bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Pharmacoepidemiologic Study of the Safety and Effectiveness of Clindamycin in Infants
Authors: Greenberg Rachel G. , Wu Huali , Maharaj Anil , Cohen-Wolkowiez Michael , Tomashek Kay M. , Osborn Blaire L. , Clark Reese H. , Walter Emmanuel B. 
Published: November 2019

Background:
Despite the absence of adequate safety or efficacy data, clindamycin is widely prescribed in the neonatal intensive care unit. We evaluated the association between clindamycin exposure and adverse events, as well as antibiotic effectiveness in infants.

Methods:
This was a retrospective cohort study of infants receiving clindamycin before postnatal day 121 who were discharged from a Pediatrix Medical Group neonatal intensive care unit (1997–2015). Using a previously developed pharmacokinetic model, we performed simulations to predict clindamycin exposure based on available dosing data. We used multivariable logistic regression to evaluate the association between clindamycin exposure and safety outcomes during and after clindamycin therapy. We reported the proportion of infants with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and clearance of MRSA bacteremia.

Results:
A total of 4089 infants received clindamycin at a median (25th–75th percentile) dose of 15 mg/kg/d (12–16). Clearance increased with older gestational age. Infants with the highest total clindamycin exposure had marginally increased odds of necrotizing enterocolitis within 7 days (adjusted odds ratio = 1.95 [1.04–3.63]), but exposure was not associated with death, sepsis, seizures, intestinal perforation or intestinal strictures. Of 25 infants who had MRSA bacteremia, 19 (76%) cleared the infection by the end of the clindamycin course.

Conclusions:
Higher clindamycin exposure was not associated with increased odds of death or nonlaboratory adverse events. The use of pharmacokinetic models combined with available electronic health record data offers a valuable, cost-effective approach to analyzing the safety and effectiveness of drugs in infants when large-scale trials are not feasible.
Performance of a Sensor to Monitor Socket Fit: Comparison With Practitioner Clinical Assessment
Authors: Larsen Brian G. , Allyn Katheryn J. , Ciol Marcia A. , Sanders Joan E. 
Published: November 2019

ABSTRACT

Introduction
A sensor that detects changes in prosthetic socket fit before they manifest clinically may be helpful towards rehabilitation after limb amputation.

Materials and Methods
Participants with transtibial amputation walked on a treadmill wearing a motor-driven, cabled-panel adjustable socket. Socket volume was slowly adjusted away from the neutral socket volume (panels flush). The percent socket volume change at which the practitioner, using visual assessment, first noted fit issues was compared with the percent socket volume change at which the sensor first detected a measurable change in fit.

Results
The median percent socket volume change at which the sensor first detected a measurable socket enlargement (0.50%) was significantly less than both the median percent socket volume change at which the research practitioner first noted a change in fit (1.69%) (P = 0.008) and the median percent socket volume change at which the participant would normally add a sock (2.30%) (P = 0.005). During socket reduction, the practitioner noted a change in fit before the participant would normally remove a sock in only 2 of 10 participants. The median percent socket volume change at which the sensor first detected a measurable socket reduction (−0.44%) was significantly smaller in absolute value than the median percent socket volume change at which the participant would normally remove a sock (−2.76%) (P = 0.005).

Conclusions
The sensor detected controlled socket fit changes before the research practitioner in this study. A next step will be to determine if the sensor detects unforced socket fit changes, and changes in user free-living environments.
Parental Perception of Cranial Orthotic Treatment for Infants with Deformational Plagiocephaly
Authors: Van Allen Camille , Mott Sandra , McGrath Jacqueline , DeGrazia Michele 
Published: November 2019

ABSTRACT

Introduction
The objective of this study is to increase understanding of the parents’ experiences while caring for their infants during cranial orthotic treatment for deformational plagiocephaly.

Methods
This study is a qualitative descriptive study consisting of interviews focused on parental perceptions of the experience caring for their infant during treatment. Data were analyzed using conventional content analysis.

Results
Ten parents participated in this qualitative study. Data revealed the pattern of a journey related to caring for an infant undergoing cranial orthotic treatment. Parents described the journey as consisting of the following phases: “making the decision,” “acclimating to the cranial orthosis,” “developing a routine,” “seeing results,” and “envisioning the future.” Minor nuisances and concerns were present throughout treatment.

Discussion
With initiation of cranial orthotic treatment, parents expressed some reservations. As treatment advanced, parents discussed their journey more positively as their infant’s head shapes improved. The availability of support, someone to answer questions, and patience facilitated a successful journey. Seeing the change in head shapes reinforced continuing with treatment.
Asthma and air pollution: recent insights in pathogenesis and clinical implications
Authors: Bontinck Annelies , Maes Tania , Joos Guy 
Published: November 2019

Purpose of review
Air pollution has adverse effects on the onset and morbidity of respiratory diseases, including asthma. In this review, we discuss recent insights into the effects of air pollution on the incidence and exacerbation of asthma. We focus on epidemiological studies that describe the association between air pollution exposure and development, mortality, persistence and exacerbations of asthma among different age groups. Moreover, we also provide an update on translational studies describing the mechanisms behind this association.

Recent findings
Mechanisms linking air pollutants such as particulate matter, nitrogen dioxide (NO2) and ozone to the development and exacerbation of asthma include the induction of both eosinophilic and neutrophilic inflammation driven by stimulation of airway epithelium and increase of pro-inflammatory cytokine production, oxidative stress and DNA methylation changes. Although exposure during foetal development is often reported as a crucial timeframe, exposure to air pollution is detrimental in people of all ages, thus influencing asthma onset as well as increase in asthma prevalence, mortality, persistence and exacerbation.

Summary
In conclusion, this review highlights the importance of reducing air pollution levels to avert the progressive increase in asthma incidence and morbidity.
Gadolinium Retention as a Safety Signal
Authors: Lancelot Eric , Desché Pierre 
Published: November 2019

Objectives
The purpose of this manuscript is to review the successive regulatory actions and decisions following the initial publication by Kanda and colleagues in 2014 regarding gadolinium retention in the human brain after multiple gadolinium-based contrast agents (GBCAs) administrations.

Materials and Methods
Starting from 2014, the actions and decisions made by all regulatory authorities were collected and summarized region by region. Volumes of GBCA sales in 2018 per region and main countries are also presented as an indicator of patients’ exposure to those products.

Results
All regulatory authorities agreed on the absence of evidence of any harmful effect of gadolinium retention in humans. However, based on the same amount of preclinical and clinical evidence available in adults and children, regulatory authorities used different approaches resulting in different actions and decisions regarding the labeling and market authorizations of GBCAs, as well as the specific actions requested to the manufacturers.

Conclusions
The manufacturers of GBCAs had to face different situations according to the countries, due to the different positions and expectations from regulatory agencies. They have adapted their responses to the different positions of the regulatory agencies and conducted specific preclinical and clinical investigations to provide the expected evidence. It is also their responsibility to continuously monitor the benefit-risk balance of the products and to propose risk minimization measures to the regulatory agencies.
Vaginal Estrogen Therapy Is Associated With Decreased Inflammatory Response in Postmenopausal Women With Recurrent Urinary Tract Infections
Authors: Meister Melanie R. , Wang Caihong , Lowder Jerry L. , Mysorekar Indira U. 
Published: November 2019

Objectives
Vaginal estrogen therapy (VET) has been shown to decrease the risk of recurrent urinary tract infections (UTIs) in postmenopausal women, but the mechanism of action has not been fully described. Our objectives were to assess whether the postmenopausal urine inflammatory profile changes in response to VET.

Methods
We prospectively enrolled postmenopausal patients into 3 groups: (1) currently using VET without a history of recurrent UTIs (rUTIs); (2) history of UTIs, currently using VET; and (3) history of rUTIs, not using VET but willing to start. We followed patients over 6 to 19 months and collected urine samples at 3 time points. We performed comprehensive cytopathologic analysis, quantitative urine inflammatory scoring, and enzyme-linked immunosorbent assay for interleukin 6.

Results
Seventy patients were recruited (group 1, n = 30; group 2, n = 20; group 3, n = 20). Urine from patients in groups 2 and 3 demonstrated increased inflammatory cells, debris, and exfoliated urothelial cells. Quantitative urine inflammatory scores and interleukin 6 were significantly higher in postmenopausal patients with rUTIs not on VET (0.12 vs 0.93, P < 0.05) and decreased significantly after initiating VET (0.93 vs 0.38, P < 0.05).

Conclusions
Postmenopausal women with rUTIs on VET demonstrate decreased cell shedding, reduced urine inflammatory scores, and decreased urine interleukin 6. Modulation of the genitourinary inflammatory profile may represent one mechanism through which VET helps prevent rUTIs in postmenopausal women.
Body mass index and carpal tunnel syndrome: a Mendelian randomization study
Authors: Daghlas Iyas , Varady Nathan 
Published: November 2019

AbstractIntroductionWe investigated whether higher body mass index (BMI) may causally increase risk of carpal tunnel syndrome using Mendelian randomization (MR).MethodsThe exposure included genetic instruments comprising independent variants associated with BMI (n=322,154). Associations of these variants with CTS were obtained from a genome-wide association study conducted in UK Biobank (UKB; 12,312 cases/389,344 controls) with replication in the FinnGen cohort (4,505 cases/86,854 controls). Causal effects were estimated using inverse-variance weighted regression, and sensitivity analyses probed robustness of results.ResultsA 1-standard deviation (4.7kg/m2) increase in genetically instrumented BMI increased the odds of CTS in UKB (OR 1.73, 95% CI 1.48-2.02, P=2.68×10−12; 16.8 additional cases per 1000 person-years [95% CI 11.0-23.5]). This effect was consistent in the replication sample and across sensitivity analyses.DiscussionThese data support a causal effect of higher BMI on susceptibility to CTS. Clinical investigations of weight loss for treatment of CTS may be warranted.
Covalent Surface Modification Effects on Single-Walled Carbon Nanotubes for Multimodal Optical Applications
Authors: Chio Linda , Pinals Rebecca L. , Murali Aishwarya , Goh Natalie S. , Landry Markita P. 
Published: November 2019

AbstractOptical nanoscale technologies often implement covalent or noncovalent strategies for the modification of nanoparticles, whereby both functionalizations are leveraged for multimodal applications but can affect the intrinsic fluorescence of nanoparticles. Specifically, single-walled carbon nanotubes (SWCNTs) can enable real-time imaging and cellular delivery; however, the introduction of covalent SWCNT sidewall functionalizations often attenuates SWCNT fluorescence. Herein, we leverage recent advances in SWCNT covalent functionalization chemistries that preserve the SWCNT’s pristine graphitic lattice and intrinsic fluorescence and demonstrate that such covalently functionalized SWCNTs maintain fluorescence-based molecular recognition of neurotransmitter and protein analytes. We show that the covalently modified SWCNT nanosensor fluorescence response towards its analyte is preserved for certain nanosensors, presumably dependent on the steric hindrance introduced by the covalent functionalization that hinders noncovalent interactions with the SWCNT surface. We further demonstrate that these SWCNT nanosensors can be functionalized via their covalent handles to self-assemble on passivated microscopy slides, and discuss future use of these dual-functionalized SWCNT materials for multiplexed applications.
BK current contributions to action potentials across the first postnatal week reflect age dependent changes in BK current kinetics in rat hippocampal neurons
Authors: Hunsberger Michael , Mynlieff Michelle 
Published: November 2019

AbstractThe large conductance calcium-activated potassium (BK) channel is a critical regulator of neuronal action potential firing and follows two distinct trends in early postnatal development: an increase in total expression and a shift from the faster activating STREX isoform to the slower ZERO isoform. We analyzed the functional consequences of developmental trends in BK channel expression in hippocampal neurons isolated from neonatal rats aged one to seven days. Following overnight cultures, action potentials were recorded using whole-cell patch clamp electrophysiology. This population of neurons undergoes a steady increase in excitability during this time and the effect of blockade of BK channel activity with 100 nM iberiotoxin, changes as the neurons mature. BK currents contribute significantly more to single action potentials in neurons of one-day old rats (with BK blockade extending action potential duration by 0.46±0.12 ms) than in those of seven-day old rats (with BK blockade extending action potential duration by 0.17±0.05 ms). BK currents also contribute consistently to maintain firing rates in neurons of one-day old rats throughout extended action potential firing; BK blockade evenly depresses action potentials frequency across action potential trains. In neurons from seven-day old rats, BK blockade initially increases firing frequency and then progressively decreases frequency as firing continues, ultimately depressing neuronal firing rates to a greater extent than in the neurons from one day old animals. These results are consistent with a transition from low expression of a fast activating BK isoform (STREX) to high expression of a slower activating isoform (ZERO).New and NoteworthyThis work describes the early developmental trends of BK channel activity. Early developmental trends in expression of BK channels, both total expression and relative isoform expression, have been previously reported, but little work describes the effect of these changes in expression patterns on excitability. Here, we show that early changes in BK channel expression patterns lead to changes in the role of BK channels in determining the action potential waveform and neuronal excitability.
Challenges in Peptide-Spectrum Matching: a Robust and Reproducible Statistical Framework for Removing Low-Accuracy, High-Scoring Hits
Authors: Hubler Shane L. , Kumar Praveen , Mehta Subina , Easterly Caleb , Johnson James E. , Jagtap Pratik D. , Griffin Timothy J. 
Published: November 2019

AbstractWorkflows for large-scale (MS)-based shotgun proteomics can potentially lead to costly errors in the form of incorrect peptide spectrum matches (PSMs). To improve robustness of these workflows, we have investigated the use of the precursor mass discrepancy (PMD) to detect and filter potentially false PSMs that have, nonetheless, a high confidence score. We identified and addressed three cases of unexpected bias in PMD results: time of acquisition within a LC-MS run, decoy PSMs, and length of peptide. We created a post-analysis Bayesian confidence measure based on score and PMD, called PMD-FDR. We tested PMD-FDR on four datasets across three types of MS-based proteomics projects: standard (single organism; reference database), proteogenomics (single organism; customized genomic-based database plus reference), and metaproteomics (microorganism community; customized conglomerate database). On a ground truth dataset and other representative data, PMD-FDR was able to detect 60-80% of likely incorrect PSMs (false-hits) while losing only 5% of correct PSMs (true-hits). PMD-FDR can also be used to evaluate data quality for results generated within different experimental PSM-generating workflows, assisting in method development. Going forward, PMD-FDR should provide detection of high-scoring but likely false-hits, aiding applications which rely heavily on accurate PSMs, such as proteogenomics and metaproteomics.
In-silico immune cell deconvolution of the airway proteomes of infants with pneumonia reveals a link between reduced airway eosinophils and an increased risk of mortality
Authors: Sande Charles J , Waeni Jacqueline M , Njunge James M , Mutunga Martin N , Gicheru Elijah , Kibinge Nelson K , Gwela Agnes 
Published: November 2019

AbstractRationalePneumonia is a leading cause of mortality in infants and young children. The mechanisms that lead to mortality in these children are poorly understood. Studies of the cellular immunology of the infant airway have traditionally been hindered by the limited sample volumes available from the young, frail children who are admitted to hospital with pneumonia. This is further compounded by the relatively low frequencies of certain immune cell phenotypes that are thought to be critical to the clinical outcome of pneumonia. To address this, we developed a novel in-silico deconvolution method for inferring the frequencies of immune cell phenotypes in the airway of children with different survival outcomes using proteomic data.MethodsUsing high-resolution mass spectrometry, we identified > 1,000 proteins expressed in the airways of children who were admitted to hospital with clinical pneumonia. 61 of these children were discharged from hospital and survived for more than 365 days after discharge, while 19 died during admission. We used machine learning by random forest to derive protein features that could be used to deconvolve immune cell phenotypes in paediatric airway samples. We applied these phenotype-specific signatures to identify airway-resident immune cell phenotypes that were differentially enriched by survival status and validated the findings using a large retrospective pneumonia cohort.Main ResultsWe identified immune-cell phenotype classification features for 33 immune cell types. Eosinophil-associated features were significantly elevated in airway samples obtained from pneumonia survivors and were downregulated in children who subsequently died. To confirm these results, we analyzed clinical parameters from >10,000 children who had been admitted with pneumonia in the previous 10 years. The results of this retrospective analysis mirrored airway deconvolution data and showed that survivors had significantly elevated eosinophils at admission compared to fatal pneumonia.ConclusionsUsing a proteomics bioinformatics approach, we identify airway eosinophils as a critical factor for pneumonia survival in infants and young children.
Human papillomavirus 16 E6 and E7 synergistically repress innate immune gene transcription
Authors: James Claire D. , Fontan Christian T. , Otoa Raymonde , Das Dipon , Prabhakar Apurva T. , Wang Xu , Bristol Molly L. , Morgan Iain M. 
Published: November 2019

AbstractHuman papillomaviruses are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More recently we demonstrated that E2 could also repress IIGs. These studies have been carried out in cells over-expressing the viral proteins and to further investigate the role of individual viral proteins in this repression we introduced stop codons into E6 and/or E7 in the entire HPV16 genome and generated N/Tert-1 cells stably maintaining the HPV16 genomes. We demonstrate that E6 or E7 individually are not sufficient to repress IIG expression in the context of the entire HPV16 genome, both are required for a synergistic repression. The DNA damage response (DDR) is activated by HPV16 irrespective of E6 and E7 expression, presumably due to viral replication; E1 is a known activator of the DDR. In addition, replication stress was apparent in the HPV16 positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies lead us to the following model. Viral replication per se can activate the DDR following infection, and this activation is a known inducer of IIG expression which could induce cellular senescence. To combat this, E6 and E7 synergistically combine to manipulate the DDR and actively repress innate immune gene expression promoting cellular growth; neither protein by itself is able to do this.ImportanceThe role of HPV16 in human cancers is well established; however, to date there are no anti-viral therapeutics that are available for combatting these cancers. To identify such targets, we must enhance understanding of the viral life cycle. Innate immune genes (IIGs) are repressed by HPV16, and we have reported that this repression persists through to cancer. Reversal of this repression would boost the immune response to HPV16 positive tumors, an area that is becoming more important given the advances in immunotherapy. This report demonstrates that E6 and E7 synergistically repress IIG expression in the context of the entire HPV16 genome. Removal of either protein activates the expression of IIGs by HPV16. Therefore, gaining a precise understanding of how the viral oncogenes repress IIG expression represents an opportunity to reverse this repression and boost the immune response to HPV16 infections for therapeutic gain.
A new measure of regional competitiveness
Authors: Sánchez de la Vega José Carlos , Buendía Azorín José Daniel , Calvo-Flores Segura Antonio , Esteban Yago Miguel 
Published: November 2019

Purpose
The purpose of this paper is to provide a measure of competitiveness of the Spanish autonomous communities from a multidimensional and dynamic perspective for the period 2008-2016.

Design/methodology/approach
This paper adopts a broad definition of competitiveness based on five key environments (productive capital, human capital, social and institutional capital, infrastructure and knowledge) and comprising 53 indicators. The method used to construct the competitiveness index is based on the P-distance proposed by Pena Trapero (1979), which objectively assigns weights to the indicators. There is an important advantage in the methodological proposal of this study, as it allows analyzing the behavior of partial and aggregated indicators from a dynamic perspective, taking the same value as a reference for the entire period. Therefore, not only a classification obtained for each year but also the variation that occurs in terms of the reference period can be analyzed.

Findings
The classification of the autonomous communities is established using common intervals based on the results obtained for the whole period, i.e. 2008-2016. The data point to the unequal situations of the autonomous communities. The results also reveal that the evolution of the regional competitiveness synthetic index is clearly cyclical and the drop recorded in the recessive period is less pronounced than the increase recorded in the growth phase.

Originality/value
The main innovation of the competitiveness index presented here lies in its allowing comparisons over time.