur study is the first to quantitatively assess the range size metrics employed in biodiversity risk assessment protocols. We show that the current methods for measuring range size are the best spatial metrics for estimating risks from stochastic threats. Our simulation framework delivers an objective assessment of the performance of hitherto untested but widely used measures of geographic range size for risk assessment.
Clinical, behavioural and social indicators for poor glycaemic control around the time of transfer to adult care: a longitudinal study of 126 young people with diabetes
Authors: Castensøe‐Seidenfaden P. , Jensen A. K. , Smedegaard H. , Hommel E. , Husted G. R. , Pedersen‐Bjergaard U. , Teilmann G. 
Published: January 2017

AbstractAimsTo describe and compare changes in glycaemic control in young people with Type 1 diabetes over time between the last 2 years in paediatric care and the first 2 years in adult care and to identify risk factors for poor glycaemic control.MethodsOur retrospective cohort study followed participants aged 14–22 years from 2 years before to 2 years after transfer from paediatric to adult care. Changes in glycaemic control were calculated using repeated measurements. We adjusted for gender, age at diabetes onset, age at transfer, duration of diabetes at transfer, gap (amount of time) between last paediatric and first adult visit, comorbidity, learning disability and/or mental health conditions and family structure. We examined associations between acute hospital admissions, low visit attendance rate, loss to follow‐up and baseline HbA1c level.ResultsAmong 126 participants, the mean HbA1c level was 80 mmol/mol (9.4%) pre‐transfer but decreased by an average of 3 mmol/mol (0.3%) each year post‐transfer (P = 0.005). Young people with a learning disability and/or a mental health condition had worse glycaemic control (P = 0.041) and the mean HbA1c of those with divorced parents was 14 mmol/mol (1.2%) higher (P = 0.014). Almost one‐third of participants were admitted to the hospital for acute diabetes care. Low visit attendance rate, high baseline HbA1c level, learning disability and/or mental health conditions and divorced parents predicted acute hospital admissions.ConclusionsGlycaemic control improved significantly after transfer to adult care, but the mean HbA1c level remained high. Future interventions should focus on young people with divorced parents, those with a learning disability and/or mental health condition and those who do not attend clinical visits to improve HbA1c levels and thereby reduce hospitalization rates.
Frequency of CNKSR2 mutation in the X‐linked epilepsy‐aphasia spectrum
Authors: Damiano John A. , Burgess Rosemary , Kivity Sara , Lerman‐Sagie Tally , Afawi Zaid , Scheffer Ingrid E. , Berkovic Samuel F. , Hildebrand Michael S. 
Published: January 2017

SummarySynaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling‐mediated neuronal proliferation, migration and differentiation. Mutations in the X‐linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy‐aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike‐waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X‐linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X‐linked EAS because of the specific genetic counseling implications.
Cartilage oligomeric matrix protein neoepitope in the synovial fluid of horses with acute lameness: A new biomarker for the early stages of osteoarthritis
Authors: Skiöldebrand E. , Ekman S. , Mattsson Hultén L. , Svala E. , Björkman K. , Lindahl A. , Lundqvist A. , Önnerfjord P. , Sihlbom C. , Rüetschi U. 
Published: January 2017

SummaryBackgroundClinical tools to diagnose the early changes of osteoarthritis (OA) that occur in the articular cartilage are lacking.ObjectivesWe sought to identify and quantify a novel cartilage oligomeric matrix protein (COMP) neoepitope in the synovial fluid from the joints of healthy horses and those with different stages of OA.Study designIn vitro quantitative proteomics and assay development with application in synovial fluids samples obtained from biobanks of well‐characterised horses.MethodsArticular cartilage explants were incubated with or without interleukin‐1β for 25 days. Media were analysed via quantitative proteomics. Synovial fluid was obtained from either normal joints (n = 15) or joints causing lameness (n = 17) or with structural OA lesions (n = 7) and analysed for concentrations of the COMP neoepitope using a custom‐developed inhibition enzyme‐linked immunosorbent assay (ELISA). Explants were immunostained with polyclonal antibodies against COMP and the COMP neoepitopes.ResultsSemitryptic COMP peptides were identified and quantified in cell culture media from cartilage explants. A rabbit polyclonal antibody was raised against the neoepitope of the N‐terminal portion of one COMP fragment (sequence SGPTHEGVC). An inhibition ELISA was developed to quantify the COMP neoepitope in synovial fluid. The mean concentration of the COMP neoepitope significantly increased in the synovial fluid from the joints responsible for acute lameness compared with normal joints and the joints of chronically lame horses and in joints with chronic structural OA. Immunolabelling for the COMP neoepitope revealed a pericellular staining in the interleukin‐1β‐stimulated explants.Main limitationsThe ELISA is based on polyclonal antisera rather than a monoclonal antibody.ConclusionsThe increase in the COMP neoepitope in the synovial fluid from horses with acute lameness suggests that this neoepitope has the potential to be a unique candidate biomarker for the early molecular changes in articular cartilage associated with OA.
Antibiotic resistance of Helicobacter pylori in Chinese children: A multicenter retrospective study over 7 years
Authors: Li Lan , Ke Yini , Yu Chaohui , Li Guogang , Yang Ningmin , Zhang Jianzhong , Li Youming 
Published: January 2017

AbstractBackgroundTo determine the prevalence of resistance to metronidazole, clarithromycin, levofloxacin, amoxicillin, and furazolidone in Helicobacter pylori isolated from Chinese children.Materials and MethodsThis multicenter retrospective study was conducted from January 2009 to December 2015. A total of 1746 isolates of H. pylori were collected from nine areas of Zhejiang province in the southeast coastal region of China. H. pylori strains were examined for antibiotics susceptibility by agar dilution method.ResultsThe resistance rates were 75.20% for metronidazole, 16.38% for clarithromycin, 6.70% for levofloxacin, 0.06% for amoxicillin, and 0.06% for furazolidone. The pattern of H. pylori antibiotic resistance demonstrated no significant changes in the rates of resistance to clarithromycin, amoxicillin, furazolidone, and metronidazole over 7 years. A significant trend of increasing resistance to metronidazole was observed as children aged, but a downward trend in clarithromycin resistance was observed as children aged. No difference in the resistance to other antibiotics was observed among different age groups. Also, there was no significant difference between male and female subjects in rates of resistance to these five types of antibiotics. The predominant dual resistance to metronidazole and clarithromycin was presented in 10.65% of the isolates.ConclusionsThe resistance rates of H. pylori in children from southeast coastal region of China were very high to metronidazole, moderate to clarithromycin and levofloxacin, and low to amoxicillin and furazolidone. It is important to continue monitoring the resistance profiles of H. pylori isolated in this region.