bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neonatal anesthesia and dysregulation of the epigenome
Authors: Cabrera Omar Hoseá , Useinovic Nemanja , Jevtovic-Todorovic Vesna 
Published: July 2021

AbstractEach year, millions of infants and children are anesthetized for medical and surgical procedures. Yet, a substantial body of preclinical evidence suggests that anesthetics are neurotoxins that cause rapid and widespread apoptotic cell death in the brains of infant rodents and nonhuman primates. These animals have persistent impairments in cognition and behavior many weeks or months after anesthesia exposure, leading us to hypothesize that anesthetics do more than simply kill brain cells. Indeed, anesthetics cause chronic neuropathology in neurons that survive the insult, which then interferes with major aspects of brain development, synaptic plasticity, and neuronal function. Understanding the phenomenon of anesthesia-induced developmental neurotoxicity is of critical public health importance because clinical studies now report that anesthesia in human infancy is associated with cognitive and behavioral deficits. In our search for mechanistic explanations for why a young and pliable brain cannot fully recover from a relatively brief period of anesthesia, we have accumulated evidence that neonatal anesthesia can dysregulate epigenetic tags that influence gene transcription such as histone acetylation and DNA methylation. In this review, we briefly summarize the phenomenon of anesthesia-induced developmental neurotoxicity. We then discuss chronic neuropathology caused by neonatal anesthesia, including disturbances in cognition, socio-affective behavior, neuronal morphology, and synaptic plasticity. Finally, we present evidence of anesthesia-induced genetic and epigenetic dysregulation within the developing brain that may be transmitted intergenerationally to anesthesia-naïve offspring.
Identification of LAMA1 mutations ends diagnostic odyssey and has prognostic implications for patients with presumed Joubert syndrome
Authors: Powell Laura , Olinger Eric , Wedderburn Sarah , Ramakumaran Vijayalakshmi Salem , Kini Usha , Clayton-Smith Jill , Ramsden Simon C , Rice Sarah J , Barroso-Gil Miguel , Wilson Ian , Cowley Lorraine , Johnson Sally , Harris Elizabeth , Montgomery Tara , Bertoli Marta ,   Genomics England Research Consortium, Boltshauser Eugen , Sayer John A 
Published: July 2021

Abstract
Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti–Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti–Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti–Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.
Incarnation, Posthumanism and Performative Anthropology: The Body of Technology and the Body of Christ
Authors: Burdett Michael S 
Published: July 2021

AbstractThis essay argues that a Christian incarnational response to posthumanism must recognize that what is at stake isn't just whether belief systems align. It seeks to relocate the interaction between the church and posthumanism to how the practices of posthumanism and Christianity perform the bodies, affections and dispositions of each. Posthuman practices seeks to habituate: (1) A preference for informational patterns over material instantiation; (2) that consciousness and the self are extended and displaced rather than discrete and localized; (3) that the body is merely a tool, the original prosthesis we learn to manipulate and (4) that human life is organized such that it is seamless with intelligent machines. The Christian performance of embodied life, on the other hand, has Christ as template and, in the Eucharist, Christians are marked by offering, sacrifice and celebration in a community that affirms the integrity of our common incarnate life.
Apixaban vs. warfarin in patients with left ventricular thrombus: a prospective multicentre randomized clinical trial
Authors: Alcalai Ronny , Butnaru Adi , Moravsky Gil , Yagel Oren , Rashad Razek , Ibrahimli Mahsati , Planer David , Amir Offer , Elbaz-Greener Gabby , Leibowitz David 
Published: July 2021

Abstract

Aims
Current guidelines recommend anticoagulation with a vitamin K antagonist to treat left ventricular (LV) thrombus after myocardial infarction (MI). Data on the use of direct oral anticoagulants (DOACs) in this setting are limited. The aim of the study was to assess the efficacy of apixaban vs. warfarin in treating LV thrombus after MI.

Methods and results
We conducted a prospective, randomized, multicentre open-label clinical trial including patients with LV thrombus detected by 2D transthoracic echocardiography 1–14 days after acute MI. Thirty-five patients were enrolled in three medical centres; 17 patients were randomized to warfarin and 18 patients to apixaban. The primary outcome was the presence and size of LV thrombus 3 months after initiation of anticoagulation. Secondary outcomes were major bleeding, stroke or systemic embolism, re-hospitalization, and all-cause mortality. Mean LV thrombus size at enrolment was 18.5 mm × 12.3 mm in the warfarin group and 19.9 mm × 12.4 mm in the apixaban group (P = NS). Thirty-two patients completed 3 months follow-up. In the warfarin group, two patients withdrew, and in the apixaban group one patient died. Thrombus completely resolved in 14 of 15 patients in the warfarin group and in 16 of 17 patients in the apixaban group (P = NS and P = 0.026 for non-inferiority). Two patients had major bleeding in the warfarin group, while no major bleeding events were recorded in the apixaban group. There was one stroke in the warfarin group and one death in the apixaban group.

Conclusion
Our results suggest that apixaban is non-inferior to warfarin for treatment of patients with LV thrombus after acute MI with a 20% non-inferiority margin.
Evidence for a force favoring GC over AT at short intronic sites in Drosophila simulans and Drosophila melanogaster
Authors: Jackson Ben , Charlesworth Brian 
Published: July 2021

Abstract
Population genetics studies often make use of a class of nucleotide site free from selective pressures, in order to make inferences about population size changes or natural selection at other sites. If such neutral sites can be identified, they offer the opportunity to avoid any confounding effects of selection. Here, we investigate evolution at putatively neutrally evolving short intronic sites in natural populations of Drosophila melanogaster and Drosophila simulans, in order to understand the properties of spontaneous mutations and the extent of GC-biased gene conversion in these species. Use of data on the genetics of natural populations is advantageous because it integrates information from large numbers of individuals over long timescales. In agreement with direct evidence from observations of spontaneous mutations in Drosophila, we find a bias in the spectrum of mutations toward AT basepairs. In addition, we find that this bias is stronger in the D. melanogaster lineage than in the D. simulans lineage. The evidence for GC-biased gene conversion in Drosophila has been equivocal. Here, we provide evidence for a weak force favoring GC in both species, which is correlated with the GC content of introns and is stronger in D. simulans than in D. melanogaster.
Distinct Retrotransposon Evolution Profile in the Genome of Rabbit (Oryctolagus cuniculus)
Authors: Yang Naisu , Zhao Bohao , Chen Yang , D’Alessandro Enrico , Chen Cai , Ji Ting , Wu Xinsheng , Song Chengyi 
Published: July 2021

AbstractAlthough the rabbit genome has already been annotated, it is mobilome remains largely unknown. Here, multiple pipelines were used to de novo mine and annotate the mobilome in rabbit. Four families and 19 subfamilies of LINE1s, two families and nine subfamilies of SINEs, and 12 ERV families were defined in rabbit based on sequence identity, structural organization, and phylogenetic tree. The analysis of insertion age and polymerase chain reaction suggests that a number of families are very young and may remain active, such as L1B, L1D, OcuSINEA, and OcuERV1. RepeatMasker annotation revealed a distinct transposable element landscape within the genome, with approximately two million copies of SINEs, representing the greatest proportion of the genome (19.61%), followed by LINEs (15.44%), and LTRs (4.11%), respectively, considerably different from most other mammal mobilomes except hedgehog and tree shrew, in which LINEs have the highest proportion. Furthermore, a very high rate of insertion polymorphisms (&gt;85%) for the youngest subfamily (OcuSINEA1) was identified by polymerase chain reaction. The majority of retrotransposon insertions overlapped with protein-coding regions (&gt;80%) and lncRNA (90%) genes. Genomic distribution bias was observed for retrotransposons, with those immediately upstream (−1 kb) and downstream (1 kb) of genes significantly depleted. Local GC content in 50-kb widows had significantly negative correlations with LINE (rs=−0.996) and LTR (rs=−0.829) insertions. The current study revealed a distinct mobilome landscape in rabbit, which will assist in the elucidation of the evolution of the genome of lagomorphs, and even other mammals.
The Drosophila HP1 family is associated with active gene expression across chromatin contexts
Authors: Schoelz John M , Feng Justina X , Riddle Nicole C 
Published: July 2021

Abstract
Drosophila Heterochromatin Protein 1a (HP1a) is essential for heterochromatin formation and is involved in transcriptional silencing. However, certain loci require HP1a to be transcribed. One model posits that HP1a acts as a transcriptional silencer within euchromatin while acting as an activator within heterochromatin. However, HP1a has been observed as an activator of a set of euchromatic genes. Therefore, it is not clear whether, or how, chromatin context informs the function of HP1 proteins. To understand the role of HP1 proteins in transcription, we examined the genome-wide binding profile of HP1a as well as two other Drosophila HP1 family members, HP1B and HP1C, to determine whether coordinated binding of these proteins is associated with specific transcriptional outcomes. We found that HP1 proteins share many of their endogenous binding targets. These genes are marked by active histone modifications and are expressed at higher levels than nontarget genes in both heterochromatin and euchromatin. In addition, HP1 binding targets displayed increased RNA polymerase pausing compared with nontarget genes. Specifically, colocalization of HP1B and HP1C was associated with the highest levels of polymerase pausing and gene expression. Analysis of HP1 null mutants suggests these proteins coordinate activity at transcription start sites to regulate transcription. Depletion of HP1B or HP1C alters expression of protein-coding genes bound by HP1 family members. Our data broaden understanding of the mechanism of transcriptional activation by HP1a and highlight the need to consider particular protein–protein interactions, rather than broader chromatin context, to predict impacts of HP1 at transcription start sites.
Embedding Community-Based Newborn Care in the Ethiopian health system: lessons from a 4-year programme evaluation
Authors: Avan Bilal Iqbal , Berhanu Della , Mekonnen Yirgalem , Beaumont Emma , Tomlin Keith , Allen Elizabeth , Schellenberg Joanna 
Published: July 2021

Abstract
Despite remarkable gains, improving neonatal survival globally remains slow paced. Innovative service-delivery packages have been developed for community health workers (CHWs) to maximize system efficiency and increase the reach of services. However, embedding these in health systems needs structural and procedural alignment. The Community-Based Newborn Care (CBNC) programme was a response to high neonatal mortality in Ethiopia. Key aspects include simplified treatment for neonatal illness, integrated outreach services and task-shifting. Using the CHW functionality model by WHO, this study evaluates the health system response to the programme, including quality of care. A before-and-after study was conducted with three survey time points: baseline (November 2013), midline (December 2015) and follow-up (December 2017—4 years after the programme started). Data were collected at a sample of primary healthcare facilities from 101 districts across four regions. Analysis took two perspectives: (1) health system response, through supplies, infrastructure support and supervision, assessed through interviews and observations at health facilities and (2) quality of care, through CHWs’ theoretical capacity to deliver services, as well as their performance, assessed through functional health literacy and direct observation of young infant case management. Results showed gains in services for young infants, with antibiotics and job aids available at over 90% of health centres. However, services at health posts remained inadequate in 2017. In terms of quality of care, only 37% of CHWs correctly diagnosed key conditions in sick young infants at midline. CHWs’ functional health literacy declined by over 70% in basic aspects of case management during the study. Although the frequency of quarterly supportive supervision visits was above 80% during 2013–2017, visits lacked support for managing sick young infants. Infrastructure and resources improved over the course of the CBNC programme implementation. However, embedding and scaling up the programme lacked the systems-thinking and attention to health system building-blocks needed to optimize service delivery.
Pre-exposure prophylaxis for transgender women and men who have sex with men: qualitative insights from healthcare providers, community organization–based leadership and end users in coastal Kenya
Authors: Kimani Makobu , Sanders Eduard J , Chirro Oscar , Mukuria Nana , Mahmoud Shally , Rinke de Wit Tobias F , Graham Susan M , Operario Don , van der Elst Elise M 
Published: July 2021

AbstractTransgender women (TW) and men who have sex with men (MSM) in Kenya are disproportionately affected by human immunodeficiency virus (HIV) and would benefit substantially from pre-exposure prophylaxis (PrEP). We conducted focus group discussions (FGDs) with healthcare providers (HCPs) and TW/MSM leadership and in-depth interviews (IDIs) with PrEP-experienced MSM and TW to learn about perceived and actual barriers to PrEP programming. Eleven HCP and 10 TW/MSM leaders participated in FGDs before PrEP roll-out (January 2018) and 12 months later. Nineteen PrEP end-users (11 MSM and 8 TW) participated in IDIs. Topic guides explored PrEP knowledge, HIV acquisition risk, gender identity, motivation for PrEP uptake and adherence and PrEP-dispensing venue preferences. Braun and Clarke thematic analysis was applied. Four themes emerged: limited preparedness of HCPs to provide PrEP to TW and MSM, varied motivation for PrEP uptake and persistence among end users, lack of recognition of TW by HCPs and suggestions for PrEP programming improvement from all stakeholders. Providers’ reluctance to prescribe PrEP to TW and distrust of TW towards providers calls for interventions to improve the capacity of service environments and staff HIV preventive care. Alternative locations for PrEP provision, including community-based sites, may be developed with TW/MSM leaders.
Ciprofloxacin population pharmacokinetics during long-term treatment of osteoarticular infections
Authors: Zahr Noël , Urien Saik , Aubry Alexandra , Chauvin Charlotte , Comets Emmanuelle , Llopis Benoit , Tissot Nadine , Noe Gaëlle , Fourniols Eric , Jaureguiberry Stéphane , Bleibtreu Alexandre , Funck-Brentano Christian ,   the Centre de Référence pour le traitement des Infections Ostéo-Articulaires Complexes (CRIOAC) Pitié-Salpêtrière Hospital, Barrut Nicolas , Bonnet Isabelle , Calin Ruxandra , Caumes Eric , Clarençon Frédéric , Daas Georges , Fautrel Bruno , Fustier Anne , Gandjbakhch Frédérique , Haddad Elie , Khiami Frédéric , Lazennec Jean Yves , Marchant Maxime , Mercy Guillaume , Metz Carole , Miu Mihaela , Mitrovic Stéphane , Monsel Gentiane , Monzani Quentin , Reubrecht Vanessa , Robert Jérôme 
Published: July 2021

Abstract

Background
Ciprofloxacin is an antibiotic used in osteoarticular infections owing to its very good bone penetration. Very few pharmacokinetic data are available in this population.

Objectives
To investigate oral ciprofloxacin population pharmacokinetics in adult patients treated for osteoarticular infections and propose guidance for more effective dosing.

Methods
A retrospective population-pharmacokinetic analysis was performed on 92 consecutive hospitalized patients in the orthopaedic department. Ciprofloxacin plasma samples were obtained on one or two occasions during treatment. Plasma concentration was measured using ultra-performance liquid chromatography system coupled with tandem mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2019R2.

Results
A total of 397 plasma samples were obtained with 11.5% and 41.6% of patients being below the therapeutic target for Gram-negative and staphylococcal infections, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model with a first-order absorption. Ciprofloxacin apparent plasma clearances and volumes of distribution were dependent on patients’ fat-free mass according to the allometric rule. Elimination clearance was also positively related to renal function through the modification of diet in renal disease equation (MDRD) and rifampicin co-administration. When patients are co-treated with rifampicin, ciprofloxacin dosage should be increased by 50% to 60%.

Conclusions
This study showed that free-fat mass was a better size predictor than total body weight for ciprofloxacin clearance and volumes terms. Moreover, both MDRD and rifampicin status were significant predictors of individual ciprofloxacin clearance. Our study suggests that individual adjustment of ciprofloxacin dose in osteoarticular infections with less-susceptible bacteria might be indicated to reach required efficacy targets.
Learning decision thresholds for risk stratification models from aggregate clinician behavior
Authors: Patel Birju S , Steinberg Ethan , Pfohl Stephen R , Shah Nigam H 
Published: July 2021

Abstract
Using a risk stratification model to guide clinical practice often requires the choice of a cutoff—called the decision threshold—on the model’s output to trigger a subsequent action such as an electronic alert. Choosing this cutoff is not always straightforward. We propose a flexible approach that leverages the collective information in treatment decisions made in real life to learn reference decision thresholds from physician practice. Using the example of prescribing a statin for primary prevention of cardiovascular disease based on 10-year risk calculated by the 2013 pooled cohort equations, we demonstrate the feasibility of using real-world data to learn the implicit decision threshold that reflects existing physician behavior. Learning a decision threshold in this manner allows for evaluation of a proposed operating point against the threshold reflective of the community standard of care. Furthermore, this approach can be used to monitor and audit model-guided clinical decision making following model deployment.
A theory-based meta-regression of factors influencing clinical decision support adoption and implementation
Authors: Liu Siru , Reese Thomas J , Kawamoto Kensaku , Del Fiol Guilherme , Weir Charlene 
Published: July 2021

Abstract

Objective
The purpose of the study was to explore the theoretical underpinnings of effective clinical decision support (CDS) factors using the comparative effectiveness results.

Materials and Methods
We leveraged search results from a previous systematic literature review and updated the search to screen articles published from January 2017 to January 2020. We included randomized controlled trials and cluster randomized controlled trials that compared a CDS intervention with and without specific factors. We used random effects meta-regression procedures to analyze clinician behavior for the aggregate effects. The theoretical model was the Unified Theory of Acceptance and Use of Technology (UTAUT) model with motivational control.

Results
Thirty-four studies were included. The meta-regression models identified the importance of effort expectancy (estimated coefficient = −0.162; P = .0003); facilitating conditions (estimated coefficient = 0.094; P = .013); and performance expectancy with motivational control (estimated coefficient = 1.029; P = .022). Each of these factors created a significant impact on clinician behavior. The meta-regression model with the multivariate analysis explained a large amount of the heterogeneity across studies (R2 = 88.32%).

Discussion
Three positive factors were identified: low effort to use, low controllability, and providing more infrastructure and implementation strategies to support the CDS. The multivariate analysis suggests that passive CDS could be effective if users believe the CDS is useful and/or social expectations to use the CDS intervention exist.

Conclusions
Overall, a modified UTAUT model that includes motivational control is an appropriate model to understand psychological factors associated with CDS effectiveness and to guide CDS design, implementation, and optimization.
Tracing the NGLY1 footprints: insights from Drosophila
Authors: Pandey Ashutosh , Jafar-Nejad Hamed 
Published: July 2021

Abstract
Recessive mutations in human N-glycanase 1 (NGLY1) cause a multisystem disorder with various phenotypes including global developmental delay. One of the models utilized to understand the biology of NGLY1 and the pathophysiology of NGLY1 deficiency is Drosophila melanogaster, a well-established, genetically tractable organism broadly used to study various biological processes and human diseases. Loss of the Drosophila NGLY1 homolog (Pngl) causes a host of phenotypes including developmental delay and lethality. Phenotypic, transcriptomic and genome-wide association analyses on Drosophila have revealed links between NGLY1 and several critical developmental and cellular pathways/processes. Further, repurposing screens of Food and Drug Administration (FDA)-approved drugs have identified potential candidates to ameliorate some of the Pngl-mutant phenotypes. Here, we will summarize the insights gained into the functions of NGLY1 from Drosophila studies. We hope that the current review article will encourage additional studies in Drosophila and other model systems towards establishing a therapeutic strategy for NGLY1 deficiency patients.