bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decision support system to evaluate VENTilation in the Acute Respiratory Distress Syndrome (DeVENT study) – Trial Protocol
Authors: Patel Brijesh , Mumby Sharon , Johnson Nicholas , Falaschetti Emanuela , Hansen Jorgen , Adcock Ian , McAuley Danny , Takata Masao , Karbing Dan S. , Jabaudon Matthieu , Schellengowski Peter , Rees Stephen E. 
Published: September 2021

AbstractBackgroundThe Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.MethodsWe will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.DiscussionDespite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic), could change the outcome of mechanically ventilated patients during the course of this and future pandemics.Trial registrationClinicalTrials.gov identifier (NCT number): NCT04115709Administrative informationNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).
High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine
Authors: Joyce KE , Onabanjo E , Brownlow S , Nur F , Olupona KO , Fakayode K , Sroya M , Thomas G , Ferguson T , Redhead J , Millar CM , Cooper N , Layton DM , Boardman-Pretty F , Caulfield MJ ,   Genomics England Research Consortium, Shovlin CL 
Published: September 2021

ABSTRACTPossession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.
Past dynamics of HIV transmission among men who have sex with men in Montréal, Canada: a mathematical modelling study
Authors: Milwid Rachael M , Xia Yiqing , Doyle Carla , Cox Joseph , Lambert Gilles , Thomas Réjean , Mishra Sharmistha , Grace Daniel , Lachowsky Nathan J , Hart Trevor A , Boily Marie-Claude , Maheu-Giroux Mathieu 
Published: September 2021

AbstractBackgroundGay, bisexual, and other men who have sex with men (gbMSM) experience disproportionate risks of HIV acquisition/transmission. In 2017, Montréal became the first Canadian Fast-Track city, setting the 2030 goal of zero new HIV infections. To inform local elimination efforts, we estimate the evolving role of prevention/risk behaviours and HIV transmission dynamics among gbMSM in Montréal between 1975-2019.MethodsData from local bio-behavioural surveys were analyzed to develop, parameterize, and calibrate an agent-based model of sexual HIV transmission. Partnership dynamics, the HIV natural history, and treatment and prevention strategies were considered. The model simulations were analyzed to estimate the fraction of HIV acquisitions/transmissions attributable to specific age-groups and unmet prevention needs.ResultsThe model-estimated HIV incidence peaked in 1985 (2.2%; 90%CrI: 1.3-2.8%) and decreased to 0.1% (90%CrI: 0.04-0.3%) in 2019. Between 1990-2017, the majority of HIV acquisitions/transmissions occurred among men aged 25-44 years, and men aged 35-44 thereafter. The unmet prevention needs of men with >10 annual anal sex partners contributed 92-94% of transmissions and 63-73% of acquisitions annually. The primary stage of HIV played an increasing role over time, contributing to 12%-27% of annual transmissions over 1990-2019. In 2019, approximately 75% of transmission events occurred from men who had discontinued, or never initiated ART.ConclusionsThe evolving HIV landscape has contributed to the recent low HIV incidence among MSM in Montréal. The shifting dynamics identified in this study highlight the need for continued population-level surveillance to identify unmet prevention needs and core groups on which to prioritize elimination efforts.
Potential Pharmacodynamic Mechanism of the Main ingredients in Licorice for Chronic Obstructive Pulmonary Disease
Authors: Chen Cai , An Jianpeng , Shen Guodong , Shen Yang 
Published: September 2021

AbstractPurposeThis study aimed to investigate the effect of essential ingredients of licorice on the chronic obstructive pulmonary disease (COPD).MethodThe ingredients information were obtained fromPubChem(https://pubchem.ncbi.nlm.nih.gov/), related genes about COPD was collected fromgeneCards(http://www.genecards.org/).Networkpharmacology was utilized in this study.ResultThe intersection data set contains 20 molecular targets between COPD and liquorice. Protein-protein interaction network showed that there are a total of 58 nodes and 137 edges involved. The link number of AKT1 in PPI network was 39, which is the highest level of interaction. MAPK1 is an important target of Licorice on COPD.ConclusionMAPK signaling pathway could be the important key target of main ingredients of licorice on COPD.
Compensatory reconfiguration of functional networks between white matter and grey matter in Alzheimer’s disease
Authors: Zhang Xingxing , Guan Qing , Dong Debo , Chen Fuyong , Yi Jing , Luo Yuejia , Zhang Haobo ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2021

AbstractThe temporal synchronization of BOLD signals within white matter (WM) and between WM and grey matter (GM) exhibited intrinsic architecture and cognitive relevance. However, few studies examined the network property within- and between-tissue in Alzheimer’s disease (AD). The hub regions with high weighted degree (WD) were prone to the neuropathological damage of AD. To systematically investigate the changes of hubs within- and between-tissue functional networks in AD patients, we used the resting-state fMRI data of 30 AD patients and 37 normal older adults (NC) from the ADNI open database, and obtained four types of voxel-based WD metrics and four types of distant-dependent WD metrics (ddWD) based on a series of Euclidean distance ranges with a 20mm increment. We found that AD patients showed decreased within-tissue ddWD in the thalamic nucleus and increased between-tissue ddWD in the occipito-temporal cortex, posterior thalamic radiation, and sagittal stratum, compared to NC. We also found that AD patients showed the increased between-tissue FCs between the posterior thalamic radiation and occipito-temporal cortex, and between the sagittal stratum and the salience and executive networks. The dichotomy of decreased and increased ddWD metrics and their locations were consistent with previous studies on the neurodegnerative and compensatory mechanisms of AD, indicating that despite the disruptions, the brain still strived to compensate for the neural inefficiency by reorganizing functional circuits. Our findings also suggested the short-to-medium ranged ddWD metrics between WM and GM as useful biomarker to detect the compensatory changes of functional networks in AD.
Explainable Machine Learning Analysis Reveals Gender Differences in the Phenotypic and Neurobiological Markers of Cannabis Use Disorder
Authors: Niklason Gregory , Rawls Eric , Ma Sisi , Kummerfeld Erich , Maxwell Andrea M. , Brucar Leyla R. , Drossel Gunner , Zilverstand Anna 
Published: September 2021

AbstractBackgroundCannabis Use Disorder (CUD) has been linked to environmental, personality, mental health, neurocognitive and neurobiological risk factors. While many studies have revealed gender differences in CUD, the relative importance of these complex factors by gender has not been described.MethodsWe conducted a data-driven examination of gender differences in CUD in a community sample of young adults (Human Connectome Project [HCP]; n = 1204, 54% female). We employed state-of-the-art machine learning methods [gradient tree boosting, XGBoost] in combination with novel factor ranking tools [SHapley’s Additive exPlanations (SHAP)] as an ‘explainable machine learning approach’ in the multimodal data collected by the HCP (phenotypic and brain data).ResultsWe were able to successfully classify both cannabis dependence and cannabis use levels. Previously identified environmental, personality, mental health, neurocognitive, and brain factors highly contributed to the classification. Predominantly-male risk factors included personality (high openness), mental health (high externalizing, high childhood conduct disorder, high fear somaticism), neurocognitive (impulsive delay discounting, slow working memory performance) and brain (low hippocampal volume) factors. Conversely, predominantly-female risk factors included environmental (low education level, low instrumental support) factors.ConclusionsOur data-driven analysis of gender differences in the multimodal risk factors underlying cannabis dependence and use levels demonstrate that environmental factors contribute more strongly to CUD in women, whereas individual factors such as personality, mental health and neurocognitive factors have a larger importance in men. This warrants further investigations, and suggests the importance of understanding how these differences relate to the development of effective treatment approaches.
Predation risk differentially affects aphid morphotypes: impacts on prey behavior, fecundity and transgenerational dispersal morphology
Authors: Hermann Sara L. , Bird Sydney A. , Ellis Danielle R. , Landis Douglas A. 
Published: September 2021

ABSTRACTTo avoid predation, prey initiate anti-predator defenses such as altered behavior, physiology and/or morphology. Prey trait changes in response to perceived predation risk can influence several aspects of prey biology that collectively contribute to individual success and thus population growth. However, studies often focus on single trait changes in a discrete life stage or morphotype. We assessed how predation risk by Harmonia axyridis affects several important traits in the aphid, Myzus persicae: host plant preference, fecundity and investment in dispersal. Importantly, we examined whether these traits changed in a similar way between winged (alate) and wingless (apterous) adult aphid morphotypes, which differ in morphology, but also in life-history characteristics important for reproduction and dispersal. Host plant preference was influenced by the presence of H.axyridis odors in choice tests; wingless aphids were deterred by the odor of plants with H.axyridis whereas winged aphids preferred plants with H.axyridis present. Wingless aphids reared in the presence of ladybeetle cues produced fewer offspring in the short-term, but significantly more when reared with exposure to predator cues for multiple generations. However, winged aphid fecundity was unaffected by H.axyridis cues. Lastly, transgenerational plasticity was demonstrated in response to predation risk via increased formation of winged aphid morphotypes in the offspring of predator cue-exposed wingless mothers. Importantly, we found that responses to risk differ across aphid polyphenism and that plasticity in aphid morphology occurs in response to predation risk. Together our results highlight the importance of considering how predation risk affects multiple life stages and morphotypes.
Systematic shifts in the variation among host individuals must be considered in climate-disease theory
Authors: Mihaljevic Joseph R , Páez David J. 
Published: September 2021

AbstractTo make more informed predictions of host-pathogen interactions under climate change, studies have incorporated the thermal performance of host, vector, and pathogen traits into disease models. However, this body of work has ignored the fact that disease spread and long-term patterns of host population dynamics are largely determined by the variation in susceptibility among individuals in the host population. Furthermore, and especially for ectothermic host species, variation in susceptibility is likely to be plastic, influenced by variables such as environmental temperature. For example, as host individuals respond idiosyncratically to temperature, this could affect the population-level variation in susceptibility, such that there may be predictable functional relationships between variation in susceptibility and temperature. Quantifying the relationship between temperature and among-host trait variation will therefore be critical for predicting how climate change and disease will interact to influence host-pathogen population dynamics. Here, we use a model to demonstrate how short-term effects of temperature on the variation of host susceptibility can drive epidemic characteristics, fluctuations in host population sizes, and probabilities of host extinction. Our results emphasize that more research is needed in disease ecology and climate biology to understand the mechanisms that shape trait variation, not just trait averages.
Coordinated drift of receptive fields during noisy representation learning
Authors: Qin Shanshan , Farashahi Shiva , Lipshutz David , Sengupta Anirvan M. , Chklovskii Dmitri B. , Pehlevan Cengiz 
Published: September 2021

AbstractLong-term memories and learned behavior are conventionally associated with stable neuronal representations. However, recent experiments showed that neural population codes in many brain areas continuously change even when animals have fully learned and stably perform their tasks. This representational “drift” naturally leads to questions about its causes, dynamics, and functions. Here, we explore the hypothesis that neural representations optimize a representational objective with a degenerate solution space, and noisy synaptic updates drive the network to explore this (near-)optimal space causing representational drift. We illustrate this idea in simple, biologically plausible Hebbian/anti-Hebbian network models of representation learning, which optimize similarity matching objectives, and, when neural outputs are constrained to be nonnegative, learn localized receptive fields (RFs) that tile the stimulus manifold. We find that the drifting RFs of individual neurons can be characterized by a coordinated random walk, with the effective diffusion constants depending on various parameters such as learning rate, noise amplitude, and input statistics. Despite such drift, the representational similarity of population codes is stable over time. Our model recapitulates recent experimental observations in hippocampus and posterior parietal cortex, and makes testable predictions that can be probed in future experiments.
Weakly activated core inflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer’s disease
Authors: Li Fuhai , Eteleeb Abdallah , Buchser William , Wang Guoqiao , Xiong Chengjie , Payne Philip R. , McDade Eric , Karch Celeste M. , Harari Oscar , Cruchaga Carlos 
Published: September 2021

AbstractNeuro-inflammation signaling has been identified as an important hallmark of Alzheimer’s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, our knowledge of neuro-inflammation is very limited; and the core signaling pathways associated with neuro-inflammation are missing. From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), in this study, we uncovered the core neuro-inflammation signaling pathways in AD. Our novel hypothesis is that weakly activated neuro-inflammation signaling pathways can cause neuro-degeneration in a chronic process; whereas, strongly activated neuro-inflammation often cause acute disease progression like in COVID-19. Using the two large-scale genomics datasets, i.e., Mayo Clinic (77 control and 81 AD samples) and RosMap (97 control and 260 AD samples), our analysis identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of genes in the virus infection, immune response and x-core signaling pathways, are associated with inflammation molecular functions. Specifically, the x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo and TNF, which indicated the core neuro-inflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia, and leading to the chronic neuro-degeneration. The core neuro-inflammation signaling pathways can be used as novel therapeutic targets for effective AD treatment and prevention.
Visible light optical coherence tomography of peripapillary retinal nerve fiber layer reflectivity in glaucoma
Authors: Song Weiye , Zhang Sui , Kim Yumi Mun , Saldlak Natalie , Fiorello Marissa G. , Desai Manishi , Yi Ji 
Published: September 2021

PurposeTo evaluate the clinical utility of visible light optical coherence tomography (VIS-OCT) and to test whether VIS-OCT reflectivity and spectroscopy of peripapillary retinal nerve fiber layer (pRNFL) are correlated with severity of glaucoma, compared with standard-of-care OCT thickness measurements.DesignCross-sectional study.MethodFifty-four eyes from three groups of subjects (normal, glaucoma suspect, and glaucoma) were scanned by a custom-designed dual-channel device that simultaneously acquired visible (VIS-OCT) and near-infrared OCT (NIR-OCT) images. A 5×5 mm2 scan was taken of the peripapillary nerve fiber layer (pRNFL).The pRNFL reflectivity was calculated for both channels and the spectroscopic marker was quantified by pVN, defined by the ratio of VIS-OCT to NIR-OCT pRNFL reflectivity. The results were compared with ophthalmic exams and clinical Zeiss OCT measurements. Mixed linear model was used to evaluate the association of imaging markers with glaucoma severity.ResultsVIS-OCT pRNFL reflectivity significantly, se uentially declined from normal to suspect to glaucoma (3.42 ± 0.35, 2.58 ± 0.37, 2.16 ± 0.39, mean ± SD), as did NIR-OCT pRNFL reflectivity (2.46 ± 0.24, 2.27 ± 0.24, 1.96 ± 0.25). The pVN also had the same decreasing trend among three groups (1.39 ± 0.08, 1.14 ± 0.08, 1.08 ± 0.10). Normal and suspect eyes were significantly different in VIS-OCT pRNFL reflectivity (p=0.002), pVN (p<0.001) but not in NIR-OCT pRNFL reflectivity (p=0.14), circumpapillary RNFL (cpRNFL) thickness (p=0.17), or macular ganglion cell layer and inner plexiform layer (GCL+IPL) thickness (p=0.07) in the mixed linear model.ConclusionVIS-OCT pRNFL reflectivity and pVN was more sensitive in separating suspect eyes from normal ones than clinical OCT thickness measurements. VIS-OCT pRNFL reflectivity and pVN could be a useful metric in early detection of glaucoma upon further longitudinal validation.
Single-Cell transcriptional changes in hypothalamic CRH-expressing neurons after early-life adversity inform enduring alterations in responses to stress
Authors: Short Annabel K , Wilcox Christina , Chen Yuncai , Pham Aidan L , Birnie Matthew T , Bolton Jessica L , Mortazavi Ali , Baram Tallie Z. 
Published: September 2021

AbstractMental and cognitive health, as well as vulnerability to neuropsychiatric disorders, involve the interplay of genes with the environment, particularly during sensitive developmental periods. Early-life stress / adversity (ELA) promotes vulnerabilities to stress-related affective disorders, yet it is unknown how a transient ELA dictates life-long neuroendocrine and behavioral reactions to stress. The population of hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons that regulate stress-responses is a promising candidate to mediate the enduring influences of ELA on stress-related behavioral and hormonal responses via enduring transcriptional and epigenetic mechanisms. Capitalizing on a well-characterized model of ELA, we examined here the ELA-induced changes in gene expression profiles of stress-sensitive CRH-neurons in the hypothalamic paraventricular nucleus (PVN) of male mice. Given the known heterogeneity of these neuronal populations, we employed single-cell RNA sequencing (RNA-seq) approaches. The use of single-cell transcriptomics identified distinct CRH-expressing neuronal populations characterized by both their gene expression repertoire and their neurotransmitter profiles. Expression changes provoked by ELA clustered around genes involved in neuronal differentiation, synapse formation, altered energy metabolism and the cellular responses to stress and injury. Notably, the ELA-induced transcriptional changes took place primarily in subpopulations of glutamatergic CRH cells. Finally, ELA-induced transcriptional reprogramming of hypothalamic CRH-expressing neurons heralded significant, enduring disruptions of both hormonal and behavioral responses to stress throughout life.