Publications by authors named "Angela Meier"

36 Publications

Intraoperative Ventilation in the High-Risk Surgical Patient.

Respir Care 2021 Aug;66(8):1337-1340

Department of Anesthesiology, University of California San Diego, San Diego, California.

Postoperative pulmonary complications contribute to perioperative morbidity and mortality in addition to being associated with increased health care costs. In this review article, we outline risk factors for the development postoperative pulmonary complications, describe their impact on perioperative outcomes, and focus on the role of intraoperative ventilation strategies in decreasing postoperative pulmonary complications.
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http://dx.doi.org/10.4187/respcare.09170DOI Listing
August 2021

The Implementation and Outcomes of a Nurse-Run Extracorporeal Membrane Oxygenation Program, a Retrospective Single-Center Study.

Crit Care Explor 2021 Jun 15;3(6):e0449. Epub 2021 Jun 15.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego, CA.

Due to a shortage of perfusionists and increasing utilization of extracorporeal membrane oxygenation in the United States, many programs are training nurses as bedside extracorporeal membrane oxygenation specialists (i.e., nurse-run extracorporeal membrane oxygenation). Our objective was to evaluate if a nurse-run extracorporeal membrane oxygenation program has noninferior survival to discharge and complication rates compared with a perfusionist-run extracorporeal membrane oxygenation program. Additionally, to sought to describe increases in extracorporeal membrane oxygenation capacity and the potential for cost savings by implementing a nurse-run extracorporeal membrane oxygenation program.
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http://dx.doi.org/10.1097/CCE.0000000000000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208419PMC
June 2021

Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

Clin Infect Dis 2021 May 14. Epub 2021 May 14.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.

Background: Increased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.

Methods: Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.

Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.

Conclusions: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.
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http://dx.doi.org/10.1093/cid/ciab437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241438PMC
May 2021

Age-related incidence and outcomes of sepsis in California, 2008-2015.

J Crit Care 2021 Apr 23;62:212-217. Epub 2020 Dec 23.

Department of Anesthesiology, University of California San Diego, San Diego, United States of America.

Purpose: Sepsis remains amongst the most common causes of death worldwide. It has been described as a disease of the elderly, but contemporary data on risk factors and mortality is lacking.

Materials And Methods: Multi-center longitudinal cohort study using non-public, state of California data from January 1, 2008 to September 31, 2015. Patients with sepsis, severe sepsis, and septic shock were identified using ICD-9-CM diagnosis and procedure codes with age subgroups of 18-44, 45-64, 65-74, 75-84, and >85 years old. Descriptive statistics and a single direct logistic regression model were used to present data on incidence and mortality and to identify independent factors associated with mortality.

Results: Of 30,282,159 total inpatient encounters, 20,358,569 met inclusion criteria and 1,566,306 met sepsis criteria. Conditions associated with mortality included metastatic cancer, age, liver disease, residing in a care facility, and a gastrointestinal source of infection as well as fungal infection. Mortality in the >85-year-old subgroup with septic shock was 45.7%, lower than previously reported.

Conclusion: Age remains an important sepsis risk factor, but other conditions correlated more closely with sepsis-associated death. Patients over 85 years of age suffering from septic shock may have a better chance of survival than previously thought.
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http://dx.doi.org/10.1016/j.jcrc.2020.12.015DOI Listing
April 2021

Reply to Letter to the Editor: "Comment on 'E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation'".

Am J Physiol Cell Physiol 2020 03;318(3):C706

Department of Anesthesiology, Division of Critical Care, University of California, San Diego, La Jolla, California.

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http://dx.doi.org/10.1152/ajpcell.00037.2020DOI Listing
March 2020

Driving Pressure for Ventilation of Patients with Acute Respiratory Distress Syndrome.

Anesthesiology 2020 06;132(6):1569-1576

From the Department of Anesthesiology and Department of Medicine, University of California, San Diego, La Jolla, California.

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http://dx.doi.org/10.1097/ALN.0000000000003195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449829PMC
June 2020

E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation.

Am J Physiol Cell Physiol 2020 01 30;318(1):C205-C214. Epub 2019 Oct 30.

Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California.

E-cigarettes are portrayed as safer relative to conventional tobacco. However, burgeoning evidence suggests that E-cigarettes may adversely affect host defenses. However, the precise mechanisms by which E-cigarette vapor alters innate immune cell function have not been fully elucidated. We determined the effects of E-cigarette exposure on the function and responses to infectious challenge of the most abundant innate immune cell, the neutrophil, using isolated human neutrophils and a mouse model of gram-negative infection. Our results revealed that human neutrophils exposed to E-cigarette vapor had 4.2-fold reductions in chemotaxis toward the bacterial cell-well component f-Met-Leu-Phe ( < 0.001). F-actin polarization and membrane fluidity were also adversely affected by E-cigarette vapor exposure. E-cigarette-exposed human neutrophils exhibited a 48% reduction in production of reactive oxygen species (ROS; < 0.001). Given the central role of ROS in neutrophil extracellular trap (NET) production, NET production was quantified, and E-cigarette vapor exposure was found to reduce NETosis by 3.5-fold ( < 0.01); formulations with and without nicotine containing propylene glycol exhibiting significant suppressive effects. However, noncanonical NETosis was unaffected. In addition, exposure to E-cigarette vapor lowered the rate of phagocytosis of bacterial bioparticles by 47% ( < 0.05). In our physiological mouse model of chronic E-cigarette exposure and sepsis, E-cigarette vapor inhalation led to reduced neutrophil migration in infected spaces and a higher burden of . These findings provide evidence that E-cigarette use adversely impacts the innate immune system and may place E-cigarette users at higher risk for dysregulated inflammatory responses and invasive bacterial infections.
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http://dx.doi.org/10.1152/ajpcell.00045.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985828PMC
January 2020

Peripartum Cardiomyopathy: Current Options for Treatment and Cardiovascular Support.

J Cardiothorac Vasc Anesth 2019 Oct 14;33(10):2814-2825. Epub 2019 Feb 14.

Department of Anesthesiology, Division of Critical Care, University of California San Diego, San Diego, CA.

Peripartum cardiomyopathy is a rare form of acute heart failure but the major cause of all deaths in pregnant patients with heart failure. Improved survival rates in recent years, however, emphasize the importance of early recognition and initiation of heart failure treatment. This article, therefore, attempts to raise awareness among cardiac and obstetric anesthesiologists as well as intensivists of this often fatal diagnosis. This review summarizes theories of the pathophysiology and outcome of peripartum cardiomyopathy. Based on the most recent literature, it further outlines diagnostic criteria and treatment options including medical management, mechanical circulatory support devices, and heart transplantation. Earlier recognition of this rare condition and a new generation of mechanical circulatory devices has contributed to the improved outcome. More frequently, patients in cardiogenic shock who fail medical management are successfully bridged to recovery on extracorporeal circulatory devices or survive with a long-lasting implantable ventricular assist device. The outcome of transplanted patients with peripartum cardiomyopathy, however, is worse compared to other recipients of heart transplants and warrants further investigation in the future.
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http://dx.doi.org/10.1053/j.jvca.2019.02.010DOI Listing
October 2019

Inhibition of Human Neutrophil Extracellular Trap (NET) Production by Propofol and Lipid Emulsion.

Front Pharmacol 2019 5;10:323. Epub 2019 Apr 5.

Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States.

Uncontrolled bacteremia is a common and life threatening condition that can lead to sepsis and septic shock with significant morbidity and mortality. Neutrophil granulocytes, the most abundant phagocytic leukocyte of the innate immune system, play an essential role in capturing and killing invading pathogens. Their antimicrobial repertoire includes the formation of Neutrophil Extracellular Traps (NETs), chromatin-based, web-like structures of DNA that facilitate the capture and killing of bacteria. In sepsis, however, it has been suggested that the uncontrolled release of NETs worsens disseminated coagulation and promotes venous thrombosis. Here, we describe how clinically relevant concentrations of the commonly used sedative propofol as well as a lipid composition similar to the propofol carrier impair NET production by human neutrophils. Drugs commonly administered in the Intensive Care Unit (ICU) may impact the inflammatory response to either worsen or improve clinical outcomes and may therefore be considered for additional therapeutic effects if clinical studies confirm such findings.
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http://dx.doi.org/10.3389/fphar.2019.00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460395PMC
April 2019

The authors reply.

Crit Care Med 2019 04;47(4):e384

Division of Critical Care, Department of Anesthesiology, University of California San Diego, San Diego, CA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego, San Diego, CA, and Department of Veterans Affairs, San Diego, CA.

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http://dx.doi.org/10.1097/CCM.0000000000003664DOI Listing
April 2019

Interaction of cell culture process parameters for modulating mAb afucosylation.

Biotechnol Bioeng 2019 04 4;116(4):831-845. Epub 2019 Feb 4.

Cell Culture, PTD, Genentech, South San Francisco, California.

The extent of afucosylation, which refers to the absence of core fucose on Fc glycans, can correlate positively with the antibody-dependent cellular cytotoxicity (ADCC) activity of a monoclonal antibody (mAb). Therefore, it is important to maintain consistent afucosylation during cell culture process scale-up in bioreactors for a mAb with ADCC activity. However, there is currently a lack of understanding about the impact of partial pressure of carbon dioxide (pCO )-a parameter that can vary with bioreactor scale-on afucosylation. Using a small-scale (3 L) bioreactor model that can modulate pCO levels through modified configurations and gassing strategies, we identified three cell culture process parameters that influence afucosylation of a mAb produced by a recombinant Chinese Hamster Ovary (CHO) cell line: pCO , media hold duration (at 37°C), and manganese. These three-independent parameters demonstrated a synergistic effect on mAb afucosylation; increase in pCO , media hold duration, and manganese consistently increased afucosylation. Our investigations into the underlying mechanisms through proteomic analysis indicated that the synergistic interactions downregulated pathways related to guanosine diphosphate-fucose synthesis and fucosylation, and upregulated manganese transport into the CHO cells. These new findings highlight the importance of considering potential differences in culture environment and operations across bioreactor scales, and understanding the impact of their interactions on product quality.
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http://dx.doi.org/10.1002/bit.26908DOI Listing
April 2019

Impact of Anesthetics on Human Neutrophil Function.

Anesth Analg 2019 03;128(3):569-574

Department of Pediatrics, Division of Host-Microbe Systems & Therapeutics, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, San Diego, California.

Anesthetics are widely used drugs administered in a multitude of clinical settings. Their impacts on various functions of the immune system have been studied but are still not fully understood. Neutrophil granulocytes are a critical first-line host defense mechanism against infections and contribute to the inflammatory phase of wound healing, but dysregulated neutrophil activation can also precipitate perioperative organ injury. A better understanding of the interactions between common anesthetics and neutrophils may reveal considerations toward optimizing treatment of our most vulnerable patients in the intensive care unit and in the perioperative setting.
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http://dx.doi.org/10.1213/ANE.0000000000003927DOI Listing
March 2019

Female Physician Leadership During Cardiopulmonary Resuscitation Is Associated With Improved Patient Outcomes.

Crit Care Med 2019 01;47(1):e8-e13

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego, San Diego, CA.

Objectives: A recently published simulation study suggested that women are inferior leaders of cardiopulmonary resuscitation efforts. The aim of this study was to compare female and male code leaders in regard to cardiopulmonary resuscitation outcomes in a real-world clinical setting.

Design: Retrospective cohort review.

Setting: Two academic, urban hospitals in San Diego, California.

Subjects: One-thousand eighty-two adult inpatients who suffered cardiac arrest and underwent cardiopulmonary resuscitation.

Interventions: None.

Measurements And Main Results: We analyzed whether physician code leader gender was independently associated with sustained return of spontaneous circulation and survival to discharge and with markers of quality cardiopulmonary resuscitation. Of all arrests, 327 (30.1%) were run by female physician code leaders with 251 (76.8%) obtaining return of spontaneous circulation, and 122 (37.3%) surviving to discharge. Male physicians ran 757 codes obtaining return of spontaneous circulation in 543 (71.7%) with 226 (29.9%) surviving to discharge. When adjusting for variables, female physician code leader gender was independently associated with a higher likelihood of return of spontaneous circulation (odds ratio, 1.36; 95% CI, 1.01-1.85; p = 0.049) and survival to discharge (odds ratio, 1.53; 95% CI, 1.15-2.02; p < 0.01). Additionally, the odds ratio for survival to discharge was 1.62 (95% CI, 1.13-2.34; p < 0.01) for female physicians with a female code nurse when compared with male physician code leaders paired with a female code nurse. Gender of code leader was not associated with cardiopulmonary resuscitation quality.

Conclusions: In contrast to data derived from a simulated setting with medical students, real life female physician leadership of cardiopulmonary resuscitation is not associated with inferior outcomes. Appropriately, trained physicians can lead high-quality cardiopulmonary resuscitation irrespective of gender.
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http://dx.doi.org/10.1097/CCM.0000000000003464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298820PMC
January 2019

Critical Consideration of Myxedema Coma in the Postoperative Setting: A Case Report.

A A Pract 2019 Feb;12(4):119-121

Department of Anesthesiology, Division of Critical Care, University of California San Diego, San Diego, California.

Myxedema coma is a rare but highly fatal condition with reported mortality >40%-50%. Early recognition and prompt treatment are critical for survival. Here we describe a case of possible postoperative myxedema coma after subacute neck hematoma evacuation after hemithyroidectomy in a patient on concurrent amiodarone therapy. Symptoms included somnolence, hypothermia, and prolonged QTc with torsades de pointes resistant to magnesium therapy requiring defibrillation and overdrive pacing. Consideration of the possible diagnosis of myxedema coma resulted in prompt therapy and symptom resolution within 48 hours. Thyroid disorders, although rare, should be considered in the postoperative setting.
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http://dx.doi.org/10.1213/XAA.0000000000000864DOI Listing
February 2019

Alterations in human neutrophil function caused by bisphenol A.

Am J Physiol Cell Physiol 2018 11 8;315(5):C636-C642. Epub 2018 Aug 8.

Department of Pharmacology, University of California, San Diego, La Jolla, California.

Bisphenol A (BPA) is a synthetic, organic compound frequently present in consumer plastics, including plastic-lined cans, water bottles, toys, and teeth sutures. Previous studies have shown that BPA can produce adverse health effects that include defects in reproductive function and altered prenatal/childhood development. However, little is known regarding the effects of BPA on immune function. In this study, we assessed the effect of BPA on human neutrophils, a critical component of the innate immune system's defense against pathogens. We found that BPA induces a concentration-dependent increase in reactive oxygen species (ROS) generation by neutrophils, which is inhibited by the estrogen receptor-β antagonist PHTPP. Furthermore, incubation with the membrane-permeable calcium chelator BAPTA-AM and/or removal of extracellular calcium inhibited BPA-induced ROS production, indicating that the process is calcium dependent. Transwell chemotaxis assays revealed that BPA exposure reduces the chemotactic capacity of neutrophils in a gradient of the bacterial cell wall component f-Met-Leu-Phe, a potent chemoattractant. Exposure to BPA also inhibits the ability of neutrophils to kill methicillin-resistant Staphylococcus aureus, a leading human pathogen. Our findings reveal that BPA alters the in vitro function of neutrophils, including ROS production, chemotaxis, and bacterial killing, and raises the possibility of altered innate immunity in vivo, especially in those with compromised immune function and who can be exposed to BPA in a wide variety of products.
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http://dx.doi.org/10.1152/ajpcell.00242.2017DOI Listing
November 2018

Isoflurane Impacts Murine Melanoma Growth in a Sex-Specific, Immune-Dependent Manner: A Brief Report.

Anesth Analg 2018 06;126(6):1910-1913

Pathology, University of California San Diego, San Diego, California.

The impact of volatile anesthetics on cancer progression has been observed for decades, but sex differences have not been described. Male and female immune systems vary considerably, and the immune system plays an important role in limiting cancer growth. Currently, mouse models describing the impact of volatile anesthetics on cancer growth are limited to same-sex models. In this brief report, we describe a sex-specific impact of isoflurane on melanoma growth observed in wild-type but not in immune-deficient mice. Future experimental designs related to anesthesia and cancer should evaluate the biological variable of sex in a systematic manner.
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http://dx.doi.org/10.1213/ANE.0000000000002902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953783PMC
June 2018

Resource utilization and charges of patients with and without diagnosed venous thromboembolism during primary hospitalization and after elective inpatient surgery: a retrospective study.

J Med Econ 2018 Jun 1;21(6):595-602. Epub 2018 Mar 1.

b Health Economics and Outcomes Research, Millennium Health , San Diego , CA , USA.

Aims: To assess incremental charges of patients experiencing venous thromboembolisms (VTE) across various types of elective inpatient surgical procedures with administration of general anesthesia in the US.

Methods: The authors performed a retrospective study utilizing data from a nationwide hospital operational records database from July 2014 through June 2015 to compare a group of inpatients experiencing a VTE event post-operatively to a propensity score matched group of inpatients who did not experience a VTE. Patients included in the analysis had a hospital admission for an elective inpatient surgical procedure with the use of general anesthesia. Procedures of the heart, brain, lungs, and obstetrical procedures were excluded, as these procedures often require a scheduled ICU stay post-operatively. Outcomes examined included VTE events during hospitalization, length of stay, unscheduled ICU transfers, number of days spent in the ICU if transferred, 3- and 30-day re-admissions, and total hospital charges incurred.

Results: The study included 17,727 patients undergoing elective inpatient surgical procedures. Of these, 36 patients who experienced a VTE event were matched to 108 patients who did not. VTE events occurred in 0.2% of the study population, with most events occurring for patients undergoing total knee replacement. VTE patients had a mean total hospital charge of $60,814 vs $48,325 for non-VTE patients, resulting in a mean incremental charge of $11,979 (p < .05). Compared to non-VTE patients, VTE patients had longer length of stay (5.9 days vs 3.7 days, p < .001), experienced a higher rate of 3-day re-admissions (3 vs 0 patients) and 30-day re-admissions (7 vs 2 patients).

Conclusions: Patients undergoing elective inpatient surgical procedures with general anesthesia who had a VTE event during their primary hospitalization had a significantly longer length of stay and significantly higher total hospital charges than comparable patients without a VTE event.
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http://dx.doi.org/10.1080/13696998.2018.1445635DOI Listing
June 2018

Emergency department visits among patients with left ventricular assist devices.

Intern Emerg Med 2018 Sep 22;13(6):907-913. Epub 2017 Dec 22.

Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Continuous-flow left ventricular assist devices (LVADs) are increasingly implanted to support patients with end-stage heart failure. These patients are at high risk for complications, many of which necessitate emergency care. While rehospitalization rates have been described, there is little data regarding emergency department (ED) visits. We hypothesize that ED visits are frequent and often require admission after LVAD implantation. We performed a retrospective review of patients in our health-care system followed by the advanced heart failure service for LVAD management after implantation between January 2011 and July 2015. We accounted for all ED visits in our system through February 2016, 7 months after the last implantation included. Clinically relevant demographic variables and ED visit details were recorded and analyzed to describe this population. We identified 81 patients with complete data, among whom there were 283 visits (3.49 visits/patient), occurring at a rate of approximately 7.3 ED visits per patient per year alive with LVAD. The most common reason for an ED visit is a complication related to bleeding (18% of visits), followed by chest pain (14%) and dizziness or syncope (13%). Thirty-six percent of patients were discharged from the ED without hospital admission. A growing populace with implanted LVADs represents an important population within emergency medicine. They are at risk for significant complications and frequently present to the ED. While many of these visits may be managed without hospital admission, this specialized patient group represents a potential area for improvement in provider education.
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http://dx.doi.org/10.1007/s11739-017-1776-8DOI Listing
September 2018

Leadership in Medical Emergencies Is "Highly Teachable".

Crit Care Med 2017 12;45(12):e1300-e1301

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA;Department of Anesthesiology, University of California, San Diego, CA;Department of Emergency Medicine, University of California, San Diego, CA;Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA.

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http://dx.doi.org/10.1097/CCM.0000000000002686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719887PMC
December 2017

The impact of a daily "medication time out" in the Intensive Care Unit.

J Crit Care 2018 Feb 12;43:366-369. Epub 2017 Sep 12.

Department of Anesthesiology, Division of Critical Care, University of California, San Diego, San Diego, CA, United States. Electronic address:

Objective: Medical errors play a large role in preventable harms within our health care system. Medications administered in the ICU can be numerous, complex and subject to daily changes. We describe a method to identify medication errors with the potential to improve patient safety.

Design: A quality improvement intervention featuring a daily medication time out for each patient was performed during rounds.

Setting: A 12-bed Cardiac Surgical ICU at a single academic institution with approximately 180 beds.

Intervention: After each patient encounter, the current medication list for the patient was read aloud from the electronic medical record, and the team would determine if any were erroneous or missing. Medication changes were recorded and graded post-hoc according to perceived significance.

Results: This intervention resulted in 285 medication changes in 347 patient encounters. 179 of the 347 encounters (51.6%) resulted in at least one change. Of the changes observed, 40.4% were categorized as trivial, 50.5% as minor and 9.1% were considered to have significant potential impact on patient care. The average time spent per patient for this intervention was 1.24 (SD 0.65) minutes.

Conclusions: A daily medication time out should be considered as an additional mechanism for patient safety in the ICU.
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http://dx.doi.org/10.1016/j.jcrc.2017.09.018DOI Listing
February 2018

Development of a new bioprocess scheme using frozen seed train intermediates to initiate CHO cell culture manufacturing campaigns.

Biotechnol Bioeng 2013 May 4;110(5):1376-85. Epub 2013 Jan 4.

Late Stage Cell Culture, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Agility to schedule and execute cell culture manufacturing campaigns quickly in a multi-product facility will play a key role in meeting the growing demand for therapeutic proteins. In an effort to shorten campaign timelines, maximize plant flexibility and resource utilization, we investigated the initiation of cell culture manufacturing campaigns using CHO cells cryopreserved in large volume bags in place of the seed train process flows that are conventionally used in cell culture manufacturing. This approach, termed FASTEC (Frozen Accelerated Seed Train for Execution of a Campaign), involves cultivating cells to high density in a perfusion bioreactor, and cryopreserving cells in multiple disposable bags. Each run for a manufacturing campaign would then come from a thaw of one or more of these cryopreserved bags. This article reviews the development and optimization of individual steps of the FASTEC bioprocess scheme: scaling up cells to greater than 70 × 10(6) cells/mL and freezing in bags with an optimized controlled rate freezing protocol and using a customized rack configuration. Flow cytometry analysis was also employed to understand the recovery of CHO cells following cryopreservation. Extensive development data were gathered to ensure that the quantity and quality of the drug manufactured using the FASTEC bioprocess scheme was acceptable compared to the conventional seed train process flow. The result of offering comparable manufacturing options offers flexibility to the cell culture manufacturing network.
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http://dx.doi.org/10.1002/bit.24808DOI Listing
May 2013

Decreasing lactate level and increasing antibody production in Chinese Hamster Ovary cells (CHO) by reducing the expression of lactate dehydrogenase and pyruvate dehydrogenase kinases.

J Biotechnol 2011 Apr 30;153(1-2):27-34. Epub 2011 Mar 30.

Department of Early Stage Cell Culture, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Large-scale fed-batch cell culture processes of CHO cells are the standard platform for the clinical and commercial production of monoclonal antibodies. Lactate is one of the major by-products of CHO fed-batch culture. In pH-controlled bioreactors, accumulation of high levels of lactate is accompanied by high osmolality due to the addition of base to control pH of the cell culture medium, potentially leading to lower cell growth and lower therapeutic protein production during manufacturing. Lactate dehydrogenase (LDH) is an enzyme that catalyzes the conversion of the substrate, pyruvate, into lactate and many factors including pyruvate concentration modulate LDH activity. Alternately, pyruvate can be converted to acetyl-CoA by pyruvate dehydrogenases (PDHs), to be metabolized in the TCA cycle. PDH activity is inhibited when phosphorylated by pyruvate dehydrogenase kinases (PDHKs). In this study, we knocked down the gene expression of lactate dehydrogenase A (LDHa) and PDHKs to investigate the effect on lactate metabolism and protein production. We found that LDHa and PDHKs can be successfully downregulated simultaneously using a single targeting vector carrying small inhibitory RNAs (siRNA) for LDHa and PDHKs. Moreover, our fed-batch shake flask evaluation data using siRNA-mediated LDHa/PDHKs knockdown clones showed that downregulating LDHa and PDHKs in CHO cells expressing a therapeutic monoclonal antibody reduced lactate production, increased specific productivity and volumetric antibody production by approximately 90%, 75% and 68%, respectively, without appreciable impact on cell growth. Similar trends of lower lactate level and higher antibody productivity on average in siRNA clones were also observed from evaluations performed in bioreactors.
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http://dx.doi.org/10.1016/j.jbiotec.2011.03.003DOI Listing
April 2011

Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1.

Nat Med 2009 Aug 13;15(8):955-9. Epub 2009 Jul 13.

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.

Manifestations of viral infections can differ between women and men, and marked sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-alpha (IFN-alpha) in response to HIV-1-encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8(+) T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8(+) T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1-associated pathology.
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http://dx.doi.org/10.1038/nm.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821111PMC
August 2009

Rapid loss of dendritic cell and monocyte responses to TLR ligands following venipuncture.

J Immunol Methods 2008 Dec 9;339(2):132-40. Epub 2008 Oct 9.

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Blood samples from multiple sites are collected in multicenter trials, and frequently shipped to centralized laboratories for processing and comparable experimental evaluation. It is therefore of crucial interest to assess the preservation of immune cell functions after overnight shipment of whole blood. Here we evaluated the ability of pDCs, mDCs and monocytes to respond to TLR ligands at multiple timepoints following venipuncture as compared to immediate processing. Our results demonstrate a profound impairment of APC function, in particular of IFN-alpha production of pDCs, if whole blood was processed later than 6 h after venipuncture. Overnight shipment or extended rest of whole blood before processing therefore severely compromises the ability of APCs to respond to TLR ligands, and this has to be taken into consideration when designing multicenter trials.
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http://dx.doi.org/10.1016/j.jim.2008.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613681PMC
December 2008

Ligand-independent exhaustion of killer immunoglobulin-like receptor-positive CD8+ T cells in human immunodeficiency virus type 1 infection.

J Virol 2008 Oct 25;82(19):9668-77. Epub 2008 Jun 25.

Partners AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Boston, MA 02129, USA.

Virus-specific CD8(+) T cells play a central role in the control of viral infections, including human immunodeficiency virus type 1 (HIV-1) infection. However, despite the presence of strong and broad HIV-specific CD8(+) T-cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions and fail to clear the infection. Mounting evidence suggests that the upregulation of several inhibitory regulatory receptors on the surface of CD8(+) T cells during HIV-1 infection may contribute directly to the impairment of T-cell function. Here, we investigated the role of killer immunoglobulin receptors (KIR), which are expressed on NK cells and on CD8(+) T cells, in regulating CD8(+) T-cell function in HIV-1 infection. KIR expression was progressively upregulated on CD8(+) T cells during HIV-1 infection and correlated with the level of viral replication. Expression of KIR was associated with a profound inhibition of cytokine secretion, degranulation, proliferation, and activation by CD8(+) T cells following stimulation with T-cell receptor (TCR)-dependent stimuli. In contrast, KIR(+) CD8(+) T cells responded potently to TCR-independent stimulation, demonstrating that these cells are functionally competent. KIR-associated suppression of CD8(+) T-cell function was independent of ligand engagement, suggesting that these regulatory receptors may constitutively repress TCR activation. This ligand-independent repression of TCR activation of KIR(+) CD8(+) T cells may represent a significant barrier to therapeutic interventions aimed at improving the quality of the HIV-specific CD8(+) T-cell response in infected individuals.
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http://dx.doi.org/10.1128/JVI.00341-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546972PMC
October 2008

Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells.

PLoS Med 2008 May;5(5):e100

Partners AIDS Research Center, Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts, United States of America.

Background: Virus-specific CD8(+) T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8(+) T cells with a "polyfunctional" profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8(+) T cell responses on the single-epitope level over time, starting in primary HIV-1 infection.

Methods And Findings: We longitudinally analyzed the polyfunctional epitope-specific CD8(+) T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8(+) T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8(+) T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%-72%) to 76% (56%-95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%-75%) to 56% (42%-70%) (SD of the effect size 0.18) (p < 0.05).

Conclusion: These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.
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http://dx.doi.org/10.1371/journal.pmed.0050100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2365971PMC
May 2008

Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands.

AIDS 2008 Mar;22(5):655-8

Partners AIDS Research Center, Massachusetts General Hospital, Division of AIDS, Harvard Medical School, Boston, Massachusetts, USA.

Increased PD-L1 expression has been reported in HIV-1-infected individuals, but the mechanisms leading to PD-L1 upregulation remain to be elucidated. Here we demonstrate that HIV-1-derived Toll-like receptor (TLR)7/8 ligands can induce MyD88-dependent upregulation of PD-L1 on plasmacytoid dendritic cells, myeloidic dendritic cells and monocytes. These data suggest a mechanism through which HIV-1-derived TLR ligands might contribute to the functional impairment of virus-specific PD-1-positive T cells by inducing the upregulation of PD-L1 on antigen-presenting cells.
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http://dx.doi.org/10.1097/QAD.0b013e3282f4de23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810187PMC
March 2008

Rapid ex vivo isolation and long-term culture of human Th17 cells.

J Immunol Methods 2008 Apr 15;333(1-2):115-25. Epub 2008 Feb 15.

Partners AIDS Research Center, Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States.

T helper (Th) 17 cells are a distinct lineage of CD4+ T cells mediating tissue inflammation through the secretion of IL-17. In addition, it has been shown that the expression of the transcriptional factor RORgammat is responsible for the induction and maintenance of this cell line. Th17 cells are believed to be involved in a variety of autoimmune disorders, but may also play an important role in host defense. Here we describe a novel technique to reproducibly isolate viable Th17 cells based on their IL-17 secreting ability. We confirmed Th17 cell enrichment by quantitative PCR analysis and demonstrate that positively selected cells using this technique express significantly increased mRNA levels of RORgammat, IL-23 receptor and CCR4 when compared to negatively selected cells. Furthermore, we show that purified Th17 cells can be maintained in long-term culture and expand in vitro. In conclusion, this technique will allow for the first time the direct, ex vivo analysis of phenotypic and functional properties of Th17 cells.
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http://dx.doi.org/10.1016/j.jim.2008.01.018DOI Listing
April 2008

Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes.

J Exp Med 2007 Nov 19;204(12):3027-36. Epub 2007 Nov 19.

Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129, USA.

Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)-B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact-dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I-dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.
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http://dx.doi.org/10.1084/jem.20070695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118524PMC
November 2007

Single-stranded RNA derived from HIV-1 serves as a potent activator of NK cells.

J Immunol 2007 Jun;178(12):7658-66

Partners AIDS Research Center, Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129, USA.

Persistent immune activation is a hallmark of chronic viremic HIV-1 infection. Activation of cells of the innate immune system, such as NK cells, occurs rapidly upon infection, and is sustained throughout the course of the disease. However, the precise underlying mechanism accounting for the persistent HIV-1-induced activation of NK cells is poorly understood. In this study, we assessed the role of uridine-rich ssRNA derived from the HIV-1 long terminal repeat (ssRNA40) on activation of NK cells via TLR7/8. Although dramatic activation of NK cells was observed following stimulation of PBMC with ssRNA40, negligible activation was observed following stimulation of purified NK cells despite their expression of TLR8 mRNA and protein. The functional activation of NK cells by this HIV-1-encoded TLR7/8 ligand could not be reconstituted with exogenous IL-12, IFN-alpha, or TNF-alpha, but was critically dependent on the direct contact of NK cells with plasmacytoid dendritic cells or CD14(+) monocytes, indicating an important level of NK cell cross-talk and regulation by accessory cells during TLR-mediated activation. Coincubation of monocyte/plasmacytoid dendritic cells, NK cells, and ssRNA40 potentiated NK cell IFN-gamma secretion in response to MHC-devoid target cells. Studies using NK cells derived from individuals with chronic HIV-1 infection demonstrated a reduction of NK cell responsiveness following stimulation with TLR ligands in viremic HIV-1 infection. These data demonstrate that HIV-1-derived TLR ligands can contribute to the immune activation of NK cells and may play an important role in HIV-1-associated immunopathogenesis and NK cell dysfunction observed during acute and chronic viremic HIV-1 infection.
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http://dx.doi.org/10.4049/jimmunol.178.12.7658DOI Listing
June 2007
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