Publications by authors named "Ryan Brown"

261 Publications

Impact of Clinician Recognition of Acute Respiratory Distress Syndrome on Evidenced-Based Interventions in the Medical ICU.

Crit Care Explor 2021 Jul 6;3(7):e0457. Epub 2021 Jul 6.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Acute respiratory distress syndrome is underrecognized in the ICU, but it remains uncertain if acute respiratory distress syndrome recognition affects evidence-based acute respiratory distress syndrome care in the modern era. We sought to determine the rate of clinician-recognized acute respiratory distress syndrome in an academic medical ICU and understand how clinician-recognized-acute respiratory distress syndrome affects clinical care and patient-centered outcomes.

Design: Observational cohort study.

Setting: Single medical ICU at an academic tertiary-care hospital.

Patients: Nine hundred seventy-seven critically ill adults (381 with expert-adjudicated acute respiratory distress syndrome) enrolled from 2006 to 2015.

Interventions: Clinician-recognized-acute respiratory distress syndrome was identified using an electronic keyword search of clinical notes in the electronic health record. We assessed the classification performance of clinician-recognized acute respiratory distress syndrome for identifying expert-adjudicated acute respiratory distress syndrome. We also compared differences in ventilator settings, diuretic prescriptions, and cumulative fluid balance between clinician-recognized acute respiratory distress syndrome and unrecognized acute respiratory distress syndrome.

Measurements And Main Results: Overall, clinician-recognized-acute respiratory distress syndrome had a sensitivity of 47.5%, specificity 91.1%, positive predictive value 77.4%, and negative predictive value 73.1% for expert-adjudicated acute respiratory distress syndrome. Among the 381 expert-adjudicated acute respiratory distress syndrome cases, we did not observe any differences in ventilator tidal volumes between clinician-recognized-acute respiratory distress syndrome and unrecognized acute respiratory distress syndrome, but clinician-recognized-acute respiratory distress syndrome patients had a more negative cumulative fluid balance (mean difference, -781 mL; 95% CI, [-1,846 to +283]) and were more likely to receive diuretics (49.3% vs 35.7%, = 0.02). There were no differences in mortality, ICU length of stay, or ventilator-free days.

Conclusions: Acute respiratory distress syndrome recognition was low in this single-center study. Although acute respiratory distress syndrome recognition was not associated with lower ventilator volumes, it was associated with differences in behaviors related to fluid management. These findings have implications for the design of future studies promoting evidence-based acute respiratory distress syndrome interventions in the ICU.
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http://dx.doi.org/10.1097/CCE.0000000000000457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263322PMC
July 2021

Socioeconomic disparities in health: Changes in sleep quality and inflammation during bereavement.

Compr Psychoneuroendocrinol 2021 Aug 22;7. Epub 2021 Apr 22.

Department of Psychological Sciences, Rice University, United States.

Widow(er)s experience significant sleep disruption that may dysregulate immune functioning. This longitudinal study aimed to determine 1) whether changes in sleep quality were associated with changes in pro-inflammatory cytokine production during the first six months of bereavement and 2) whether these relationships depended on objective socioeconomic status (SES) and/or subjective social status. One hundred and six bereaved spouses ( = 68.49 years, = 9.35, 69 females) completed the following assessments at approximately three months post-death and six-month post-death: a venous blood draw and self-report questionnaires on sleep quality (Pittsburgh Sleep Quality Index), SES (MacArthur Sociodemographic Questionnaire), health, and demographic information. T-cell stimulated pro-inflammatory cytokines were assessed, including IL-6, TNF-α, IFN-γ, IL-17A, and IL-2. Worsening sleep quality was associated with increased levels of pro-inflammatory activity even after adjusting for confounding variables. The present study also identified SES as an important factor for understanding health following spousal bereavement: individuals with low SES were more susceptible to sleep-related changes in immune function. Compared to more educated widow(er)s, less educated widow(er)s showed greater increases and decreases in inflammation when sleep quality worsened or improved, respectively, over time. Findings provide evidence for a biobehavioral pathway linking bereavement to disease risk, highlight SES disparities in late adulthood, and identify individuals who may require tailored interventions to offset SES-related burden that impedes adaptive grief recovery.
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http://dx.doi.org/10.1016/j.cpnec.2021.100056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238458PMC
August 2021

Identifying as American Indian/Alaska Native in Urban Areas: Implications for Adolescent Behavioral Health and Well-Being.

Youth Soc 2021 Jan 3;53(1):54-75. Epub 2019 Apr 3.

RAND Corporation, Santa Monica, CA, USA.

American Indian and Alaska Native (AI/AN) youth exhibit multiple health disparities, including high rates of alcohol and other drug (AOD) use, violence and delinquency, and mental health problems. Approximately 70% of AI/AN youth reside in urban areas, where negative outcomes on behavioral health and well-being are often high. Identity development may be particularly complex in urban settings, where youth may face more fragmented and lower density AI/AN communities, as well as mixed racial-ethnic ancestry and decreased familiarity with AI/AN lifeways. This study examines racial-ethnic and cultural identity among AI/AN adolescents and associations with behavioral health and well-being by analyzing quantitative data collected from a baseline assessment of 185 AI/AN urban adolescents from California who were part of a substance use intervention study. Adolescents who identified as AI/AN on their survey reported better mental health, less alcohol and marijuana use, lower rates of delinquency, and increased happiness and spiritual health.
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http://dx.doi.org/10.1177/0044118x19840048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232344PMC
January 2021

Catalyst control of selectivity in the C-O bond alumination of biomass derived furans.

Chem Sci 2020 Jul 8;11(30):7850-7857. Epub 2020 Jul 8.

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London 80 Wood Lane, Shepherds Bush London W12 0BZ UK

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C-O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)CH}Al] (Ar = 2,6-di-iso-propylphenyl, ) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp C-O bond into a sp C-Al bond. The kinetics of the reaction of with furan were found to be 1st order with respect to with activation parameters Δ = +19.7 (±2.7) kcal mol, Δ = -18.8 (±7.8) cal K mol and Δ = +25.3 (±0.5) kcal mol and a KIE of 1.0 ± 0.1. DFT calculations support a stepwise mechanism involving an initial (4 + 1) cycloaddition of with furan to form a bicyclic intermediate that rearranges by an α-migration. The selectivity of ring-expansion is influenced by factors that weaken the sp C-O bond through population of the σ*-orbital. Inclusion of [Pd(PCy)] as a catalyst in these reactions results in expansion of the substrate scope to include 2,3-dihydrofurans and 3,4-dihydropyrans and improves selectivity. Under catalysed conditions, the C-O bond that breaks is that adjacent to the spC-H bond. The aluminium(iii) dihydride reagent [{(MesNCMe)CH}AlH] (Mes = 2,4,6-trimethylphenyl, ) can also be used under catalytic conditions to effect a dehydrogenative ring-expansion of furans. Further mechanistic analysis shows that C-O bond functionalisation occurs an initial C-H bond alumination. Kinetic products can be isolated that are derived from installation of the aluminium reagent at the 2-position of the heterocycle. C-H alumination occurs with a KIE of 4.8 ± 0.3 consistent with a turnover limiting step involving oxidative addition of the C-H bond to the palladium catalyst. Isomerisation of the kinetic C-H aluminated product to the thermodynamic C-O ring expansion product is an intramolecular process that is again catalysed by [Pd(PCy)]. DFT calculations suggest that the key C-O bond breaking step involves attack of an aluminium based metalloligand on the 2-palladated heterocycle. The new methodology has been applied to important platform chemicals from biomass.
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http://dx.doi.org/10.1039/d0sc01918fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163288PMC
July 2020

Palladium-catalysed C-F alumination of fluorobenzenes: mechanistic diversity and origin of selectivity.

Chem Sci 2020 Jul 21;11(30):7842-7849. Epub 2020 Jul 21.

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London 80 Wood Lane, Shepherds Bush London W12 0BZ UK

A palladium pre-catalyst, [Pd(PCy)] is reported for the efficient and selective C-F alumination of fluorobenzenes with the aluminium(i) reagent [{(ArNCMe)CH}Al] (, Ar = 2,6-di-iso-propylphenyl). The catalytic protocol results in the transformation of sp C-F bonds to sp C-Al bonds and provides a route to reactive organoaluminium complexes () from fluorocarbons. The catalyst is highly active. Reactions proceed within 5 minutes at 25 °C (and at appreciable rates at even -50 °C) and the scope includes low-fluorine-content substrates such as fluorobenzene, difluorobenzenes and trifluorobenzenes. The reaction proceeds with complete chemoselectivity (C-F C-H) and high regioselectivities (>90% for C-F bonds adjacent to the most acidic C-H sites). The heterometallic complex [Pd(PCy)()] was shown to be catalytically competent. Catalytic C-F alumination proceeds with a KIE of 1.1-1.3. DFT calculations have been used to model potential mechanisms for C-F bond activation. These calculations suggest that two competing mechanisms may be in operation. Pathway 1 involves a ligand-assisted oxidative addition to [Pd()] and leads directly to the product. Pathway 2 involves a stepwise C-H → C-F functionalisation mechanism in which the C-H bond is broken and reformed along the reaction coordinate, guiding the catalyst to an adjacent C-F site. This second mechanism explains the experimentally observed regioselectivity. Experimental support for this C-H activation playing a key role in C-F alumination was obtained by employing [{(MesNCMe)CH}AlH] (, Mes = 2,4,6-tri-methylphenyl) as a reagent in place of . In this instance, the kinetic C-H alumination intermediate could be isolated. Under catalytic conditions this intermediate converts to the thermodynamic C-F alumination product.
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http://dx.doi.org/10.1039/d0sc01915aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163258PMC
July 2020

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease.

Int J Mol Sci 2021 May 9;22(9). Epub 2021 May 9.

Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK.

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.
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http://dx.doi.org/10.3390/ijms22095018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125985PMC
May 2021

Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy.

Theranostics 2021 15;11(13):6120-6137. Epub 2021 Apr 15.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.

Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source. We examined the IFN1 response and expression of immune susceptibility markers in B78 and B16 melanomas and MOC2 head and neck cancer murine models using qPCR and western blot. For TRT, we used Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2. We observed significant IFN1 activation in all cell lines, with peak activation in B78, B16, and MOC2 cell lines occurring 7, 7, and 1 days, respectively, following RT for all doses. This effect was STING-dependent. Select IFN response genes remained upregulated at 14 days following RT. IFN1 activation following STING agonist treatment was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. delivery of EBRT and TRT to B78 and MOC2 tumors resulted in a comparable time course and magnitude of IFN1 activation. In the MOC2 model, the combination of Y-NM600 and dual checkpoint blockade therapy reduced tumor growth and prolonged survival compared to single agent therapy and cumulative dose equivalent combination EBRT and dual checkpoint blockade therapy. We report the time course of the STING-dependent IFN1 response following radiation in multiple murine tumor models. We show the potential of TRT to stimulate IFN1 activation that is comparable to that observed with EBRT and this may be critical to the therapeutic integration of TRT with immunotherapies.
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http://dx.doi.org/10.7150/thno.54881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120207PMC
April 2021

Dihydroceramide Desaturase Functions as an Inducer and Rectifier of Apoptosis: Effect of Retinol Derivatives, Antioxidants and Phenolic Compounds.

Cell Biochem Biophys 2021 May 15. Epub 2021 May 15.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK.

Dihydroceramide desaturase (Degs1) catalyses the introduction of a 4,5-trans double bond into dihydroceramide to form ceramide. We show here that Degs1 is polyubiquitinated in response to retinol derivatives, phenolic compounds or anti-oxidants in HEK293T cells. The functional predominance of native versus polyubiquitinated forms of Degs1 appears to govern cytotoxicity. Therefore, 4-HPR or celecoxib appear to stimulate the de novo ceramide pathway (with the exception of C24:0 ceramide), using native Degs1, and thereby promote PARP cleavage and LC3B-I/II processing (autophagy/apoptosis). The ubiquitin-proteasomal degradation of Degs1 is positively linked to cell survival via XBP-1s and results in a concomitant increase in dihydroceramides and a decrease in C24:0 ceramide levels. However, in the case of 4-HPR or celecoxib, the native form of Degs1 functionally predominates, such that the apoptotic programme is sustained. In contrast, 4-HPA or AM404 do not produce apoptotic ceramide, using native Degs1, but do promote a rectifier function to induce ubiquitin-proteasomal degradation of Degs1 and are not cytotoxic. Therefore, Degs1 appears to function both as an 'inducer' and 'rectifier' of apoptosis in response to chemical cellular stress, the dynamic balance for which is dependent on the nature of chemical stress, thereby determining cytotoxicity. The de novo synthesis of ceramide or the ubiquitin-proteasomal degradation of Degs1 in response to anti-oxidants, retinol derivatives and phenolic compounds appear to involve sensors, and for rectifier function, this might be Degs1 itself.
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http://dx.doi.org/10.1007/s12013-021-00990-1DOI Listing
May 2021

Longitudinal changes in HRV across pregnancy and postpartum: Effect of negative partner relationship qualities.

Psychoneuroendocrinology 2021 Jul 21;129:105216. Epub 2021 Apr 21.

Department of Psychiatry & Behavioral Health and the Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

During pregnancy, there are significant physiological changes to support a healthy fetus. Parasympathetic activity normatively decreases across pregnancy, and psychological stress can promote even further decreased heart rate variability (HRV). This study evaluated (1) changes in vagally-mediated HRV from pregnancy to postpartum, (2) changes in vagally-mediated HRV from pregnancy to postpartum based on negative partner relationship qualities, and (3) changes in depressive symptoms from pregnancy to postpartum based on negative partner relationship qualities. 78 participants in their 3rd trimester self-reported their relationship quality with their partner at the first visit. Depressive symptoms and vagally-mediated HRV were evaluated at rest at five time points from 3rd trimester to 12 months postpartum. On average, the only significant increase in vagally-mediated HRV occurred between the 3rd trimester and 4-6 weeks postpartum. However, those who reported more negative partner relationship qualities during their 3rd trimester of pregnancy maintained lower vagally-mediated HRV levels across all of the first year postpartum and significantly lower vagally-mediated HRV at both 4 and 8 months postpartum as compared to people who reported fewer negative partner relationship qualities. Across the first year postpartum, people reporting more negative partner relationship qualities experienced more severe depressive symptoms than their counterparts with fewer negative partner relationship qualities; however, there was no difference in the rate of change of depressive symptoms across the first year postpartum based on negative partner relationship qualities. Because lower vagally-mediated HRV is associated with depressive symptoms, future work should explore the temporal relationship between vagally-mediated HRV and depressive symptoms in the postpartum period.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105216DOI Listing
July 2021

Combination of Bempegaldesleukin and Anti-CTLA-4 Prevents Metastatic Dissemination After Primary Resection or Radiotherapy in a Preclinical Model of Non-Small Cell Lung Cancer.

Front Oncol 2021 15;11:645352. Epub 2021 Apr 15.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.

Surgical resection or hypo-fractionated radiation therapy (RT) in early-stage non-small cell lung cancer (NSCLC) achieves local tumor control, but metastatic relapse remains a challenge. We hypothesized that immunotherapy with anti-CTLA-4 and bempegaldesleukin (BEMPEG; NKTR-214), a CD122-preferential IL2 pathway agonist, after primary tumor RT or resection would reduce metastases in a syngeneic murine NSCLC model. Mice bearing Lewis Lung Carcinoma (LLC) tumors were treated with combinations of BEMPEG, anti-CTLA-4, and primary tumor treatment (surgical resection or RT). Primary tumor size, mouse survival, and metastatic disease at the time of death were assessed. Flow cytometry, qRT-PCR, and cytokine analyses were performed on tumor specimens. All mice treated with RT or surgical resection of primary tumor alone succumbed to metastatic disease, and all mice treated with BEMPEG and/or anti-CTLA-4 succumbed to primary tumor local progression. The combination of primary tumor RT or resection and BEMPEG and anti-CTLA-4 reduced spontaneous metastasis and improved survival without any noted toxicity. Flow cytometric immunoprofiling of primary tumors revealed increased CD8 T and NK cells and decreased T-regulatory cells with the combination of BEMPEG, anti-CTLA-4, and RT compared to RT alone. Increased expression of genes associated with tumor cell immune susceptibility, immune cell recruitment, and cytotoxic T lymphocyte activation were observed in tumors of mice treated with BEMPEG, anti-CTLA-4, and RT. The combination of BEMPEG and anti-CTLA-4 with primary tumor RT or resection enabled effective control of local and metastatic disease in a preclinical murine NSCLC model. This therapeutic combination has important translational potential for patients with early-stage NSCLC and other cancers.
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http://dx.doi.org/10.3389/fonc.2021.645352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083981PMC
April 2021

Global decrease in brain sodium concentration after mild traumatic brain injury.

Brain Commun 2021 23;3(2):fcab051. Epub 2021 Mar 23.

Department of Radiology, Center for Biomedical Imaging, New York University Grossman School of Medicine, New York, NY 10016, USA.

The pathological cascade of tissue damage in mild traumatic brain injury is set forth by a perturbation in ionic homeostasis. However, whether this class of injury can be detected and serve as a surrogate marker of clinical outcome is unknown. We employ sodium MRI to test the hypotheses that regional and global total sodium concentrations: (i) are higher in patients than in controls and (ii) correlate with clinical presentation and neuropsychological function. Given the novelty of sodium imaging in traumatic brain injury, effect sizes from (i), and correlation types and strength from (ii), were compared to those obtained using standard diffusion imaging metrics. Twenty-seven patients (20 female, age 35.9 ± 12.2 years) within 2 months after injury and 19 controls were scanned with proton and sodium MRI at 3 Tesla. Total sodium concentration, fractional anisotropy and apparent diffusion coefficient were obtained with voxel averaging across 12 grey and white matter regions. Linear regression was used to obtain global grey and white matter total sodium concentrations. Patient outcome was assessed with global functioning, symptom profiles and neuropsychological function assessments. In the regional analysis, there were no statistically significant differences between patients and controls in apparent diffusion coefficient, while differences in sodium concentration and fractional anisotropy were found only in single regions. However, for each of the 12 regions, sodium concentration effect sizes were uni-directional, due to lower mean sodium concentration in patients compared to controls. Consequently, linear regression analysis found statistically significant lower global grey and white matter sodium concentrations in patients compared to controls. The strongest correlation with outcome was between global grey matter sodium concentration and the composite -score from the neuropsychological testing. In conclusion, both sodium concentration and diffusion showed poor utility in differentiating patients from controls, and weak correlations with clinical presentation, when using a region-based approach. In contrast, sodium linear regression, capitalizing on partial volume correction and high sensitivity to global changes, revealed high effect sizes and associations with patient outcome. This suggests that well-recognized sodium imbalances in traumatic brain injury are (i) detectable non-invasively; (ii) non-focal; (iii) occur even when the antecedent injury is clinically mild. Finally, in contrast to our principle hypothesis, patients' sodium concentrations were than controls, indicating that the biological effect of traumatic brain injury on the sodium homeostasis may differ from that in other neurological disorders. Note: This figure has been annotated.
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http://dx.doi.org/10.1093/braincomms/fcab051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066885PMC
March 2021

A new model for regulation of sphingosine kinase 1 translocation to the plasma membrane in breast cancer cells.

J Biol Chem 2021 Jan-Jun;296:100674. Epub 2021 Apr 16.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK. Electronic address:

The translocation of sphingosine kinase 1 (SK1) to the plasma membrane (PM) is crucial in promoting oncogenesis. We have previously proposed that SK1 exists as both a monomer and dimer in equilibrium, although it is unclear whether these species translocate to the PM via the same or different mechanisms. We therefore investigated the structural determinants involved to better understand how translocation might potentially be targeted for therapeutic intervention. We report here that monomeric WT mouse SK1 (GFP-mSK1) translocates to the PM of MCF-7L cells stimulated with carbachol or phorbol 12-myristate 13-acetate, whereas the dimer translocates to the PM in response to sphingosine-1-phosphate; thus, the equilibrium between the monomer and dimer is sensitive to cellular stimulus. In addition, carbachol and phorbol 12-myristate 13-acetate induced translocation of monomeric GFP-mSK1 to lamellipodia, whereas sphingosine-1-phosphate induced translocation of dimeric GFP-mSK1 to filopodia, suggesting that SK1 regulates different cell biological processes dependent on dimerization. GFP-mSK1 mutants designed to modulate dimerization confirmed this difference in localization. Regulation by the C-terminal tail of SK1 was investigated using GFP-mSK1 truncations. Removal of the last five amino acids (PPEEP) prevented translocation of the enzyme to the PM, whereas removal of the last ten amino acids restored translocation. This suggests that the penultimate five amino acids (SRRGP) function as a translocation brake, which can be released by sequestration of the PPEEP sequence. We propose that these determinants alter the arrangement of N-terminal and C-terminal domains in SK1, leading to unique surfaces that promote differential translocation to the PM.
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http://dx.doi.org/10.1016/j.jbc.2021.100674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135045PMC
April 2021

Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult ENaC-Tg Mice.

Mediators Inflamm 2021 19;2021:6682657. Epub 2021 Mar 19.

Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.

Background: Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile -epithelial Na+ channel-overexpressing transgenic (ENaC-Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult ENaC-Tg mice with established disease.

Methods: ENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS ENaC-Tg mice were analysed at 6 weeks of age. Bronchoalveolar lavage (BAL) fluid inflammatory cell counts were quantified, and lung tissue destruction and mucus obstruction were analysed histologically.

Results: At 6 weeks of age, ENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS ENaC-Tg mice and ENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS ENaC-Tg mice, therapeutic inhibition of CatS in ENaC-Tg mice had no effect on established emphysema-like lung tissue damage.

Conclusions: These results suggest that while early CatS targeting may be required to prevent the onset and progression of lung tissue damage, therapeutic CatS targeting effectively inhibited airway inflammation and mucus obstruction. These results indicate the important role CatS may play in the pathogenesis and progression of mucoobstructive lung disease.
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http://dx.doi.org/10.1155/2021/6682657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004367PMC
March 2021

Protocolized Post-Extubation Respiratory Support to Prevent Reintubation: A Randomized Clinical Trial.

Am J Respir Crit Care Med 2021 Apr 1. Epub 2021 Apr 1.

Vanderbilt University, 5718, Department of Medicine, Nashville, Tennessee, United States.

Rationale: Respiratory support (non-invasive ventilation or high flow nasal cannula) applied at the time of extubation has been reported to reduce reintubation rates, but concerns regarding effectiveness have limited uptake into practice.

Objectives: To determine if providing post-extubation respiratory support to all patients undergoing extubation in a medical ICU would decrease the incidence of reintubation.

Methods: We conducted a pragmatic, two-armed, cluster-crossover trial of adults undergoing extubation from invasive mechanical ventilation between October 1, 2017 and March 31, 2019 in the medical intensive care unit of an academic medical center. Patients were assigned to either protocolized post-extubation respiratory support (a respiratory therapist-driven protocol in which patients with suspected hypercapnia received non-invasive ventilation and patients without suspected hypercapnia received high flow nasal cannula) or usual care (post-extubation management at the discretion of treating clinicians). The primary outcome was reintubation within 96 hours of extubation.

Measurements And Main Results: A total of 751 patients were enrolled. Of the 359 patients assigned to protocolized support, 331 (92.2%) received post-extubation respiratory support, compared to 66 of 392 patients (16.8%) assigned to usual care, a difference driven by differential use of high flow nasal cannula (74.7% vs. 2.8%). A total of 57 patients (15.9%) in the protocolized support group experienced reintubation, compared to 52 patients (13.3%) in the usual care group (odds ratio, 1.23; 95% confidence interval, 0.82 to 1.84; P-value = 0.32).

Conclusions: Among a broad population of critically ill adults undergoing extubation from invasive mechanical ventilation at an academic medical center, protocolized post-extubation respiratory support, primarily characterized by an increase in the use of high flow nasal cannula, did not prevent reintubation, compared to usual care. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03288311.
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http://dx.doi.org/10.1164/rccm.202009-3561OCDOI Listing
April 2021

High Dietary Fat Consumption Impairs Axonal Mitochondrial Function .

J Neurosci 2021 May 30;41(19):4321-4334. Epub 2021 Mar 30.

Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom.

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca levels and impairs impulse conduction within the saphenous nerve in prediabetic PN. Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia .
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http://dx.doi.org/10.1523/JNEUROSCI.1852-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143198PMC
May 2021

Improved whole-brain SNR with an integrated high-permittivity material in a head array at 7T.

Magn Reson Med 2021 08 23;86(2):1167-1174. Epub 2021 Mar 23.

Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, New York, USA.

Purpose: To demonstrate that strategic use of materials with high electric permittivity along with integrated head-sized coil arrays can improve SNR in the entire brain.

Methods: Numerical simulations were used to design a high-permittivity material (HPM) helmet for enhancing SNR throughout the brain in receive arrays of 8 and 28 channels. Then, two 30-channel head coils of identical geometry were constructed: one fitted with a prototype helmet-shaped ceramic HPM helmet, and the second with a helmet-shaped low-permittivity shell, each 8-mm thick. An eight-channel dipole array was used for excitation. In vivo maps of excitation flip angle and SNR were acquired.

Results: Simulation results showed improvement in transmit efficiency by up to 65% and in receive-side SNR by up to 47% on average through the head with use of an HPM helmet. Experimental results showed that experimental transmit efficiency was improved by approximately 56% at the center of brain, and experimental receive-side SNR (SNR normalized to flip angle) was improved by approximately 21% on average through orthogonal planes through the cerebrum, including at the center of the brain, with the HPM.

Conclusion: Although HPM is used increasingly to improve transmit efficiency locally in situations in which the transmit coil and imaging volume are much larger than the HPM, here we demonstrate that HPM can also be used to improve transmit efficiency and receive-side SNR throughout the brain by improving performance of a head-sized receive array. This includes the center of the brain, where it is difficult to improve SNR by other means.
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http://dx.doi.org/10.1002/mrm.28780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208524PMC
August 2021

Multinuclear MRI to disentangle intracellular sodium concentration and extracellular volume fraction in breast cancer.

Sci Rep 2021 Mar 4;11(1):5156. Epub 2021 Mar 4.

Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, New York University Grossman School of Medicine, New York, NY, 10016, USA.

The purpose of this work was to develop a novel method to disentangle the intra- and extracellular components of the total sodium concentration (TSC) in breast cancer from a combination of proton ([Formula: see text]H) and sodium ([Formula: see text]) magnetic resonance imaging (MRI) measurements. To do so, TSC is expressed as function of the intracellular sodium concentration ([Formula: see text]), extracellular volume fraction (ECV) and the water fraction (WF) based on a three-compartment model of the tissue. TSC is measured from [Formula: see text] MRI, ECV is calculated from baseline and post-contrast [Formula: see text]H [Formula: see text] maps, while WF is measured with a [Formula: see text]H chemical shift technique. [Formula: see text] is then extrapolated from the model. Proof-of-concept was demonstrated in three healthy subjects and two patients with triple negative breast cancer. In both patients, TSC was two to threefold higher in the tumor than in normal tissue. This alteration mainly resulted from increased [Formula: see text] ([Formula: see text] 30 mM), which was [Formula: see text] 130% greater than in healthy conditions (10-15 mM) while the ECV was within the expected range of physiological values (0.2-0.25). Multinuclear MRI shows promise for disentangling [Formula: see text] and ECV by taking advantage of complementary [Formula: see text]H and [Formula: see text] measurements.
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http://dx.doi.org/10.1038/s41598-021-84616-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933187PMC
March 2021

Effects of ploidy and salmonid alphavirus infection on the skin and gill microbiome of Atlantic salmon (Salmo salar).

PLoS One 2021 19;16(2):e0243684. Epub 2021 Feb 19.

Department of Biology, Center for Evolutionary and Theoretical Immunology (CETI), The University of New Mexico, Albuquerque, New Mexico, United States of America.

The microbial communities that live in symbiosis with the mucosal surfaces of animals provide the host with defense strategies against pathogens. These microbial communities are largely shaped by the environment and the host genetics. Triploid Atlantic salmon (Salmo salar) are being considered for aquaculture as they are reproductively sterile and thus cannot contaminate the natural gene pool. It has not been previously investigated how the microbiome of triploid salmon compares to that of their diploid counterparts. In this study, we compare the steady-state skin and gill microbiome of both diploid and triploid salmon, and determine the effects of salmonid alphavirus 3 experimental infection on their microbial composition. Our results show limited differences in the skin-associated microbiome between triploid and diploid salmon, irrespective of infection. In the gills, we observed a high incidence of the bacterial pathogen Candidatus Branchiomonas, with higher abundance in diploid compared to triploid control fish. Diploid salmon infected with SAV3 showed greater histopathological signs of epitheliocystis compared to controls, a phenomenon not observed in triploid fish. Our results indicate that ploidy can affect the alpha diversity of the gills but not the skin-associated microbial community. Importantly, during a natural outbreak of Branchiomonas sp. the gill microbiome of diploid Atlantic salmon became significantly more dominated by this pathogen than in triploid animals. Thus, our results suggest that ploidy may play a role on Atlantic salmon gill health and provide insights into co-infection with SAV3 and C. Branchiomonas in Atlantic salmon.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243684PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894865PMC
July 2021

Simultaneous T , T , and T relaxation mapping of the lower leg muscle with MR fingerprinting.

Magn Reson Med 2021 07 8;86(1):372-381. Epub 2021 Feb 8.

Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, New York, USA.

Purpose: To develop a novel MR-fingerprinting (MRF) pulse sequence that is insensitive to and B imperfections for simultaneous T , T , and T relaxation mapping.

Methods: We implemented a totally balanced spin-lock (TB-SL) module to encode T relaxation into an existing MRF framework that encoded T and T . The spin-lock module used two 180° pulses with compensatory phases to reduce T sensitivity to B and B inhomogeneities. We compared T measured using TB-SL MRF in Bloch simulations, model agar phantoms, and in vivo experiments to those with a self-compensated spin-lock preparation module (SC-SL). The TB-SL MRF repeatability was evaluated in maps acquired in the lower leg skeletal muscle of 12 diabetic peripheral neuropathy patients, scanned two times each during visits separated by about 30 days.

Results: The phantom relaxation times measured with TB-SL and SC-SL MRF were in good agreement with reference values in regions with low B inhomogeneities. Compared with SC-SL, TB-SL MRF showed in experiments greater robustness against severe B inhomogeneities and in Bloch simulations greater robustness against B and B . We measured with TB-SL MRF an average T = 950.1 ± 28.7 ms, T = 26.0 ± 1.2 ms, and T = 31.7 ± 3.2 ms in skeletal muscle across patients. Bland-Altman analysis demonstrated low bias between TB-SL and SC-SL MRF and between TB-SL MRF maps acquired in two visits. The coefficient of variation was less than 3% for all measurements.

Conclusion: The proposed TB-SL MRF sequence is fast and insensitive to and B imperfections. It can simultaneously map T , T , T , and in a single scan and can potentially be used to study muscle composition.
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http://dx.doi.org/10.1002/mrm.28704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005468PMC
July 2021

Effect of balanced crystalloids versus saline on urinary biomarkers of acute kidney injury in critically ill adults.

BMC Nephrol 2021 02 5;22(1):54. Epub 2021 Feb 5.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, C-1216 MCN, 1161 21st Ave South, Nashville, TN, 37232, USA.

Background: Recent trials have suggested use of balanced crystalloids may decrease the incidence of major adverse kidney events compared to saline in critically ill adults. The effect of crystalloid composition on biomarkers of early acute kidney injury remains unknown.

Methods: From February 15 to July 15, 2016, we conducted an ancillary study to the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) comparing the effect of balanced crystalloids versus saline on urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) among 261 consecutively-enrolled critically ill adults admitted from the emergency department to the medical ICU. After informed consent, we collected urine 36 ± 12 h after hospital admission and measured NGAL and KIM-1 levels using commercially available ELISAs. Levels of NGAL and KIM-1 at 36 ± 12 h were compared between patients assigned to balanced crystalloids versus saline using a Mann-Whitney U test.

Results: The 131 patients (50.2%) assigned to the balanced crystalloid group and the 130 patients (49.8%) assigned to the saline group were similar at baseline. Urinary NGAL levels were significantly lower in the balanced crystalloid group (median, 39.4 ng/mg [IQR 9.9 to 133.2]) compared with the saline group (median, 64.4 ng/mg [IQR 27.6 to 339.9]) (P < 0.001). Urinary KIM-1 levels did not significantly differ between the balanced crystalloid group (median, 2.7 ng/mg [IQR 1.5 to 4.9]) and the saline group (median, 2.4 ng/mg [IQR 1.3 to 5.0]) (P = 0.36).

Conclusions: In this ancillary analysis of a clinical trial comparing balanced crystalloids to saline among critically ill adults, balanced crystalloids were associated with lower urinary concentrations of NGAL and similar urinary concentrations of KIM-1, compared with saline. These results suggest only a modest reduction in early biomarkers of acute kidney injury with use of balanced crystalloids compared with saline.

Trial Registration: ClinicalTrials.gov number: NCT02444988 . Date registered: May 15, 2015.
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http://dx.doi.org/10.1186/s12882-021-02236-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863046PMC
February 2021

Chronic Pain and Psychological Distress Among Undocumented Latinx Immigrants in the USA.

J Gen Intern Med 2021 03 11;36(3):585-591. Epub 2021 Jan 11.

Center for Research to Advance Community Health (ReACH) and Department of Medicine, Long School of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, USA.

Background: Undocumented immigration is often accompanied by multiple and complex stressors, which over time may increase the risk for chronic pain.

Objective: This study aimed to identify the prevalence of chronic pain and its association with psychological distress among undocumented Latinx immigrants in the USA.

Design/participants: We used respondent-driven sampling to collect and analyze data from clinical interviews with 254 undocumented Latinx immigrants, enabling inference to a population of 22,000.

Main Measures: Chronic pain was assessed using the World Health Organization Composite International Diagnostic Interview (CIDI) Chronic Conditions Module. For all analyses, inferential statistics accounted for design effects and sample weights to produce weighted estimates. We conducted logistic regression analyses to assess the association between chronic pain and psychological distress after controlling for age, years in the USA, and history of trauma.

Results: A total of 28% of undocumented Latinx immigrants reported having chronic pain, and 20% of those had clinically significant psychological distress. Significant differences in the prevalence of chronic pain were reported across age groups, years in the USA, and trauma history. After controlling for relevant covariates, chronic pain was significantly associated with psychological distress (OR = 1.06, 95% CI [1.02, 1.09]), age (OR = 1.05, 95% CI [1.02; 1.09]), and history of trauma (OR = 1.10 per additional traumatic event, 95% CI [1.02; 1.19]; C-statistic = 0.79).

Conclusion: Among undocumented Latinx immigrants, chronic pain is significantly associated with psychological distress, older age, and trauma history. Given that undocumented immigrants have restricted access to healthcare and are at high risk for chronic pain, developing alternatives to facilitate access to chronic pain interventions and risk-reduction prevention are needed.
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http://dx.doi.org/10.1007/s11606-020-05910-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947071PMC
March 2021

Comparison of TG43 and Hounsfield Unit-based TG186 brachytherapy dose metrics in Oncentra Brachy for 100 patients receiving interstitial partial breast irradiation.

Brachytherapy 2021 May-Jun;20(3):655-663. Epub 2021 Jan 7.

St George Cancer Care Centre, Kogarah, New South Wales, Australia; School of Medicine, University of New South Wales, Randwick, New South Wales, Australia.

Purpose: The aim of the study was to conduct a retrospective analysis of 100 patients who received interstitial accelerated partial breast irradiation at a single institution, comparing the standard American Association of Physicists in Medicine Task Group (TG) 43 dose calculation algorithm to the model-based dose calculation algorithms (MBDCAs) available in the Oncentra Brachy treatment planning system.

Methods And Materials: Dose-volume histogram parameters were compared between the different dose calculation algorithms for the planning target volume and organs at risk. and a statistical analysis was performed. The resulting changes in isodose distribution were assessed, with the worst-case data presented.

Results: The TG43 algorithm calculated higher doses to all structures compared with the MBDCAs. The largest discrepancy was observed for the skin, with maximum doses on average 2.0% lower with the MBDCA. The newly released Hounsfield Unit-based algorithm further decreased the skin dose compared with TG43 by <0.5%.

Conclusions: This study demonstrates that the differences between TG43 and MBDCA as implemented in Oncentra Brachy for accelerated partial breast irradiation are clinically insignificant in the treatment area and nearby organs at risk. Justification for investing in MBDCAs for this treatment site is limited when considering the additional calculation time, introduced uncertainties, and cost.
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http://dx.doi.org/10.1016/j.brachy.2020.11.013DOI Listing
January 2021

Comparison between Graphene and GaAs Quantized Hall Devices with a Dual Probe.

IEEE Trans Instrum Meas 2020 ;69:9374-9380

National Institute of Standards and Technology, Gaithersburg, MD 20899, USA.

A graphene quantized Hall resistance (QHR) device fabricated at the National Institute of Standards and Technology (NIST) was measured alongside a GaAs QHR device fabricated by the National Research Council of Canada (NRC) by comparing them to a 1 kΩ standard resistor using a cryogenic current comparator. The two devices were mounted in a custom developed dual probe that was then assessed for its viability as a suitable apparatus for precision measurements. The charge carrier density of the graphene device exhibited controllable tunability when annealed after Cr(CO) functionalization. These initial measurement results suggest that making resistance comparisons is possible with a single probe wired for two types of quantum standards - GaAs, the established material, and graphene, the newer material that may promote the development of more user-friendly equipment.
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http://dx.doi.org/10.1109/tim.2020.3004678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739376PMC
January 2020

Recruitment and retention in randomized controlled trials with urban American Indian/Alaska Native adolescents: Challenges and lessons learned.

Clin Trials 2021 02 24;18(1):83-91. Epub 2020 Nov 24.

RAND Corporation, Santa Monica, CA, USA.

Background: Although the majority of American Indians/Alaska Natives reside in urban areas, there are very few randomized controlled trials analyzing culturally centered substance use prevention interventions for this population.

Methods: We describe methods employed to recruit and retain urban American Indian/Alaska Native adolescents into a randomized controlled trial, which was focused on testing the potential benefits of a substance use prevention intervention for this population. We also report challenges encountered in recruitment and retention of participants and strategies employed addressing these challenges. Data collection occurred from August 2014 to October 2017.

Results: We partnered with two community-based organizations in different cities in California. We utilized American Indian/Alaska Native recruiters from communities, placed flyers in community-based organizations, and asked organizations to post flyers on their web and social media sites. We also offered gift cards for participants. Our initial recruitment and retention model was moderately successful; however, we encountered five main challenges: (1) transportation, (2) increasing trust and interest, (3) adding research sites, (4) getting the word out about the project, and (5) getting youth to complete follow-up surveys. Strategies employed to overcome transportation challenges included shortening the number of sessions, offering sessions on both weekends and weekdays, and increasing bus tokens and transportation options. We hired more staff from American Indian/Alaska Native communities, added more research sites from our previously established relationships, and were more proactive in getting the word out on the project in American Indian/Alaska Native communities. We also utilized more field tracking and emailed and mailed survey invitations to reach more participants for their follow-up surveys. Because of our efforts, we were nearly able to reach our initial recruitment and retention goals.

Conclusion: Although our research team had previously established relationships with various urban American Indian/Alaska Native communities, we encountered various recruitment and retention challenges in our study. However, by identifying challenges and employing culturally appropriate strategies, we were able to collect valuable data on the potential effectiveness of a substance use prevention intervention for urban American Indian/Alaska Native adolescents. Findings from this study assist toward the development of potentially successful strategies to successfully recruit and retain urban American Indian/Alaska Native adolescents in randomized controlled trials.
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http://dx.doi.org/10.1177/1740774520971774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878293PMC
February 2021

Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials.

JAMA Netw Open 2020 11 2;3(11):e2024596. Epub 2020 Nov 2.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Saline (0.9% sodium chloride), the fluid most commonly used to treat diabetic ketoacidosis (DKA), can cause hyperchloremic metabolic acidosis. Balanced crystalloids, an alternative class of fluids for volume expansion, do not cause acidosis and, therefore, may lead to faster resolution of DKA than saline.

Objective: To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with DKA.

Design, Setting, And Participants: This study was a subgroup analysis of adults with DKA in 2 previously reported companion trials-Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). These trials, conducted between January 2016 and March 2017 in an academic medical center in the US, were pragmatic, multiple-crossover, cluster, randomized clinical trials comparing balanced crystalloids vs saline in emergency department (ED) and intensive care unit (ICU) patients. This study included adults who presented to the ED with DKA, defined as a clinical diagnosis of DKA, plasma glucose greater than 250 mg/dL, plasma bicarbonate less than or equal to 18 mmol/L, and anion gap greater than 10 mmol/L. Data analysis was performed from January to April 2020.

Interventions: Balanced crystalloids (clinician's choice of Ringer lactate solution or Plasma-Lyte A solution) vs saline for fluid administration in the ED and ICU according to the same cluster-randomized multiple-crossover schedule.

Main Outcomes And Measures: The primary outcome was time between ED presentation and DKA resolution, as defined by American Diabetes Association criteria. The secondary outcome was time between initiation and discontinuation of continuous insulin infusion.

Results: Among 172 adults included in this secondary analysis of cluster trials, 94 were assigned to balanced crystalloids and 78 to saline. The median (interquartile range [IQR]) age was 29 (24-45) years, and 90 (52.3%) were women. The median (IQR) volume of isotonic fluid administered in the ED and ICU was 4478 (3000-6372) mL. Cumulative incidence analysis revealed shorter time to DKA resolution in the balanced crystalloids group (median time to resolution: 13.0 hours; IQR: 9.5-18.8 hours) than the saline group (median: 16.9 hours; IQR: 11.9-34.5 hours) (adjusted hazard ratio [aHR] = 1.68; 95% CI, 1.18-2.38; P = .004). Cumulative incidence analysis also revealed shorter time to insulin infusion discontinuation in the balanced crystalloids group (median: 9.8 hours; IQR: 5.1-17.0 hours) than the saline group (median: 13.4 hours; IQR: 11.0-17.9 hours) (aHR = 1.45; 95% CI, 1.03-2.03; P = .03).

Conclusions And Relevance: In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA.

Trial Registration: ClinicalTrials.gov Identifiers: NCT02614040; NCT02444988.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.24596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670314PMC
November 2020

The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview.

Front Med (Lausanne) 2020 26;7:589553. Epub 2020 Oct 26.

Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.

Acute respiratory distress syndrome (ARDS) is associated with increased morbidity and mortality in the elderly population (≥65 years of age). Additionally, age is widely reported as a risk factor for the development of ARDS. However, the underlying pathophysiological mechanisms behind the increased risk of developing, and increased severity of, ARDS in the elderly population are not fully understood. This is compounded by the significant heterogeneity observed in patients with ARDS. With an aging population worldwide, a better understanding of these mechanisms could facilitate the development of therapies to improve outcomes in this population. In this review, the current clinical evidence of age as a risk factor and prognostic indicator in ARDS and the potential underlying mechanisms that may contribute to these factors are outlined. In addition, research on age-dependent treatment options and biomarkers, as well as future prospects for targeting these underlying mechanisms, are discussed.
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http://dx.doi.org/10.3389/fmed.2020.589553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649269PMC
October 2020

Insights From Rapid Deployment of a "Virtual Hospital" as Standard Care During the COVID-19 Pandemic.

Ann Intern Med 2021 02 11;174(2):192-199. Epub 2020 Nov 11.

Center for Outcomes Research and Evaluation, Atrium Health, Charlotte, North Carolina (M.K., S.C., A.M.).

Background: Pandemics disrupt traditional health care operations by overwhelming system resource capacity but also create opportunities for care innovation.

Objective: To describe the development and rapid deployment of a virtual hospital program, Atrium Health hospital at home (AH-HaH), within a large health care system.

Design: Prospective case series.

Setting: Atrium Health, a large integrated health care organization in the southeastern United States.

Patients: 1477 patients diagnosed with coronavirus disease 2019 (COVID-19) from 23 March to 7 May 2020 who received care via AH-HaH.

Intervention: A virtual hospital model providing proactive home monitoring and hospital-level care through a virtual observation unit (VOU) and a virtual acute care unit (VACU) in the home setting for eligible patients with COVID-19.

Measurements: Patient demographic characteristics, comorbid conditions, treatments administered (intravenous fluids, antibiotics, supplemental oxygen, and respiratory medications), transfer to inpatient care, and hospital outcomes (length of stay, intensive care unit [ICU] admission, mechanical ventilation, and death) were collected from electronic health record data.

Results: 1477 patients received care in either the AH-HaH VOU or VACU or both settings, with a median length of stay of 11 days. Of these, 1293 (88%) patients received care in the VOU only, with 40 (3%) requiring inpatient hospitalization. Of these 40 patients, 16 (40%) spent time in the ICU, 7 (18%) required ventilator support, and 2 (5%) died during their hospital admission. In total, 184 (12%) patients were ever admitted to the VACU, during which 21 patients (11%) required intravenous fluids, 16 (9%) received antibiotics, 40 (22%) required respiratory inhaler or nebulizer treatments, 41 (22%) used supplemental oxygen, and 24 (13%) were admitted as an inpatient to a conventional hospital. Of these 24 patients, 10 (42%) required ICU admission, 1 (3%) required a ventilator, and none died during their hospital admission.

Limitation: Generalizability is limited to patients with a working telephone and the ability to comply with the monitoring protocols.

Conclusion: Virtual hospital programs have the potential to provide health systems with additional inpatient capacity during the COVID-19 pandemic and beyond.

Primary Funding Source: Atrium Health.
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http://dx.doi.org/10.7326/M20-4076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711652PMC
February 2021

Assessment of primary care practitioners' attitudes and interest in pharmacogenomic testing.

Pharmacogenomics 2020 10 24;21(15):1085-1094. Epub 2020 Sep 24.

MedStar Health, Columbia, MD 21044, USA.

Identify the attitudes and interests of primary care providers (PCPs) in applying clinical pharmacogenomics (PGx) test results. A questionnaire was designed and then disseminated to PCPs across the MedStar Health System. Ninety of 312 (29%) PCPs responded and were included in analyses. Seventy-six (84%) had heard of PGx and 12 (13%) previously ordered PGx testing. Most, 68 (76%), believed PGx can improve care; however, a minority, 23 (26%), reported confidence in using PGx in prescribing decisions. Sixty-four (70%) wanted a pharmacist consultation. PCPs desired PGx for antidepressants (75%), proton pump inhibitors (72%) and other medications. Most PCPs felt unprepared to interpret PGx results and desired pharmacist consultations. These data can inform future PGx implementations with PCPs.
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http://dx.doi.org/10.2217/pgs-2020-0064DOI Listing
October 2020

Airway Inflammation and Host Responses in the Era of CFTR Modulators.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

Airway Innate Immunity Research (AiiR) group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.
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http://dx.doi.org/10.3390/ijms21176379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504341PMC
September 2020

Towards real time in-vivo rectal dosimetry during trans-rectal ultrasound based high dose rate prostate brachytherapy using MOSkin dosimeters.

Radiother Oncol 2020 10 13;151:273-279. Epub 2020 Aug 13.

St George Hospital Cancer Care Centre, Kogarah, Australia; Centre for Medical Radiation Physics, University of Wollongong, Australia.

Purpose: To compare the dose measured by MOSkin dosimeters coupled to a trans-rectal ultrasound (TRUS) probe to the dose predicted by the brachytherapy treatment planning system (BTPS) during high dose rate (HDR) prostate brachytherapy (pBT), and to examine the feasibility of performing real-time catheter-by-catheter analysis of in-vivo rectal dosimetry during TRUS based HDR pBT.

Method: Four MOSkin dosimeters were coupled to a TRUS probe during 20 TRUS-based HDR pBT treatment fractions. The measured MOSkin doses were retrospectively compared to those predicted by the BTPS for the total treatment fraction, as well as on a per catheter basis.

Results: The average relative percentage difference between MOSkin measured and BTPS predicted doses for a total treatment fraction was 0.3% ± 11.6% (k = 1), with a maximum of 23.2% and a minimum of -29.0%. The average relative percentage difference per catheter was +2.5% ± 16.9% (k = 1). The majority (64%) of per catheter MOSkin measured doses agreed with the treatment planning system within the calculated uncertainty budget of 12.3%.

Conclusion: The results of the study agreed well with previously published data, despite differences in clinical workflows. To improve the redundancy to potential dosimeter errors, a minimum of 4 MOSkin dosimeters should be used when performing real-time in-vivo rectal dosimetry for HDR pBT, and error thresholds should be based off the total combined uncertainty estimate of measurement. 'Real time' error thresholds can be more confidently applied in the future through enhanced integration between IVD systems with both the imaging device and the BTPS/afterloader.
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http://dx.doi.org/10.1016/j.radonc.2020.08.003DOI Listing
October 2020
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