Browsing by Author "Machado, Roberto"

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    The CYB5R3c.350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease
    (Wiley, 2020-11) Gordeuk, Victor R.; Shah, Binal N.; Zhang, Xu; Thuma, Philip E.; Zulu, Stenford; Moono, Rodgers; Reading, N. Scott; Song, Jihyun; Zhang, Yingze; Nouraie, Mehdi; Campbell, Andrew; Minniti, Caterina P.; Rana, Sohail R.; Darbari, Deepika S.; Kato, Gregory J.; Niu, Mei; Castro, Oswaldo L.; Machado, Roberto; Gladwin, Mark T.; Prchal, Josef T.; Medicine, School of Medicine
    Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3c.350C > G encoding CYB5R3T117S , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A- status among 165 Zambian children with malaria. CYB5R3c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A- heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A- hemizygotes/homozygotes. We also examined the relationship of CYB5R3c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (β = 0.29, P = .022 children; β = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3c.350C > G selection and its high prevalence.
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    Delirium Incidence, Duration and Severity in Critically Ill Patients with COVID-19
    (2020-06-01) Khan, Sikandar H.; Lindroth, Heidi; Perkins, Anthony J.; Jamil, Yasser; Wang, Sophia; Roberts, Scott; Farber, Mark O.; Rahman, Omar; Gao, Sujuan; Marcantonio, Edward R.; Boustani, Malaz; Machado, Roberto; Khan, Babar A.; Medicine, School of Medicine
    Background: Delirium incidence, duration and severity in patients admitted to the intensive care unit (ICU) due to COVID-19 is not known. Methods: We conducted an observational study at two large urban academic Level 1 trauma centers. Consecutive patients admitted to the ICU with a positive SARS-CoV-2 nasopharyngeal swab polymerase chain reaction test from March 1st, 2020 to April 27, 2020, were included. Individuals younger than 18 years of age, without any documented delirium assessments (CAM-ICU), or without a discharge disposition were excluded. The primary outcomes were delirium rates and delirium duration and the secondary outcome was delirium severity. Outcomes were assessed for up to the first 14 days of ICU stay. Results: Of 243 consecutive patients with confirmed COVID-19 admitted to the ICU, 144 met eligibility criteria and were included in the analysis. Delirium occurred in 73.6% (106/144) and delirium or coma occurred in 76.4% (110/144). Sixty-three percent of patients were positive for delirium on the first CAM-ICU assessment. The median duration of delirium and coma was 7 days (IQR: 3-10), and the median delirium duration was 5 days (IQR: 2-7). The median CAM-ICU-7 score was 6 (IQR: 4-7) representing severe delirium. Mechanical ventilation was associated with greater odds of developing delirium (OR: 42.1, 95%CI: 13.0-137.1). Mortality was 26.4% in patients with delirium compared to 15.8% in patients without delirium. Conclusions: 73.6% of patients admitted to the ICU with COVID-19 experience delirium that persists for approximately 1 week. Invasive mechanical ventilation is significantly associated with odds of delirium. Clinical attention to prevent and manage delirium and reduce delirium duration and severity is urgently needed for patients with COVID-19.
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    Delirium Incidence, Duration, and Severity in Critically Ill Patients With Coronavirus Disease 2019
    (Wolters Kluwer, 2020-12) Khan, Sikandar H.; Lindroth, Heidi; Perkins, Anthony J.; Jamil, Yasser; Wang, Sophia; Roberts, Scott; Farber, Mark; Rahman, Omar; Gao, Sujuan; Marcantonio, Edward R.; Boustani, Malaz; Machado, Roberto; Khan, Babar A.; Medicine, School of Medicine
    Objectives: To determine delirium occurrence rate, duration, and severity in patients admitted to the ICU with coronavirus disease 2019. Design: Retrospective data extraction study from March 1, 2020, to June 7, 2020. Delirium outcomes were assessed for up to the first 14 days in ICU. Setting: Two large, academic centers serving the state of Indiana. Patients: Consecutive patients admitted to the ICU with positive severe acute respiratory syndrome coronavirus 2 nasopharyngeal swab polymerase chain reaction test from March 1, 2020, to June 7, 2020, were included. Individuals younger than 18 years of age, without any delirium assessments, or without discharge disposition were excluded. Measurements and Main Results: Primary outcomes were delirium rates and duration, and the secondary outcome was delirium severity. Two-hundred sixty-eight consecutive patients were included in the analysis with a mean age of 58.4 years (sd, 15.6 yr), 40.3% were female, 44.4% African American, 20.7% Hispanic, and a median Acute Physiology and Chronic Health Evaluation II score of 18 (interquartile range, 13–25). Delirium without coma occurred in 29.1% of patients, delirium prior to coma in 27.9%, and delirium after coma in 23.1%. The first Confusion Assessment Method for the ICU assessment was positive for delirium in 61.9%. Hypoactive delirium was the most common subtype (87.4%). By day 14, the median number of delirium/coma-free were 5 days (interquartile range, 4–11 d), and median Confusion Assessment Method for the ICU-7 score was 6.5 (interquartile range, 5–7) indicating severe delirium. Benzodiazepines were ordered for 78.4% of patients in the cohort. Mechanical ventilation was associated with greater odds of developing delirium (odds ratio, 5.0; 95% CI, 1.1–22.2; p = 0.033) even after adjusting for sedative medications. There were no between-group differences in mortality. Conclusions: Delirium without coma occurred in 29.1% of patients admitted to the ICU. Delirium persisted for a median of 5 days and was severe. Mechanical ventilation was significantly associated with odds of delirium even after adjustment for sedatives. Clinical attention to manage delirium duration and severity, and deeper understanding of the virus’ neurologic effects is needed for patients with coronavirus disease 2019.
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    Delirium Incidence, Duration, and Severity in Critically Ill Patients With Coronavirus Disease 2019
    (Wolters Kluwer, 2020-11-25) Khan, Sikandar H.; Lindroth, Heidi; Perkins, Anthony J.; Jamil, Yasser; Wang, Sophia; Roberts, Scott; Farber, Mark; Rahman, Omar; Gao, Sujuan; Marcantonio, Edward R.; Boustani, Malaz; Machado, Roberto; Khan, Babar A.; Medicine, School of Medicine
    Objectives: To determine delirium occurrence rate, duration, and severity in patients admitted to the ICU with coronavirus disease 2019. Design: Retrospective data extraction study from March 1, 2020, to June 7, 2020. Delirium outcomes were assessed for up to the first 14 days in ICU. Setting: Two large, academic centers serving the state of Indiana. Patients: Consecutive patients admitted to the ICU with positive severe acute respiratory syndrome coronavirus 2 nasopharyngeal swab polymerase chain reaction test from March 1, 2020, to June 7, 2020, were included. Individuals younger than 18 years of age, without any delirium assessments, or without discharge disposition were excluded. Measurements and main results: Primary outcomes were delirium rates and duration, and the secondary outcome was delirium severity. Two-hundred sixty-eight consecutive patients were included in the analysis with a mean age of 58.4 years (sd, 15.6 yr), 40.3% were female, 44.4% African American, 20.7% Hispanic, and a median Acute Physiology and Chronic Health Evaluation II score of 18 (interquartile range, 13-25). Delirium without coma occurred in 29.1% of patients, delirium prior to coma in 27.9%, and delirium after coma in 23.1%. The first Confusion Assessment Method for the ICU assessment was positive for delirium in 61.9%. Hypoactive delirium was the most common subtype (87.4%). By day 14, the median number of delirium/coma-free were 5 days (interquartile range, 4-11 d), and median Confusion Assessment Method for the ICU-7 score was 6.5 (interquartile range, 5-7) indicating severe delirium. Benzodiazepines were ordered for 78.4% of patients in the cohort. Mechanical ventilation was associated with greater odds of developing delirium (odds ratio, 5.0; 95% CI, 1.1-22.2; p = 0.033) even after adjusting for sedative medications. There were no between-group differences in mortality. Conclusions: Delirium without coma occurred in 29.1% of patients admitted to the ICU. Delirium persisted for a median of 5 days and was severe. Mechanical ventilation was significantly associated with odds of delirium even after adjustment for sedatives. Clinical attention to manage delirium duration and severity, and deeper understanding of the virus' neurologic effects is needed for patients with coronavirus disease 2019.
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    Exercise Induced Changes of Vital Signs in Adults with Sickle Cell Disease
    (Wiley, 2021) Johnson, Solomon; Gordeuk, Victor R.; Machado, Roberto; Gibbs, J. Simon R.; Hildesheim, Mariana; Little, Jane A.; Kato, Gregory J.; Gladwin, Mark T.; Nouraie, Mehdi; Medicine, School of Medicine
    The six-minute walk test (6MWT) has been used in patients with sickle cell disease (SCD), in conjunction with tricuspid regurgitant velocity (TRV) and plasma N-terminal pro-brain natriuretic peptide (NT-pro BNP), to assess risk of having pulmonary hypertension. Exercise-induced vital sign changes (VSCs) are predictors of clinical outcomes in other diseases. In this study, we assess the predictors and prognostic value of 6MWT VSC in adult SCD patients. Data from a multinational study of SCD patients (Treatment of Pulmonary Hypertension with Sildenafil: walk-PHaSST) were used to calculate the 6MWT VSC. Predictors of VSC were identified by a multivariable analysis, and a survival analysis was conducted by the Cox proportional hazard method. An increase in heart rate was observed in 90% of the 630 SCD adults, 77% of patients had an increase in systolic blood pressure (SBP), and 50% of patients had a decrease in oxygen saturation. TRV (odds ratio [OR] = 1.82, p = .020), absolute reticulocyte count (OR = 1.03, p < .001), and hemoglobin (OR = 0.99, p = .035) predicted oxygen desaturation ≥ 3% during the 6MWT. In the adjusted analysis, SBP increase during the 6MWT was associated with improved survival (hazards ratio = 0.3, 95% confidence interval: 0.1-0.8). Increases in heart rate and blood pressure, as well as oxygen desaturation, are common in adults with SCD during the 6MWT. VSC is associated with markers of anemia and TRV and can be used for risk stratification. Any increase in SBP during the 6MWT was associated with improved survival and may be indicative of a patient's ability to increase stroke volume.
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    Mortality Rates in a Diverse Cohort of Mechanically Ventilated Patients With Novel Coronavirus in the Urban Midwest
    (Wolters Kluwer, 2020-08) Twigg, Homer L. III; Khan, Sikandar H.; Perkins, Anthony J.; Roberts, Scott; Sears, Catherine R.; Rahman, Omar; Smith, Joseph P.; Kapoor, Rajat; Farber, Mark O.; Ellender, Timothy; Carlos, Graham; Gilroy, Grant; Buckley, John; Bosslet, Gabriel; Machado, Roberto; Gao, Sujuan; Khan, Babar A.; Medicine, School of Medicine
    Objectives: Differences in mortality rates previously reported in critically ill patients with coronavirus disease 2019 have increased the need for additional data on mortality and risk factors for death. We conducted this study to describe length of stay, mortality, and risk factors associated with in-hospital mortality in mechanically ventilated patients with coronavirus disease 2019. Design: Observational study. Setting: Two urban, academic referral hospitals in Indianapolis, Indiana. Patients or Subjects: Participants were critically ill patients 18 years old and older, admitted with coronavirus disease 2019 between March 1, 2020, and April 27, 2020. Interventions: None. Measurements and Main Results: Outcomes included in-hospital mortality, duration of mechanical ventilation, and length of stay. A total of 242 patients were included with mean age of 59.6 years (sd, 15.5 yr), 41.7% female and 45% African American. Mortality in the overall cohort was 19.8% and 20.5% in the mechanically ventilated subset. Patients who died were older compared with those that survived (deceased: mean age, 72.8 yr [sd, 10.6 yr] vs patients discharged alive: 54.3 yr [sd, 14.8 yr]; p < 0.001 vs still hospitalized: 59.5 yr [sd, 14.4 yr]; p < 0.001) and had more comorbidities compared with those that survived (deceased: 2 [0.5–3] vs survived: 1 [interquartile range, 0–1]; p = 0.001 vs still hospitalized: 1 [interquartile range, 0–2]; p = 0.015). Older age and end-stage renal disease were associated with increased hazard of in-hospital mortality: age 65–74 years (hazard ratio, 3.1 yr; 95% CI, 1.2–7.9 yr), age 75+ (hazard ratio, 4.1 yr; 95% CI, 1.6–10.5 yr), and end-stage renal disease (hazard ratio, 5.9 yr; 95% CI, 1.3–26.9 yr). The overall median duration of mechanical ventilation was 9.3 days (interquartile range, 5.7–13.7 d), and median ICU length of stay in those that died was 8.7 days (interquartile range, 4.0–14.9 d), compared with 9.2 days (interquartile range, 4.0–14.0 d) in those discharged alive, and 12.7 days (interquartile range, 7.2–20.3 d) in those still remaining hospitalized. Conclusions: We found mortality rates in mechanically ventilated patients with coronavirus disease 2019 to be lower than some previously reported with longer lengths of stay.
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    Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2α Inhibitor
    (American Thoracic Society, 2018-12-01) Dai, Zhiyu; Dai, Zhiyu; Zhu, Maggie M.; Peng, Yi; Machireddy, Narsa; Evans, Colin E.; Machado, Roberto; Zhang, Xianming; Zhao, You-Yang; Medicine, School of Medicine
    Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive vasoconstriction and obliterative vascular remodeling that leads to right heart failure (RHF) and death. Current therapies do not target vascular remodeling and RHF, and result in only modest improvement of morbidity and mortality. Objectives: To determine whether targeting HIF-2α (hypoxia-inducible factor-2α) with a HIF-2α–selective inhibitor could reverse PAH and RHF in various rodent PAH models. Methods: HIF-2α and its downstream genes were evaluated in lung samples and pulmonary arterial endothelial cells and smooth muscle cells from patients with idiopathic PAH as well as various rodent PAH models. A HIF-2α–selective inhibitor was used in human lung microvascular endothelial cells and in Egln1Tie2Cre mice, and in Sugen 5416/hypoxia- or monocrotaline-exposed rats. Measurements and Main Results: Upregulation of HIF-2α and its target genes was observed in lung tissues and isolated pulmonary arterial endothelial cells from patients with idiopathic PAH and three distinct rodent PAH models. Pharmacological inhibition of HIF-2α by the HIF-2α translation inhibitor C76 (compound 76) reduced right ventricular systolic pressure and right ventricular hypertrophy and inhibited RHF and fibrosis as well as obliterative pulmonary vascular remodeling in Egln1Tie2Cre mice and Sugen 5416/hypoxia PAH rats. Treatment of monocrotaline-exposed PAH rats with C76 also reversed right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling; prevented RHF; and promoted survival. Conclusions: These findings demonstrate that pharmacological inhibition of HIF-2α is a promising novel therapeutic strategy for the treatment of severe vascular remodeling and right heart failure in patients with PAH.