Publications by authors named "Andrew Young"

616 Publications

The Agreement Between an iPad Visual Field App and Humphrey Frequency Doubling Technology in Visual Field Screening at Health Fairs.

J Glaucoma 2021 Jun 24. Epub 2021 Jun 24.

Center for Community Outreach and Policy, Department of Ophthalmology, UCLA Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States Division of Ophthalmology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States Department of Internal Medicine, University of California, Riverside School of Medicine, Riverside, California, United States Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, California, United States Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, United States.

Prcis: This is the first exploratory study demonstrating the promising potential of app-based visual fields testing in a low-resource health fair setting for community screening of high-risk Latino adults.

Purpose: To compare the "Visual Fields Easy" (VFE) iPad application against the Humphrey FDT N-30-5 in detecting abnormal visual fields in a low-resource health fair setting.

Methods: Latinos aged 40 to 80 years were recruited at a health fair in Los Angeles, California, in November 2017. Both eyes were tested using VFE and FDT. To account for possible nested correlations between participants and eyes, linear mixed effects models were used to estimate the difference in test time and the association in percent of missed points. A Bland-Altman plot and receiver operator characteristic (ROC) curve were constructed for further comparisons.

Results: Forty-five participants with a mean age of 58.5 years (Standard deviation [SD]=9.5▒y) were recruited and both eyes were tested (90 eyes). VFE testing took on average 141 seconds longer per eye than FDT (95% confidence interval [CI]: 137 to 145 seconds), and FDT resulted in having 7.50% more missed points than VFE (95% CI: 2.56 to 12.43%, P=0.002). The Bland-Altman plot depicted reduced agreement with increasing average of percent of points missed. The sensitivity and specificity of VFE were 67% and 77%, respectively, with an area under the ROC curve of 0.71.

Conclusions: In this exploratory study, VFE exhibited moderate discrimination for identifying Latino adults with abnormal visual fields compared to FDT. Agreement between FDT and VFE was greater for patients with mild-to-moderate visual field loss. Further software enhancements of app-based fields testing, in concert with other portable testing, represents promising screening methods for high-risk groups in resource-limited environments.
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http://dx.doi.org/10.1097/IJG.0000000000001902DOI Listing
June 2021

Metabolomic profiles are reflective of hypoxia-induced insulin resistance during exercise in healthy young adult males.

Am J Physiol Regul Integr Comp Physiol 2021 Jul 5;321(1):R1-R11. Epub 2021 May 5.

United States Army Research Institute of Environmental Medicine, Natick, Massachusetts.

Hypoxia-induced insulin resistance appears to suppress exogenous glucose oxidation during metabolically matched aerobic exercise during acute (<8 h) high-altitude (HA) exposure. However, a better understanding of this metabolic dysregulation is needed to identify interventions to mitigate these effects. The objective of this study was to determine if differences in metabolomic profiles during exercise at sea level (SL) and HA are reflective of hypoxia-induced insulin resistance. Native lowlanders ( = 8 males) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically matched treadmill exercise at SL (757 mmHg) and HA (460 mmHg) after 5-h exposure. Exogenous glucose oxidation and glucose turnover were determined using indirect calorimetry and dual tracer technique ([C]glucose and [6,6-H]glucose). Metabolite profiles were analyzed in serum as change (Δ), calculated by subtracting postprandial/exercised state SL (ΔSL) and HA (ΔHA) from fasted, rested conditions at SL. Compared with SL, exogenous glucose oxidation, glucose rate of disappearance, and glucose metabolic clearance rate (MCR) were lower ( < 0.05) during exercise at HA. One hundred and eighteen metabolites differed between ΔSL and ΔHA ( < 0.05, <0.10). Differences in metabolites indicated increased glycolysis, tricarboxylic acid cycle, amino acid catabolism, oxidative stress, and fatty acid storage, and decreased fatty acid mobilization for ΔHA. Branched-chain amino acids and oxidative stress metabolites, Δ3-methyl-2-oxobutyrate ( = -0.738) and Δγ-glutamylalanine ( = -0.810), were inversely associated ( < 0.05) with Δexogenous glucose oxidation. Δ3-Hydroxyisobutyrate ( = -0.762) and Δ2-hydroxybutyrate/2-hydroxyisobutyrate ( = -0.738) were inversely associated ( < 0.05) with glucose MCR. Coupling global metabolomics and glucose kinetic data suggest that the underlying cause for diminished exogenous glucose oxidative capacity during aerobic exercise is acute hypoxia-mediated peripheral insulin resistance.
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http://dx.doi.org/10.1152/ajpregu.00076.2021DOI Listing
July 2021

Staying on Target: Maintaining a Balanced Resuscitation During Damage Control Resuscitation Improves Survival.

J Trauma Acute Care Surg 2021 Apr 24. Epub 2021 Apr 24.

Division of Traumatology, Surgical Critical Care & Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Penn Acute Research Collaboration (PARC), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, USA Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA Arcos, Inc., Missouri City, TX, USA Center for Resuscitation Science, Department of Emergency Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Division of Trauma, Critical Care, and Burn, Department of Surgery, The Ohio State University, Columbus, OH, USA Department of Nursing, Penn Presbyterian Medical Center, Philadelphia, PA, USA Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Background: Damage control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesize that maintaining a balanced resuscitation during DCR is independently associated with improved survival.

Methods: This was a secondary analysis of the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving ≥3 units packed red blood cells (PRBC) in one-hour over the first 6-hours and surviving beyond 30-minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden's index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (On-Target) with all others (Off-Target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival.

Results: Of 1,245 PROMMTT patients, 524 met inclusion criteria. Optimal targets were plasma:PRBC and platelet:PRBC of 0.75 and ≥40% time spent over this threshold. For plasma:PRBC, On-Target (n=213) vs Off-Target (n=311) patients were younger (median 31-years, interquartile range [22, 50] vs 40 [25, 54], p=0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet:PRBC On-Target (n=116) and Off-Target (n=408) patients. After adjusting for differences, On-Target plasma:PRBC patients had significantly improved 24-hour (OR 2.25, 95% CI, 1.20-4.23) and 30-day (OR 1.97, 95% CI 1.14-3.41) survival while On-Target platelet:PRBC patients did not.

Conclusion: Maintaining a high ratio of plasma:PRBC during damage control resuscitation is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range.

Level Of Evidence: Epidemiologic/prognostic study, Level II.
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http://dx.doi.org/10.1097/TA.0000000000003245DOI Listing
April 2021

The Development of Cognitive Reflection in China.

Cogn Sci 2021 Apr;45(4):e12966

Department of Psychology, Occidental College.

Cognitive reflection is the tendency to override an intuitive response so as to engage in the reflection necessary to derive a correct response. Here, we examine the emergence of cognitive reflection in a culture that values nonanalytic thinking styles, Chinese culture. We administered a child-friendly version of the cognitive reflection test, the CRT-D, to 130 adults and 111 school-age children in China and compared performance on the CRT-D to several measures of rational thinking (belief bias syllogisms, base rate sensitivity, denominator neglect, and other-side thinking) and normative thinking dispositions (actively open-minded thinking and need for cognition). The CRT-D was a significant predictor of rational thinking and normative thinking dispositions in both children and adults, as previously found in American samples. Adults' performance on the CRT-D correlated with their performance on the original CRT, and children's performance on the CRT-D predicted rational thinking and normative thinking dispositions even after adjusting for age. These results demonstrate that cognitive reflection, rational thinking, and normative thinking dispositions converge even in a culture that emphasizes holistic, nonanalytic reasoning.
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http://dx.doi.org/10.1111/cogs.12966DOI Listing
April 2021

Autophagy and senescence, converging roles in pathophysiology as seen through mouse models.

Adv Cancer Res 2021 8;150:113-145. Epub 2021 Mar 8.

Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom. Electronic address:

Both senescence and autophagy have been strongly linked to aging and also cancer development. Numerous molecular, cellular, and physiological changes are known to correlate with an increasing age, yet our understanding of what underlies these changes or how they combine to give rise to the various pathologies associated with aging is still unclear. Levels of autophagy activity are known to decrease with advancing age, in a variety of organisms including mammals. Whereas senescent cells are known to accumulate in our bodies with age. Herein we review evidence from some elegant genetic mouse models linking senescence and also autophagy to aging and cancer. It is especially interesting to note the convergence in the pathological phenotypes of these two processes, senescence and autophagy, in these mouse models.
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http://dx.doi.org/10.1016/bs.acr.2021.02.001DOI Listing
March 2021

Modulation of stimulated dopamine release in rat nucleus accumbens shell by GABA in vitro: Effect of sub-chronic phencyclidine pretreatment.

J Neurosci Res 2021 Jul 13;99(7):1885-1901. Epub 2021 Apr 13.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, LE1 9HN, UK.

Dopamine signaling in nucleus accumbens (NAc) is modulated by γ-aminobutyric acid (GABA), acting through GABA-A and GABA-B receptors: dysregulation of GABAergic control of dopamine function may be important in behavioral deficits in schizophrenia. We investigated the effect of GABA-A (muscimol) and GABA-B (baclofen) receptor agonists on electrically stimulated dopamine release. Furthermore, we explored whether drug-induced changes were disrupted by pretreatment with phencyclidine, which provides a well-validated model of schizophrenia. Using brain slices from female rats, fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in NAc shell. Both muscimol and baclofen caused concentration-dependent attenuation of evoked dopamine release: neither effect was changed by dihydro-β-erythroidine, a nicotinic acetylcholine receptor antagonist, or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), precluding indirect mechanisms using these transmitter systems in the GABAergic actions. In slices taken from rats pretreated with phencyclidine, the attenuation of evoked dopamine release by baclofen was abolished, but the attenuation by muscimol was unaffected. Since phencyclidine pretreatment was followed by drug-free washout period of at least a week, the drug was not present during recording. Therefore, disruption of GABA-B modulation of dopamine is due to long-term functional changes resulting from the treatment, rather than transient changes due to the drug's presence at test. This enduring dysregulation of GABA-B modulation of accumbal dopamine release provides a plausible mechanism through which GABA dysfunction influences accumbal dopamine leading to behavioral changes seen in schizophrenia and may provide a route for novel therapeutic strategies to treat the condition.
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http://dx.doi.org/10.1002/jnr.24843DOI Listing
July 2021

Preclinical development of a molecular clamp-stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2.

Clin Transl Immunology 2021 5;10(4):e1269. Epub 2021 Apr 5.

CSIRO Manufacturing Parkville VIC Australia.

Objectives: Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion-stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 'MF59C.1' (Seqirus, Parkville, Australia).

Methods: A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened to select a lead vaccine candidate. The structure of this antigen was determined by cryo-electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat.

Results: In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S-specific CD4 and cytotoxic CD8 T cells . In the Syrian hamster challenge model ( = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level.

Conclusion: The SARS-CoV-2 Sclamp vaccine candidate is compatible with large-scale commercial manufacture, stable at 2-8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T-cell responses and provides protection in animal challenge models.
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http://dx.doi.org/10.1002/cti2.1269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021130PMC
April 2021

Worldwide prevalence estimates of burning mouth syndrome: A systematic review and meta-analysis.

Oral Dis 2021 Apr 5. Epub 2021 Apr 5.

Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing, China.

Objectives: To evaluate the worldwide prevalence and epidemiology profile of burning mouth syndrome.

Material And Methods: A systematic review and meta-analysis was conducted. Search strategies were performed in PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database for studies published before January 31, 2021, for the prevalence of burning mouth syndrome.

Results: Eighteen articles were included. The overall pooled prevalence of burning mouth syndrome was 1.73% (95% CI = 0.176-0.351, n = 26,632) in general population, and 7.72% (95% CI = 0.434-0.691, n = 86,591) in clinical patients. The subgroup analysis by continent showed that among the population-based studies the prevalence in Asia (1.05%) lower than in Europe (5.58%) and North America (1.10%). The subgroup analysis by gender showed the prevalence of female (1.15%) was higher than male (0.38%) in general population. The subgroup analysis by age showed the prevalence was higher for people over 50 (3.31%) than under 50 (1.92%).

Conclusions: The pooled prevalence of burning mouth syndrome was relatively high in both general population and clinical patients, varies in different regions with the highest prevalence in Europe, and females over 50 years were the most susceptible group. More epidemiological surveys on the prevalence of burning mouth syndrome are needed.
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http://dx.doi.org/10.1111/odi.13868DOI Listing
April 2021

The interplay between gaze cueing and facial trait impressions.

Q J Exp Psychol (Hove) 2021 Apr 5:17470218211007791. Epub 2021 Apr 5.

Dipartimento di Psicologia, Università degli studi di Milano-Bicocca, Milano, Italy.

The gaze cueing effect involves the rapid orientation of attention to follow the gaze direction of another person. Previous studies reported reciprocal influences between social variables and the gaze cueing effect, with modulation of gaze cueing by social features of face stimuli and modulation of the observer's social judgements from the validity of the gaze cues themselves. However, it remains unclear which social dimensions can affect-and be affected by-gaze cues. We used computer-averaged prototype face-like images with high and low levels of perceived trustworthiness and dominance to investigate the impact of these two fundamental social impression dimensions on the gaze cueing effect. Moreover, by varying the proportions of valid and invalid gaze cues across three experiments, we assessed whether gaze cueing influences observers' impressions of dominance and trustworthiness through incidental learning. Bayesian statistical analyses provided clear evidence that the gaze cueing effect was not modulated by facial social trait impressions (Experiments 1-3). However, there was uncertain evidence of incidental learning of social evaluations following the gaze cueing task. A decrease in perceived trustworthiness for non-cooperative low dominance faces (Experiment 2) and an increase in dominance ratings for faces whose gaze behaviour contradicted expectations (Experiment 3) appeared, but further research is needed to clarify these effects. Thus, this study confirms that attentional shifts triggered by gaze direction involve a robust and relatively automatic process, which could nonetheless influence social impressions depending on perceived traits and the gaze behaviour of faces providing the cues.
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http://dx.doi.org/10.1177/17470218211007791DOI Listing
April 2021

Trait evaluations of faces and voices: Comparing within- and between-person variability.

J Exp Psychol Gen 2021 Mar 18. Epub 2021 Mar 18.

Department of Speech, Hearing and Phonetic Sciences.

Human faces and voices are rich sources of information that can vary in many different ways. Most of the literature on face/voice perception has focused on understanding how people look and sound different to each other (between-person variability). However, recent studies highlight the ways in which the same person can look and sound different on different occasions (within-person variability). Across three experiments, we examined how within- and between-person variability relate to one another for social trait impressions by collecting trait ratings attributed to multiple face images and voice recordings of the same people. We find that within-person variability in social trait evaluations is at least as great as between-person variability. Using different stimulus sets across experiments, trait impressions of voices are consistently more variable within people than between people-a pattern that is only evident occasionally when judging faces. Our findings highlight the importance of understanding within-person variability, showing how judgments of the same person can vary widely on different encounters and quantify how this pattern differs for voice and face perception. The work consequently has implications for theoretical models proposing that voices can be considered "auditory faces" and imposes limitations to the "kernel of truth" hypothesis of trait evaluations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/xge0001019DOI Listing
March 2021

Face perception across the adult lifespan: evidence for age-related changes independent of general intelligence.

Cogn Emot 2021 Mar 18:1-12. Epub 2021 Mar 18.

Department of Psychology, Royal Holloway, University of London, Egham, England.

It is well-documented that face perception - including facial expression and identity recognition ability - declines with age. To date, however, it is not yet well understood whether this age-related decline reflects face-specific effects, or instead can be accounted for by well-known declines in general intelligence. We examined this issue using a relatively large, healthy, age-diverse (18-88 years) sample ( = 595) who were assessed on well-established measures of face perception and general intelligence. Replicating previous work, we observed that facial expression recognition, facial identity recognition, and general intelligence all showed declines with age. Of importance, the age-related decline of expression and identity recognition was present even when the effects of general intelligence were statistically controlled. Moreover, facial expression and identity ability each showed significant unique associations with age. These results indicate that face perception ability becomes poorer as we age, and that this decline is to some extent relatively focal in nature. Results are in line with a hierarchical structure of face perception ability, and suggest that age appears to have independent effects on the general and specific face processing levels within this structure.
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http://dx.doi.org/10.1080/02699931.2021.1901657DOI Listing
March 2021

COX2 regulates senescence secretome composition and senescence surveillance through PGE.

Cell Rep 2021 Mar;34(11):108860

CRUK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address:

Senescent cells trigger their own immune-mediated destruction, termed senescence surveillance. This is dependent on the inflammatory senescence-associated secretory phenotype (SASP), which includes COX2, an enzyme with complex roles in cancer. The role COX2 plays during senescence surveillance is unknown. Here, we show that during RAS-induced senescence (RIS), COX2 is a critical regulator of SASP composition and senescence surveillance in vivo. COX2 regulates the expression of multiple inflammatory SASP components through an autocrine feedback loop involving its downstream product, prostaglandin E2 (PGE), binding to EP4. During in vivo hepatocyte RIS, Cox2 is critical to tumor suppression, Cxcl1 expression, and immune-mediated senescence surveillance, partially through PGE. Loss of Cox2 in RIS dysregulates the intrahepatic immune microenvironment, with enrichment of immunosuppressive immature myeloid cells and CD4 regulatory T lymphocytes. Therefore, COX2 and PGE play a critical role in senescence, shaping SASP composition, promoting senescence surveillance and tumor suppression in the earliest stages of tumorigenesis.
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http://dx.doi.org/10.1016/j.celrep.2021.108860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972992PMC
March 2021

Social dominance and rainfall predict telomere dynamics in a cooperative arid-zone bird.

Mol Ecol 2021 Mar 3. Epub 2021 Mar 3.

Centre for Ecology & Conservation, University of Exeter, Penryn, UK.

In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their nonbreeding subordinates. Here, we used extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their nonreproductive subordinates.
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http://dx.doi.org/10.1111/mec.15868DOI Listing
March 2021

Depression-/Anxiety-Like Behavior Alterations in Adult Slit2 Transgenic Mice.

Front Behav Neurosci 2020 5;14:622257. Epub 2021 Feb 5.

School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, China.

Slit2 is a member of the Slit family of secreted glycoproteins that plays highly conserved roles in neuronal axon guidance and cellular migration. Our previous experimental results showed Alzheimer's disease-like alterations and increased permeability of the blood-brain barrier in Slit2-overexpressing transgenic (Slit2-Tg) mice aged 8-9 months. Nevertheless, relatively little is known about behavioral alterations in adult Slit2-Tg mice (2-6 months of age). To observe the age-related behavioral effects of Slit2 overexpression in adult mice, we performed a battery of behavioral tests with adult Slit2-Tg mice at 2-6 months of age. The body weight of Slit2-Tg mice was lower than that of the wild-type mice from 15 weeks of age. Compared with the control mice, depression-like behaviors were found in Slit2-Tg mice from 15 to 21 weeks of age in the sucrose preference test, although Slit2-Tg mice were hyperactive in the tail suspension test. The anxiety-like behaviors were found in Slit2-Tg mice in the open field test, as well as increased locomotor activity. The anxiety-like behaviors were also found in adult Slit2-Tg mice in the elevated plus maze. Compared to wild-type mice at 23 weeks old, impairment of the hippocampal neurons were found in Slit2-Tg mice at the same age in hematoxylin-eosin staining (H&E), including some eccentric dispersion and expansion of neuronal bodies. In addition, the messenger RNA (mRNA) expression of TNF-α was elevated in the hippocampus of adult Slit2-Tg mice. Slit2 overexpression causes depression-/anxiety-like behaviors in adult mice that may be related to an increase in inflammatory factors and damage to hippocampal neurons.
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http://dx.doi.org/10.3389/fnbeh.2020.622257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892588PMC
February 2021

Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption.

Eur J Neurosci 2021 03 2;53(6):1809-1821. Epub 2021 Feb 2.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Disruptions in attention, salience and increased distractibility are implicated in multiple psychiatric conditions. The ventral tegmental area (VTA) is a potential site for converging information about external stimuli and internal states to be integrated and guide adaptive behaviours. Given the dual role of dopamine signals in both driving ongoing behaviours (e.g., feeding) and monitoring salient environmental stimuli, understanding the interaction between these functions is crucial. Here, we investigate VTA neuronal activity during distraction from ongoing feeding. We developed a task to assess distraction exploiting self-paced licking in rats. Rats trained to lick for saccharin were given a distraction test, in which three consecutive licks within 1 s triggered a random distractor (e.g. light and tone stimulus). On each trial they were quantified as distracted or not based on the length of their pauses in licking behaviour. We expressed GCaMP6s in VTA neurons and used fibre photometry to record calcium fluctuations during this task as a proxy for neuronal activity. Distractor stimuli caused rats to interrupt their consumption of saccharin, a behavioural effect which quickly habituated with repeat testing. VTA neural activity showed consistent increases to distractor presentations and, furthermore, these responses were greater on distracted trials compared to non-distracted trials. Interestingly, neural responses show a slower habituation than behaviour with consistent VTA responses seen to distractors even after they are no longer distracting. These data highlight the complex role of the VTA in maintaining ongoing appetitive and consummatory behaviours while also monitoring the environment for salient stimuli.
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http://dx.doi.org/10.1111/ejn.15108DOI Listing
March 2021

ACE2 and Furin Expressions in Oral Epithelial Cells Possibly Facilitate COVID-19 Infection via Respiratory and Fecal-Oral Routes.

Front Med (Lausanne) 2020 10;7:580796. Epub 2020 Dec 10.

Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly transfers from human to human via respiratory and gastrointestinal routes. The S-glycoprotein in the virus is the key factor for the entry of SARS-CoV-2 into the cell, which contains two functional domains: S1 is an angiotensin-converting enzyme 2 (ACE2) receptor binding domain, and S2 is necessary for fusion of the coronavirus and cell membranes. Moreover, it has been reported that ACE2 is likely to be the receptor for SARS-CoV-2. In addition, mRNA level expression of Furin enzyme and ACE2 receptor had been reported in airway epithelia, cardiac tissue, and enteric canals. However, the expression patterns of ACE2 and Furin in different cell types of oral tissues are still unclear. In order to investigate the potential infective channel of the new coronavirus via the oropharyngeal cavity, we analyze the expression of ACE2 and Furin in human oral mucosa using the public single-cell sequence datasets. Furthermore, immunohistochemistry was performed in mucosal tissue from different oral anatomical sites to confirm the expression of ACE2 and Furin at the protein level. The bioinformatics results indicated the differential expression of ACE2 and Furin on epithelial cells from different oral anatomical sites. Immunohistochemistry results revealed that both the ACE2-positive and Furin-positive cells in the target tissues were mainly positioned in the epithelial layers, partly expressed in fibroblasts, further confirming the bioinformatics results. Based on these findings, we speculated that SARS-CoV-2 could invade oral mucosal cells through two possible routes: binding to the ACE2 receptor and fusion with cell membrane activated by Furin protease. Our results indicated that oral mucosa tissues are susceptible to SARS-CoV-2 that could facilitate COVID-19 infection via respiratory and fecal-oral routes.
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http://dx.doi.org/10.3389/fmed.2020.580796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758442PMC
December 2020

Outcomes in Delayed Drainage of Hemothorax.

Am Surg 2020 Dec 19:3134820956343. Epub 2020 Dec 19.

University of Pennsylvania Division of Traumatology, Surgical Critical Care, and Emergency Surgery, Philadelphia, PA, USA.

Background: Prompt drainage of traumatic hemothorax is recommended to prevent empyema and trapped lung. Some patients do not present the day of their trauma, leading to their delayed treatment. Delayed drainage could be challenging as clotted blood may not evacuate through a standard chest tube. We hypothesized that such delays would increase the need for surgery or secondary interventions.

Methods: Our trauma registry was reviewed for patients with a hemothorax admitted to our level 1 trauma center from 1/1/00 to 4/30/19. Patients were included in the delayed group if they received a drainage procedure >24 hours after injury. These patients were matched 1:1 by chest abbreviated injury score to patients who received drainage <24 hours from injury.

Results: A total of 19 patients with 22 hemothoraces received delayed drainage. All but 3 patients had a chest tube placed as initial treatment. Four patients received surgery, including 3 who initially had chest tubes placed. Longer time to drainage increased the odds of requiring intrathoracic thrombolytics or surgery. In comparison, 2 patients who received prompt drainage received thrombolytics ( = .11) and none required surgery ( = .02). Patients needed surgery when initial drainage was on or after post-injury day 5, but pigtail catheter drainage was effective 26 days after injury.

Discussion: Longer times from injury to intervention are associated with increased likelihood of needing surgery for hemothorax evacuation, but outcomes were not uniform. A larger, multicenter study will be necessary to provide better characterization of treatment outcomes for these patients.
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http://dx.doi.org/10.1177/0003134820956343DOI Listing
December 2020

CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis.

J Neuroinflammation 2020 Nov 22;17(1):349. Epub 2020 Nov 22.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, BT9 7BL, UK.

Background: Multiple sclerosis (MS) is an immune-mediated disease that damages myelin in the central nervous system (CNS). We investigated the profile of CCN3, a known regulator of immune function and a potential mediator of myelin regeneration, in multiple sclerosis in the context of disease state and disease-modifying treatment.

Methods: CCN3 expression was analysed in plasma, immune cells, CSF and brain tissue of MS patient groups and control subjects by ELISA, western blot, qPCR, histology and in situ hybridization.

Results: Plasma CCN3 levels were comparable between collective MS cohorts and controls but were significantly higher in progressive versus relapsing-remitting MS and between patients on interferon-β versus natalizumab. Higher body mass index was associated with higher CCN3 levels in controls as reported previously, but this correlation was absent in MS patients. A significant positive correlation was found between CCN3 levels in matched plasma and CSF of MS patients which was absent in a comparator group of idiopathic intracranial hypertension patients. PBMCs and CD4 T cells significantly upregulated CCN3 mRNA in MS patients versus controls. In the CNS, CCN3 was detected in neurons, astrocytes and blood vessels. Although overall levels of area immunoreactivity were comparable between non-affected, demyelinated and remyelinated tissue, the profile of expression varied dramatically.

Conclusions: This investigation provides the first comprehensive profile of CCN3 expression in MS and provides rationale to determine if CCN3 contributes to neuroimmunological functions in the CNS.
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http://dx.doi.org/10.1186/s12974-020-02025-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681974PMC
November 2020

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Nat Genet 2020 11 26;52(11):1219-1226. Epub 2020 Oct 26.

Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
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http://dx.doi.org/10.1038/s41588-020-00710-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891089PMC
November 2020

Maternal-Neonatal Dyad Outcomes of Maternal COVID-19 Requiring Extracorporeal Membrane Support: A Case Series.

Am J Perinatol 2021 01 17;38(1):82-87. Epub 2020 Oct 17.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of California, Los Angeles.

Objective: This study aimed to describe two cases of acute respiratory distress syndrome (ARDS) secondary to novel coronavirus disease 2019 (COVID-19) in pregnant women requiring extracorporeal membrane oxygenation (ECMO), and resulting in premature delivery.

Study Design: The clinical course of two women hospitalized with ARDS due to COVID-19 care in our intensive care (ICU) is summarized; both participants provided consent to be included in this case series.

Results: Both women recovered with no clinical sequelae. Neonatal outcomes were within the realm of expected for prematurity with the exception of coagulopathy. There was no vertical transmission to the neonates.

Conclusion: This case series highlights that ECMO is a feasible treatment in the pregnant woman with severe COVID-19 and that delivery can be performed safely on ECMO with no additional risk to the fetus. While ECMO carries its natural risks, it should be considered a viable option during pregnancy and the postpartum period.

Key Points: · COVID-19 may present with a more severe course in pregnancy.. · ECMO may be used in pregnant woman with severe COVID-19.. · Delivery can be performed on ECMO without added fetal risk..
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http://dx.doi.org/10.1055/s-0040-1718694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869039PMC
January 2021

Children's Cognitive Reflection Predicts Conceptual Understanding in Science and Mathematics.

Psychol Sci 2020 11 5;31(11):1396-1408. Epub 2020 Oct 5.

Department of Psychology, Occidental College.

The Cognitive Reflection Test (CRT) is a widely used measure of adults' propensity to engage in reflective analytic thought. The CRT is strongly predictive of many diverse psychological factors but unsuitable for use with developmental samples. Here, we examined a children's CRT, the CRT-Developmental (CRT-D), and investigated its predictive utility in the domains of science and mathematics. School-age children ( = 152) completed the CRT-D, measures of executive functioning, measures of rational thinking, and measures of vitalist-biology and mathematical-equivalence concepts. CRT-D performance predicted conceptual understanding in both domains after we adjusted for children's age, executive functioning, and rational thinking. These findings suggest that cognitive reflection supports conceptual knowledge in early science and mathematics and, moreover, demonstrate the theoretical and practical importance of children's cognitive reflection. The CRT-D will allow researchers to investigate the development, malleability, and consequences of children's cognitive reflection.
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http://dx.doi.org/10.1177/0956797620954449DOI Listing
November 2020

Repeated phencyclidine disrupts nicotinic acetylcholine regulation of dopamine release in nucleus accumbens: Implications for models of schizophrenia.

Neurochem Int 2020 11 24;140:104836. Epub 2020 Aug 24.

Department of Neuroscience, Psychology & Behaviour, University of Leicester, Lancaster Road, Leicester, LE2 9HN, UK. Electronic address:

Dopaminergic dysregulation in nucleus accumbens has been implicated in the origin of schizophrenia. Accumbal cholinergic interneurons exert powerful modulatory control of local dopamine function, through nicotinic receptors located on dopamine terminals. Fast-scan cyclic voltammetry in rat brain slices in vitro was used to measure dopamine release evoked by high-frequency electrical stimulation, mimicking phasic dopamine activity. We investigated whether cholinergic regulation of stimulated dopamine release was disrupted by pretreatment with phencyclidine, a non-competitive NMDA receptor antagonist, which provides a well validated animal model of schizophrenia. Dihydro-β-erythroidine, an antagonist at β2-subuit containing nicotinic receptors, caused a concentration-dependent enhancement of stimulated dopamine release, indicating cholinergic inhibitory control over dopamine release. The agonist, nicotine, also caused concentration-dependent increases in release, consistent with rapid desensitisation of the receptors previously described. In slices taken from animals pretreated with phencyclidine, the augmentation of electrically-stimulated dopamine release elicited by both drugs was attenuated, particularly when each drug was applied at high concentration. In addition, the concentration-dependence of each drug effect was lost. Taken together these findings indicate that pretreatment with phencyclidine causes changes in acetylcholine systems modulating dopamine release in accumbens. Since phencyclidine treatment was terminated at least a week before the slices were taken, the effects are due to long-term changes in function resulting from the treatment, rather than from transient changes due to the presence of the drug at test. Such enduring dysregulation of cholinergic control of phasic dopamine release could account for deficits in behaviours mediated by accumbal dopamine seen in schizophrenia, and may provide a route for novel therapeutic strategies to treat the disease.
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http://dx.doi.org/10.1016/j.neuint.2020.104836DOI Listing
November 2020

Using Machine Learning to Make Predictions in Patients Who Fall.

J Surg Res 2021 01 18;257:118-127. Epub 2020 Aug 18.

Division of Trauma, Critical Care, and Burn, Department of Surgery, The Ohio State University, Columbus, Ohio.

Background: As the population ages, the incidence of traumatic falls has been increasing. We hypothesize that a machine learning algorithm can more accurately predict mortality after a fall compared with a standard logistic regression (LR) model based on immediately available admission data. Secondary objectives were to predict who would be discharged home and determine which variables had the largest effect on prediction.

Methods: All patients who were admitted for fall between 2012 and 2017 at our level 1 trauma center were reviewed. Fourteen variables describing patient demographics, injury characteristics, and physiology were collected at the time of admission and were used for prediction modeling. Algorithms assessed included LR, decision tree classifier (DTC), and random forest classifier (RFC). Area under the receiver operating characteristic curve (AUC) values were calculated for each algorithm for mortality and discharge to home.

Results: About 4725 patients met inclusion criteria. The mean age was 61 ± 20.5 y, Injury Severity Score 8 ± 7, length of stay 5.8 ± 7.6 d, intensive care unit length of stay 1.8± 5.2 d, and ventilator days 0.7 ± 4.2 d. The mortality rate was 3% and three times greater for elderly (aged 65 y and older) patients (5.0% versus 1.6%, P < 0.001). The AUC for predicting mortality for LR, DTC, and RFC was 0.78, 0.64, and 0.86, respectively. The AUC for predicting discharge to home for LR, DTC, and RFC was 0.72, 0.61, and 0.74, respectively. The top five variables that contribute to the prediction of mortality in descending order of importance are the Glasgow Coma Score (GCS) motor, GCS verbal, respiratory rate, GCS eye, and temperature.

Conclusions: RFC can accurately predict mortality and discharge home after a fall. This predictive model can be implemented at the time of patient arrival and may help identify candidates for targeted intervention as well as improve prognostication and resource utilization.
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http://dx.doi.org/10.1016/j.jss.2020.07.047DOI Listing
January 2021

Insights from computational models of face recognition: A reply to Blauch, Behrmann and Plaut.

Cognition 2021 03 13;208:104422. Epub 2020 Aug 13.

Department of Psychology, University of York, York YO10 5DD, UK. Electronic address:

We agree with Blauch, Behrmann, and Plaut (2020) on a number of points, and are reassured that their data bear out our previous findings. We discuss differences in modelling style, and the usefulness of different types of model for supporting psychological understanding. We emphasise the role that within-person variability plays in recognising familiar faces and clarify the range over which it is idiosyncratic. The combination of image analysis with top-down support to cohere different images of the same person seems to be an important characteristic of successful models.
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http://dx.doi.org/10.1016/j.cognition.2020.104422DOI Listing
March 2021

Testosterone supplementation upregulates androgen receptor expression and translational capacity during severe energy deficit.

Am J Physiol Endocrinol Metab 2020 10 10;319(4):E678-E688. Epub 2020 Aug 10.

Military Nutrition Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts.

Testosterone supplementation during energy deficit promotes whole body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before, 1 h, and 6 h after exercise and a mixed meal (40 g protein, 1 h postexercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active nonobese men treated with 200 mg testosterone enanthate/wk (TEST) or placebo (PLA) during the ED. Participants ( = 10/group) exhibiting substantial increases in leg lean mass and total testosterone (TEST) were compared with those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 gene expression was lower in TEST vs. PLA during ED relative to WM ( < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA ( < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.
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http://dx.doi.org/10.1152/ajpendo.00157.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750513PMC
October 2020

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity.

Acta Physiol (Oxf) 2020 12 12;230(4):e13543. Epub 2020 Aug 12.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, UK.

Aim: Aggression is a behavioural trait characterized by the intention to harm others for offensive or defensive purposes. Neurotransmitters such as serotonin and dopamine are important mediators of aggression. However, the physiological role of the histaminergic system during this behaviour is currently unclear. Here, we aimed to better understand histaminergic signalling during aggression by characterizing the involvement of the histamine H3 receptor (Hrh3).

Methods: We have generated a novel zebrafish Hrh3 null mutant line using CRISPR-Cas9 genome engineering and investigated behavioural changes and alterations to neural activity using whole brain Ca imaging in zebrafish larvae and ribosomal protein S6 (rpS6) immunohistochemistry in adults.

Results: We show that genetic inactivation of the histamine H3 receptor (Hrh3) reduces aggression in zebrafish, an effect that can be reproduced by pharmacological inhibition. In addition, hrh3 zebrafish show behavioural impairments consistent with heightened anxiety. Larval in vivo whole brain Ca imaging reveals higher neuronal activity in the forebrain of mutants, but lower activity in specific hindbrain areas and changes in measures of functional connectivity between subregions. Adult hrh3 zebrafish display brain region-specific neural activity changes in response to aggression of both key regions of the social decision-making network, and the areas containing histaminergic neurons in the zebrafish brain.

Conclusion: These results highlight the importance of zebrafish Hrh3 signalling for aggression and anxiety and uncover the brain areas involved. Targeting this receptor might be a potential novel therapeutic route for human conditions characterized by heightened aggression.
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http://dx.doi.org/10.1111/apha.13543DOI Listing
December 2020

Age-dependent effects of protein restriction on dopamine release.

Neuropsychopharmacology 2021 01 31;46(2):394-403. Epub 2020 Jul 31.

Department of Neuroscience, Psychology & Behaviour, University of Leicester, Leicester, UK.

Despite the essential role of protein intake for health and development, very little is known about the impact of protein restriction on neurobiological functions, especially at different stages of the lifespan. The dopamine system is a central actor in the integration of food-related processes and is influenced by physiological state and food-related signals. Moreover, it is highly sensitive to dietary effects during early life periods such as adolescence due to its late maturation. In the present study, we investigated the impact of protein restriction either during adolescence or adulthood on the function of the mesolimbic (nucleus accumbens) and nigrostriatal (dorsal striatum) dopamine pathways using fast-scan cyclic voltammetry in rat brain slices. In the nucleus accumbens, protein restriction in adults increased dopamine release in response to low and high frequency trains of stimulation (1-20 Hz). By contrast, protein restriction during adolescence decreased nucleus accumbens dopamine release. In the dorsal striatum, protein restriction at adulthood has no impact on dopamine release but the same diet during adolescence induced a frequency-dependent increase in stimulated dopamine release. Taken together, our results highlight the sensitivity of the different dopamine pathways to the effect of protein restriction, as well as their vulnerability to deleterious diet effects at different life stages.
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http://dx.doi.org/10.1038/s41386-020-0783-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852901PMC
January 2021

High-Performance Trauma Centers in a Single-State Trauma System : Big Saves or Marginal Gains?

Am Surg 2020 Jul 29;86(7):766-772. Epub 2020 Jul 29.

Division of Traumatology, Emergency Surgery, and Surgical Critical Care, Perelman School of Medicine at the University of Pennsylvania, PA, USA.

Background: Trauma centers with low observed:expected (O:E) mortality ratios are considered high performers; however, it is unknown whether improvements in this ratio are due to a small number of unexpected survivors with high mortality risk (big saves) or a larger number of unexpected survivors with moderate mortality risk (marginal gains). We hypothesized that the highest-performing centers achieve that status via larger numbers of unexpected survivors with moderate mortality risk.

Methods: We calculated O:E ratios for trauma centers in Pennsylvania for 2016 using a risk-adjusted mortality model. We identified high and low performers as centers whose 95% CIs did not cross 1. We visualized differences between these centers by plotting patient-level observed and expected mortality; we then examined differences in a subset of patients with a predicted mortality of ≥10% using the chi-squared test.

Results: One high performer and 1 low performer were identified. The high performer managed a population with more blunt injuries (97.2% vs 93.6%, < .001) and a higher median Injury Severity Score (14 vs 11, < .001). There was no difference in survival between these centers in patients with an expected mortality of <10% (98.0% vs 96.7%, = .11) or ≥70% (23.5% vs 10.8%, = .22), but there was a difference in the subset with an expected mortality of ≥10% (77.5% vs 43.1%, < .001).

Conclusions: Though patients with very low predicted mortality do equally well in high-performing and low-performing centers, the fact that performance seems determined by outcomes of patients with moderate predicted mortality favors a "marginal gains" theory.
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http://dx.doi.org/10.1177/0003134820934415DOI Listing
July 2020

Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition.

Cell 2020 08 22;182(3):625-640.e24. Epub 2020 Jul 22.

VIB Center for Brain and Disease Research, VIB, Leuven 3000, Belgium; Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven 3000, Belgium; Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK. Electronic address:

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69 CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427333PMC
August 2020