Publications by authors named "Michael Insel"

9 Publications

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The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.

Chest 2021 Oct 9. Epub 2021 Oct 9.

Department of Medicine, University of Arizona, Tucson, AZ; Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Arizona, Tucson, AZ. Electronic address:

Background: Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect as most patients remain in intermediate or high risk after initial treatment with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.

Research Question: Does RV adaptation predict therapeutic response over time?

Study Design And Methods: We evaluated 52 incident treatment naïve patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 mo.) and follow-up 2 (∼18 mo.). All patients were placed on goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I-II was not achieved. Therapeutic response was evaluated at follow-up 1 as non-responders (died) or responders and again at follow-up 2 as super-responders (low risk) or partial-responders (high/intermediate risk). Multiparametric risk was based on a simplified ERS/ESC guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean±SD or odds ratio [95%CI].

Results: Nine patients (17%) were non-responders. PAH-directed therapy improved ERS low risk from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was non-significantly higher in responders (0.9±0.4) versus non-responders (0.6±0.4, p=0.09) but was unable to predict super-responder status at follow-up 2 (odds ratio 1.40 [0.28-7.0], p=0.84). Baseline RVEF and change in Eed successfully predicted super-responder status at follow-up 2 (odds ratio 1.15 [1.0-1.27], p=0.009 and 0.29 [0.86-0.96], p=0.04, respectively).

Interpretation: In patients with advanced PAH, RV-PA coupling could not discriminate irreversible RV failure (non-responders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RVEF were the best predictors of therapeutic response.
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http://dx.doi.org/10.1016/j.chest.2021.09.040DOI Listing
October 2021

SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus.

Biomedicines 2021 May 12;9(5). Epub 2021 May 12.

Office of the Senior Vice-President for Health Sciences, University of Arizona, Tucson, AZ 85724, USA.

SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
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http://dx.doi.org/10.3390/biomedicines9050539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150898PMC
May 2021

Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity.

Immunity 2020 11 14;53(5):925-933.e4. Epub 2020 Oct 14.

Division of Geriatrics, General Medicine and Palliative Care, Department of Medicine, University of Arizona College of Medicine, Tucson, Tucson, AZ, USA.

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.immuni.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554472PMC
November 2020

Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure.

medRxiv 2020 Aug 15. Epub 2020 Aug 15.

Division of Geriatrics, General Medicine and Palliative Care, Department of Medicine, University of Arizona College of Medicine-Tucson, Tucson, USA.

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.08.14.20174490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430613PMC
August 2020

Bacteria in Asthma Pathogenesis.

Immunol Allergy Clin North Am 2019 08 7;39(3):377-389. Epub 2019 May 7.

Department of Medicine, College of Medicine Tucson, Asthma and Airway Disease Research Center, University of Arizona Health Sciences, University of Arizona College of Medicine - Tucson, 1501 North Campbell Avenue, PO Box 245017, Tucson, AZ 85724, USA. Electronic address:

The airways are under continuous assault from aerosolized bacteria and oral flora. The bacteria present in the airways and gastrointestinal tract of neonates promote immune maturation and protect against asthma pathogenesis. Later bacterial infections and perturbations to the microbiome can contribute to asthma pathogenesis, persistence, and severity.
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http://dx.doi.org/10.1016/j.iac.2019.03.006DOI Listing
August 2019

Club Cell Secretory Protein Deficiency Leads to Altered Lung Function.

Am J Respir Crit Care Med 2019 02;199(3):302-312

1 Asthma and Airway Disease Research Center.

Rationale: CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.

Objectives: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.

Methods: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16 mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.

Measurements And Main Results: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16 mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16 mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.

Conclusions: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.
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http://dx.doi.org/10.1164/rccm.201807-1345OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363971PMC
February 2019

The Association of Non-Cardiac ECMO With Influenza Incidence: A Time Series Analysis.

Respir Care 2019 Mar 30;64(3):279-284. Epub 2018 Oct 30.

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, University of Arizona Health Sciences, Tucson, Arizona.

Background: The 2009 H1N1 influenza epidemic saw a rise in the use of extracorporeal membrane oxygenation (ECMO) as a supportive therapy for refractory ARDS. We sought to determine whether ECMO utilization follows a seasonal pattern that matches the influenza season, and whether it can further be explained by the incidence of each influenza subtype.

Methods: We performed a longitudinal analysis of non-cardiac and cardiac-associated ECMO cases from the National In-patient Sample from 2005 to 2014, using overdispersed Poisson regression to evaluate associations with influenza incidence categorized by influenza-like illness and total positive influenza tests divided by subtype from the Centers for Disease Control and Prevention.

Results: Non-cardiac ECMO use was positively associated with influenza-like illness incidence in the current month (incidence risk ratio [IRR] 1.11, 95% confidence interval [CI] 1.07-1.15, < .001) and with influenza-like illness in the previous month (IRR 1.09, 95% CI 1.05-1.14, < .001). The 2009 H1N1 subtype had the strongest association with non-cardiac ECMO (IRR 1.19, 95% CI 1.09-1.31, < .001). Cardiac ECMO was also positively associated with the incidence of influenza-like illness (IRR 1.05, 95% CI 1.01-1.09, = .02).

Conclusion: Non-cardiac and cardiac ECMO use in the United States were significantly associated with influenza incidence. The influenza A, H1N1 2009, subtype had the strongest association.
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http://dx.doi.org/10.4187/respcare.06145DOI Listing
March 2019

Bioavailable estradiol concentrations are elevated and predict mortality in septic patients: a prospective cohort study.

Crit Care 2016 10 21;20(1):335. Epub 2016 Oct 21.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA.

Background: Experimental studies demonstrate beneficial immunological and hemodynamic effects of estradiol in animal models of sepsis. This raises the question whether estradiol contributes to sex differences in the incidence and outcomes of sepsis in humans. Yet, total estradiol levels are elevated in sepsis patients, particularly nonsurvivors. Bioavailable estradiol concentrations have not previously been reported in septic patients. The bioavailable estradiol concentration accounts for aberrations in estradiol carrier protein concentrations that could produce discrepancies between total and bioavailable estradiol levels. We hypothesized that bioavailable estradiol levels are low in septic patients and sepsis nonsurvivors.

Methods: We conducted a combined case-control and prospective cohort study. Venous blood samples were obtained from 131 critically ill septic patients in the medical and surgical intensive care units at the University of Rochester Medical Center and 51 control subjects without acute illness. Serum bioavailable estradiol concentrations were calculated using measurements of total estradiol, sex hormone-binding globulin, and albumin. Comparisons were made between patients with severe sepsis and control subjects and between hospital survivors and nonsurvivors. Multivariable logistic regression analysis was also performed.

Results: Bioavailable estradiol concentrations were significantly higher in sepsis patients than in control subjects (211 [78-675] pM vs. 100 [78-142] pM, p < 0.01) and in sepsis nonsurvivors than in survivors (312 [164-918] pM vs. 167 [70-566] pM, p = 0.04). After adjustment for age and comorbidities, patients with bioavailable estradiol levels above the median value had significantly higher risk of hospital mortality (OR 4.27, 95 % CI 1.65-11.06, p = 0.003). Bioavailable estradiol levels were directly correlated with severity of illness and did not differ between men and women.

Conclusions: Contrary to our hypothesis, bioavailable estradiol levels were elevated in sepsis patients, particularly nonsurvivors, and were independently associated with mortality. Whether estradiol's effects are harmful, beneficial, or neutral in septic patients remains unknown, but our findings raise caution about estradiol's therapeutic potential in this setting. Our findings do not provide an explanation for sex-based differences in sepsis incidence and outcomes.
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http://dx.doi.org/10.1186/s13054-016-1525-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073735PMC
October 2016

Scrotal Calcinosis.

J Gen Intern Med 2016 09 26;31(9):1104. Epub 2016 Feb 26.

California Pacific Medical Center, 2333 Buchanan St., San Francisco, CA, 94115, USA.

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http://dx.doi.org/10.1007/s11606-016-3600-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978666PMC
September 2016
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