Publications by authors named "H Ballentine Carter"

1,019 Publications

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Mass Casualty Decontamination for Chemical Incidents: Research Outcomes and Future Priorities.

Int J Environ Res Public Health 2021 03 17;18(6). Epub 2021 Mar 17.

COVID-19 Behavioural Science and Insights Unit, Public Health England, Public Health England, London SE1 8UG, UK.

Planning for major incidents involving the release of hazardous chemicals has been informed by a multi-disciplinary research agenda which has sought to inform all aspects of emergency response, but with a focus in recent years on mass casualty decontamination. In vitro and human volunteer studies have established the relative effectiveness of different decontamination protocols for a range of chemical agents. In parallel, a programme of research has focused on communicating with and managing large numbers of contaminated casualties at the scene of an incident. We present an accessible overview of the evidence underpinning current casualty decontamination strategies. We highlight where research outcomes can directly inform response planning, including the critical importance of beginning the decontamination process as soon as possible, the benefits of early removal of contaminated clothing, the evidence under-pinning dry and wet decontamination and how effective communication is essential to any decontamination response. We identify a range of priority areas for future research including establishing the significance of the 'wash-in' effect and developing effective strategies for the decontamination of hair. We also highlight several areas of future methodological development, such as the need for novel chemical simulants. Whilst considerable progress has been made towards incorporating research outcomes into operational policy and practice, we outline how this developing evidence-base might be used to inform future iterations of mass casualty decontamination guidance.
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http://dx.doi.org/10.3390/ijerph18063079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002470PMC
March 2021

The Impact of Lower Limb Immobilization and Rehabilitation on Angiogenic Proteins and Capillarization in Skeletal Muscle.

Med Sci Sports Exerc 2021 Mar 25. Epub 2021 Mar 25.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark Technical University of Munich, Germany. Sylvia Lawry Centre for Multiple Sclerosis Research, Munich, Germany.

Purpose: Skeletal muscle vascularization is important for tissue regeneration after injury and immobilization. We examined whether complete immobilization influences capillarization and oxygen delivery to the muscle and assessed the efficacy of rehabilitation by aerobic exercise training.

Methods: Young healthy males had one leg immobilized for 14 days and subsequently completed four weeks of intense aerobic exercise training. Biopsies were obtained from m.vastus lateralis and a-v blood sampling for assessment of oxygen extraction and leg blood flow during exercise was done before and after immobilization and training. Muscle capillarization, muscle and platelet content of vascular endothelial growth factor (VEGF) and muscle thrombospondin-1 were determined.

Results: Immobilization did not have a significant impact on capillary per fiber ratio or capillary density. The content of VEGF protein in muscle samples was reduced by 36% (P=0.024) and VEGF to thrombospondin-1 ratio was 94 % lower (P=0.046). The subsequent four-week training period increased the muscle VEGF content and normalized the muscle VEGF to thrombospondin-1 ratio but did not influence capillarization. Platelet VEGF content followed the trend of muscle VEGF. At the functional level, oxygen extraction, blood flow and oxygen delivery at rest and during submaximal exercise were not affected by immobilization or training.

Conclusion: The results demonstrate that just two weeks of leg immobilization leads to a strongly reduced angiogenic potential as evidenced by reduced muscle and platelet VEGF content and a reduced muscle VEGF to thrombospondin-1 ratio. Moreover, a subsequent period of intensive aerobic exercise training fails to increase capillarization in the previously immobilized leg, possibly due to the angiostatic condition caused by immobilization.
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http://dx.doi.org/10.1249/MSS.0000000000002665DOI Listing
March 2021

Adaptation to Exercise Training in Conduit Arteries and Cutaneous Microvessels in Humans: An Optical Coherence Tomography Study.

Med Sci Sports Exerc 2021 Mar 12. Epub 2021 Mar 12.

Physiology Department, Faculty of Medicine, Airlangga University, Surabaya, Indonesia Cardiovascular Research Group, School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Perth, Australia Integrative Physiology Laboratory, Department of Kinesiology and Nutrition, College of Health Sciences, The University of Illinois, Chicago, IL Australian Research Council Centre of Excellence for Nanoscale Biophotonics, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia Institute for Photonics and Advanced Sensing, The University of Adelaide, Adelaide, Australia School of Electrical, Electronic and Computer Engineering, The University of Western Australia, Perth, Australia.

Introduction: Exercise training has anti-atherogenic impacts on conduit and resistance artery function and structure in humans and induces angiogenic changes in skeletal muscle. However, training-induced adaptation in cutaneous microvessels is poorly understood, partly due to technological limitations. Optical coherence tomography (OCT) is a novel high resolution imaging technique capable of visualising cutaneous microvasculature at a resolution of ~30μm. We utilised OCT to visualise the impacts of training on cutaneous microvessels, alongside assessment of conduit artery flow mediated dilation (FMD).

Methods: We assessed brachial FMD and cutaneous microcirculatory responses at rest and in response to local heating and reactive hyperaemia; pre- and post-training in 8 healthy men compared to age-matched untrained controls (n=8). Participants in the training group underwent supervised cycling at 80% HRmax, 3x/week for 8 weeks.

Results: We found a significant interaction (P=0.04), whereby increase in FMD was observed after training (post 9.83±3.27 % vs pre 6.97±1.77 %, P=0.01), with this post training value higher compared to control group (6.9±2.87 %, P=0.027). FMD was not altered in the controls (P=0.894). There was a significant interaction for OCT-derived speed (P=0.038) whereby a significant decrease in the local disc heating response was observed after training (post 98.6±3.9 μm.sec-1 vs pre 102±5 μm.sec-1, P=0.012), whilst no changes was observed for OCT-derived speed in the control group (P=0.877). Other OCT responses (diameter, flow-rate and density) to local heating and reactive hyperaemia were unaffected by training.

Conclusions: Our findings suggest that vascular adaptation to exercise training is not uniform across all levels of the arterial tree; while exercise training improves larger artery function, this was not accompanied by unequivocal evidence for cutaneous microvascular adaptation in young healthy subjects.
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http://dx.doi.org/10.1249/MSS.0000000000002654DOI Listing
March 2021

Assessment of a Hotel-Based COVID-19 Isolation and Quarantine Strategy for Persons Experiencing Homelessness.

JAMA Netw Open 2021 03 1;4(3):e210490. Epub 2021 Mar 1.

Benioff Homelessness and Housing Initiative, University of California, San Francisco.

Importance: Several jurisdictions in the United States have secured hotels to temporarily house people experiencing homelessness who require isolation or quarantine for confirmed or suspected coronavirus disease 2019 (COVID-19). To our knowledge, little is known about how these programs serve this vulnerable population outside the hospital setting.

Objective: To assess the safety of a hotel-based isolation and quarantine (I/Q) care system and its association with inpatient hospital capacity.

Design, Setting, And Participants: This retrospective cohort study of a hotel-based I/Q care system for homeless and unstably housed individuals in San Francisco, California, was conducted from March 19 to May 31, 2020. Individuals unable to safely isolate or quarantine at home with mild to moderate COVID-19, persons under investigation, or close contacts were referred from hospitals, outpatient settings, and public health surveillance to 5 I/Q hotels. Of 1009 I/Q hotel guests, 346 were transferred from a large county public hospital serving patients experiencing homelessness.

Exposure: A physician-supervised team of nurses and health workers provided around-the-clock support, including symptom monitoring, wellness checks, meals, harm-reduction services, and medications for opioid use disorder.

Main Outcomes And Measures: Characteristics of I/Q hotel guests, program retention, county hospital readmissions, and mean length of stay.

Results: Overall, the 1009 I/Q hotel guests had a median age of 44 years (interquartile range, 33-55 years), 756 (75%) were men, 454 (45%) were Latinx, and 501 (50%) were persons experiencing sheltered (n = 295) or unsheltered (n = 206) homelessness. Overall, 463 (46%) received a diagnosis of COVID-19; 303 of 907 (33%) had comorbid medical disorders, 225 of 907 (25%) had comorbid mental health disorders, and 236 of 907 (26%) had comorbid substance use disorders. A total of 776 of 955 guests (81%) completed their I/Q hotel stay; factors most strongly associated with premature discontinuation were unsheltered homelessness (adjusted odds ratio, 4.5; 95% CI, 2.3-8.6; P < .001) and quarantine status (adjusted odds ratio, 2.6; 95% CI, 1.5-4.6; P = .001). In total, 346 of 549 patients (63%) were transferred from the county hospital; of 113 ineligible referrals, 48 patients (42%) had behavioral health needs exceeding I/Q hotel capabilities. Thirteen of the 346 patients transferred from the county hospital (4%) were readmitted for worsening COVID-19. Overall, direct transfers to I/Q hotels from emergency and outpatient departments were associated with averting many hospital admissions. There was a nonsignificant decrease in the mean hospital length of stay for inpatients with confirmed or suspected COVID-19 from 5.5 to 2.7 days from March to May 2020 (P = .11).

Conclusions And Relevance: To support persons experiencing homelessness during the COVID-19 pandemic, San Francisco rapidly and safely scaled a hotel-based model of I/Q that was associated with reduced strain on inpatient capacity. Strategies to improve guest retention and address behavioral health needs not met in hotel settings are intervention priorities.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926291PMC
March 2021

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Department of Pharmacology, School of Medicine, University of California San Diego, CA 92093;

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8 CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
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http://dx.doi.org/10.1073/pnas.2025840118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923353PMC
February 2021

In silico analysis suggests less effective MHC-II presentation of SARS-CoV-2 RBM peptides: Implication for neutralizing antibody responses.

PLoS One 2021 11;16(2):e0246731. Epub 2021 Feb 11.

Division of Medical Genetics, Department of Medicine, University of California San Diego, La Jolla, CA, United States of America.

SARS-CoV-2 antibodies develop within two weeks of infection, but wane relatively rapidly post-infection, raising concerns about whether antibody responses will provide protection upon re-exposure. Here we revisit T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction. We evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, we found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population. Additionally, we found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246731PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877779PMC
February 2021

Targeting of Mammalian Glycans Enhances Phage Predation in the Gastrointestinal Tract.

mBio 2021 02 9;12(1). Epub 2021 Feb 9.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA

The human gastrointestinal mucosal surface consists of a eukaryotic epithelium, a prokaryotic microbiota, and a carbohydrate-rich interface that separates them. In the gastrointestinal tract, the interaction of bacteriophages (phages) and their prokaryotic hosts influences the health of the mammalian host, especially colonization with invasive pathobionts. Antibiotics may be used, but they also kill protective commensals. Here, we report a novel phage whose lytic cycle is enhanced in intestinal environments. The tail fiber gene, whose protein product binds human heparan sulfated proteoglycans and localizes the phage to the epithelial cell surface, positions it near its bacterial host, a type of locational targeting mechanism. This finding offers the prospect of developing mucosal targeting phage to selectively remove invasive pathobiont species from mucosal surfaces. Invasive pathobionts or microbes capable of causing disease can reside deep within the mucosal epithelium of our gastrointestinal tract. Targeted effective antibacterial therapies are needed to combat these disease-causing organisms, many of which may be multidrug resistant. Here, we isolated a lytic bacteriophage (phage) that can localize to the epithelial surface by binding heparan sulfated glycans, positioning it near its host, This targeted therapy can be used to selectively remove invasive pathobionts from the gastrointestinal tract, preventing the development of disease.
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http://dx.doi.org/10.1128/mBio.03474-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885116PMC
February 2021

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression, and drug response.

Cancer Res 2021 Feb 8. Epub 2021 Feb 8.

Institute for Cancer and Genomic Sciences, University of Birmingham

Insights into oncogenesis derived from cancer susceptibility loci (single nucleotide polymorphisms, SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, while both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of pro-survival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacological inhibition of the pro-survival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0177DOI Listing
February 2021

Can exercise training enhance the repeated remote ischaemic preconditioning stimulus on peripheral and cerebrovascular function in high-risk individuals?

Eur J Appl Physiol 2021 Apr 28;121(4):1167-1178. Epub 2021 Jan 28.

Research Institute of Sports and Exercise Science, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool, L3 3AF, UK.

Background: Repeated exposure to remote ischaemic preconditioning (rIPC; short bouts of non-lethal ischaemia) enhances peripheral vascular function within 1 week; whereas, longer periods of rIPC (~ 1 year) may improve cerebral perfusion. Increasing the 'dose' of rIPC may lead to superior effects. Given the similarities between exercise and rIPC, we examined whether adding exercise to the rIPC stimulus leads to greater adaptation in systemic vascular function.

Methods: Nineteen individuals with increased risk for cardiovascular disease (CVD) were randomly allocated to either 8 weeks of rIPC (n = 9) or 8 weeks of rIPC + exercise (rIPC + Ex) (n = 10). rIPC was applied three times per week in both conditions, and exercise consisted of 50 min (70% heart rate max) of cycling 3 times per week. Peripheral endothelial function was assessed using flow-mediated dilation (FMD) before and after ischaemia-reperfusion (IR). Cerebrovascular function was assessed by dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity (CVR), and cardio-respiratory fitness (VO) using a maximal aerobic capacity test.

Results: FMD% increased by 1.6% (95% CI, 0.4, 2.8) following rIPC + Ex and by 0.3% (- 1.1, 1.5) in the only rIPC but this did not reach statistical significance (P = 0.65). Neither intervention evoked a change in dCA or in CVR (P > 0.05). VO increased by 2.8 ml/kg/min (1.7, 3.9) following the rIPC + Ex and by 0.1 ml/kg/min (- 1.0, 1.4) following the rIPC only intervention (P = 0.69).

Conclusion: Combining exercise with rIPC across an 8-week intervention does not lead to superior effects in cerebrovascular and peripheral vascular function compared to a repeated rIPC intervention in individuals at risk of CVD.
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http://dx.doi.org/10.1007/s00421-020-04580-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966185PMC
April 2021

Phenotypically supervised single-cell sequencing parses within-cell-type heterogeneity.

iScience 2021 Jan 26;24(1):101991. Epub 2020 Dec 26.

Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

To better understand cellular communication driving diverse behaviors, we need to uncover the molecular mechanisms of within-cell-type functional heterogeneity. While single-cell RNA sequencing (scRNAseq) has advanced our understanding of cell heterogeneity, linking individual cell phenotypes to transcriptomic data remains challenging. Here, we used a phenotypic cell sorting technique to ask whether phenotypically supervised scRNAseq analysis (pheno-scRNAseq) can provide more insight into heterogeneous cell behaviors than unsupervised scRNAseq. Using a simple 3D breast cancer (BRCA) model, we conducted pheno-scRNAseq on invasive and non-invasive cells and compared the results to phenotype-agnostic scRNAseq analysis. Pheno-scRNAseq identified unique and more selective differentially expressed genes than unsupervised scRNAseq analysis. Functional studies validated the utility of pheno-scRNAseq in understanding within-cell-type functional heterogeneity and revealed that migration phenotypes were coordinated with specific metabolic, proliferation, stress, and immune phenotypes. This approach lends new insight into the molecular systems underlying BRCA cell phenotypic heterogeneity.
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http://dx.doi.org/10.1016/j.isci.2020.101991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808958PMC
January 2021

Current preoperative physiotherapy management strategies for patients awaiting Anterior Cruciate Ligament Reconstruction (ACLR): A worldwide survey of physiotherapy practice.

Knee 2021 Jan 20;28:300-310. Epub 2021 Jan 20.

University Hospitals of Derby and Burton NHS Foundation Trust, Department of Physiotherapy, London Road Community Hospital, Derby, UK; Division of Rehabilitation, Ageing and Wellbeing, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Anterior cruciate ligament ruptures are the most common ligament injury to the knee with surgical reconstruction considered standard treatment. This study aimed to explore the current physiotherapy management strategies used during the preoperative phase of rehabilitation for patients awaiting anterior cruciate ligament reconstruction (ACLR).

Methods: An anonymous survey was disseminated online via Twitter and the 'interactive Chartered Society of Physiotherapy' message board. Practising physiotherapists who treated at least one patient prior to ACLR in the past year were invited to take part. Responses were collected over a 4-week period in March 2020. Data were analysed using descriptive statistics.

Results: In total, 183 respondents replied; 122 completed the full survey. Responses were collected from 20 countries across 3 settings, NHS/public health services, private and sports. Most respondents reported prescribing exercises, advice and education to patients during prehabilitation. Up to 40% also utilised passive treatments including manual therapy, taping/bracing and electrotherapy. The frequency of recommended exercise completion and length of treatment varied. Most respondents (n = 103/84.4%) felt that many patients waiting for ACLR did not receive prehabilitation. Many physiotherapists reported that patients expressed concerns regarding their readiness for surgery (n = 61/50%) and return to preinjury levels of physical activity (n = 112/91.8%). Almost all respondents would discuss non-operative management with patients (n = 112/91.8%) if they had returned to their preinjury level of physical activity before their ACLR.

Conclusion: Overall, this survey provides some insight as to how physiotherapists manage patients awaiting ACLR. Areas of uncertainty in physiotherapy practice have also been highlighted that require further high-quality research.
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http://dx.doi.org/10.1016/j.knee.2020.12.018DOI Listing
January 2021

Targeted Coronary Artery Calcium Screening in High-Risk Younger Individuals Using Consumer Genetic Screening Results.

JACC Cardiovasc Imaging 2021 Jan 4. Epub 2021 Jan 4.

Department of Bioengineering, University of California San Diego, San Diego, California, USA; Department of Radiology, University of California San Diego, San Diego, California, USA; Department of Medicine, Cardiovascular Division, University of California San Diego, San Diego, California, USA. Electronic address:

Objectives: The goal of this study was to assess the utility of a genetic risk score (GRS) in targeted coronary artery calcium (CAC) screening among young individuals.

Background: Early CAC screening and preventive therapy may reduce long-term risk of a coronary heart disease (CHD) event. However, identifying younger individuals at increased risk remains a challenge. GRS for CHD are age independent and can stratify individuals on various risk trajectories.

Methods: Using 142 variants associated with CHD events, we calculated a GRS in 1,927 individuals in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (aged 32 to 47 years) and 6,600 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (aged 44 to 87 years). We assessed GRS utility to predict CAC presence in the CARDIA cohort and stratify individuals of varying risk for CAC presence over the lifetime in both cohorts.

Results: The GRS predicted CAC presence in CARDIA males. It was not predictive in CARDIA females, which had a CAC prevalence of 6.4%. In combined analysis of the CARDIA and MESA cohorts, the GRS was predictive of CAC in both males and females and was used to derive an equation for the age at which CAC probability crossed a predetermined threshold. When assessed in combination with traditional risk factors, the GRS further stratified individuals. For individuals with an equal number of traditional risk factors, probability of CAC reached 25% approximately 10 years earlier for those in the highest GRS quintile compared to the lowest.

Conclusions: The GRS may be used to target high-risk younger individuals for early CAC screening.
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http://dx.doi.org/10.1016/j.jcmg.2020.11.013DOI Listing
January 2021

MHC-II constrains the natural neutralizing antibody response to the SARS-CoV-2 spike RBM in humans.

bioRxiv 2020 Dec 28. Epub 2020 Dec 28.

SARS-CoV-2 antibodies develop within two weeks of infection, but wane relatively rapidly post-infection, raising concerns about whether antibody responses will provide protection upon re-exposure. Here we revisit T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction. We evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, we found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population. Additionally, we found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory.

Graphical Abstract:
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http://dx.doi.org/10.1101/2020.12.26.424449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781323PMC
December 2020

Human social defeat and approach-avoidance: Escalating social-evaluative threat and threat of aggression increases social avoidance.

J Exp Anal Behav 2021 Jan 28;115(1):157-184. Epub 2020 Dec 28.

Department of Psychology, Georgia State University.

Basic research on avoidance by Murray Sidman laid the foundation for advances in the classification, conceptualization and treatment of avoidance in psychological disorders. Contemporary avoidance research is explicitly translational and increasingly focused on how competing appetitive and aversive contingencies influence avoidance. In this laboratory investigation, we examined the effects of escalating social-evaluative threat and threat of social aggression on avoidance of social interactions. During social-defeat learning, 38 adults learned to associate 9 virtual peers with an increasing probability of receiving negative evaluations. Additionally, 1 virtual peer was associated with positive evaluations. Next, in an approach-avoidance task with social-evaluative threat, 1 peer associated with negative evaluations was presented alongside the peer associated with positive evaluations. Approaching peers produced a positive or a probabilistic negative evaluation, while avoiding peers prevented a negative evaluation (and forfeited a positive evaluation). In an approach-avoidance task with social aggression, virtual peers gave and took money away from participants. Escalating social-evaluative threat and aggression increased avoidance, ratings of feeling threatened and threat expectancy and decreased ratings of peer favorableness. These findings underscore the potential of coupling social defeat and approach-avoidance paradigms for translational research on the neurobehavioral mechanisms of social approach-avoidance decision-making and anxiety.
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http://dx.doi.org/10.1002/jeab.654DOI Listing
January 2021

The emergence of digital mental health in low-income and middle-income countries: A review of recent advances and implications for the treatment and prevention of mental disorders.

J Psychiatr Res 2021 Jan 13;133:223-246. Epub 2020 Dec 13.

The Mental Health for All Lab, Harvard Medical School, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA. Electronic address:

In low-income and middle-income countries (LMICs), emerging digital mental health interventions should be accompanied by regular and comprehensive assessment of available scientific evidence. This review aims to support efforts to monitor progress in digital mental health research, ensuring new evidence can guide researchers, clinicians, policymakers and program managers positioned to adopt and implement these digitally-enabled treatments. In accordance with PRISMA guidelines, an electronic database search from 2016 to 2020 yielded 37 digital intervention studies for detection, diagnosis, prevention, treatment, and/or management of a broad range of mental disorders in 13 LMICs. This date range was selected to update previous reviews. Most studies involved online interventions and many reported feasibility and acceptability, reflected by participant satisfaction or program adherence. About half the studies (N = 23) reported clinical benefits based on changes in mental health. For depression and mood disorders, some digital interventions showed improvements in depressive symptoms, quality of life, treatment adherence, and recovery. However, sample sizes were small and studies focused primarily on adults. Further limiting generalizability was the lack of consistency in clinical assessment and measurement tools between studies. No studies reported worsening symptoms, negative acceptability or dissatisfaction with digital interventions, suggesting possible publication bias. While digital interventions show promise, it remains difficult to conclude that digital interventions are effective from these studies, as it is prudent to exercise caution before drawing conclusions about clinical effectiveness. This review reflects continued growth in digital mental health research in LMICs and further highlights the need for rigorous evaluation of effectiveness and cost-effectiveness.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.016DOI Listing
January 2021

Public Perceptions of the "Remove, Remove, Remove" Information Campaign Before and During a Hazardous Materials Incident: A Survey.

Health Secur 2021 Jan-Feb;19(1):100-107. Epub 2020 Dec 17.

Holly Elisabeth Carter, PhD, is Principal Behavioural Scientist; Louis Gauntlett, PhD, is a Research Assistant; and Richard Amlôt, PhD, is Head of Behavioural Science; all on the Behavioural Science Team, Emergency Response Department, Public Health England, Porton Down, Salisbury, Wiltshire, UK.

In the event of an incident involving the release of hazardous material (eg, chemical, biological, radiological, or nuclear agents), key actions can be taken to reduce harm and protect the people involved. The quicker actions can be taken, the less harm will occur. Guidance is, therefore, needed to help nonspecialist members of the public to act rapidly before emergency responders arrive. The "Remove, Remove, Remove" campaign includes critical information for anyone who is at or near the immediate scene of a hazardous material release. Using a representative sample of 1,000 members of the UK population, this study examined the impact of the information campaign on knowledge and perceptions both before and during the immediate response to an incident. Findings showed that perceptions of the information were positive, with respondents stating that the information was useful and that the recommended actions would be effective. Respondents also stated they would be willing and able to perform the actions during a real incident. Additionally, the respondents' knowledge and confidence in taking protective actions increased significantly after receiving the campaign information, and they overwhelmingly agreed that they would want to receive this information if it were available before an incident. The findings of the survey support the use of the "Remove, Remove, Remove" information before and during hazardous materials incidents.
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http://dx.doi.org/10.1089/hs.2020.0049DOI Listing
March 2021

The effectiveness and cost effectiveness of a hospital avoidance program in a residential aged care facility: a prospective cohort study and modelled decision analysis.

BMC Geriatr 2020 12 7;20(1):527. Epub 2020 Dec 7.

Duke NUS-Medical School, Singapore, Singapore.

Background: Residential aged care facility residents experience high rates of hospital admissions which are stressful, costly and often preventable. The EDDIE program is a hospital avoidance initiative designed to enable nursing and care staff to detect, refer and quickly respond to early signals of a deteriorating resident. The program was implemented in a 96-bed residential aged care facility in regional Australia.

Methods: A prospective pre-post cohort study design was used to collect data on costs of program delivery, hospital admission rates and length of stay for the 12 months prior to, and following, the intervention. A Markov decision model was developed to synthesize study data with published literature in order to estimate the cost-effectiveness of the program. Quality adjusted life years (QALYs) were adopted as the measure of effectiveness.

Results: The EDDIE program was associated with a 19% reduction in annual hospital admissions and a 31% reduction in the average length of stay. The cost-effectiveness analysis found the program to be both more effective and less costly than usual care, with 0.06 QALYs gained and $249,000 health system costs saved in a modelled cohort of 96 residents. A probabilistic sensitivity analysis estimated that there was an 86% probability that the program was cost-effective after taking the uncertainty of the model inputs into account.

Conclusions: This study provides promising evidence for the effectiveness and cost-effectiveness of a nurse led, early intervention program in preventing unnecessary hospital admissions within a residential aged care facility. Further research in multi-site randomised studies is needed to confirm the generalisability of these results.
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http://dx.doi.org/10.1186/s12877-020-01904-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720399PMC
December 2020

Public behaviour in response to the COVID-19 pandemic: understanding the role of group processes.

BJPsych Open 2020 Dec 7;7(1):e11. Epub 2020 Dec 7.

School of Psychology, University of Sussex, UK.

Background: In the absence of a vaccine, behaviour by the public is key to the response to the COVID-19 pandemic. Yet, as with other types of crises and emergencies, there have been doubts about the extent to which the public are able to engage effectively with the required behaviour. These doubts are based on outdated models of group psychology.

Aims And Argument: We analyse the role of group processes in the COVID-19 pandemic in three domains: recognition of threat, adherence by the public to the required public health behaviours (and the factors that increase such adherence) and actions of the many community mutual aid groups that arose during lockdown. In each case, we draw upon the accumulated research on behaviour in emergencies and disasters, as well as the latest findings in relation to the COVID-19 pandemic, to show that explanations in terms of social identity processes make better sense of the patterns of evidence than alternative explanations.

Conclusions: If behaviour in the pandemic is a function of mutable group processes rather than fixed tendencies, then behavioural change is possible. There was evidence of significant change in behaviour from the public, particularly in the early days of the pandemic. Understanding the role of group processes means we can help design more effective interventions to support collective resilience in the public in the face of the pandemic and other threats. We draw out from the evidence a set of recommendations on facilitating the public response to COVID-19 by harnessing group processes.
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http://dx.doi.org/10.1192/bjo.2020.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844149PMC
December 2020

Chemicals with increasingly complex modes of action result in greater variation in sensitivity between earthworm species.

Environ Pollut 2021 Mar 3;272:115914. Epub 2020 Nov 3.

UK Centre for Ecology & Hydrology, Maclean Building, Crowmarsh Gifford, Wallingford, Oxfordshire, OX10 8BB, UK. Electronic address:

The scale of variation in species sensitivity to toxicants has been theoretically linked to mode of action. Specifically, it has been proposed there will be greater variations for chemicals with a putative specific biological target than for toxicants with a non-specific narcotic mechanism. Here we test the hypothesis that mode of action is related to variation in sensitivity in a specifically designed experiment for species from a single ecologically important terrestrial taxa, namely earthworms. Earthworm toxicity tests were conducted with five species for four chemicals, providing a series of increasingly complex modes of action: a putative narcotic polycyclic aromatic hydrocarbon (fluoranthene), and three insecticides (chlorpyrifos, cypermethrin, imidacloprid) with known neuronal receptor targets. Across all the chemicals, the standard epigeic test species Eisenia fetida and Lumbricus rubellus, were generally among the two least sensitive, while the endogenic Aporrectodea caliginosa and Megascolecidae Amynthas gracilis were generally more sensitive (never being among the two least sensitive species). This indicates a potential for bias in the earthworm ecotoxicology literature, which is dominated by studies in epigeic Lumbricidae, but contains few endogeic or Megascolecidae data. Results confirmed the lowest range of variation in sensitivities for effects on reproduction was for fluoranthene (2.5 fold). All insecticides showed greater variation for species sensitivity (cypermethrin: 7.5 fold, chlorpyrifos: 10.3 fold, imidacloprid: 31.5 fold) consistent with the specific mechanisms of the pesticides. Difference in toxicodynamics, based on mode of action specificity and receptor complexity was reflected in the magnitude of sensitivity variation. However, measurements of tissue concentrations also indicated the potential importance of toxicokinetics in explaining species sensitivity variations for chlorpyrifos and cypermethrin.
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http://dx.doi.org/10.1016/j.envpol.2020.115914DOI Listing
March 2021

Time for nutrition in medical education.

BMJ Nutr Prev Health 2020 16;3(1):40-48. Epub 2020 Apr 16.

NNEdPro Global Centre for Nutrition and Health, St John's Innovation Centre, Cambridge, UK.

Aim: To synthesise a selection of UK medical students' and doctors' views surrounding nutrition in medical education and practice.

Methods: Information was gathered from surveys of medical students and doctors identified between 2015 and 2018 and an evaluation of nutrition teaching in a single UK medical school. Comparative analysis of the findings was undertaken to answer three questions: the perceived importance of nutrition in medical education and practice, adequacy of nutrition training, and confidence in current nutrition knowledge and skills.

Results: We pooled five heterogeneous sources of information, representing 853 participants. Most agreed on the importance of nutrition in health (>90%) and in a doctor's role in nutritional care (>95%). However, there was less desire for more nutrition education in doctors (85%) and in medical students (68%). Most felt their nutrition training was inadequate, with >70% reporting less than 2 hours. There was a preference for face-to-face rather than online training. At one medical school, nutrition was included in only one module, but this increased to eight modules following an increased nutrition focus. When medical students were asked about confidence in their nutrition knowledge and on advising patients, there was an even split between agree and disagree (p=0.869 and p=0.167, respectively), yet few were confident in the UK dietary guidelines. Only 26% of doctors were confident in their nutrition knowledge and 74% gave nutritional advice less than once a month, citing lack of knowledge (75%), time (64%) and confidence (62%) as the main barriers. There was some recognition of the importance of a collaborative approach, yet 28% of doctors preferred to get specialist advice rather than address nutrition themselves.

Conclusion: There is a desire and a need for more nutrition within medical education, as well as a need for greater clarity of a doctor's role in nutritional care and when to refer for specialist advice. Despite potential selection bias and limitations in the sampling frame, this synthesis provides a multifaceted snapshot via a large number of insights from different levels of training through medical students to doctors from which further research can be developed.
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http://dx.doi.org/10.1136/bmjnph-2019-000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664491PMC
April 2020

Making the Case for Centralized Dementia Care Through Adaptive Reuse in the Time of COVID-19.

Inquiry 2020 Jan-Dec;57:46958020969305

Oklahoma State University, Stillwater, USA, USA.

It is estimated that 5.4 million Americans have some form of dementia and these numbers are expected to rise in the coming decades, leading to an unprecedented demand for memory care housing and services. At the same time, infectious disease outbreaks like the COVID-19 pandemic have raised great concerns for the future of care settings for people living with dementia. In searching for innovative options to create more autonomy and better quality of life in dementia care settings, while at the same time improving infectious disease control, repurposing existing structures, in particular vacant urban malls, may be one option for the large sites needed for the European model of dementia villages. This editorial paper makes the case for the Dementia Friendly City Center model for centralized dementia programs, medical services and housing. By working across multiple disciplines, this research team has simultaneously addressed numerous issues, including community revitalization, building sustainability, and the strengthening of infectious disease control in care sites which are inclusive, progressive and convergent with the needs of an aging population.
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http://dx.doi.org/10.1177/0046958020969305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607757PMC
November 2020

The effectiveness of preoperative rehabilitation programmes on postoperative outcomes following anterior cruciate ligament (ACL) reconstruction: a systematic review.

BMC Musculoskelet Disord 2020 Oct 3;21(1):647. Epub 2020 Oct 3.

Department of Physiotherapy, London Road Community Hospital, University Hospitals of Derby and Burton NHS Foundation Trust, London Road Community Hospital, Derby, DE1 2QY, UK.

Background: To explore the effectiveness of preoperative rehabilitation programmes (PreHab) on postoperative physical and psychological outcomes following anterior cruciate ligament reconstruction (ACLR).

Method: A systematic search was conducted from inception to November 2019. Randomised controlled trials (RCTs) published in English were included. Risk of bias was assessed using Version 2 of the Cochrane risk-of-bias tool, and the Grading of Recommendations Assessment system was used to evaluate the quality of evidence.

Results: The search identified 739 potentially eligible studies, three met the inclusion criteria. All included RCTs scored 'high' risk of bias. PreHab in all three RCTs was an exercise programme, each varied in content (strength, control, balance and perturbation training), frequency (10 to 24 sessions) and length (3.1- to 6-weeks). Statistically significant differences (p < 0.05) were reported for quadriceps strength (one RCT) and single leg hop scores (two RCTs) in favour of PreHab three months after ACLR, compared to no PreHab. One RCT reported no statistically significant between-group difference for pain and function. No RCT evaluated post-operative psychological outcomes.

Conclusion: Very low quality evidence suggests that PreHab that includes muscular strength, balance and perturbation training offers a small benefit to quadriceps strength and single leg hop scores three months after ACLR compared with no PreHab. There is no consensus on the optimum PreHab programme content, frequency and length. Further research is needed to develop PreHab programmes that consider psychosocial factors and the measurement of relevant post-operative outcomes such as psychological readiness and return to sport.

Trial Registration: PROSPERO trial registration number. CRD42020162754 .
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http://dx.doi.org/10.1186/s12891-020-03676-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533034PMC
October 2020

Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection.

PLoS Pathog 2020 09 28;16(9):e1008851. Epub 2020 Sep 28.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States of America.

Enteroaggregative Escherichia coli (EAEC) is a significant cause of acute and chronic diarrhea, foodborne outbreaks, infections of the immunocompromised, and growth stunting in children in developing nations. There is no vaccine and resistance to antibiotics is rising. Unlike related E. coli pathotypes that are often associated with acute bouts of infection, EAEC is associated with persistent diarrhea and subclinical long-term colonization. Several secreted virulence factors have been associated with EAEC pathogenesis and linked to disease in humans, less certain are the molecular drivers of adherence to the intestinal mucosa. We previously established human intestinal enteroids (HIEs) as a model system to study host-EAEC interactions and aggregative adherence fimbriae A (AafA) as a major driver of EAEC adherence to HIEs. Here, we report a large-scale assessment of the host response to EAEC adherence from all four segments of the intestine across at least three donor lines for five E. coli pathotypes. The data demonstrate that the host response in the duodenum is driven largely by the infecting pathotype, whereas the response in the colon diverges in a patient-specific manner. Major pathways altered in gene expression in each of the four enteroid segments differed dramatically, with responses observed for inflammation, apoptosis and an overwhelming response to different mucin genes. In particular, EAEC both associated with large mucus droplets and specific mucins at the epithelial surface, binding that was ameliorated when mucins were removed, a process dependent on AafA. Pan-screening for glycans for binding to purified AafA identified the human ligand as heparan sulfate proteoglycans (HSPGs). Removal of HSPG abrogated EAEC association with HIEs. These results may mean that the human intestine responds remarkably different to distinct pathobionts that is dependent on the both the individual and intestinal segment in question, and uncover a major role for surface heparan sulfate proteoglycans as tropism-driving factor in adherence and/or colonization.
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http://dx.doi.org/10.1371/journal.ppat.1008851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553275PMC
September 2020

Public responses to the Salisbury Novichok incident: a cross-sectional survey of anxiety, anger, uncertainty, perceived risk and avoidance behaviour in the local community.

BMJ Open 2020 09 25;10(9):e036071. Epub 2020 Sep 25.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Objectives: Malicious incidents involving chemical agents sometimes trigger high public concern. We aimed to (1) identify levels of emotion, perceived risk and behaviour change with regard to visiting Salisbury, 1 month after three people were poisoned with a nerve agent; and (2) test whether factors including receipt of information, beliefs about personal exposure and trust in government were associated with these outcomes.

Design: A cross-sectional telephone survey of a random sample of Salisbury residents.

Setting: Conducted between 5 and 13 April 2018.

Participants: 500 residents aged 18 or over.

Outcome Measures: Self-reported anxiety, anger, uncertainty, perceived risk to self and avoidance of Salisbury.

Results: Any degree of anxiety, anger and uncertainty was reported by 40.6%, 29.8% and 30.6% of participants, respectively. For the majority, the level of emotion reported was mild. Only 7.0% met the criteria for high anxiety and 5.2% reported feeling any risk to their health, whereas 18.6% reported avoiding Salisbury. Factors associated with avoidance of Salisbury included being female, unable to rule out exposure for oneself or of loved ones, believing the incident was targeted against the general public, and lower trust in the government and responding agencies. Hearing a lot or a little about the recovery support (eg, financial packages), as opposed to nothing at all, and being satisfied with this information were associated with reduced avoidance.

Conclusions: Although the March 2018 Salisbury incident had a relatively modest impact on emotion and risk perception in the community, the number who reported avoiding the city was notable. In this, and in future incidents, assuring people that contamination resulted from a targeted, rather than indiscriminate, incident; demonstrating that contamination is contained within specific areas; improving communication about any financial support; and promoting trust in responding agencies should help provide additional reassurance to the community.
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http://dx.doi.org/10.1136/bmjopen-2019-036071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520835PMC
September 2020

New-Onset Nephrotic Syndrome in a Child Associated With COVID-19 Infection.

Front Pediatr 2020 20;8:471. Epub 2020 Aug 20.

Bowling Green Internal Medicine and Pediatric Associates, Bowling Green, KY, United States.

The COVID-19 outbreak has become a worldwide public health emergency. The renal histopathological features of acute tubular necrosis or thrombotic microangiopathy have been previously reported in adults with severe COVID-19 infections. In children, the renal manifestations associated with COVID-19 disease are not widely reported. Here we describe a case report of a child with new-onset nephrotic syndrome associated with COVID-19 infection. An 8-year-old boy with no previous significant medical history presented with bilateral eyelid and facial swelling soon after his parents were diagnosed with COVID-19 infection. He had diarrhea but no fever or shortness of breath. At 1 week after the onset of swelling, the boy tested positive for the COVID-19 virus. Based on clinical findings of significant proteinuria (urine protein and creatinine ratio of 11.4), hypoalbuminemia (serum albumin of 2 g/dl), and hypercholesterolemia (total cholesterol of 384 mg/dl), he was diagnosed with nephrotic syndrome. He responded well to standard-dose prednisone treatment for nephrotic syndrome. At 1 week after starting the prednisone treatment, he went into clinical remission. Lymphopenia continued to be present for 4 weeks after the onset of symptoms. There were no complications related to clot formation or secondary infections with this presentation. COVID-19 can be associated with new-onset nephrotic syndrome in children. The patient responded well to the standard-dose prednisone treatment that is typically used for new-onset nephrotic syndrome. We describe the unique presentation of COVID-19 in a child as new-onset nephrotic syndrome. We offer insight on the success of standard treatment of nephrotic syndrome with COVID-19.
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http://dx.doi.org/10.3389/fped.2020.00471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469478PMC
August 2020

Angiogenic potential is reduced in skeletal muscle of aged women.

J Physiol 2020 11 22;598(22):5149-5164. Epub 2020 Sep 22.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Key Points: The risk of cardiovascular disease and associated skeletal muscle microvascular rarefaction is enhanced in women after menopause, yet knowledge about the angiogenic potential in ageing women is generally sparse. Aged healthy and sedentary women were found to present a markedly impaired capacity for proliferation of skeletal muscle derived microvascular endothelial cells compared to young women. Vascular endothelial growth factor (VEGF) levels in skeletal muscle myocytes and release of VEGF from myocytes tended to be lower in aged compared to young women. The aged women did not show a detectable increase in skeletal muscle capillarization with 8 weeks of intense aerobic cycle training. Combined, the findings indicate that aged women have a reduced potential for capillary growth in skeletal muscle which, with ageing, may lead to age-induced microvascular rarefaction.

Abstract: Skeletal muscle angiogenic potential was examined in cell cultures derived from aged and young women, and the effect of 8 weeks of intense cycle training on muscle capillary growth was determined in the group of aged women. Basal muscle samples were obtained from healthy sedentary aged (n = 12; 64 ± 4.2 years) and young women (n = 5; 24 ± 3.2 years) for endothelial cell and skeletal muscle myocyte isolation and experiments. In addition, the aged women completed an 8-week training intervention. Peak oxygen uptake and muscle samples for histology and protein determination were obtained before and after the training period. Before training, muscle microdialysate was collected from the aged women at rest and during exercise. In Part 1 of the experiments, growth-supplement stimulated proliferation of endothelial cells was ∼75% lower in cells from aged compared to young women (P < 0.001). There was a tendency for a lower vascular endothelial growth factor (VEGF) concentration in muscle conditioned media (P = 0.0696) and for a lower VEGF content in the myocytes (P = 0.0705) from aged compared to young women. Endothelial proliferation was found to be highly dependent on mitochondrial function. Acute exercise resulted in a modest (1.3-fold; P = 0.0073) increase in muscle interstitial VEGF protein in the aged women. In Part 2, 8 weeks of intense training did not change muscle capillarization (P ≥ 0.1502) in the aged women, but led to an increased amount of muscle VEGF (P = 0.0339). In conclusion, aged women have impaired angiogenic potential, which is associated with a compromised response both at the skeletal muscle myocyte and microvascular endothelial cell level.
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http://dx.doi.org/10.1113/JP280189DOI Listing
November 2020

Visualizing and quantifying cutaneous microvascular reactivity in humans by use of optical coherence tomography: impaired dilator function in diabetes.

Am J Physiol Endocrinol Metab 2020 11 21;319(5):E923-E931. Epub 2020 Sep 21.

Cardiovascular Research Group, School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Perth, Australia.

The pathophysiology and time course of impairment in cutaneous microcirculatory function and structure remain poorly understood in people with diabetes, partly due to the lack of investigational tools capable of directly imaging and quantifying the microvasculature in vivo. We applied a new optical coherence tomography (OCT) technique, at rest and during reactive hyperemia (RH), to assess the skin microvasculature in people with diabetes with foot ulcers (DFU, = 13), those with diabetes without ulcers (DNU, = 9), and matched healthy controls (CON, = 13). OCT images were obtained from the dorsal part of the foot at rest and following 5 min of local ischemia induced by inflating a cuff around the thigh at suprasystolic level (220 mmHg). One-way ANOVA was used to compare the OCT-derived parameters (diameter, speed, flow rate, and density) at rest and in response to RH, with repeated-measures two-way ANOVA performed to analyze main and interaction effects between groups. Data are means ± SD. At rest, microvascular diameter in the DFU (84.89 ± 14.84 µm) group was higher than CON (71.25 ± 7.6 µm, = 0.012) and DNU (71.33 ± 12.04 µm, = 0.019) group. Speed in DFU (65.56 ± 4.80 µm/s, = 0.002) and DNU (63.22 ± 4.35 µm/s, = 0.050) were higher than CON (59.58 ± 3.02 µm/s). Microvascular density in DFU (22.23 ± 13.8%) was higher than in CON (9.83 ± 2.94%, = 0.008), but not than in the DNU group (14.8 ± 10.98%, = 0.119). All OCT-derived parameters were significantly increased in response to RH in the CON group (all < 0.01) and DNU group (all < 0.05). Significant increase in the DFU group was observed in speed ( = 0.031) and density ( = 0.018). The change in density was lowest in the DFU group (44 ± 34.1%) compared with CON (199.2 ± 117.5%, = 0.005) and DNU (148.1 ± 98.4, = 0.054). This study proves that noninvasive OCT microvascular imaging is feasible in people with diabetes, provides powerful new physiological insights, and can distinguish between healthy individuals and patients with diabetes with distinct disease severity.
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http://dx.doi.org/10.1152/ajpendo.00233.2020DOI Listing
November 2020

Enteropathogenic Escherichia coli Infection in Cancer and Immunosuppressed Patients.

Clin Infect Dis 2020 Sep 15. Epub 2020 Sep 15.

Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center Center, Houston, TX, USA.

Background: The role of enteropathogenic Escherichia coli (EPEC) as cause of diarrhea in cancer and immunocompromised patients is controversial. Quantitation of bacterial loads has been proposed as a method to differentiate colonized from truly infected patients.

Methods: We studied 77 adult cancer and immunosuppressed patients with diarrhea and EPEC identified in stools by FilmArray, 25 patients with pathogen-negative diarrhea and 21 healthy adults without diarrhea. Stools were studied by qRT-PCR for EPEC genes eaeA, and lifA/efa-1 and strains characterized for virulence factors and adherence to human intestinal enteroids (HIEs).

Results: Patients with EPEC were more likely to have community acquired diarrhea (p=0.009 OR 3.82, [95% CI 1.5-10.0]) when compared to pathogen negative cases. Although EPEC was identified in 3 of 21 (14%) of healthy subjects by qRT-PCR, the bacterial burden was low when compared to patients with diarrhea (≤55 vs. 6x10 4 bacteria/mg stool, p<0.001). Among EPEC patients, the bacterial burden was higher in those receiving immunosuppression (median 6.7x10 3 vs. 55 bacteria/mg, p<0.001) and those with fecal lifA/efa1 (median 5x10 4 vs. 120 bacteria/mg, p=0.015). Response to antimicrobial therapy was seen in 44/48 (92%) of patients with EPEC as the sole pathogen. Antimicrobial resistance was common and strains exhibited distinct patterns of adherence with variable cytotoxicity when studied in HIEs. Cancer care was delayed in 13% of patients.

Conclusions: Immunosuppressed cancer patients with EPEC associated diarrhea carry high burden of EPEC with strains that are resistant to antibiotics, exhibit novel patterns of adherence when studied in HIEs, and interfere with cancer care.
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http://dx.doi.org/10.1093/cid/ciaa1394DOI Listing
September 2020

Loss of RNA-Binding Protein RBMS1 Promotes a Metastatic Transcriptional Program in Colorectal Cancer.

Authors:
Hannah Carter

Cancer Discov 2020 Sep;10(9):1261-1262

Division of Medical Genetics, Department of Medicine, University of California, San Diego, La Jolla, California.

Yu and colleagues combined computational and experimental techniques to identify a new post-transcriptional regulator of metastatic potential in colon cancer. This study reveals that the RNA-binding protein RBMS1 is a positive regulator of mRNA stability for multiple genes, including the tumor suppressor and a WNT pathway interacting protein, , and its loss is a common event associated with poor prognosis..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0993DOI Listing
September 2020

Optical coherence tomography: a novel imaging approach to visualize and quantify cutaneous microvascular structure and function in patients with diabetes.

BMJ Open Diabetes Res Care 2020 08;8(1)

Cardiovascular Research Group, School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Crawley, Western Australia, Australia

Introduction: The pathophysiology of microvascular disease is poorly understood, partly due to the lack of tools to directly image microvessels in vivo.

Research Design And Methods: In this study, we deployed a novel optical coherence tomography (OCT) technique during local skin heating to assess microvascular structure and function in diabetics with (DFU group, n=13) and without (DNU group, n=10) foot ulceration, and healthy controls (CON group, n=13). OCT images were obtained from the dorsal foot, at baseline (33°C) and 30 min following skin heating.

Results: At baseline, microvascular density was higher in DFU compared with CON (21.9%±11.5% vs 14.3%±5.6%, p=0.048). Local heating induced significant increases in diameter, speed, flow rate and density in all groups (all p<0.001), with smaller changes in diameter for the DFU group (94.3±13.4 µm), compared with CON group (115.5±11.7 µm, p<0.001) and DNU group (106.7±12.1 µm, p=0.014). Heating-induced flow rate was lower in the DFU group (584.3±217.0 pL/s) compared with the CON group (908.8±228.2 pL/s, p<0.001) and DNU group (768.8±198.4 pL/s, p=0.014), with changes in density also lower in the DFU group than CON group (44.7%±15.0% vs 56.5%±9.1%, p=0.005).

Conclusions: This proof of principle study indicates that it is feasible to directly visualize and quantify microvascular function in people with diabetes; and distinguish microvascular disease severity between patients.
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http://dx.doi.org/10.1136/bmjdrc-2020-001479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451490PMC
August 2020