bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracheostomy in children promotes persistent neutrophilic airway inflammation
Authors: Powell Jason , Powell Steven , Mather Michael W , Beck Lauren , Nelson Andrew , Palmowski Pawel , Porter Andrew , Coxhead Jonathan , Hedley Ann , Scott Jonathan , Rostron Anthony J , Hellyer Thomas P , Zaidi Fatima , Davey Tracey , Garnett James P , Agbeko Rachel , Ward Chris , Stewart Christopher J , Taggart Clifford C , Brodlie Malcolm , Simpson A John 
Published: August 2022

ABSTRACTBackgroundTracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs, and excess mortality. The underlying mechanisms facilitating adverse outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses.MethodsTracheal aspirates, tracheal cytology brushings, nasal swabs and stool samples were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic, and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome.ResultsChildren followed up serially from the time of tracheostomy up to three months post-procedure (n=9) were studied. A validation cohort of children with a long-term tracheostomy was also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Tracheostomy was associated with new, rapidly emergent and sustained airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. In contrast, reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter.ConclusionsChildhood tracheostomy is associated with rapidly emergent and persistent airway neutrophil recruitment and activation, with sustained proteolysis and superoxide generation. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.Key messageThe effect tracheostomy has on children is not described. Tracheostomy in children results in persistent local airway neutrophilic inflammation, proteolysis, superoxide production and dysbiosis.
Phenotype and genetic analysis of data collected within the first year of NeuroDev
Authors: Kipkemoi Patricia , Kim Heesu Ally , Christ Bjorn , O’Heir Emily , Allen Jake , Austin-Tse Christina , Baxter Samantha , Brand Harrison , Bryant Sam , Buser Nick , de Menil Victoria , Eastman Emma , Murugasen Serini , Galvin Alice , Kombe Martha , Ngombo Alfred , Mkubwa Beatrice , Mwangi Paul , Kipkoech Collins , Lovgren Alysia , MacArthur Daniel G. , Melly Brigitte , Mwangasha Katini , Martin Alicia , Nkambule Lethukuthula L. , Sanchis-Juan Alba , Singer-Berk Moriel , Talkowski Michael E. , VanNoy Grace , van der Merwe Celia ,   The NeuroDev Project, Newton Charles , O’Donnell-Luria Anne , Abubakar Amina , Donald Kirsten A , Robinson Elise 
Published: August 2022

SummaryGenetic association studies have made significant contributions to our understanding of the aetiology of neurodevelopmental disorders (NDDs). However, the vast majority of these studies have focused on populations of European ancestry, and few include individuals from the African continent. The NeuroDev project aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from Kenya and South Africa. Here we present results from NeuroDev’s first year of data collection, including phenotype data from 206 cases and clinical genetic analysis of 99 parent-child trios. The majority of the cases met criteria for global developmental delay/intellectual disability (GDD/ID, 80.3%). Approximately half of the children with GDD/ID also met criteria for autism, and 14.6% met criteria for autism alone. Analysis of exome sequencing data identified a pathogenic or likely pathogenic variant in 13 (17%) of the 75 cases from South Africa and 9 (38%) of the 24 cases from Kenya, as well as 7 total cases with suspicious variants of uncertain significance (VUS) in emerging disease genes that were matched through the MatchMaker Exchange. Data from the trio pilot cases has already been made publicly available, and the NeuroDev project will continue to develop resources for the global genetics community.
Expanding the Phenotypic spectrum ofNAA10-related neurodevelopmental syndrome andNAA15-related neurodevelopmental syndrome
Authors: Lyon Gholson J. , Vedaie Marall , Besheim Travis , Park Agnes , Marchi Elaine , Gottlieb Leah , Hsieh Tzung-Chien , Klinkhammer Hannah , Sandomirsky Katherine , Cheng Hanyin , Starr Lois J. , Preddy Isabelle , Tseng Marcellus , Li Quan , Hu Yu , Wang Kai , Carvalho Ana , Martinez Francisco , Caro-Llopis Alfonso , Gavin Maureen , Amble Karen , Krawitz Peter , Marmorstein Ronen , Herr-Israel Ellen 
Published: August 2022

AbstractAmino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene,NAA10,encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation inNAA10andNAA15in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals withNAA10variants and 19 individuals withNAA15variants, which were added to all known cases (N=106 forNAA10and N=66 forNAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands withNAA10variants is significantly lower than the probands withNAA15variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with anNAA15frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end ofNAA10have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.
Model Choice Metrics to Optimize Profile-QSAR Performance
Authors: He Stewart , Kim Sookyung , McLoughlin Kevin S. , Ranganathan Hiranmayi , Shi Da , Allen Jonathan E. 
Published: August 2022

AbstractBackgroundPredicting molecular activity against protein targets is difficult because of the paucity of experimental data. Approaches like multitask modeling and collaborative filtering seek to improve model accuracy by leveraging results from multiple targets, but are limited because different compounds are measured with different assays, leading to sparse data matrices. Profile-QSAR (pQSAR) 2.0 addresses this problem by fitting a series of partial least squares models for each target, using as features the predictions from single-task models on the remaining targets. This method has been shown to produce better results than single task and multitask models. However, the factors determining the success of pQSAR 2.0 have as yet not been characterized.In this paper we examine the experimental conditions that lead to better pQSAR models. We limit the amount of data available to the method by retraining with decreasing amounts of data and explore the model’s ability to generalize to compounds that have never been assayed. Finally, we look at the properties of training data needed to demonstrate pQSAR improvement.ResultsWe apply pQSAR 2.0 on a collection of GPCR and safety targets collected from Drug Target Commons, ExcapeDB, and ChEMBL. We found that pQSAR improved models on 34 of the 149 assays selected. In the other 115 assays, single task random forests offered better performance. There are many factors that contribute to an increase in performance, but the main factor is compound assay coverage. The pQSAR model improves when more compounds are measured in multiple assays.ConclusionIt is necessary to consider the available data before applying pQSAR. Successful pQSAR models require a profile made of correlated targets that share compounds with other assays. This technique is best used when experimental data is available as random forest regressors often do not generalize well enough for virtual drug search applications.
Midbrain structure volume, estimated myelin and functional connectivity in idiopathic generalised epilepsy
Authors: McKavanagh Andrea , Ridzuan-Allen Adam , Kreilkamp Barbara A.K. , Chen Yachin , Manjón José V. , Coupé Pierrick , Bracewell Martyn , Das Kumar , Taylor Peter N. , Marson Anthony G. , Keller Simon S. 
Published: August 2022

AbstractBackgroundPrevious neuroimaging studies reported functional and structural impairments of the upper basal ganglia (specifically, the striatum) in idiopathic generalised epilepsy (IGE). However, these studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired volumetric T1-weighted scans. Here, we acquired 3D isotropic T1-weighted, T2-weighted and resting state functional MR images to investigate differences in volume, estimated myelin content and functional connectivity in three midbrain and midbrain-adjacent structures in patients with IGE: the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN).MethodsA total of 33 patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex matched healthy controls underwent MR imaging. The SN, SubTN and RN were automatically segmented from T2-weighted images. Estimated median myelin content for each structure was determined using a previously described T1-weighted/T2-weighted ratio method. Functional connectivity analysis between midbrain structures and the rest of the brain was performed using seed-based resting state fMRI analysis and compared between participant groups using the CONN toolbox running in SPM12 (pFDR<0.05, cluster corrected).ResultsAn increased volume of the right RN was found in patients with IGE relative to healthy controls. Structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. No myelin alterations of midbrain structures were found in patients with IGE or between treatment outcome groups. Functional connectivity alterations were found for all midbrain regions in patients with IGE, including significantly decreased functional connectivity between the left SN and the thalamus compared to controls, and significantly increased functional connectivity observed between the right SubTN and the left superior frontal gyrus in patients with IGE relative to controls. Connectivity alterations specific to patients with non-refractory IGE were also found.ConclusionWe report volumetric and functional connectivity alterations of midbrain and lower basal ganglia structures in patients with IGE. We postulate that an increased structural volume of the RN in patients is due to increased iron deposition that impacts on T2-weighted contrast. These findings are consistent with previous experiential work demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy.
Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: insights into disease mechanisms and tissue characterization
Authors: Assis-Mendonça Guilherme Rossi , Pedro Athié Maria Carolina , Gerdulli Tamanini João Vitor , de Souza Arethusa , Zanetti Gabriel Gerardini , de Aguiar Araújo Patrícia Aline Oliveira Ribeiro , Ghizoni Enrico , Tedeschi Helder , Machado Alvim Marina Koutsodontis , de Almeida Vanessa Simão , de Souza Welliton , Coras Roland , Yasuda Clarissa Lin , Blümcke Ingmar , Vieira André Schwambach , Cendes Fernando , Lopes-Cendes Iscia , Rogerio Fabio 
Published: August 2022

ABSTRACTFocal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. The top enriched cellular pathway in IIa and IIb gray matter was cholesterol biosynthesis, the genes HMGCS1, HMGCR, and SQLE being upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gay or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.
Knowledge, attitude, and practice of ward attendant and housekeeping staffs towards dead body care of COVID-19 patient at tertiary care hospital : A cross sectional study
Authors: Saini Giriraj , Panda Prasan K , Sharma Maneesh , Singh Mahendra , Meshram Ravi 
Published: August 2022

AbstractBackgroundHealthcare workers worked untiringly during entire pandemic period and taken efforts to protect individuals, families and communities in adverse situations with stretched resources. Among health care workers role of ward attendant and housekeeping staffs have been very significant particularly in infection control practices and dead body management. Present study’s aim is to gain an understanding of the knowledge, attitudes, and practices (KAP) of ward attendant and housekeeping staffs towards dead body management.MethodsHospital-based cross-sectional study design was conducted among ward attendant and housekeeping staffs working in COVID units. A total of 62 participants were selected using simple random sampling technique. Self-administered questionnaire was used to collect data. Binary logistic regression model was used to see association between outcome and independent variables.ResultPresent study found mean knowledge, attitude and practice score of participants were 6.1, 49.9 and 12.28 indicates good knowledge, positive attitude and inappropriate practice towards dead body care. Study result also shows that odds of good knowledge were not significantly associated with demographic variables. However, the participants who didn’t receive any training on dead body care were found to have positive attitude towards dead body care(AOR=3.90,95%CI=1.092-13.92), whereas gender (AOR=1.85,95%CI=.430-7.96), working experience in COVID units (AOR=99.5,95%CI=.913-98.8) and educational qualification (AOR=30.33,95%CI=1.5-577) were significantly associated with practice of dead body care of COVID-19 patients.ConclusionThe study found that majority of participants were having good knowledge, positive attitude and inappropriate practice towards dead body care of COVID-19 patients. Hospital administration should conduct regular training of dead body care of COVID-19 patients for all the housekeeping staffs and ward attendant to minimise the risk of exposure to infections and better management of dead bodies.
Hierarchical machine learning predicts geographical origin of Salmonella within four minutes of sequencing
Authors: Bayliss Sion C. , Locke Rebecca K. , Jenkins Claire , Chattaway Marie Anne , Dallman Timothy J. , Cowley Lauren A. 
Published: August 2022

AbstractSalmonella enterica serovar Enteritidis is one of the most frequent causes of Salmonellosis globally and is commonly transmitted from animals to humans by the consumption of contaminated foodstuffs. Herein, we detail the development and application of a hierarchical machine learning model to rapidly identify and trace the geographical source of S. Enteritidis infections from whole genome sequencing data. 2,313 S. Enteritidis genomes collected by the UKHSA between 2014-2019 were used to train a ‘local classifier per node’ hierarchical classifier to attribute isolates to 4 continents, 11 sub-regions and 38 countries (53 classes). Highest classification accuracy was achieved at the continental level followed by the sub-regional and country levels (macro F1: 0.954, 0.718, 0.661 respectively). A number of countries commonly visited by UK travellers were predicted with high accuracy (hF1: >0.9). Longitudinal analysis and validation with publicly accessible international samples indicated that predictions were robust to prospective external datasets. The hierarchical machine learning framework provides granular geographical source prediction directly from sequencing reads in <4 minutes per sample, facilitating rapid outbreak resolution and real-time genomic epidemiology.
Understanding Waiting Lists Pressures
Authors: Fong Kevin , Mushtaq Yasser , House Thomas , Gordon Dan , Chen Yingrae , Griffths Darren , Ahmad Shazaad , Walton Neil 
Published: August 2022

AbstractNHS waiting lists currently sit at record lengths due to a combination of the immediate impact of the pandemic and, as well as, long-run pressures requiring investment on NHS resources. These factors have left managers and clinicians with increasingly complex decisions when scheduling elective operations. It is imperative that managers understand the basic dynamics, tradeoffs, and pressures when managing waiting lists.Queueing theory is a key part of operational research, extensively used throughout manufacturing, retail, information technology and other sectors. This article provides an exposition of the theory of queues within the context of the current NHS backlog. With this information a manager will be able understand the demand, queue size, waiting times, capacity requirements and trade-offs for different waiting lists. We describe the metrics and a reporting system developed to understand waiting list pressures in a large NHS trust. Our aim is to enable managers to better understand their waiting lists, to achieve targets and improve health outcomes.
Sleep Instability in Paradoxical Insomnia is Associated with Perception of Sleep
Authors: Lo Evelyn , Tsai Hsin-Jung , Yang Albert C. 
Published: August 2022

AbstractObjectiveThe main clinical characteristics that diversify paradoxical insomniacs from objective insomnia patients remain unclear. The current study systematically examined the difference in sleep-related, subjective-and objective parameters between insomnia patients with or without misperception.MethodsPatients who reported having poor sleep quality (subjective sleep efficiency; SE ≤ 85%) on both weekends and weekdays and difficulty falling asleep in the Sleep Heart Health Study were examined in this study. Patients with objective SE ≤ 85% and > 85% were then classified as objective insomnia (n = 58) and paradoxical insomnia (n = 61), respectively. The differences in demographic data, subjective sleep quality, daytime function, and objective sleep architecture measured by polysomnography, were assessed between the groups.ResultsThough there were no significant group differences in the demographics between objective insomniacs and paradoxical insomniacs, paradoxical insomniacs reported significantly poorer daytime function than patients with objective insomnia. Moreover, paradoxical insomniacs’ subjective sleep evaluation on recording day was significantly higher than habitual reports. The main finding from this research was that the transition indices from stage N3 to stage N2 or N1 was significantly different between the two groups, which could indicate that sleep instability may be a factor in leading paradoxical insomnia patients to underestimate their sleep efficiency.ConclusionsOur findings indicated a possible link between sleep misperception and the microstructure of sleep, specifically the sleep-state instability. The interplay between the neurobiology of sleep instability and perception of sleep needs further investigation.
The Role of Modelling and Analytics in South African COVID-19 Planning and Budgeting
Authors: Meyer-Rath Gesine , Hounsell Rachel A , Pulliam Juliet RC , Jamieson Lise , Nichols Brooke E , Moultrie Harry , Silal Sheetal P 
Published: August 2022

ABSTRACTBackgroundThe South African COVID-19 Modelling Consortium (SACMC) was established in late March 2020 to support planning and budgeting for COVID-19 related healthcare in South Africa. We developed several tools in response to the needs of decision makers in the different stages of the epidemic, allowing the South African government to plan several months ahead of time.MethodsOur tools included epidemic projection models, several cost and budget impact models, and online dashboards to help government and the public visualise our projections, track case development and forecast hospital admissions. Information on new variants, including Delta and Omicron, were incorporated in real time to allow the shifting of scarce resources when necessary.ResultsGiven the rapidly changing nature of the outbreak globally and in South Africa, the model projections were updated regularly. The updates reflected 1) the changing policy priorities over the course of the epidemic; 2) the availability of new data from South African data systems; and 3) the evolving response to COVID-19 in South Africa such as changes in lockdown levels and ensuing mobility and contact rates, testing and contact tracing strategies, and hospitalisation criteria. Insights into population behaviour required updates by incorporating notions of behavioural heterogeneity and behavioural responses to observed changes in mortality. We incorporated these aspects into developing scenarios for the third wave and developed additional methodology that allowed us to forecast required inpatient capacity. Finally, real-time analyses of the most important characteristics of the Omicron variant first identified in South Africa in November 2021 allowed us to advise policymakers early in the fourth wave that a relatively lower admission rate was likely.ConclusionThe SACMC’s models, developed rapidly in an emergency setting and regularly updated with local data, supported national and provincial government to plan several months ahead of time, expand hospital capacity when needed, allocate budgets, and procure additional resources where possible. Across four waves of COVID-19 cases, the SACMC continued to serve the planning needs of the government, tracking waves and supporting the national vaccine rollout.