bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case Fatality Ratio Estimates for the 2013–2016 West African Ebola Epidemic: Application of Boosted Regression Trees for Imputation
Authors: Forna Alpha , Nouvellet Pierre , Dorigatti Ilaria , Donnelly Christl A 
Published: July 2019

Abstract

Background
The 2013–2016 West African Ebola epidemic has been the largest to date with &gt;11 000 deaths in the affected countries. The data collected have provided more insight into the case fatality ratio (CFR) and how it varies with age and other characteristics. However, the accuracy and precision of the naive CFR remain limited because 44% of survival outcomes were unreported.

Methods
Using a boosted regression tree model, we imputed survival outcomes (ie, survival or death) when unreported, corrected for model imperfection to estimate the CFR without imputation, with imputation, and adjusted with imputation. The method allowed us to further identify and explore relevant clinical and demographic predictors of the CFR.

Results
The out-of-sample performance (95% confidence interval [CI]) of our model was good: sensitivity, 69.7% (52.5–75.6%); specificity, 69.8% (54.1–75.6%); percentage correctly classified, 69.9% (53.7–75.5%); and area under the receiver operating characteristic curve, 76.0% (56.8–82.1%). The adjusted CFR estimates (95% CI) for the 2013–2016 West African epidemic were 82.8% (45.6–85.6%) overall and 89.1% (40.8–91.6%), 65.6% (61.3–69.6%), and 79.2% (45.4–84.1%) for Sierra Leone, Guinea, and Liberia, respectively. We found that district, hospitalisation status, age, case classification, and quarter (date of case reporting aggregated at three-month intervals) explained 93.6% of the variance in the naive CFR.

Conclusions
The adjusted CFR estimates improved the naive CFR estimates obtained without imputation and were more representative. Used in conjunction with other resources, adjusted estimates will inform public health contingency planning for future Ebola epidemics, and help better allocate resources and evaluate the effectiveness of future inventions.
Advances and challenges for hemophilia gene therapy
Authors: Batty Paul , Lillicrap David 
Published: July 2019

Abstract
Hemophilia is an X-linked inherited bleeding disorder, resulting from defects in the F8 (hemophilia A) or F9 (hemophilia B) genes. Persons with hemophilia have bleeding episodes into the soft tissues and joints, which are treated with self-infusion of factor VIII or IX concentrates. Hemophilia provides an attractive target for gene therapy studies, due to the monogenic nature of these disorders and easily measurable endpoints (factor levels and bleed rates). All successful, pre-clinical and clinical studies to date have utilized recombinant adeno-associated viral (AAV) vectors for factor VIII or IX hepatocyte transduction. Recent clinical data have presented normalization of factor levels in some patients with improvements in bleed rate and quality of life. The main toxicity seen within these studies has been early transient elevation in liver enzymes, with variable effect on transgene expression. Although long-term data are awaited, durable expression has been seen within the hemophilia dog model with no late-toxicity or oncogenesis. There are a number of phase III studies currently recruiting; however, there may be some limitations in translating these data to clinical practice, due to inclusion/exclusion criteria. AAV-based gene therapy is one of a number of novel approaches for treatment of hemophilia with other gene therapy (in vivo and ex vivo) and non-replacement therapies progressing through clinical trials. Availability of these high-cost novel therapeutics will require evolution of both clinical and financial healthcare services to allow equitable personalization of care for persons with hemophilia.
Improved Population Pharmacokinetic Model for Predicting Optimized Infliximab Exposure in Pediatric Inflammatory Bowel Disease
Authors: Bauman Laura E , Xiong Ye , Mizuno Tomoyuki , Minar Philip , Fukuda Tsuyoshi , Dong Min , Rosen Michael J , Vinks Alexander A 
Published: July 2019

Abstract

Background
Many pediatric patients with inflammatory bowel disease (IBD) lose response to infliximab (IFX) within the first year, and achieving a minimal target IFX trough concentration is associated with higher remission rates and longer durability. Population pharmacokinetic (PK) modeling can predict trough concentrations for individualized dosing. The object of this study was to refine a population PK model that accurately predicts individual IFX exposure during maintenance therapy using longitudinal real-practice data.

Methods
We exported data from the electronic health records of pediatric patients with IBD treated with originator IFX at a single center between January 2011 and March 2017. Subjects were divided into discovery and validation cohorts. A population PK model was built and then validated.

Results
We identified 228 pediatric patients with IBD who received IFX and had at least 1 drug concentration measured, including 135 and 93 patients in the discovery and validation cohorts, respectively. Weight, albumin, antibodies to IFX (ATI) detected by a drug-tolerant assay, and erythrocyte sedimentation rate (ESR) were identified as covariates significantly associated with IFX clearance and incorporated into the model. The model exhibited high accuracy for predicting target IFX trough concentrations with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% confidence interval [CI], 0.81–0.91) for population-based predictions without prior drug-level input. Accuracy increased further for individual-based predictions when prior drug levels were known, with an AUROC of 0.93 (95% CI, 0.90–0.97).

Conclusions
A population PK model utilizing weight, albumin, ordinal drug-tolerant ATI, and ESR accurately predicts IFX trough concentrations during maintenance therapy in real-practice pediatric patients with IBD. This model, which incorporates dynamic clinical information, could be used for individualized dosing decisions to increase response durability.
Impact of 13-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Meningitis, Burkina Faso, 2016–2017
Authors: Soeters Heidi M , Kambiré Dinanibè , Sawadogo Guetawendé , Ouédraogo-Traoré Rasmata , Bicaba Brice , Medah Isaïe , Sangaré Lassana , Ouédraogo Abdoul-Salam , Ouangraoua Soumeya , Yaméogo Issaka , Congo-Ouédraogo Malika , Ky Ba Absatou , Aké Flavien , Srinivasan Velusamy , Novak Ryan T , McGee Lesley , Whitney Cynthia G , Van Beneden Chris 
Published: July 2019

Abstract

Background
In 2013, Burkina Faso introduced 13-valent pneumococcal conjugate vaccine (PCV13) into the routine childhood immunization program, to be administered to children at 8, 12, and 16 weeks of age. We evaluated the impact of PCV13 on pneumococcal meningitis.

Methods
Using nationwide surveillance, we gathered demographic/clinical information and cerebrospinal fluid (CSF) results for meningitis cases. Pneumococcal cases were confirmed by culture, polymerase chain reaction (PCR), or latex agglutination; strains were serotyped using PCR. We compared annual incidence (cases per 100 000) 4 years after PCV13’s introduction (2017) to average pre-PCV13 incidence (2011–2013). We adjusted incidence for age and proportion of cases with CSF tested at national laboratories.

Results
In 2017, pneumococcal meningitis incidence was 2.7 overall and 10.5 (<1 year), 3.8 (1–4 years), 3.5 (5–14 years), and 1.4 (≥15 years) by age group. Compared to 2011–2013, PCV13-serotype incidence was significantly lower among all age groups, with the greatest decline among children aged <1 year (77%; 95% confidence interval [CI], 65%–84%). Among all ages, the drop in incidence was larger for PCV13 serotypes excluding serotype 1 (79%; 95% CI, 72%–84%) than for serotype 1 (52%; 95% CI, 44%–59%); incidence of non-PCV13 serotypes also declined (53%; 95% CI, 37%–65%). In 2017, 45% of serotyped cases among all ages were serotype 1 and 12% were other PCV13 serotypes.

Conclusions
In Burkina Faso, meningitis caused by PCV13 serotypes continues to decrease, especially among young children. However, the concurrent decline in non-PCV13 serotypes and short pre-PCV13 observation period complicate evaluation of PCV13’s impact. Efforts to improve control of serotype 1, such as switching from a 3 + 0 schedule to a 2 + 1 schedule, may improve overall control of pneumococcal meningitis in this setting.
Electrical stimulation of cell growth and neurogenesis using conductive and nonconductive microfibrous scaffolds
Authors: Grossemy Simon , Chan Peggy P Y , Doran Pauline M 
Published: July 2019

AbstractThe effect of exogenous electrical stimulation on cell viability, attachment, growth, and neurogenesis was examined using PC12 cells in microfibrous viscose-rayon scaffolds immersed in culture medium. The scaffolds were applied either in their nonconductive state or after coating the fibres with 200 nm of gold to give a scaffold sheet resistivity of (13 ± 1.3) Ω square−1. The cells were treated for 12 days using direct current electrical stimulation of 2 h per day. No cytotoxic effects were observed when up to 500 mV (8.3 mV mm−1) was applied to the scaffolds without gold, or when up to 100 mV (1.7 mV mm−1) was applied to the scaffolds with gold. Compared with unstimulated cells, whereas electrical stimulation significantly enhanced cell growth and attachment in the nonconductive scaffolds without gold, similar effects were not found for the conductive scaffolds with gold. Neural differentiation in the presence of nerve growth factor was improved by electrical stimulation in both scaffolds; however, neurite development and the expression of key differentiation markers were greater in the nonconductive scaffolds without gold than in the scaffolds with gold. Application of the same current to scaffolds with and without gold led to much higher levels of neurogenesis in the scaffolds without gold. This work demonstrates that substantial benefits in terms of cell growth and neural differentiation can be obtained using electric fields exerted across nonconductive microfibrous scaffolds, and that this approach to electrical stimulation can be more effective than when the stimulus is applied to cells on conductive scaffolds.
Durability of antimicrobial activity of antibiotic-impregnated external ventricular drains: a prospective study
Authors: Mounier Roman , Lang Elodie , Hulin Anne , Woerther Paul-Louis , Lobo David , Martin Mathieu , Bitot Valérie , Flores Lyse , Cherruault Marlene , Jost Paul-Henri , Couffin Severine , Tomberli Françoise , Bardon Jean , Lahiani Wissem , Dhonneur Gilles , Cook Fabrice , Lebeaux David 
Published: July 2019

Abstract

Background
Antibiotic-impregnated external ventricular drains (AI-EVDs) have a debated efficacy in clinical studies.

Objectives
Our aim was to assess the durability of antimicrobial activity of AI-EVDs used in clinical settings.

Methods
From April 2017 to January 2018, all consecutive AI-EVDs (Bactiseal™) inserted in adult patients were prospectively included. After removal, each AI-EVD was cultured and assessed for antimicrobial activity on both internal and external sides of AI-EVDs. Catheters were each challenged with a single Staphylococcus strain [MSSA, MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE)]. MS was used to measure residual concentrations of rifampicin and clindamycin.

Results
Sixty-five AI-EVDs were included (56 patients). Among these, 21 were challenged with MSSA, 23 with MRSA and 21 with MRSE. Five ventriculostomy-related colonizations (9%) and two ventriculostomy-related infections (4%) occurred. Staphylococcus was the main bacterium responsible for colonization (4/5). AI-EVD inhibition decreased significantly against MRSA and MRSE according to duration of catheterization (for external and internal sides, P < 0.02) and overall volume of CSF drained (P < 0.005 for both sides against MRSE, P < 0.005 for external side against MRSA), but not against MSSA. Clindamycin concentration was not correlated with duration of catheterization or CSF volume drained, but <20% of initial concentration was recovered even after 5 days of AI-EVD dwelling. Conversely, rifampicin concentration showed a rapid and significant decline correlated to duration and CSF volume (P < 0.001 and P = 0.03, respectively).

Conclusions
Antimicrobial activity of AI-EVDs dropped quickly in vivo. Antimicrobial impregnation did not prevent AI-EVD colonization by susceptible strains in 9% of the cases.
Socio-economic Consequences of Displacement and Resettlement: A Case on the Planned Oil-refinery-development Project in the Albertine Region of Uganda
Authors: Aboda Caroline , Vedeld Paul , Byakagaba Patrick , Mugagga Frank , Nabanoga Goretti , Ruguma Tumwine Fredrick , Mukwaya Paul 
Published: July 2019

AbstractMillions of people are every year forcefully displaced from their places of residence and alienated from access to livelihood assets through large-scale development projects. This article examines different socio-economic consequences of displacement and resettlement caused by the planned oil-refinery site in Uganda. Household survey and interviews were employed to elicit the necessary data, analysed through descriptive statistics, logistic-regression and content analysis. Although the resettlement process exposed households to some benefits, most households were exposed to substantial risks. Over 81 per cent of households experiencing displacement lost their land and experienced reduced resource access. The results also showed significant relationships between consequences and socio-economic characteristics of respondents in that both male and female respondents had access to more and productive assets; and larger land sizes and incomes were reported to have been more affected. Also vulnerable groups including females and those with low or no education levels were more risk-prone than before the resettlement. In future development projects, the government should take into consideration the effect of the displacement and resettlement on asset access.
DREAM and RB cooperate to induce gene repression and cell-cycle arrest in response to p53 activation
Authors: Uxa Sigrid , Bernhart Stephan H , Mages Christina F S , Fischer Martin , Kohler Robin , Hoffmann Steve , Stadler Peter F , Engeland Kurt , Müller Gerd A 
Published: July 2019

AbstractMost human cancers acquire mutations causing defects in the p53 signaling pathway. The tumor suppressor p53 becomes activated in response to genotoxic stress and is essential for arresting the cell cycle to facilitate DNA repair or to initiate apoptosis. p53-induced cell cycle-arrest is mediated by expression of the CDK inhibitor p21WAF1/Cip1, which prevents phosphorylation and inactivation of the pocket proteins RB, p130, and p107. In a hypophosphorylated state, pocket proteins bind to E2F factors forming RB-E2F and DREAM transcriptional repressor complexes. Here, we analyze the influence of RB and DREAM on p53-induced gene repression and cell-cycle arrest. We show that abrogation of DREAM function by knockout of the DREAM component LIN37 results in a reduced repression of cell-cycle genes. We identify the genes repressed by the p53-DREAM pathway and describe a set of genes that is downregulated by p53 independent of LIN37/DREAM. Most strikingly, p53-dependent repression of cell-cycle genes is completely abrogated in LIN37−/−;RB−/− cells leading to a loss of the G1/S checkpoint. Taken together, we show that DREAM and RB are key factors in the p53 signaling pathway to downregulate a large number of cell-cycle genes and to arrest the cell cycle at the G1/S transition.
FICC-Seq: a method for enzyme-specified profiling of methyl-5-uridine in cellular RNA
Authors: Carter Jean-Michel , Emmett Warren , Mozos Igor Rdl , Kotter Annika , Helm Mark , Ule Jernej , Hussain Shobbir 
Published: July 2019

AbstractMethyl-5-uridine (m5U) is one the most abundant non-canonical bases present in cellular RNA, and in yeast is found at position U54 of tRNAs where modification is catalysed by the methyltransferase Trm2. Although the mammalian enzymes that catalyse m5U formation are yet to be identified via experimental evidence, based on sequence homology to Trm2, two candidates currently exist, TRMT2A and TRMT2B. Here we developed a genome-wide single-nucleotide resolution mapping method, Fluorouracil-Induced-Catalytic-Crosslinking-Sequencing (FICC-Seq), in order to identify the relevant enzymatic targets. We demonstrate that TRMT2A is responsible for the majority of m5U present in human RNA, and that it commonly targets U54 of cytosolic tRNAs. By comparison to current methods, we show that FICC-Seq is a particularly robust method for accurate and reliable detection of relevant enzymatic target sites. Our associated finding of extensive irreversible TRMT2A-tRNA crosslinking in vivo following 5-Fluorouracil exposure is also intriguing, as it suggests a tangible mechanism for a previously suspected RNA-dependent route of Fluorouracil-mediated cytotoxicity.
Maternal and child gluten intake and risk of type 1 diabetes: The Norwegian Mother and Child Cohort Study
Authors: Lund-Blix Nicolai A , Tapia German , Mårild Karl , Brantsaeter Anne Lise , Njølstad Pål R , Joner Geir , Skrivarhaug Torild , Størdal Ketil , Stene Lars C 
Published: July 2019

ABSTRACTOBJECTIVETo examine the association between maternal and child gluten intake and risk of type 1 diabetes in children.DESIGNPregnancy cohortSETTINGPopulation-based, nation-wide study in NorwayPARTICIPANTS86,306 children in The Norwegian Mother and Child Cohort Study born from 1999 through 2009, followed to April 15, 2018.MAIN OUTCOME MEASURESClinical type 1 diabetes, ascertained in a nation-wide childhood diabetes registry. Hazard ratios were estimated using Cox regression for the exposures maternal gluten intake up to week 22 of pregnancy and child’s gluten intake when the child was 18 months old.RESULTSDuring a mean follow-up of 12.3 years (range 0.7-16.0), 346 children (0.4%) developed type 1 diabetes (incidence rate 32.6 per 100,000 person-years). The average gluten intake was 13.6 grams/day for mothers during pregnancy, and 8.8 grams/day for the child at 18 months of age. Maternal gluten intake in mid-pregnancy was not associated with the development of type 1 diabetes in the child (adjusted hazard ratio 1.02 (95% confidence interval 0.73 to 1.43) per 10 grams/day increase in gluten intake). However, the child’s gluten intake at 18 months of age was associated with an increased risk of later developing type 1 diabetes (adjusted hazard ratio 1.46 (95% confidence interval 1.06 to 2.01) per 10 grams/day increase in gluten intake).CONCLUSIONSThis study suggests that the child’s gluten intake at 18 months of age, and not the maternal intake during pregnancy, could increase the risk of type 1 diabetes in the child.WHAT IS ALREADY KNOWN ON THIS TOPICA national prospective cohort study from Denmark found that a high maternal gluten intake during pregnancy could increase the risk of type 1 diabetes in the offspring (adjusted hazard ratio 1.31 (95% confidence interval 1.001 to 1.72) per 10 grams/day increase in gluten intake). No studies have investigated the relation between the amount of gluten intake by both the mother during pregnancy and the child in early life and risk of developing type 1 diabetes in childhood.WHAT THIS STUDY ADDSIn this prospective population-based pregnancy cohort with 86,306 children of whom 346 developed type 1 diabetes we found that the child’s gluten intake at 18 months of age was associated with the risk of type 1 diabetes (adjusted hazard ratio 1.46 (95% confidence interval 1.06 to 2.01) per 10 grams/day increase in gluten intake). This study suggests that the child’s gluten intake at 18 months of age, and not the maternal intake during pregnancy, could increase the child’s risk of type 1 diabetes.
Prolonged podocyte depletion in larval zebrafish resembles mammalian focal and segmental glomerulosclerosis
Authors: Ingeborg Hansen Kerrin Ursula , Siegerist Florian , Daniel Sophie , Schindler Maximilian , Blumenthal Antje , Zhou Weibin , Endlich Karlhans , Endlich Nicole 
Published: July 2019

AbstractAlthough FSGS has been in the scientific focus for many years, it is still a massive burden for patients with no causal therapeutic option. In FSGS, podocytes are injured, parietal epithelial cells (PECs) are activated and engage in the formation of cellular lesions leading to progressive glomerular scarring. Herein we show that podocyte-depleted zebrafish larvae develop acute proteinuria, severe foot process effacement and activate PECs which create cellular lesions and deposit extracellular matrix on the glomerular tuft. We therefore propose that this model shows features of human FSGS and show its applicability for a high-throughput drug screening assay.
Probing protein-protein and protein-substrate interactions in the dynamic membrane-associated ternary complex of Cytochromes P450, b5, and Reductase
Authors: Gentry Katherine A. , Anantharamaiah G. M. , Ramamoorthy Ayyalusamy 
Published: July 2019

AbstractCytochrome P450 (cytP450) interacts with two redox partners, cytP450 reductase and cytochrome-b5, to metabolize substrates. Using NMR, we reveal changes in the dynamic interplay when all three proteins are incorporated into lipids nanodiscs in the absence and presence of substrates.
ARABIDOPSIS NITRATE REGULATED 1 acts as a negative modulator of seed germination by activatingABI3expression
Authors: Lin Jia-Hui , Yu Lin-Hui , Xiang Cheng-Bin 
Published: July 2019

ABSTRACTSeed germination is a crucial transition point in plant life and is tightly regulated by environmental conditions through the coordination of two phytohormones, gibberellin and abscisic acid (ABA). To avoid unfavorable conditions, plants have evolved safeguard mechanisms for seed germination. Here, we report a novel function of the Arabidopsis MADS-box transcription factor ARABIDOPSIS NITRATE REGULATED 1 (ANR1) in seed germination.ANR1knockout mutant is insensitive to ABA, salt, and osmotic stress during the seed germination and early seedling development stages, whereasANR1-overexpressing lines are hypersensitive. ANR1 is responsive to ABA and abiotic stresses and upregulates the expression ofABI3to suppress seed germination.ANR1andABI3have similar expression pattern during seed germination. Genetically,ABI3acts downstream ofANR1. Chromatin immunoprecipitation and yeast-one-hybrid assays showed that ANR1 could bind to theABI3promoter to regulate its expression. In addition, ANR1 acts synergistically with AGL21 to suppress seed germination in response to ABA as evidenced byanr1 agl21double mutant. Taken together, our results demonstrate that the ANR1 plays an important role in regulating seed germination and early post-germination growth. ANR1 and AGL21 together constitutes a safeguard mechanism for seed germination to avoid unfavorable conditions.