bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prehospital shock index and systolic blood pressure are highly specific for pediatric massive transfusion
Authors: Zhu Caroline S. , Braverman Maxwell , Goddard Sabrina , McGinity Ashley C. , Pokorny Douglas , Cotner-Pouncy Tracy , Eastridge Brian J. , Epley Sondra , Greebon Leslie J. , Jonas Rachelle B. , Liao Lillian , Nicholson Susannah E. , Schaefer Randall , Stewart Ronald M. , Winckler Christopher J. , Jenkins Donald H. 
Published: May 2021

BACKGROUND
While massive transfusion protocols (MTPs) are associated with decreased mortality in adult trauma patients, there is limited research on the impact of MTP on pediatric trauma patients. The purpose of this study was to compare pediatric trauma patients requiring massive transfusion with all other pediatric trauma patients to identify triggers for MTP activation in injured children.

METHODS
Using our level I trauma center’s registry, we retrospectively identified all pediatric trauma patients from January 2015 to January 2018. Massive transfusion (MT) was defined as infusion of 40 mL/kg of blood products in the first 24 hours of admission. Patients missing prehospital vital sign data were excluded from the study. We retrospectively collected data including demographics, blood utilization, variable outcome data, prehospital vital signs, prehospital transport times, and Injury Severity Scores. Statistical significance was determined using Mann-Whitney U test and χ2 test. p Values of less than 0.05 were considered significant.

RESULTS
Thirty-nine (1.9%) of the 2,035 pediatric patients met the criteria for MT. All-cause mortality in MT patients was 49% (19 of 39 patients) versus 0.01% (20 of 1996 patients) in non-MT patients. The two groups significantly differed in Injury Severity Score, prehospital vital signs, and outcome data.
Both systolic blood pressure (SBP) of <100 mm Hg and shock index (SI) of >1.4 were found to be highly specific for MT with specificities of 86% and 92%, respectively. The combination of SBP of <100 mm Hg and SI of >1.4 had a specificity of 94%. The positive and negative predictive values of SBP of <100 mm Hg and SI of >1.4 in predicting MT were 18% and 98%, respectively. Based on positive likelihood ratios, patients with both SBP of <100 mm Hg and SI of >1.4 were 7.2 times more likely to require MT than patients who did not meet both of these vital sign criteria.

CONCLUSION
Pediatric trauma patients requiring early blood transfusion present with lower blood pressures and higher heart rates, as well as higher SIs and lower pulse pressures. We found that SI and SBP are highly specific tools with promising likelihood ratios that could be used to identify patients requiring early transfusion.

LEVEL OF EVIDENCE
Therapeutic/care management, level V.
Advanced prehospital resuscitative care: Can we identify trauma patients who might benefit?
Authors: Irfan Ahmer , Juneja Kavina , Abraham Peter , Smedley W. Andrew , Stephens Shannon W. , Griffin Russell L. , Ward William , Hallmark Robert , Qasim Zaffer , Carroll Shannon L. , Reiff Donald , Holcomb John B. , Jansen Jan O. 
Published: May 2021

BACKGROUND
Uncontrolled truncal hemorrhage remains the most common cause of potentially preventable death after injury. The notion of earlier hemorrhage control and blood product resuscitation is therefore attractive. Some systems have successfully implemented prehospital advanced resuscitative care (ARC) teams. Early identification of patients is key and is reliant on rapid decision making and communication. The purpose of this simulation study was to explore the feasibility of early identification of patients who might benefit from ARC in a typical US setting.

METHODS
We conducted a prospective observational/simulation study at a level I trauma center and two associated emergency medical service (EMS) agencies over a 9-month period. The participating EMS agencies were asked to identify actual patients who might benefit from the activation of a hypothetical trauma center-based ARC team. This decision was then communicated in real time to the study team.

RESULTS
Sixty-three patients were determined to require activation. The number of activations per month ranged from 2 to 15. The highest incidence of calls occurred between 4 pm to midnight. Of the 63 patients, 33 were transported to the trauma center. The most common presentation was with penetrating trauma. The median age was 27 years (interquartile range, 24–45 years), 75% were male, and the median Injury Severity Score was 11 (interquartile range, 7–20). Based on injury patterns, treatment received, and outcomes, it was determined that 6 (18%) of 33 patients might have benefited from ARC. Three of the patients died en-route to or soon after arrival at the trauma center.

CONCLUSION
The prehospital identification of patients who might benefit from ARC is possible but faces challenges. Identifying strategies to adapt existing processes may allow better utilization of the existing infrastructure and should be a focus of future efforts.

LEVEL OF EVIDENCE
Prognostic/Epidemiologic, level III.
SARS-CoV-2 Beta Variant Substitutions Alter Spike Glycoprotein Receptor Binding Domain Structure and Stability
Authors: Moss Daniel L. , Rappaport Jay 
Published: May 2021

AbstractThe emergence of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and the subsequent COVID-19 pandemic has visited a terrible cost on the world in the forms of disease, death, and economic turmoil. The rapid development and deployment of extremely effective vaccines against SARS-CoV-2 have seemingly brought within reach the end of the pandemic. However, the virus has acquired mutations; and emerging variants of concern (VOC) are more infectious and reduce the efficacy of existing vaccines. While promising efforts to combat these variants are underway, the evolutionary pressures leading to these variants are poorly understood. To that end, here we have studied the effects on the structure and function of the SARS-CoV-2 spike glycoprotein receptor-binding domain of three amino-acid substitutions found in several variants of concern, including alpha (B.1.1.7), beta (B.1.351), and gamma (P.1). We found that these substitutions alter the RBD structure, stability, and ability to bind to ACE2, in such a way as to possibly have opposing and compensatory effects. These findings provide new insights into how these VOC may have been selected for infectivity while maintaining the structure and stability of the receptor binding domain.
Regulatory interplay between RNase III and asRNAs in E. coli; the case of AsflhD and the master regulator of motility, flhDC
Authors: Lejars Maxence , Caillet Joël , Guillier Maude , Plumbridge Jacqueline , Hajnsdorf Eliane 
Published: May 2021

AbstractIn order to respond to ever-changing environmental cues, bacteria have evolved resilient regulatory mechanisms controlling gene expression. At the post-transcriptional level, this is achieved by a combination of RNA-binding proteins, such as ribonucleases (RNases) and RNA chaperones, and regulatory RNAs including antisense RNAs (asRNAs). AsRNAs bound to their complementary mRNA are primary targets for the double-strand-specific endoribonuclease, RNase III. By comparing primary and processed transcripts in an rnc strain, mutated for RNase III, and its isogenic wild type strain, we detected several asRNAs. We confirmed the existence of RNase III-sensitive asRNA for crp, ompR, phoP and flhD genes, encoding master regulators of gene expression. AsflhD, the asRNA to the master regulator of motility flhDC, is slightly induced under heat-shock conditions in a sigma24 (RpoE)-dependent manner. We demonstrate that expression of AsflhD asRNA is involved in the transcriptional attenuation of flhD and thus participates in the control of the whole motility cascade. This study demonstrates that AsflhD and RNase III are additional players in the complex regulation ensuring a tight control of flagella synthesis and motility.ImportanceThe importance of asRNAs in the regulation of gene expression has long been underestimated. Here, we confirm that asRNAs can be part of layered regulatory networks since some are found opposite to genes encoding global regulators. In particular, we show how an antisense RNA (AsflhD) to the gene expressing a transcription factor serving as the primary regulator of bacterial swimming motility (FlhD4C2) is involved in the transcriptional attenuation of flhD, which in turn impacts the expression of other genes of the motility cascade. The role of AsflhD highlights the importance of discrete fine-tuning mechanisms in the control of complex regulatory networks.
Computational modelling of COVID-19: A study of compliance and superspreaders
Authors: Lee Faith , Ortiz Maria Perez , Shawe-Taylor John 
Published: May 2021

AbstractBackgroundThe success of social distancing implementations of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) depends heavily on population compliance. Mathematical modelling has been used extensively to assess the rate of viral transmission from behavioural responses. Previous epidemics of SARS-Cov-2 have been characterised by superspreaders, a small number of individuals who transmit a disease to a large group of individuals, who contribute to the stochasticity (or randomness) of transmission compared to other pathogens such as Influenza. This growing evidence proves an urgent matter to understand transmission routes in order to target and combat outbreaks.ObjectiveTo investigate the role of superspreaders in the rate of viral transmission with various levels of compliance.MethodA SEIRS inspired social network model is adapted and calibrated to observe the infected links of a general population with and without superspreaders on four compliance levels. Local and global connection parameters are adjusted to simulate close contact networks and travel restrictions respectively and each performance assessed. The mean and standard deviation of infections with superspreaders and non-superspreaders were calculated for each compliance level.ResultsIncreased levels of compliance of superspreaders proves a significant reduction in infections. Assuming long-lasting immunity, superspreaders could potentially slow down the spread due to their high connectivity.DiscussionThe main advantage of applying the network model is to capture the heterogeneity and locality of social networks, including the role of superspreaders in epidemic dynamics. The main challenge is the immediate attention on social settings with targeted interventions to tackle superspreaders in future empirical work.ConclusionSuperspreaders play a central role in slowing down infection spread following compliance guidelines. It is crucial to adjust social distancing measures to prevent future outbreaks accompanied by population-wide testing and effective tracing.
Distinct immune responses in patients infected with influenza or SARS-CoV-2, and in COVID-19 survivors, characterised by transcriptomic and cellular abundance differences in blood
Authors: Legebeke Jelmer , Lord Jenny , Penrice-Randal Rebekah , Vallejo Andres F. , Poole Stephen , Brendish Nathan J. , Dong Xiaofeng , Hartley Catherine , Holloway John W. , Lucas Jane S. , Williams Anthony P. , Wheway Gabrielle , Strazzeri Fabio , Gardner Aaron , Schofield James P.R. , Skipp Paul J. , Hiscox Julian A. , Polak Marta E. , Clark Tristan W. , Baralle Diana 
Published: May 2021

AbstractBackgroundThe worldwide pandemic caused by SARS-CoV-2 has claimed millions of lives and has had a profound effect on global life. Understanding the pathogenicity of the virus and the body’s response to infection is crucial in improving patient management, prognosis, and therapeutic strategies. To address this, we performed functional transcriptomic profiling to better understand the generic and specific effects of SARS-CoV-2 infection.MethodsWhole blood RNA sequencing was used to profile a well characterised cohort of patients hospitalised with COVID-19, during the first wave of the pandemic prior to the availability of approved COVID-19 treatments and who went on to survive or die of COVID-19, and patients hospitalised with influenza virus infection between 2017 and 2019. Clinical parameters between patient groups were compared, and several bioinformatic tools were used to assess differences in transcript abundances and cellular composition.ResultsThe analyses revealed contrasting innate and adaptive immune programmes, with transcripts and cell subsets associated with the innate immune response elevated in patients with influenza, and those involved in the adaptive immune response elevated in patients with COVID-19. Topological analysis identified additional gene signatures that differentiated patients with COVID-19 from patients with influenza, including insulin resistance, mitochondrial oxidative stress and interferon signalling. An efficient adaptive immune response was furthermore associated with patient survival, while an inflammatory response predicted death in patients with COVID-19. A potential prognostic signature was found based on a selection of transcript abundances, associated with circulating immunoglobulins, nucleosome assembly, cytokine production and T cell activation, in the blood transcriptome of COVID-19 patients, upon admission to hospital, which can be used to stratify patients likely to survive or die.ConclusionsThe results identified distinct immunological signatures between SARS-CoV-2 and influenza, prognostic of disease progression and indicative of different targeted therapies. The altered transcript abundances associated with COVID-19 survivors can be used to predict more severe outcomes in patients with COVID-19.
Seven-day COVID-19 quarantine may be too short: assessing post-quarantine transmission risk in four university cohorts
Authors: Liu Andrew Bo , Davidi Dan , Landsberg Hannah Emily , Francesconi Maria , Platt Judy T. , Nguyen Giang T. , Yune Sehyo , Deckard Anastasia , Puglin Jamie , Haase Steven B. , Hamer Davidson H. , Springer Michael 
Published: May 2021

AbstractBackgroundDespite rising rates of vaccination, quarantine remains critical to control SARS-CoV-2 transmission. COVID-19 quarantine length around the world varies in part due to the limited amount of empirical data.ObjectiveTo assess post-quarantine transmission risk for various quarantine lengths.DesignCohort study.SettingFour US universities, September 2020 to February 2021.Participants3,641 students and staff were identified as close contacts to SARS-CoV-2-positive individuals. They entered strict or non-strict quarantine and were tested on average twice per week for SARS-CoV-2. Strict quarantine included designated housing with a private room, private bathroom and meal delivery. Non-strict quarantine potentially included interactions with household members.MeasurementsDates of exposure and last negative and first positive tests during quarantine.ResultsOf the 418 quarantined individuals who eventually converted to positive, 11%, 4.2%, and 1.2% were negative and asymptomatic on days 7, 10 and 14, respectively. The US CDC recently shortened its quarantine guidance from 14 to 7 days based on estimates of 2.3-8.6% post-quarantine transmission risk at day 7, significantly below the 11% risk we report here. Notably, 6% of individuals tested positive after day 7 in strict quarantine, versus 14% in non-strict quarantine. Ongoing exposure during quarantine likely explains the higher rate of COVID-19 in non-strict quarantine.LimitationsQuarantine should be longer for individuals using antigen testing, given antigen testing’s lower sensitivity than qPCR. Results apply in settings in which SAR-CoV-2 variants do not affect latent period.ConclusionsTo maintain the 5% transmission risk that the CDC used in its guidance, our data suggest that quarantine with qPCR testing 1 day before intended release should extend to 10 days for non-strict quarantine.Funding SourceNone.
Calorie Restriction in combination with GABA: improved glycaemic control in type 2 diabetes mouse model
Authors: Rathwa Nirali , Parmar Nishant , Palit Sayantani Pramanik , Patel Roma , Bhaskaran Ravi Shankar , Ramachandran A. V. , Begum Rasheedunnisa 
Published: May 2021

AbstractAimDysfunctional adipocytes and β-cells are crucial in the advancement of obesity-induced type 2 diabetes (T2D). Calorie restriction (CR) improves insulin sensitivity and fasting blood glucose (FBG) levels, while γ-aminobutyric acid (GABA), a neurotransmitter secreted by β-cells, exerts regenerative effects.MethodsHigh-fat diet (HFD) and streptozotocin (STZ) induced T2D mouse model was used to assess the effect of CR and GABA combination therapy. The mice were fed with CR diet (30% reduction of HFD) and treated with GABA (2.5 mg/kg i.p) daily for 5 weeks. Assessment of FBG, body weight (BW), insulin sensitivity, glucose tolerance, and estimation of plasma insulin and lipid profile were carried out by standard methods. The mRNA expression of target genes [liver (glucoregulatory enzymes), adipose tissue (lipid metabolism markers) and skeletal muscle (mitochondrial biogenesis markers)] was assessed by SYBR Green-qPCR. Oxygen consumption rate for mitochondrial complex I, II and III was measured in skeletal muscle using Oxytherm Clark-type oxygen electrode. The effect of monotherapies and combination treatment on pancreatic β-cell regeneration and apoptosis was analysed by IHC.ResultsCR+GABA group showed significant reduction in FBG levels, improved lipid profile and whole-body insulin responsiveness as indicated by increased insulin levels, insulin sensitivity and glucose tolerance compared to the monotherapies. The transcript expression profile of glucoregulatory enzymes in the liver showed significant reduction in G6Pase, PEPCK, Glycogen Phosphorylase and increased GCK expression in CR+GABA group as compared to the monotherapies The ACC and ATG expression was up-regulated in adipose tissue; and significant increase in SIRT-1, PGC-1α and TFAM expression with up-regulated mitochondrial complex I and III activities was observed in CR+GABA group as compared to the monotherapies. Percentage of BrdU/Insulin and PDX1/Ngn3/Insulin co-positive cells was significantly higher in CR+GABA treated group than the monotherapy and HFD+STZ groups. Finally, there was a significant reduction in TUNEL/Insulin co-positive cells suggesting reduced apoptosis in CR+GABA treated group.ConclusionOur results suggest that CR in combination with GABA ameliorates T2D in HFD+STZ treated mice, by GABA induced β-cell regeneration and CR mediated insulin sensitivity.
Functional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols
Authors: Bean Björn D.M. , Mulvihill Colleen J. , Garge Riddhiman K. , Boutz Daniel R. , Rousseau Olivier , Floyd Brendan M. , Cheney William , Gardner Elizabeth C. , Ellington Andrew D. , Marcotte Edward M. , Gollihar Jimmy D. , Whiteway Malcolm , Martin Vincent J.J. 
Published: May 2021

ABSTRACTThe yeast Saccharomyces cerevisiae is a powerful tool for studying G protein-coupled receptors (GPCRs) as they can be functionally coupled to its pheromone response pathway. However, some exogenous GPCRs, including the mu opioid receptor, are non-functional in yeast, which may be due to the presence of the fungal sterol ergosterol instead of the animal sterol cholesterol. We engineered yeast to produce cholesterol and introduced the human mu opioid receptor, creating an opioid biosensor capable of detecting the peptide DAMGO at an EC50 of 62 nM and the opiate morphine at an EC50 of 882 nM. Furthermore, introducing mu, delta, and kappa opioid receptors from diverse vertebrates consistently yielded active opioid biosensors that both recapitulated expected agonist binding profiles with EC50s as low as 2.5 nM and were inhibited by the antagonist naltrexone. Additionally, clinically relevant human mu opioid receptor alleles, or variants with terminal mutations, resulted in biosensors that largely displayed the expected changes in activity. We also tested mu opioid receptor-based biosensors with systematically adjusted biosynthetic intermediates of cholesterol, enabling us to relate sterol profiles with biosensor sensitivity. Finally, cholesterol-producing and sterol intermediate biosensor backgrounds were applied to other human GPCRs, resulting in SSTR5, 5-HTR4, FPR1 and NPY1R signaling with varying degrees of cholesterol dependence. Our sterol-optimized platform will be a valuable tool in generating human GPCR-based biosensors, aiding in ongoing receptor deorphanization efforts, and providing a framework for high-throughput screening of receptors and effectors.
Reprogramming adult tendon healing using regenerative neonatal regulatory T cells
Authors: Arvind Varun , Howell Kristen , Huang Alice H. 
Published: May 2021

ABSTRACTTendinopathy is a common clinical problem leading to significant musculoskeletal disability. Using a neonatal mouse model of tendon regeneration compared to adult tendon fibrosis, we identified a unique immune profile in regeneration that is associated with type 2 macrophage polarization and regulatory T cell (Treg) infiltration. Neonatal Treg ablation resulted in a dysregulated immune response leading to failed tenocyte recruitment and loss of functional regeneration. Transcriptional profiling of adult and neonatal tendon Tregs revealed distinct type 1 and type 2 immune signatures that facilitate macrophage polarization following injury. Finally, adoptive transfer of mouse and human neonatal Tregs was sufficient to improve functional regeneration, in contrast to adult Treg transfer. Collectively, these studies uncover a critical role for neonatal Tregs in controlling immune polarization to promote an environment permissive for tendon regeneration. Our findings provide a basis for immune modulating therapies to facilitate regenerative adult tendon healing.
Diurnal variation in neuronal chloride levels and seizure susceptibility, in neocortex, reflecting changes in activity of chloride-cation-cotransporters
Authors: Pracucci Enrico , Graham Robert , Alberio Laura , Nardi Gabriele , Cozzolino Olga , Pillai Vinoshene , Saieva Luciano , Walsh Darren , Landi Silvia , Zhang Jinwei , Trevelyan Andrew J. , Ratto Gian-Michele 
Published: May 2021

SummaryThe main inhibitory synaptic currents, gated by gamma-aminobutyric acid (GABA), are mediated by Cl--conducting channels1–3, and are therefore sensitive to changes in the chloride electrochemical gradient. GABAergic activity dictates the neuronal firing range4,5 and timing6–9, which in turn influences the rhythms of the brain, synaptic plasticity, and flow of information in neuronal networks7,10–12. The intracellular chloride concentration [Cl-]i is, therefore, ideally placed to be a regulator of neuronal activity. Chloride levels have been thought to be stable in adult cortical networks, except when associated with pathological activation13–16. Here, we used 2-photon LSSmClopHensor imaging, in anaesthetized young adult mice13, to show that [Cl-] inside pyramidal cells shows a physiological diurnal rhythm, with an approximately 1.8-fold range, equating to an ~15mV positive shift in ECl at times when mice are typically awake (midnight), relative to when they are usually asleep (midday). This change of [Cl-]i alters the stability of cortical networks, as demonstrated by a greater than 3-fold longer latency to seizures induced by 4-aminopyridine at midday, compared to midnight. Importantly, both [Cl-]i and latency to seizure, in night-time experiments, were shifted in line with day-time measures, by inhibition of NKCC1. The redistribution of [Cl-]i reflects diurnal changes in surface expression and phosphorylation states of the cation-chloride-co-transporters, KCC2 and NKCC1, leading to a greatly reduced chloride-extrusion capacity at night (awake period). Our data demonstrate a means by which changes in the biochemical state of neurons are transduced into altered brain states.