Publications by authors named "Thomas Murray"

243 Publications

External assessment of the EUROMACS right-sided heart failure risk score.

Sci Rep 2021 Aug 9;11(1):16064. Epub 2021 Aug 9.

Department of Medicine, Division of Cardiology, University of Minnesota, 401 East River Parkway, Variety Club Research Center (VCRC), 1st Floor - Suite 131, Minneapolis, MN, 55455, USA.

The EUROMACS Right-Sided Heart Failure Risk Score was developed to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. The predictive ability of the EUROMACS score has not been tested in other cohorts. We performed a single center analysis of a continuous-flow (CF) LVAD cohort (n = 254) where we calculated EUROMACS risk scores and assessed for right ventricular heart failure after LVAD implantation. Thirty-nine percent of patients (100/254) had post-operative RVF, of which 9% (23/254) required prolonged inotropic support and 5% (12/254) required RVAD placement. For patients who developed RVF after LVAD implantation, there was a 45% increase in the hazards of death on LVAD support (HR 1.45, 95% CI 0.98-2.2, p = 0.066). Two variables in the EUROMACS score (Hemoglobin and Right Atrial Pressure to Pulmonary Capillary Wedge Pressure ratio) were not predictive of RVF in our cohort. Overall, the EUROMACS score had poor external discrimination in our cohort with area under the curve of 58% (95% CI 52-66%). Further work is necessary to enhance our ability to predict RVF after LVAD implantation.
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http://dx.doi.org/10.1038/s41598-021-94792-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352910PMC
August 2021

Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4.

Shock 2021 08;56(2):268-277

King's College London, British Heart Foundation Centre for Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK.

Abstract: Leukocyte Nox2 is recognized to have a fundamental microbicidal function in sepsis but the specific role of Nox2 in endothelial cells (EC) remains poorly elucidated. Here, we tested the hypothesis that endothelial Nox2 participates in the pathogenesis of systemic inflammation and hypotension induced by LPS. LPS was injected intravenously in mice with Tie2-targeted deficiency or transgenic overexpression of Nox2. Mice with Tie2-targeted Nox2 deficiency had increased circulating levels of TNF-α, enhanced numbers of neutrophils trapped in lungs, and aggravated hypotension after LPS injection, as compared to control LPS-injected animals. In contrast, Tie2-driven Nox2 overexpression attenuated inflammation and prevented the hypotension induced by LPS. Because Tie2-Cre targets both EC and myeloid cells we generated bone marrow chimeric mice with Nox2 deletion restricted to leukocytes or ECs. Mice deficient in Nox2 either in leukocytes or ECs had reduced LPS-induced neutrophil trapping in the lungs and lower plasma TNF-α levels as compared to control LPS-injected mice. However, the pronounced hypotensive response to LPS was present only in mice with EC-specific Nox2 deletion. Experiments in vitro with human vein or aortic endothelial cells (HUVEC and HAEC, respectively) treated with LPS revealed that EC Nox2 controls NF-κB activation and the transcription of toll-like receptor 4 (TLR4), which is the recognition receptor for LPS. In conclusion, these results suggest that endothelial Nox2 limits NF-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by LPS.
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http://dx.doi.org/10.1097/SHK.0000000000001706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284354PMC
August 2021

A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19.

EClinicalMedicine 2021 Jul 17;37:100957. Epub 2021 Jun 17.

Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease.

Methods: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants).

Findings: From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test [losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%)]; proportion difference -3.5% (95% CI -13.2, 4.8%);  = 0.32]. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly [0.33 (95% CI 0.22-0.49) for losartan vs. 0.37 (95% CI 0.25-0.55) for placebo]. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early.

Interpretation: In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients.
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http://dx.doi.org/10.1016/j.eclinm.2021.100957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225661PMC
July 2021

Headland bypassing timescales: Processes and driving forces.

Sci Total Environ 2021 Nov 24;793:148591. Epub 2021 Jun 24.

Coastal and Marine Research Centre, Griffith University, Gold Coast campus, G51, QLD 4222, Australia.

In this paper, a natural headland bypassing is investigated in terms of its short (months to years) and long-term (years to decades) variability and its relationship with wave conditions, climate drivers and anthropogenic interventions. The research is focused on Fingal Head (New South Wales, Australia) where nine detailed topo-bathymetric surveys were undertaken between June 2018 and January 2020. To extend the analysis in time, over 30 years of satellite and aerial images were used to describe the headland bypassing variability based on the shoreline and sandbar position changes. Shoreline and sandbar positions presented moderate to strong correlation between updrift and immediate downdrift of the headland highlighting the influence of the bypassing process for the longshore transport on the study area. Results indicate that the headland bypassing around Fingal Head is governed by two distinct processes and their dominance is controlled by waves and sediment availability. The sandbar-driven bypassing scenario requires a storm wave event to trigger the sandbar system and over seven months to complete the full bypassing cycle. A quicker bypassing cycle (i.e. few months) happens when sediment leaks around the headland following a persistent low energy wave condition that largely accretes the updrift upper beach. Headland bypassing cycles occur in multiple timescales, including seasonal variability of the wave climate to interannual and decadal cycles of shoreline progradation and retreat. Shifts in the large-scale climate drivers such as El Niño-Southern Oscillation, Pacific Decadal Oscillation and Interdecadal Pacific Oscillation were observed to influence on changes to the low frequency of variability of the headland bypassing in the study area by affecting the predominant wave direction and updrift beach sand availability. The understanding of this intermittent nature of the headland bypassing process and particularly considering its periodicity and the related driving forces is crucial to predict future coastal hazards and develop management strategies.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148591DOI Listing
November 2021

Morbidity and Mortality Trends of Pancreatitis: An Observational Study.

Surg Infect (Larchmt) 2021 Jun 15. Epub 2021 Jun 15.

Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

Pancreatitis accounts for more than $2.5 billion of healthcare costs and remains the most common gastrointestinal (GI) admission. Few contemporary studies have assessed temporal trends of incidence, complications, management, and outcomes for acute pancreatitis in hospitalized patients at the national level. We used data from one of the largest hospital-based databases available in the United States, the Healthcare Cost and Utilization Project's (HCUP) State Inpatient Database, from 10 states between 2008 and 2015. We included patients with a diagnosis of acute pancreatitis (ICD-9 CM 577.0). Patient- and hospital-level data were used to estimate incidence and inpatient mortality rates. From 80,736,256 hospitalizations, 929,914 (1.15%) cases of acute pancreatitis were identified, 186,226 (20.2%) of which were caused by gallbladder disease). The median age was 53 years (interquartile range [IQR], 41-67) and 50.8% were men. In-hospital mortality was 2.5% and crude mortality rates declined from 2.9% to 2.0% over the study period. Admission year remained significant after adjusting for patient demographics and comorbidities (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.89-0.90; p < 0.001). Gallbladder disease was associated with decreased odds of mortality (OR, 0.60; 95% CI, 0.57-0.62). Median length of stay was four days (IQR, 2-7) and decreased over time. The rates of surgical and endoscopic interventions were highest in 2011 (peak incidence of 16.1% and 9.5%, respectively) and have been decreasing since. Surgical providers were, on average, more likely than medical providers to perform surgery in both those with and without gallbladder disease etiology (gallbladder disease OR, 7.11; 95% CI, 5.46-9.25; non-gallbladder disease OR, 20.50; 95% CI, 16.81-25.01), endoscopy (gallbladder disease OR, 1.22; 95% CI, 0.87-1.72; non-gallbladder disease OR, 1.60; 95% CI, 1.18-2.16), or both (gallbladder disease OR, 7.00; 95% CI, 5.22-9.37; non-gallbladder disease OR, 8.85; 95% CI, 5.61-13.96). The incidence of pancreatitis, from 2008 to 2015, has increased whereas inpatient mortality (i.e., case fatality) has decreased. Understanding temporal trends in outcomes and management along with provider, hospital, and regional variation can better identify areas for future research and collaboration in managing these patients.
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http://dx.doi.org/10.1089/sur.2020.473DOI Listing
June 2021

Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2.

JAMA Netw Open 2021 06 1;4(6):e2116420. Epub 2021 Jun 1.

Division of Hospital Medicine, Department of Pediatrics, Hackensack University Medical Center, Hackensack, New Jersey.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is associated with recent or current SARS-CoV-2 infection. Information on MIS-C incidence is limited.

Objective: To estimate population-based MIS-C incidence per 1 000 000 person-months and to estimate MIS-C incidence per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years.

Design, Setting, And Participants: This cohort study used enhanced surveillance data to identify persons with MIS-C during April to June 2020, in 7 jurisdictions reporting to both the Centers for Disease Control and Prevention national surveillance and to Overcoming COVID-19, a multicenter MIS-C study. Denominators for population-based estimates were derived from census estimates; denominators for incidence per 1 000 000 SARS-CoV-2 infections were estimated by applying published age- and month-specific multipliers accounting for underdetection of reported COVID-19 case counts. Jurisdictions included Connecticut, Georgia, Massachusetts, Michigan, New Jersey, New York (excluding New York City), and Pennsylvania. Data analyses were conducted from August to December 2020.

Exposures: Race/ethnicity, sex, and age group (ie, ≤5, 6-10, 11-15, and 16-20 years).

Main Outcomes And Measures: Overall and stratum-specific adjusted estimated MIS-C incidence per 1 000 000 person-months and per 1 000 000 SARS-CoV-2 infections.

Results: In the 7 jurisdictions examined, 248 persons with MIS-C were reported (median [interquartile range] age, 8 [4-13] years; 133 [53.6%] male; 96 persons [38.7%] were Hispanic or Latino; 75 persons [30.2%] were Black). The incidence of MIS-C per 1 000 000 person-months was 5.1 (95% CI, 4.5-5.8) persons. Compared with White persons, incidence per 1 000 000 person-months was higher among Black persons (adjusted incidence rate ratio [aIRR], 9.26 [95% CI, 6.15-13.93]), Hispanic or Latino persons (aIRR, 8.92 [95% CI, 6.00-13.26]), and Asian or Pacific Islander (aIRR, 2.94 [95% CI, 1.49-5.82]) persons. MIS-C incidence per 1 000 000 SARS-CoV-2 infections was 316 (95% CI, 278-357) persons and was higher among Black (aIRR, 5.62 [95% CI, 3.68-8.60]), Hispanic or Latino (aIRR, 4.26 [95% CI, 2.85-6.38]), and Asian or Pacific Islander persons (aIRR, 2.88 [95% CI, 1.42-5.83]) compared with White persons. For both analyses, incidence was highest among children aged 5 years or younger (4.9 [95% CI, 3.7-6.6] children per 1 000 000 person-months) and children aged 6 to 10 years (6.3 [95% CI, 4.8-8.3] children per 1 000 000 person-months).

Conclusions And Relevance: In this cohort study, MIS-C was a rare complication associated with SARS-CoV-2 infection. Estimates for population-based incidence and incidence among persons with infection were higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons. Further study is needed to understand variability by race/ethnicity and age group.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.16420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193431PMC
June 2021

Persistent Leg Drainage in a Pediatric Trauma Patient.

Pediatr Infect Dis J 2021 06;40(6):597-599

From the Section Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1097/INF.0000000000003004DOI Listing
June 2021

Alternative models and randomization techniques for Bayesian response-adaptive randomization with binary outcomes.

Clin Trials 2021 08 30;18(4):417-426. Epub 2021 Apr 30.

Division of Biostatistics, University of Minnesota Twin Cities, Minneapolis, MN, USA.

Background: Bayesian response-adaptive designs, which data adaptively alter the allocation ratio in favor of the better performing treatment, are often criticized for engendering a non-trivial probability of a subject imbalance in favor of the inferior treatment, inflating type I error rate, and increasing sample size requirements. The implementation of these designs using the Thompson sampling methods has generally assumed a simple beta-binomial probability model in the literature; however, the effect of these choices on the resulting design operating characteristics relative to other reasonable alternatives has not been fully examined. Motivated by the Advanced R Eperfusion STrategies for Refractory Cardiac Arrest trial, we posit that a logistic probability model coupled with an urn or permuted block randomization method will alleviate some of the practical limitations engendered by the conventional implementation of a two-arm Bayesian response-adaptive design with binary outcomes. In this article, we discuss up to what extent this solution works and when it does not.

Methods: A computer simulation study was performed to evaluate the relative merits of a Bayesian response-adaptive design for the Advanced R Eperfusion STrategies for Refractory Cardiac Arrest trial using the Thompson sampling methods based on a logistic regression probability model coupled with either an urn or permuted block randomization method that limits deviations from the evolving target allocation ratio. The different implementations of the response-adaptive design were evaluated for type I error rate control across various null response rates and power, among other performance metrics.

Results: The logistic regression probability model engenders smaller average sample sizes with similar power, better control over type I error rate, and more favorable treatment arm sample size distributions than the conventional beta-binomial probability model, and designs using the alternative randomization methods have a negligible chance of a sample size imbalance in the wrong direction.

Conclusion: Pairing the logistic regression probability model with either of the alternative randomization methods results in a much improved response-adaptive design in regard to important operating characteristics, including type I error rate control and the risk of a sample size imbalance in favor of the inferior treatment.
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http://dx.doi.org/10.1177/17407745211010139DOI Listing
August 2021

Logistic retainment interval dose exploration design for Phase I clinical trials of cytotoxic agents.

Authors:
Thomas A Murray

Pharm Stat 2021 07 18;20(4):850-863. Epub 2021 Mar 18.

Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA.

Phase I studies of a cytotoxic agent often aim to identify the dose that provides an investigator specified target dose-limiting toxicity (DLT) probability. In practice, an initial cohort receives a dose with a putative low DLT probability, and subsequent dosing follows by consecutively deciding whether to retain the current dose, escalate to the adjacent higher dose, or de-escalate to the adjacent lower dose. This article proposes a Phase I design derived using a Bayesian decision-theoretic approach to this sequential decision-making process. The design consecutively chooses the action that minimizes posterior expected loss where the loss reflects the distance on the log-odds scale between the target and the DLT probability of the dose that would be given to the next cohort under the corresponding action. A logistic model is assumed for the log odds of a DLT at the current dose with a weakly informative t-distribution prior centered at the target. The key design parameters are the pre-specified odds ratios for the DLT probabilities at the adjacent higher and lower doses. Dosing rules may be pre-tabulated, as these only depend on the outcomes at the current dose, which greatly facilitates implementation. The recommended default version of the proposed design improves dose selection relative to many established designs across a variety of scenarios.
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http://dx.doi.org/10.1002/pst.2114DOI Listing
July 2021

Conformational Constraint between Aromatic Residue Side Chains in the "Message" Sequence of the Peptide Arodyn Using Ring Closing Metathesis Results in a Potent and Selective Kappa Opioid Receptor Antagonist.

J Med Chem 2021 03 10;64(6):3153-3164. Epub 2021 Mar 10.

Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States.

Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and mood disorders. The linear acetylated dynorphin A analog arodyn (Ac[Phe,Arg,d-Ala]dynorphin A-(1-11)NH), synthesized in our laboratory, demonstrated potent and selective KOR antagonism. Cyclization of arodyn could potentially stabilize the bioactive conformation and enhance its metabolic stability. The cyclization strategy employed involved ring closing metathesis between adjacent - or -substituted Tyr(allyl) residues in the "message" sequence that were predicted in a docking study to yield analogs that would bind to the KOR with binding poses similar to arodyn. Consistent with the modeling, the resulting analogs retained KOR affinity similar to arodyn; the peptides involving cyclization between -allyl groups also retained high KOR selectivity, with one analog exhibiting KOR antagonist potency ( = 15 nM) similar to arodyn. These promising cyclized analogs with constrained aromatic residues represent novel leads for further exploration of KOR pharmacology.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01984DOI Listing
March 2021

Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.

Lancet Healthy Longev 2021 Jan 3;2(1):e34-e41. Epub 2020 Dec 3.

Division of Acute Care Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.

Background: Type 2 diabetes and obesity, as states of chronic inflammation, are risk factors for severe COVID-19. Metformin has cytokine-reducing and sex-specific immunomodulatory effects. Our aim was to identify whether metformin reduced COVID-19-related mortality and whether sex-specific interactions exist.

Methods: In this retrospective cohort analysis, we assessed de-identified claims data from UnitedHealth Group (UHG)'s Clinical Discovery Claims Database. Patient data were eligible for inclusion if they were aged 18 years or older; had type 2 diabetes or obesity (defined based on claims); at least 6 months of continuous enrolment in 2019; and admission to hospital for COVID-19 confirmed by PCR, manual chart review by UHG, or reported from the hospital to UHG. The primary outcome was in-hospital mortality from COVID-19. The independent variable of interest was home metformin use, defined as more than 90 days of claims during the year before admission to hospital. Covariates were comorbidities, medications, demographics, and state. Heterogeneity of effect was assessed by sex. For the Cox proportional hazards, censoring was done on the basis of claims made after admission to hospital up to June 7, 2020, with a best outcome approach. Propensity-matched mixed-effects logistic regression was done, stratified by metformin use.

Findings: 6256 of the 15 380 individuals with pharmacy claims data from Jan 1 to June 7, 2020 were eligible for inclusion. 3302 (52·8%) of 6256 were women. Metformin use was not associated with significantly decreased mortality in the overall sample of men and women by either Cox proportional hazards stratified model (hazard ratio [HR] 0·887 [95% CI 0·782-1·008]) or propensity matching (odds ratio [OR] 0·912 [95% CI 0·777-1·071], p=0·15). Metformin was associated with decreased mortality in women by Cox proportional hazards (HR 0·785, 95% CI 0·650-0·951) and propensity matching (OR 0·759, 95% CI 0·601-0·960, p=0·021). There was no significant reduction in mortality among men (HR 0·957, 95% CI 0·82-1·14; p=0·689 by Cox proportional hazards).

Interpretation: Metformin was significantly associated with reduced mortality in women with obesity or type 2 diabetes who were admitted to hospital for COVID-19. Prospective studies are needed to understand mechanism and causality. If findings are reproducible, metformin could be widely distributed for prevention of COVID-19 mortality, because it is safe and inexpensive.

Funding: National Heart, Lung, and Blood Institute; Agency for Healthcare Research and Quality; Patient-Centered Outcomes Research Institute; Minnesota Learning Health System Mentored Training Program, M Health Fairview Institutional Funds; National Center for Advancing Translational Sciences; and National Cancer Institute.
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http://dx.doi.org/10.1016/S2666-7568(20)30033-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832552PMC
January 2021

Mobile Health Intervention to Close the Guidelines-To-Practice Gap in Hypertension Treatment: Protocol for the mGlide Randomized Controlled Trial.

JMIR Res Protoc 2021 Jan 25;10(1):e25424. Epub 2021 Jan 25.

Department of Medicine and Program in Health Disparities Research, Medical School, University of Minnesota, Minneapolis, MN, United States.

Background: Suboptimal treatment of hypertension remains a widespread problem, particularly among minorities and socioeconomically disadvantaged groups. We present a health system-based intervention with diverse patient populations using readily available smartphone technology. This intervention is designed to empower patients and create partnerships between patients and their provider team to promote hypertension control.

Objective: The mGlide randomized controlled trial is a National Institutes of Health-funded study, evaluating whether a mobile health (mHealth)-based intervention that is an active partnership between interprofessional health care teams and patients results in better hypertension control rates than a state-of-clinical care comparison.

Methods: We are recruiting 450 participants including stroke survivors and primary care patients with elevated cardiovascular disease risk from diverse health systems. These systems include an acute stroke service (n=100), an academic medical center (n=150), and community medical centers including Federally Qualified Health Centers serving low-income and minority (Latino, Hmong, African American, Somali) patients (n=200). The primary aim tests the clinical effectiveness of the 6-month mHealth intervention versus standard of care. Secondary aims evaluate sustained hypertension control rates at 12 months; describe provider experiences of system usability and satisfaction; examine patient experiences, including medication adherence and medication use self-efficacy, self-rated health and quality of life, and adverse event rates; and complete a cost-effectiveness analysis.

Results: To date, we have randomized 107 participants (54 intervention, 53 control).

Conclusions: This study will provide evidence for whether a readily available mHealth care model is better than state-of-clinical care for bridging the guideline-to-practice gap in hypertension treatment in health systems serving diverse patient populations.

Trial Registration: Clinicaltrials.gov NCT03612271; https://clinicaltrials.gov/ct2/show/NCT03612271.

International Registered Report Identifier (irrid): DERR1-10.2196/25424.
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http://dx.doi.org/10.2196/25424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870345PMC
January 2021

Mass severe acute respiratory coronavirus 2 (SARS-CoV-2) testing of asymptomatic healthcare personnel.

Infect Control Hosp Epidemiol 2021 05 25;42(5):625-626. Epub 2021 Jan 25.

Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.

Mass asymptomatic SARS-CoV-2 nucleic acid amplified testing of healthcare personnel (HCP) was performed at a large tertiary health system. A low period-prevalence of positive HCP was observed. Of those who tested positive, half had mild symptoms in retrospect. HCP with even mild symptoms should be isolated and tested.
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http://dx.doi.org/10.1017/ice.2021.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853752PMC
May 2021

Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1 Activated T Cells.

Cancer Discov 2021 May 8;11(5):1100-1117. Epub 2021 Jan 8.

Antibody Discovery and Protein Engineering, R&D, AstraZeneca, Gaithersburg, Maryland.

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1 activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1 T cells versus PD-1 T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 . Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1 T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1 T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1445DOI Listing
May 2021

Severe Acute Respiratory Syndrome Coronavirus 2 Testing in Children in a Large Regional US Health System During the Coronavirus Disease 2019 Pandemic.

Pediatr Infect Dis J 2021 03;40(3):175-181

Department of Infection Prevention, Yale New Haven Hospital.

Background: The objective was to evaluate patterns of pediatric coronavirus disease 2019 testing in a large health system throughout the pandemic, before and after school reopening.

Methods: This was a cross-sectional time-series study of clinical virology results from children tested for severe acute respiratory syndrome coronavirus 2 in Southern Connecticut and areas of New York and Rhode Island. Data collected include demographics, hospital admission, changes in percent positive tests over time, detection intervals in persistently positive children and cycle threshold values. The setting was the Yale New Haven Health System has 6 hospitals at 4 Connecticut locations, 1 hospital in Rhode Island and ambulatory locations in Connecticut, Rhode Island and New York. Participants included twenty-three-thousand one-hundred thirty-seven children ≤ 18 years of age, tested for coronavirus disease 2019 at an ambulatory testing site, the emergency department or on an inpatient unit within the Yale New Haven Health System.

Results: Among all tests, 3.2% were positive. Older children consistently made up the larger portion of positive pediatric cases, regardless of community prevalence. Increased pediatric cases later in the pandemic when prevalence in adults was relatively low correlates with a higher number of tests performed in children and not with an increased positivity rate. No significant changes in trends of positivity were detected after the reopening of schools. Symptomatic and asymptomatic children had similar cycle threshold values regardless of age, and a subset of children demonstrated persistent viral detection, some for as long as 6 weeks.

Conclusion: An increase in pediatric cases documented in the late summer was predominately due to increased access to testing for children. The percent positivity in children did not change in the first 3 weeks after school opened. A subset of children has detectable severe acute respiratory syndrome coronavirus 2 RNA in the upper respiratory tract for weeks after the initial infection.
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http://dx.doi.org/10.1097/INF.0000000000003024DOI Listing
March 2021

Risk factors for de novo and therapy-related myelodysplastic syndromes (MDS).

Cancer Causes Control 2021 Mar 4;32(3):241-250. Epub 2021 Jan 4.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Purpose: Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS.

Methods: The study population included 346 de novo MDS cases, 37 tMDS cases and 682 population controls frequency matched by age and sex. Polytomous logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI).

Results: After adjustment, former smoking status (OR = 1.45, 95% CI: 1.10-1.93), personal history of autoimmune disease (OR = 1.34, 95% CI: 0.99-1.82) and exposure to benzene (OR = 1.48, 95% CI: 1.00-2.19) were associated with de novo MDS. Risk estimates for the associations between smoking, autoimmune disease, and benzene exposure were similar in magnitude but non-significant in tMDS cases. Among individuals with a previous diagnosis of cancer, de novo MDS cases and controls were more likely to have had a previous solid tumor, while tMDS cases more commonly had a previous hematologic malignancy.

Conclusions: We observed similar associations between smoking, history of autoimmune disease and benzene exposure in de novo and tMDS although estimates for tMDS were imprecise due to small sample sizes. Future analyses with larger sample sizes will be required to confirm whether environmental factors influence risk of tMDS.
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http://dx.doi.org/10.1007/s10552-020-01378-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878335PMC
March 2021

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

N Engl J Med 2021 03 22;384(10):905-914. Epub 2020 Dec 22.

From the CHIP Center of Excellence for Health, Immunity, and Infections (J.D.L., D.D.M.), and the Department of Infectious Diseases (J.D.L., D.D.M., J.-U.J.), Rigshospitalet, Copenhagen, the Department of Infectious Diseases, Copenhagen University Hospital, Amager and Hvidovre (T.B.), the Department of Internal Medicine, Respiratory Medicine Section, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup (J.-U.J.), the Department of Infectious Diseases, Odense University Hospital, Odense (I.S.J.), and the Department of Infectious Diseases, Aarhus University Hospital, Skejby (L.Ø.) - all in Denmark; the School of Statistics (B.G.) and the Division of Biostatistics, School of Public Health (T.A.M., C.R., S.S., D.W., J.D.N.), University of Minnesota, Hennepin Healthcare Research Institute (J.V.B.), and the University of Minnesota (J.V.B.), Minneapolis; the Divisions of Pulmonary, Allergy, and Critical Care Medicine (C.E.B.) and Infectious Disease (T.L.H.), Department of Medicine, Duke University, Durham, and the Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy, and Immunology, Wake Forest School of Medicine, Winston-Salem (D.C.F.) - both in North Carolina; the Center for Advanced Heart and Lung Disease (R.L.G.) and the Division of Infectious Diseases (U.S.), Baylor University Medical Center, and the Department of Internal Medicine, UT Southwestern Medical Center (M.K.J.), Dallas; the Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray (S.M.B.), and the Department of Internal Medicine, University of Utah (S.M.B., E.S.H.) and Intermountain Healthcare (K.U.K.), Salt Lake City - both in Utah; the Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville (W.H.S.); the Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles (M.E.B.), the Department of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco (M.A.M.), and Gilead Sciences, Foster City (H.C.) - all in California; the Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta (B.G.L.); Denver Public Health, Denver Health and Hospital Authority, Denver (E.M.G.), and the Department of Emergency Medicine, University of Colorado School of Medicine, Aurora (A.A.G.); the Department of Infectious Diseases, Henry Ford Hospital, Detroit (N.M.); the Kirby Institute, University of New South Wales (C.C.C., M.N.P.), and St. Vincent's Hospital (M.N.P.), Sydney; the Department of Veterans Affairs (V.J.D.), the Veterans Affairs Medical Center (V.L.K.), and George Washington University School of Medicine and Health Sciences (V.L.K.), Washington, DC; the Medical Research Council Clinical Trials Unit at UCL (A.G., A.G.B., M.K.B.P.), the Institute of Clinical Trials and Methodology (M.K.B.P.), and the Institute for Global Health (A.N.P.), University College London, and Guy's and St. Thomas' NHS Foundation Trust (A.G.), London; the National Institute of Allergy and Infectious Diseases, Bethesda (E.S.H., H.C.L.), and Leidos Biomedical Research, Frederick (R.L.D., M.T.) - both in Maryland; the Infectious Diseases Department and IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (R.P.); Eli Lilly, Indianapolis (P.K.); the Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (A.C.G.); and the Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston (B.T.T.).

Background: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.

Methods: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.

Results: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).

Conclusions: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).
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http://dx.doi.org/10.1056/NEJMoa2033130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781100PMC
March 2021

Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3).

medRxiv 2021 Apr 8. Epub 2021 Apr 8.

CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.

Background: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership initiated the Therapeutics for Inpatients with COVID-19 (TICO). TICO is a multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. Four agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed.

Protocol Design And Implementation: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. TICO utilizes a MAMS design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo as well as the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and DSMB schedule was developed for the study of agents with limited in-human data.

Challenges: Challenges included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff, and obtaining regulatory approvals across a global network of sites.

Conclusion: Through a robust multi-network partnership, the TICO protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required.
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http://dx.doi.org/10.1101/2020.11.08.20227876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675662PMC
April 2021

Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.

Lancet 2020 12 13;396(10265):1807-1816. Epub 2020 Nov 13.

Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Among patients with out-of-hospital cardiac arrest (OHCA) and ventricular fibrillation, more than half present with refractory ventricular fibrillation unresponsive to initial standard advanced cardiac life support (ACLS) treatment. We did the first randomised clinical trial in the USA of extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation versus standard ACLS treatment in patients with OHCA and refractory ventricular fibrillation.

Methods: For this phase 2, single centre, open-label, adaptive, safety and efficacy randomised clinical trial, we included adults aged 18-75 years presenting to the University of Minnesota Medical Center (MN, USA) with OHCA and refractory ventricular fibrillation, no return of spontaneous circulation after three shocks, automated cardiopulmonary resuscitation with a Lund University Cardiac Arrest System, and estimated transfer time shorter than 30 min. Patients were randomly assigned to early ECMO-facilitated resuscitation or standard ACLS treatment on hospital arrival by use of a secure schedule generated with permuted blocks of randomly varying block sizes. Allocation concealment was achieved by use of a randomisation schedule that required scratching off an opaque layer to reveal assignment. The primary outcome was survival to hospital discharge. Secondary outcomes were safety, survival, and functional assessment at hospital discharge and at 3 months and 6 months after discharge. All analyses were done on an intention-to-treat basis. The study qualified for exception from informed consent (21 Code of Federal Regulations 50.24). The ARREST trial is registered with ClinicalTrials.gov, NCT03880565.

Findings: Between Aug 8, 2019, and June 14, 2020, 36 patients were assessed for inclusion. After exclusion of six patients, 30 were randomly assigned to standard ACLS treatment (n=15) or to early ECMO-facilitated resuscitation (n=15). One patient in the ECMO-facilitated resuscitation group withdrew from the study before discharge. The mean age was 59 years (range 36-73), and 25 (83%) of 30 patients were men. Survival to hospital discharge was observed in one (7%) of 15 patients (95% credible interval 1·6-30·2) in the standard ACLS treatment group versus six (43%) of 14 patients (21·3-67·7) in the early ECMO-facilitated resuscitation group (risk difference 36·2%, 3·7-59·2; posterior probability of ECMO superiority 0·9861). The study was terminated at the first preplanned interim analysis by the National Heart, Lung, and Blood Institute after unanimous recommendation from the Data Safety Monitoring Board after enrolling 30 patients because the posterior probability of ECMO superiority exceeded the prespecified monitoring boundary. Cumulative 6-month survival was significantly better in the early ECMO group than in the standard ACLS group. No unanticipated serious adverse events were observed.

Interpretation: Early ECMO-facilitated resuscitation for patients with OHCA and refractory ventricular fibrillation significantly improved survival to hospital discharge compared with standard ACLS treatment.

Funding: National Heart, Lung, and Blood Institute.
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http://dx.doi.org/10.1016/S0140-6736(20)32338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856571PMC
December 2020

COVID-19 Transmission in US Child Care Programs.

Pediatrics 2021 01 14;147(1). Epub 2020 Oct 14.

Yale Institute for Global Health.

Objectives: Central to the debate over school and child care reopening is whether children are efficient coronavirus disease 2019 (COVID-19) transmitters and are likely to increase community spread when programs reopen. We compared COVID-19 outcomes in child care providers who continued to provide direct in-person child care during the first 3 months of the US COVID-19 pandemic with outcomes in those who did not.

Methods: Data were obtained from US child care providers ( = 57 335) reporting whether they had ever tested positive or been hospitalized for COVID-19 ( = 427 cases) along with their degree of exposure to child care. Background transmission rates were controlled statistically, and other demographic, programmatic, and community variables were explored as potential confounders. Logistic regression analysis was used in both unmatched and propensity score-matched case-control analyses.

Results: No association was found between exposure to child care and COVID-19 in both unmatched (odds ratio [OR], 1.06; 95% confidence interval [CI], 0.82-1.38) and matched (OR, 0.94; 95% CI, 0.73-1.21) analyses. In matched analysis, being a home-based provider (as opposed to a center-based provider) was associated with COVID-19 (OR, 1.59; 95% CI, 1.14-2.23) but revealed no interaction with exposure.

Conclusions: Within the context of considerable infection mitigation efforts in US child care programs, exposure to child care during the early months of the US pandemic was not associated with an elevated risk for COVID-19 transmission to providers. These findings must be interpreted only within the context of background transmission rates and the considerable infection mitigation efforts implemented in child care programs.
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http://dx.doi.org/10.1542/peds.2020-031971DOI Listing
January 2021

Unmasking symptomatic dermatographism in the time of COVID-19.

Postgrad Med J 2021 06 10;97(1148):402. Epub 2020 Sep 10.

Section of Allergy and Immunology, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.

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http://dx.doi.org/10.1136/postgradmedj-2020-138688DOI Listing
June 2021

Rationale and methods of the Advanced REperfusion STrategies for Refractory Cardiac Arrest (ARREST) trial.

Am Heart J 2020 11 15;229:29-39. Epub 2020 Jul 15.

Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI.

Background: Venoarterial extracorporeal membrane oxygenation has emerged as a prominent therapy for patients with refractory cardiac arrest. However, the optimal time of initiation remains unknown.

Aim: The aim was to assess the rate of survival to hospital discharge in adult patients with refractory ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest treated with 1 of 2 local standards of care: (1) early venoarterial extracorporeal membrane oxygenation-facilitated resuscitation for circulatory support and percutaneous coronary intervention, when needed, or (2) standard advanced cardiac life support resuscitation.

Design: Phase II, single-center, partially blinded, prospective, intention-to-treat, safety and efficacy clinical trial.

Population: Adults (aged 18-75), initial out-of-hospital cardiac arrest rhythm of ventricular fibrillation/pulseless ventricular tachycardia, no ROSC following 3 shocks, body morphology to accommodate a Lund University Cardiac Arrest System automated cardiopulmonary resuscitation device, and transfer time of <30 minutes.

Setting: Hospital-based.

Outcomes: Primary: survival to hospital discharge. Secondary: safety, survival, and functional assessment at hospital discharge and 3 and 6 months, and cost.

Sample Size: Assuming success rates of 12% versus 37% in the 2 arms and 90% power, a type 1 error rate of .05, and a 15% rate of withdrawal prior to hospital discharge, the required sample size is N = 174 evaluated patients.

Conclusions: The ARREST trial will generate safety/effectiveness data and comparative costs associated with extracorporeal cardiopulmonary resuscitation, informing broader implementation and a definitive Phase III clinical trial.
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http://dx.doi.org/10.1016/j.ahj.2020.07.006DOI Listing
November 2020

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles.

Molecules 2020 Sep 2;25(17). Epub 2020 Sep 2.

Department of Medicinal Chemistry, The University of Florida, Gainesville, FL 32610, USA.

The macrocyclic tetrapeptide [Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer [Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues' stereochemistry on the peptides' opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, [d-Phe-d-Pro-d-Phe-Trp] () and [Phe-d-Pro-d-Phe-d-Trp] (), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.
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http://dx.doi.org/10.3390/molecules25173999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504817PMC
September 2020

Surface coatings alter transcriptional responses to silver nanoparticles following oral exposure.

NanoImpact 2020 Jan 24;17. Epub 2019 Dec 24.

Cancer Research Center, University at Albany, State University of New York, Rensselaer, NY, USA.

Silver nanoparticles (AgNPs) are used in food packaging materials, dental care products and other consumer goods and can result in oral exposure. To determine whether AgNP coatings modulate transcriptional responses to AgNP exposure, we exposed mice orally to 20 nm citrate (cit)-coated AgNPs (cit-AgNPs) or polyvinylpyrrolidone (PVP)-coated AgNPs (PVP-AgNPs) at a 4 mg/kg dose for 7 consecutive days and analyzed changes in the expression of protein-coding genes and long noncoding RNAs (lncRNAs), a new class of regulatory RNAs, in the liver. We identified unique and common expression signatures of protein-coding and lncRNA genes, altered biological processes and signaling pathways, and coding-non-coding gene interactions for cit-AgNPs and PVP-AgNPs. Commonly regulated genes comprised only about 10 and 20 percent of all differentially expressed genes in PVP-AgNP and cit-AgNP exposed mice, respectively. Commonly regulated biological processes included glutathione metabolic process and cellular oxidant detoxification. Commonly regulated pathways included Keap-Nrf2, PPAR, MAPK and IL-6 signaling pathways. The coding-non-coding gene co-expression analysis revealed that protein-coding genes were co-expressed with a variable number of lncRNAs ranging from one to twenty three and may share functional roles with the protein-coding genes. PVP-AgNP exposure induced a more robust transcriptional response than cit-AgNP exposure characterized by more than two-fold higher number of differentially expressed both protein- coding and lncRNA genes. Our data demonstrate that the surface coating strongly modulates the spectrum and the number of differentially expressed genes after oral AgNP exposure. On the other hand, our data suggest that AgNP exposure can alter drug and chemical sensitivity, metabolic homeostasis and cancer risk irrespective of the coating type, warranting further investigations.
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http://dx.doi.org/10.1016/j.impact.2019.100205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453744PMC
January 2020

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis.

Front Pharmacol 2020 14;11:1059. Epub 2020 Jul 14.

Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States.

In individuals with cystic fibrosis (CF), lung hyper-inflammation starts early in life and is perpetuated by mucus obstruction and persistent bacterial infections. The continuous tissue damage and scarring caused by non-resolving inflammation leads to bronchiectasis and, ultimately, respiratory failure. Macrophages (MΦs) are key regulators of immune response and host defense. We and others have shown that, in CF, MΦs are hyper-inflammatory and exhibit reduced bactericidal activity. Thus, MΦs contribute to the inability of CF lung tissues to control the inflammatory response or restore tissue homeostasis. The non-resolving hyper-inflammation in CF lungs is attributed to an impairment of several signaling pathways associated with resolution of the inflammatory response, including the heme oxygenase-1/carbon monoxide (HO-1/CO) pathway. HO-1 is an enzyme that degrades heme groups, leading to the production of potent antioxidant, anti-inflammatory, and bactericidal mediators, such as biliverdin, bilirubin, and CO. This pathway is fundamental to re-establishing cellular homeostasis in response to various insults, such as oxidative stress and infection. Monocytes/MΦs rely on abundant induction of the HO-1/CO pathway for a controlled immune response and for potent bactericidal activity. Here, we discuss studies showing that blunted HO-1 activation in CF-affected cells contributes to hyper-inflammation and defective host defense against bacteria. We dissect potential cellular mechanisms that may lead to decreased HO-1 induction in CF cells. We review literature suggesting that induction of HO-1 may be beneficial for the treatment of CF lung disease. Finally, we discuss recent studies highlighting how endogenous HO-1 can be induced by administration of controlled doses of CO to reduce lung hyper-inflammation, oxidative stress, bacterial infection, and dysfunctional ion transport, which are all hallmarks of CF lung disease.
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http://dx.doi.org/10.3389/fphar.2020.01059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372134PMC
July 2020

Workforce Planning for Embedded Mental Health Care in the U.S. Navy.

Mil Med 2020 12;185(11-12):e1961-e1967

Defense Health Agency, 7400 Arlington Blvd, Falls Church, VA 22042.

Introduction: Embedding mental health providers directly into operational units provides opportunities for holistic individual and population focused mental health support. To effectively provide clinical mental health care to a large number of Sailors and Marines while supporting the larger command, it is crucial to arrive at an optimal number of mental health (MH) care staff. In response to an increasing demand for MH care by operational units distributed globally, the U.S. Navy (USN) critically analyzed the current MH staffing levels, estimated future demand for MH care providers, and evaluated several staffing options. The following article illustrates a case study of workforce planning for the USN's embedded MH delivery model.

Materials And Methods: Several existing data sources were used to calculate current number of MH care staff across all USN platforms and to estimate demand for MH care. An open source Linear Programming application was used to estimate staffing solutions that meet business requirements in the most efficient manner possible.

Results: Results suggested different conclusions for embedded mental health staffing across USN communities. Depending on existing staffing levels and the number of Sailors or Marines anticipated to require care, the Linear Programming algorithm estimated needed staffing levels to address demand.

Conclusion: The current project represents the first systematic workforce planning initiative designed to help staff the USN's global demand for community focused MH care. The results of this project have identified areas where additional embedded mental health resources should be made available. By systematically documenting all services and capabilities and carefully examining the operational demands of each community, the current solution was able to identify precisely what type of MH resources should be allocated to a given community.
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http://dx.doi.org/10.1093/milmed/usaa195DOI Listing
December 2020

Epicortical Brevetoxin Treatment Promotes Neural Repair and Functional Recovery after Ischemic Stroke.

Mar Drugs 2020 Jul 21;18(7). Epub 2020 Jul 21.

Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68123, USA.

Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.
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http://dx.doi.org/10.3390/md18070374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404386PMC
July 2020

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19.

medRxiv 2020 Jun 28. Epub 2020 Jun 28.

Department of Surgery, University of Minnesota Division of Acute Care Surgery, Minneapolis, MN.

Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex. Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNF-alpha inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983). Conclusions Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in Covid-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.
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http://dx.doi.org/10.1101/2020.06.19.20135095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325185PMC
June 2020
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