Publications by authors named "Emily Brown"

176 Publications

Chronic stress primes innate immune responses in mice and humans.

Cell Rep 2021 Sep;36(10):109595

Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA; Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY, USA. Electronic address:

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
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http://dx.doi.org/10.1016/j.celrep.2021.109595DOI Listing
September 2021

Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease.

Clin Ther 2021 Aug 23. Epub 2021 Aug 23.

Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom.

Purpose: Nonalcoholic fatty liver disease (NAFLD), more recently referred to as metabolic-associated fatty liver disease, refers to a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, associated with hepatic complications (including liver fibrosis, cirrhosis, and hepatocellular carcinoma) and extrahepatic complications (particularly cardiometabolic complications, including type 2 diabetes and cardiovascular disease). Treatment options include lifestyle interventions (dietary modification and physical activity programs) and pharmacologic interventions. Treatment aims should be broad, with a hepatic focus (to improve/reverse hepatic inflammation, fibrosis, and steatohepatitis), ideally with additional extrahepatic effects affecting metabolic co-morbidities (eg, insulin resistance, glucose dysregulation, dyslipidemia), causing weight loss and affording cardiovascular protection. NASH and fibrosis represent the main histopathological features that warrant treatment to prevent disease progression. Despite a paucity of established treatments, the array of potential molecular targets, pathways, and potential treatments is continually evolving. The goal of this article was to provide a narrative review summarizing the emerging and more established therapeutic options considering the complex pathophysiology of NAFLD and the important long-term sequelae of this condition.

Methods: The literature was reviewed by using PubMed, conference abstracts, and press releases from early-phase clinical studies to provide an overview of the evidence.

Findings: As understanding of the pathophysiology of NASH/NAFLD evolves, drugs with different mechanisms of action, targeting different molecular targets and aberrant pathways that mediate hepatic steatosis, inflammation, and fibrosis, have been developed and are being tested in clinical trials. Pharmacologic therapies fall into 4 main categories according to the molecular targets/pathways they disrupt: (1) meta-bolic targets, targeting insulin resistance, hepatic de novo lipogenesis, or substrate utilization; (2) inflam-matory pathways, inhibiting inflammatory cell recruitment/signaling, reduce oxidative/endoplasmic reticulum stress or are antiapoptotic; (3) the liver-gut axis, which modulates bile acid enterohepatic circulation/signaling or alters gut microbiota; and (4) antifibrotic targets, targeting hepatic stellate cells, decrease collagen deposition or increase fibrinolysis.

Implications: Lifestyle modification must remain the cornerstone of treatment. Pharmacologic treatment is reserved for NASH or fibrosis, the presence of which requires histopathological confirmation. The disease complexity provides a strong rationale for combination therapies targeting multiple pathways simultaneously.
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http://dx.doi.org/10.1016/j.clinthera.2021.07.013DOI Listing
August 2021

Fatty liver index predicts incident risk of prediabetes, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).

Ann Med 2021 12;53(1):1256-1264

Department of Medicine, University of Turku, Turku, Finland.

Aims: To investigate the association between overweight/obesity and fatty liver index (FLI) on the odds of incident prediabetes/type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in 2020 participants after 10 years follow up.

Methods: At baseline (in 2001) 2020 participants, males and females, aged 24-39 years, were stratified according to body mass index (BMI), normal weight (<25 kg/m), overweight (≥25-<30 kg/m), or obese (≥30 kg/m) and FLI (as high FLI ≥60 or low FLI <60). We examined the incidence of prediabetes/type 2 diabetes and NAFLD (ultrasound assessed) over 10 years to 2011 to determine the relative impact of FLI and BMI.

Results: 514 and 52 individuals developed prediabetes and type 2 diabetes during follow-up. Such individuals were older, with higher BMI, serum glucose, insulin, alanine aminotransferase (ALT) and triglyceride (TG) concentrations than those who did not develop prediabetes or type 2 diabetes ( = 1454). The additional presence of high FLI significantly increased the risk of developing prediabetes and type 2 diabetes above the risk of being overweight/obese. Compared with normal weight, low FLI participants, the odds of prediabetes were ∼2-fold higher and the odds of type 2 diabetes were 9-10-fold higher respectively in the overweight/obese, high FLI group. No difference was observed between normal weight, low FLI and overweight/obese and low FLI groups.

Conclusions: An increased FLI significantly increases the odds of incident prediabetes, type 2 diabetes and NAFLD in individuals with overweight/obese highlighting the contributory role of liver fat accumulation in the pathophysiology of prediabetes/type 2 diabetes.Key messagesObesity is a risk factor for non-alcoholic fatty liver disease (NAFLD), prediabetes and type 2 diabetes.Additionally, NAFLD is more prevalent in people with prediabetes and type 2 diabetes when compared to age- and BMI-matched individuals.The presence of a raised fatty liver index (FLI) confers a significantly increased risk of developing prediabetes, type 2 diabetes and NAFLD above that conferred by being overweight/obese.The degree of elevation of FLI can risk stratify for incident prediabetes and type 2 diabetes in people with obesity.
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http://dx.doi.org/10.1080/07853890.2021.1956685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317942PMC
December 2021

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression.

Circ Res 2021 Aug 22;129(5):530-546. Epub 2021 Jul 22.

NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine (M. Schlegel, M. Sharma, E.J.B., A.A.C.N., Y.C., M.S.A., E.M.C., G.J.K., C.v.S., J.G., R.F., C.A.N., L.C.S., D.P., E.A.F., K.J.M.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319313DOI Listing
August 2021

A andomisd, controlled, double blind tudy to assess mechanstic effects of combination therapy of dapagflozin with xenatide QW versus dapagliflozin alone i obese patients with ype 2 diabetes mellitus (RESILIENT): study protocol.

BMJ Open 2021 07 20;11(7):e045663. Epub 2021 Jul 20.

Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

Introduction: The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity.

Methods And Analysis: 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) (energy intake and energy expenditure measured by indirect calorimetry); (2) (between and within meals) and satiety quotient; (3) including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and (using transthoracic echocardiography, cardiac MR and duplex ultrasonography).

Ethics And Dissemination: This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants.

Trial Sponsor: University of Liverpool.

Trial Registration Number: ISRCTN 52028580; EUDRACT number 2015-005242-60.
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http://dx.doi.org/10.1136/bmjopen-2020-045663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292819PMC
July 2021

Plasticity in Intrinsic Excitability of Hypothalamic Magnocellular Neurosecretory Neurons in Late-Pregnant and Lactating Rats.

Int J Mol Sci 2021 Jul 1;22(13). Epub 2021 Jul 1.

Brain Health Research Centre, University of Otago, Dunedin 9054, New Zealand.

Oxytocin and vasopressin secretion from the posterior pituitary gland are required for normal pregnancy and lactation. Oxytocin secretion is relatively low and constant under basal conditions but becomes pulsatile during birth and lactation to stimulate episodic contraction of the uterus for delivery of the fetus and milk ejection during suckling. Vasopressin secretion is maintained in pregnancy and lactation despite reduced osmolality (the principal stimulus for vasopressin secretion) to increase water retention to cope with the cardiovascular demands of pregnancy and lactation. Oxytocin and vasopressin secretion are determined by the action potential (spike) firing of magnocellular neurosecretory neurons of the hypothalamic supraoptic and paraventricular nuclei. In addition to synaptic input activity, spike firing depends on intrinsic excitability conferred by the suite of channels expressed by the neurons. Therefore, we analysed oxytocin and vasopressin neuron activity in anaesthetised non-pregnant, late-pregnant, and lactating rats to test the hypothesis that intrinsic excitability of oxytocin and vasopressin neurons is increased in late pregnancy and lactation to promote oxytocin and vasopressin secretion required for successful pregnancy and lactation. Hazard analysis of spike firing revealed a higher incidence of post-spike hyperexcitability immediately following each spike in oxytocin neurons, but not in vasopressin neurons, in late pregnancy and lactation, which is expected to facilitate high frequency firing during bursts. Despite lower osmolality in late-pregnant and lactating rats, vasopressin neuron activity was not different between non-pregnant, late-pregnant, and lactating rats, and blockade of osmosensitive ΔN-TRPV1 channels inhibited vasopressin neurons to a similar extent in non-pregnant, late-pregnant, and lactating rats. Furthermore, supraoptic nucleus ΔN-TRPV1 mRNA expression was not different between non-pregnant and late-pregnant rats, suggesting that sustained activity of ΔN-TRPV1 channels might maintain vasopressin neuron activity to increase water retention during pregnancy and lactation.
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http://dx.doi.org/10.3390/ijms22137140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268815PMC
July 2021

SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications.

Lancet 2021 07 30;398(10296):262-276. Epub 2021 Jun 30.

Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK.

SGLT2 inhibitors and GLP-1 receptor agonists are used in patients with type 2 diabetes as glucose lowering therapies, with additional benefits of weight loss and blood pressure reduction. Data from cardiovascular outcome trials have highlighted that these drugs confer protection against major cardiovascular disease in those with established atherosclerotic cardiovascular disease, reduce the risk of admission to hospital for heart failure, and reduce cardiovascular and all-cause mortality. Ongoing research using hard renal endpoints such as end stage kidney disease rather than surrogate markers might clarify the renoprotective benefits of both agents. When used for glucose lowering, SGLT2 inhibitors are most effective if the estimated glomerular filtration rate is more than 60 ml per min per 1·73m at initiation and should be avoided where there is a risk of diabetic ketoacidosis. GLP-1 receptor agonists are contraindicated in those with a history of medullary thyroid cancer and used with caution in patients with a history of pancreatitis of a known cause. These drugs are now second-line, or even arguably first-line, glucose lowering therapies in patients with cardiorenal disease, irrespective of glycaemic control. If an SGLT2 inhibitor or GLP-1 receptor agonist is considered suitable in patients with type 2 diabetes, treatment should be prioritised according to existing evidence: GLP-1 receptor agonists should be considered in patients at a high risk of, or with established, cardiovascular disease and SGLT2 inhibitors considered for patients with heart failure (with reduced ejection fraction) or chronic kidney disease (with or without established cardiovascular disease). There is now compelling data on the benefits of these drugs for a range of other clinical indications even without type 2 diabetes, including for GLP-1 receptor agonists in patients with obesity and overweight with weight-related comorbidities.
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http://dx.doi.org/10.1016/S0140-6736(21)00536-5DOI Listing
July 2021

Adaptation of a Mailed-FIT Kit and Patient Navigation Intervention to Increase Colorectal Cancer (CRC) Screening Among Spanish-Speaking Hispanic/Latino Patients.

Hisp Health Care Int 2021 Jun 23:15404153211024116. Epub 2021 Jun 23.

Fred Hutchison Cancer Research Center, Seattle, WA, USA.

Background: Hispanic/Latino populations experience significant barriers to colorectal cancer (CRC) screening. ProCRCScreen is a multicomponent CRC screening program that can help primary care clinics improve CRC screening rates, but it needs adaptation to better meet the health care needs of Spanish-speaking Hispanic/Latino populations.

Methods: We conducted four focus groups with 22 Spanish-speaking Latino patients and used inductive qualitative content analysis to identify potential program adaptations.

Results: We identified lack of social support for CRC screening and confusion about completing stool-based testing as important barriers to CRC screening. Participants recommended increased specificity of the fecal immunochemical test (FIT) instructions to increase the likelihood of successful test completion, especially for first-time screening. They also endorsed patient navigation for support in completing CRC screening.

Discussion: We adapted the informational materials and workflows for the ProCRCScreen program. Future research to test the adapted program is needed.
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http://dx.doi.org/10.1177/15404153211024116DOI Listing
June 2021

Prevalence of peripheral neuropathy in pre-diabetes: a systematic review.

BMJ Open Diabetes Res Care 2021 05;9(1)

Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK

There is growing evidence of excess peripheral neuropathy in pre-diabetes. We aimed to determine its prevalence, including the impact of diagnostic methodology on prevalence rates, through a systematic review conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive electronic bibliographic search was performed in MEDLINE, EMBASE, PubMed, Web of Science and the Cochrane Central Register of Controlled Trials from inception to June 1, 2020. Two reviewers independently selected studies, extracted data and assessed risk of bias. An evaluation was undertaken by method of neuropathy assessment. After screening 1784 abstracts and reviewing 84 full-text records, 29 studies (9351 participants) were included. There was a wide range of prevalence estimates (2%-77%, IQR: 6%-34%), but the majority of studies (n=21, 72%) reported a prevalence ≥10%. The three highest prevalence estimates of 77% (95% CI: 54% to 100%), 71% (95% CI: 55% to 88%) and 66% (95% CI: 53% to 78%) were reported using plantar thermography, multimodal quantitative sensory testing and nerve conduction tests, respectively. In general, studies evaluating small nerve fiber parameters yielded a higher prevalence of peripheral neuropathy. Due to a variety of study populations and methods of assessing neuropathy, there was marked heterogeneity in the prevalence estimates. Most studies reported a higher prevalence of peripheral neuropathy in pre-diabetes, primarily of a small nerve fiber origin, than would be expected in the background population. Given the marked rise in pre-diabetes, further consideration of targeting screening in this population is required. Development of risk-stratification tools may facilitate earlier interventions.
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http://dx.doi.org/10.1136/bmjdrc-2020-002040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137250PMC
May 2021

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Circulation 2021 Jul 5;144(1):7-19. Epub 2021 May 5.

Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.

Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.

Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (, , , , , , , , , , ) or strong () evidence. Seven genes (14%; , , , , , , ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.

Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247549PMC
July 2021

Mitochondria: The Retina's Achilles' Heel in AMD.

Adv Exp Med Biol 2021 ;1256:237-264

Department of Ophthalmology, University of Florida, Gainesville, FL, USA.

Strong experimental evidence from studies in human donor retinas and animal models supports the idea that the retinal pathology associated with age-related macular degeneration (AMD) involves mitochondrial dysfunction and consequent altered retinal metabolism. This chapter provides a brief overview of mitochondrial structure and function, summarizes evidence for mitochondrial defects in AMD, and highlights the potential ramifications of these defects on retinal health and function. Discussion of mitochondrial haplogroups and their association with AMD brings to light how mitochondrial genetics can influence disease outcome. As one of the most metabolically active tissues in the human body, there is strong evidence that disruption in key metabolic pathways contributes to AMD pathology. The section on retinal metabolism reviews cell-specific metabolic differences and how the metabolic interdependence of each retinal cell type creates a unique ecosystem that is disrupted in the diseased retina. The final discussion includes strategies for therapeutic interventions that target key mitochondrial pathways as a treatment for AMD.
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http://dx.doi.org/10.1007/978-3-030-66014-7_10DOI Listing
April 2021

International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.

Circ Genom Precis Med 2021 Jun 8;14(3):e003273. Epub 2021 Apr 8.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, the Netherlands (R.L.D., J.P.v.T.).

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes.

Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework.

Results: Of 26 reported ARVC genes, only 6 (, , , , , and ) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, and . The remaining 18 genes had limited or no evidence. was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%).

Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (, , , , , , , and ) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.
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http://dx.doi.org/10.1161/CIRCGEN.120.003273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205996PMC
June 2021

Addressing the social needs of individuals with food allergy and celiac disease during COVID-19: A new practice model for sustained social care.

Soc Work Health Care 2021 28;60(2):187-196. Epub 2021 Mar 28.

Division of Allergy, Clinical Immunology and Rheumatology, University of Kansas Medical Center, Kansas City, Kansas, USA.

COVID-19 has led to high rates of food insecurity. Food insecure patients with food allergy and celiac disease are especially vulnerable during the pandemic when foods become limited. This paper describes a practice innovation implemented by a community-based organization, Food Equality Initiative (FEI), whose mission is improving health and ending hunger among individuals with food allergy and celiac disease. FEI responded to the pandemic by converting their in-person pantries to a contactless delivery of safe foods. The practice innovation is discussed in relation to three system-level elements necessary to sustain the integration of social care into the delivery of healthcare.
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http://dx.doi.org/10.1080/00981389.2021.1904323DOI Listing
May 2021

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Commun Biol 2021 03 26;4(1):420. Epub 2021 Mar 26.

Department of Microbiology, NYU School of Medicine, New York, NY, USA.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68 and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68 upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
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http://dx.doi.org/10.1038/s42003-021-01925-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997930PMC
March 2021

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis.

Elife 2021 03 15;10. Epub 2021 Mar 15.

Department of Medicine, Leon H. Charney Division of Cardiology, Cardiovascular Research Program, New York University Grossman School of Medicine, New York, United States.

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE/STAT3 axis.
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http://dx.doi.org/10.7554/eLife.67932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994001PMC
March 2021

Mutant Nmnat1 leads to a retina-specific decrease of NAD+ accompanied by increased poly(ADP-ribose) in a mouse model of NMNAT1-associated retinal degeneration.

Hum Mol Genet 2021 May;30(8):644-657

Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is required for nuclear nicotinamide adenine mononucleotide (NAD+) biosynthesis in all nucleated cells, and despite its functional ubiquity, mutations in this gene lead to an isolated retinal degeneration. The mechanisms underlying how mutant NMNAT1 causes disease are not well understood, nor is the reason why the pathology is confined to the retina. Using a mouse model of NMNAT1-associated retinal degeneration that harbors the p.Val9Met mutation, we tested the hypothesis that decreased function of mutant NMNAT1 has a greater effect on the levels of NAD+ in the retina than elsewhere in the body. Measurements by liquid chromatography with tandem mass spectrometry showed an early and sustained decrease of NAD+ in mutant retinas that was not observed in other tissues. To understand how consumers of nuclear NAD+ are affected by the reduced availability of NAD+ in mutant retinas, poly(ADP-ribose) polymerase (PARP) and nuclear sirtuin activity were evaluated. PARP activity was elevated during disease progression, as evidenced by overproduction of poly(ADP-ribose) (PAR) in photoreceptors, whereas histone deacetylation activity of nuclear sirtuins was not altered. We hypothesized that PARP could be activated because of elevated levels of oxidative stress; however, we did not observe oxidative DNA damage, lipid peroxidation, or a low glutathione to oxidized glutathione ratio. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed that photoreceptors appear to ultimately die by apoptosis, although the low NAD+ levels and overproduction of PAR suggest that cell death may include aspects of the parthanatos cell death pathway.
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http://dx.doi.org/10.1093/hmg/ddab070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127407PMC
May 2021

SARS-CoV-2 S1 NanoBiT: A nanoluciferase complementation-based biosensor to rapidly probe SARS-CoV-2 receptor recognition.

Biosens Bioelectron 2021 May 2;180:113122. Epub 2021 Mar 2.

Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. Electronic address:

As the COVID-19 pandemic continues, there is an imminent need for rapid diagnostic tools and effective antivirals targeting SARS-CoV-2. We have developed a novel bioluminescence-based biosensor to probe a key host-virus interaction during viral entry: the binding of SARS-CoV-2 viral spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2). Derived from Nanoluciferase binary technology (NanoBiT), the biosensor is composed of Nanoluciferase split into two complementary subunits, Large BiT and Small BiT, fused to the Spike S1 domain of the SARS-CoV-2 S protein and ACE2 ectodomain, respectively. The ACE2-S1 interaction results in reassembly of functional Nanoluciferase, which catalyzes a bioluminescent reaction that can be assayed in a highly sensitive and specific manner. We demonstrate the biosensor's large dynamic range, enhanced thermostability and pH tolerance. In addition, we show the biosensor's versatility towards the high-throughput screening of drugs which disrupt the ACE2-S1 interaction, as well as its ability to act as a surrogate virus neutralization assay. Results obtained with our biosensor correlate well with those obtained with a Spike-pseudotyped lentivirus assay. This rapid in vitro tool does not require infectious virus and should enable the timely development of antiviral modalities targeting SARS-CoV-2 entry.
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http://dx.doi.org/10.1016/j.bios.2021.113122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921772PMC
May 2021

Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.

Despite sequence similarity to SARS-CoV-1, SARS-CoV-2 has demonstrated greater widespread virulence and unique challenges to researchers aiming to study its pathogenicity in humans. The interaction of the viral receptor binding domain (RBD) with its main host cell receptor, angiotensin-converting enzyme 2 (ACE2), has emerged as a critical focal point for the development of anti-viral therapeutics and vaccines. In this study, we selectively identify and characterize the impact of mutating certain amino acid residues in the RBD of SARS-CoV-2 and in ACE2, by utilizing our recently developed NanoBiT technology-based biosensor as well as pseudotyped-virus infectivity assays. Specifically, we examine the mutational effects on RBD-ACE2 binding ability, efficacy of competitive inhibitors, as well as neutralizing antibody activity. We also look at the implications the mutations may have on virus transmissibility, host susceptibility, and the virus transmission path to humans. These critical determinants of virus-host interactions may provide more effective targets for ongoing vaccines, drug development, and potentially pave the way for determining the genetic variation underlying disease severity.
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http://dx.doi.org/10.3390/ijms22052268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956771PMC
February 2021

Evaluation of an Emergency Department High-risk Bruising Screening Protocol.

Pediatrics 2021 04 2;147(4). Epub 2021 Mar 2.

Seattle Children's Hospital and.

Objectives: The objective of this study was to describe the outcomes of implementing a high-risk bruise screening pathway in a pediatric emergency department (ED).

Methods: A retrospective observational study was performed of children aged 0 to <48 months who presented to the ED between December 1, 2016, and April 1, 2019, and had bruising that is high-risk for physical abuse on a nurse screening examination. A high-risk bruise was defined as any bruise if aged <6 months or a bruise to the torso, ears, or neck if aged 6 to <48 months. Records of children with provider-confirmed high-risk bruising were reviewed.

Results: Of the 49 726 age-eligible children presenting to the ED, 43 771 (88%) were screened for bruising. Seven hundred eighty-three (1.8%) of those children had positive screen results and 163 (0.4%) had provider-confirmed high-risk bruising. Of the 8635 infants aged <6 months who were screened, 48 (0.6%) had high-risk bruising and 24 of 48 (50%) were classified as cases of likely or definite abuse. Skeletal surveys were performed in 29 of 48 (60%) infants, and 11 of 29 (38%) had occult fracture. Of the 35 136 children aged 6 to <48 months who were screened, 115 of 35 136 (0.3%) had high-risk bruising and 32 of 115 (28%) were classified as cases of likely or definite abuse.

Conclusions: High-risk bruising was rarely present. When infants aged <6 months were evaluated per recommendations, occult fracture was identified in one-third of patients. The screening pathway could help other institutions identify occult injuries in pediatric ED patients.
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http://dx.doi.org/10.1542/peds.2020-002444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015159PMC
April 2021

miR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques.

Circ Res 2021 Apr 17;128(8):1122-1138. Epub 2021 Feb 17.

Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine (M.S.A., M. Sharma, M. Schlegel, C.v.S., G.J.K., L.C.S., L.B., D.P., K.R., E.J.B., E.A.F., K.J.M.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049965PMC
April 2021

Nanoluciferase complementation-based bioreporter reveals the importance of N-linked glycosylation of SARS-CoV-2 S for viral entry.

Mol Ther 2021 06 10;29(6):1984-2000. Epub 2021 Feb 10.

Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address:

The ongoing COVID-19 pandemic has highlighted the immediate need for the development of antiviral therapeutics targeting different stages of the SARS-CoV-2 life cycle. We developed a bioluminescence-based bioreporter to interrogate the interaction between the SARS-CoV-2 viral spike (S) protein and its host entry receptor, angiotensin-converting enzyme 2 (ACE2). The bioreporter assay is based on a nanoluciferase complementation reporter, composed of two subunits, large BiT and small BiT, fused to the S receptor-binding domain (RBD) of the SARS-CoV-2 S protein and ACE2 ectodomain, respectively. Using this bioreporter, we uncovered critical host and viral determinants of the interaction, including a role for glycosylation of asparagine residues within the RBD in mediating successful viral entry. We also demonstrate the importance of N-linked glycosylation to the RBD's antigenicity and immunogenicity. Our study demonstrates the versatility of our bioreporter in mapping key residues mediating viral entry as well as screening inhibitors of the ACE2-RBD interaction. Our findings point toward targeting RBD glycosylation for therapeutic and vaccine strategies against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.ymthe.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872859PMC
June 2021

Clinical and laboratory evaluation of patients with SARS-CoV-2 pneumonia treated with high-titer convalescent plasma.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

Hackensack University Medical Center, Hackensack, New Jersey, USA.

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.
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http://dx.doi.org/10.1172/jci.insight.143196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026191PMC
March 2021

The genetic counselor's role in management of patients with dyslipidemia.

Authors:
Emily E Brown

Curr Opin Lipidol 2021 04;32(2):83-88

Center for Inherited Heart Disease, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA.

Purpose Of Review: The role of genetic testing in diagnosis and management of dyslipidemias continues to grow. Consequently, it is increasingly important for patients to have access to clinicians who have expertise in medical genetics and the psychological implications related to this type of testing. Often a lipidologist has had limited training in this regard, and this review explores the role of the genetic counselor to fill this gap.

Recent Findings: Genetic counselors are key members of the healthcare team, and their specialized training in medical genetics and counseling allows them to fill this professional knowledge gap within the lipid clinic.

Summary: With the continued emphasis on precision medicine, the utility of genetic testing for dyslipidemias will continue to grow. This will in turn increase the demand for provider expertise in medical genetics and counseling around these complex issues. Integrating a genetic counselor within the lipid clinic provides an ideal management scenario providing patients and families with access to not only medical information but also emotional support regarding their hereditary condition.
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http://dx.doi.org/10.1097/MOL.0000000000000732DOI Listing
April 2021

"Blood pressure monitoring should be a habit": adaptation of the Check. Change. Control. program for Asian American older adults, from group-based in-person to one-on-one telephone delivery.

Transl Behav Med 2021 06;11(6):1244-1253

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center and Department of Health Services, University of Washington, Seattle, WA, USA.

Asian Americans have the lowest rate of awareness about hypertension, including controlled hypertension, among all racial/ethnic groups in the USA. A high proportion of Asian American older adults have limited English proficiency (LEP) and hypertension. This study adapted the Check. Change. Control. (CCC) program, a community-based intervention for hypertension control delivered in a face-to-face group setting, to phone-based delivery and evaluated the acceptability of the program among Asian American older adults with LEP. Thirteen participants received phone-based educational sessions on hypertension control over 4 months. After 4 months of interventions, we interviewed the 13 Asian American older adults and 4 counselors to examine the acceptability of the adapted CCC program. Both Asian American older adults and counselors found the phone-based delivery of the CCC program to be acceptable, and some participants recommended holding an in-person meeting before telephone delivery to review the program content and clarify information. Future study needs to explore the effectiveness of the phone-based delivery of the program on blood pressure management among larger groups of Asian American older adults.
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http://dx.doi.org/10.1093/tbm/ibaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212031PMC
June 2021

Understanding the healthfulness of outlets providing lunch and dinner meals: a census of a rural food retail environment in Victoria, Australia.

Aust N Z J Public Health 2021 Feb 21;45(1):65-70. Epub 2020 Dec 21.

Global Obesity Centre (GLOBE), Institute for Health Transformation, Faculty of Health, Deakin University, Victoria.

Objective: To undertake a census of the healthfulness of food venues providing lunch or dinner meals in a rural Australian setting and compare healthfulness by remoteness, using two measurement tools.

Methods: A census of the rural local government area food venues was undertaken using two validated tools: the Healthfulness Rating Classification System (HRCS) and the Nutrition Environment Measures Survey (NEMS-R). Data were collected covering an area of 3,438 square kilometres in Victoria, Australia, with a population of >21,000. Healthfulness by remoteness was described and variability between tools was explored.

Results: Data were collected from all 95 eligible food venues. Both tools classified the food venues as relatively unhealthy. The mean HRCS score was -2.9 (unhealthy) and the mean NEMS-R score was 10.8 (SD 7.0; possible range -27 to 64). There were no significant differences in healthiness of venues by remoteness (as measured by the Modified Monash Model), although the outer-rural region had lower scores.

Conclusions: This census of a rural food retail environment showed low access to healthy menu options along with minimal provision of nutrition information and promotion of healthy food in food venues. This environment has the potential to affect the dietary intake of more than 21,000 rural-dwelling Australians and action to improve rural food environments is desperately needed. Implications for public health: If unhealthful rural food environments are not addressed, inequalities in the diet-related disease burden for rural Australians will continue to persist. This study shows that interventions are needed for independent venues that could be targeted by researchers, local health promotion officers, community nutritionists or community education programs.
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http://dx.doi.org/10.1111/1753-6405.13057DOI Listing
February 2021

Tenofovir diphosphate concentrations in dried blood spots from pregnant and postpartum adolescent and young women receiving daily observed pre-exposure prophylaxis in sub-Saharan Africa.

Clin Infect Dis 2020 Dec 20. Epub 2020 Dec 20.

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Intracellular tenofovir diphosphate (TFV-DP) concentration measured in dried blood spots (DBS) is used to monitor cumulative adherence to pre-exposure prophylaxis (PrEP). We evaluated TFV-DP in DBS following daily oral PrEP (emtricitabine 200mg/tenofovir diphosphate 300mg) among pregnant and postpartum adolescent girls and young women (AGYW).

Methods: Directly observed PrEP was administered for 12 weeks in a pregnancy group (14-24 weeks gestation, n=20) and a postpartum group (6-12 weeks postpartum, n=20) of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with the Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated.

Results: Participant median age was 20 years (IQR:19,22). Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median half-life was ten days (IQR:7, 12) in pregnancy and 17 days (IQR:14, 21) postpartum, with steady-state achieved by five and eight weeks, respectively. Observed median steady-state TFV-DP was 965 fmol/punch (IQR:691, 1166) in pregnancy vs 1406 fmol/punch (IQR:1053, 1859) postpartum (p=0.006). Modelled median steady-state TFV-DP was 881 fmol/punch (IQR: 667,1105) in pregnancy vs 1438 fmol/punch (IQR: 1178,1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations.

Conclusion: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. Population-specific benchmarks provided by this study can be used to guide PrEP adherence support in pregnant/postpartum African women.
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http://dx.doi.org/10.1093/cid/ciaa1872DOI Listing
December 2020

The effect of imaging modality (magnetic resonance imaging vs. computed tomography) and patient position (supine vs. prone) on target and organ at risk doses in partial breast irradiation.

J Med Radiat Sci 2021 Jun 7;68(2):157-166. Epub 2020 Dec 7.

Liverpool and Macarthur Cancer Therapy Centers, Liverpool, NSW, Australia.

Introduction: Conventionally computed tomography (CT) has been used to delineate target volumes in radiotherapy; however, magnetic resonance imaging (MRI) is being continually integrated into clinical practice; therefore, the investigation into targets derived from MRI is warranted. The purpose of this study was to evaluate the impact of imaging modality (MRI vs. CT) and patient positioning (supine vs. prone) on planning target volumes (PTVs) and organs at risk (OARs) for partial breast irradiation (PBI).

Methods: A retrospective data set, of 35 patients, was accessed where each patient had undergone MRI and CT imaging for tangential whole breast radiotherapy in both the supine and prone position. PTVs were defined from seroma cavity (SC) volumes delineated on each respective image, resulting in 4 PTVs per patient. PBI plans were generated with 6MV external beam radiotherapy (EBRT) using the TROG 06.02 protocol guidelines. A prescription of 38.5Gy in 10 fractions was used for all cases. The impact analysis of imaging modality and patient positioning included dose to PTVs, and OARs based on agreed criteria. Statistical analysis was conducted though Mann-Whitey U, Fisher's exact and chi-squared testing (P < 0.005).

Results: Twenty-four patients were eligible for imaging analysis. However, positioning analysis could only be investigated on 19 of these data sets. No statistically significant difference was found in OAR doses based on imaging modality. Supine patient position resulted in lower contralateral breast dose (0.10Gy ± 0.35 vs. 0.33Gy ± 0.78, p = 0.011). Prone positioning resulted in a lower dose to ipsilateral lung volumes (10.85Gy ± 11.37 vs. 3.41Gy ± 3.93, P = <0.001).

Conclusions: PBI plans with PTVs derived from MRI exhibited no clinically significant differences when compared to plans created from CT in relation to plan compliance and OAR dose. Patient position requires careful consideration regardless of imaging modality chosen. Although there was no proven superiority of MRI derived target volumes, it indicates that MRI could be considered for PBI target delineation.
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http://dx.doi.org/10.1002/jmrs.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168067PMC
June 2021

Microbial and chemical dynamics of a toxic dinoflagellate bloom.

PeerJ 2020 21;8:e9493. Epub 2020 Jul 21.

School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, United States of America.

Harmful Algal Blooms (HABs) exert considerable ecological and economic damage and are becoming increasingly frequent worldwide. However, the biological factors underlying HABs remain uncertain. Relationships between algae and bacteria may contribute to bloom formation, strength, and duration. We investigated the microbial communities and metabolomes associated with a HAB of the toxic dinoflagellate off the west coast of Florida in June 2018. Microbial communities and intracellular metabolite pools differed based on both bacterial lifestyle and bloom level, suggesting a complex role for blooms in reshaping microbial processes. Network analysis identified as an ecological hub in the planktonic ecosystem, with significant connections to diverse microbial taxa. These included four flavobacteria and one sequence variant unidentified past the domain level, suggesting uncharacterized diversity in phytoplankton-associated microbial communities. Additionally, intracellular metabolomic analyses associated high levels with higher levels of aromatic compounds and lipids. These findings reveal water column microbial and chemical characteristics with potentially important implications for understanding HAB onset and duration.
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http://dx.doi.org/10.7717/peerj.9493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676380PMC
July 2020

Genetic Dilated Cardiomyopathy Due to TTN Variants Without Known Familial Disease.

Circ Genom Precis Med 2020 12 15;13(6):e003082. Epub 2020 Nov 15.

Division of Cardiology (E.E.B., B.M., J.V., E.T., L.A.B., C.J., D.P.J.), Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1161/CIRCGEN.120.003082DOI Listing
December 2020

Delays in care seeking for young children with accidental skull fractures are common.

Acta Paediatr 2021 06 25;110(6):1890-1894. Epub 2020 Nov 25.

Children's Protection Program, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.

Aim: We sought to determine the frequency and patterns of delayed medical care seeking for young children with skull fractures.

Methods: We identified accidental skull fractures <4 years old, 2011-2012. Child abuse paediatricians abstracted retrospective data and paediatric radiologists re-reviewed images. 'Delays' were defined as presentation at ≥6 h. 'Minor accidents' included falls <4 feet and low force trauma, while 'major accidents' included higher height falls and major force events. We studied the frequency and duration of care delays, the signs or symptoms leading to care, and the duration of delays after signs or symptoms developed.

Results: Two hundred and ten children had accidental skull fractures. Delays were less likely with major accidents (4.9%), than with minor accidents (25.8%) (RR = 0.32 [0.15-0.70]). Children came to care for scalp swelling (STS) (39%), the injury event (36.2%), altered consciousness (15.2%) and vomiting (10.5%). Delayed onset of STS (78.6%) caused most delayed care. Early STS was firm, (17.6%) versus delayed (5.0%), as opposed to soft or fluctuant.

Conclusion: Delayed care seeking is common for minor, but not major accidental infant and toddler skull fractures. Most followed delayed onset of signs and symptoms. Delayed care seeking alone should not imply child abuse.
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http://dx.doi.org/10.1111/apa.15660DOI Listing
June 2021
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