Browsing by Author "Murdoch, David M"

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    Asthma, Airflow Obstruction, and Eosinophilic Airway Inflammation Prevalence in Western Kenya: A Population-Based Cross-Sectional Study.
    (International journal of public health, 2023-01) Navuluri, Neelima; Lagat, David; Egger, Joseph R; Birgen, Elcy; Diero, Lameck; Murdoch, David M; Thielman, Nathan; Kussin, Peter S; Que, Loretta G; Paul, Devon
    Objectives: Determine the prevalence of airway disease (e.g., asthma, airflow obstruction, and eosinophilic airway inflammation) in Kenya, as well as related correlates of airway disease and health-related quality of life. Methods: A three-stage, cluster-randomized cross-sectional study in Uasin Gishu County, Kenya was conducted. Individuals 12 years and older completed questionnaires (including St. George's Respiratory Questionnaire for COPD, SGRQ-C), spirometry, and fractional exhaled nitric oxide (FeNO) testing. Prevalence ratios with 95% confidence intervals (CIs) were calculated. Multivariable models were used to assess correlates of airflow obstruction and high FeNO. Results: Three hundred ninety-two participants completed questionnaires, 369 completed FeNO testing, and 305 completed spirometry. Mean age was 37.5 years; 64% were women. The prevalence of asthma, airflow obstruction on spirometry, and eosinophilic airway inflammation was 21.7%, 12.3% and 15.7% respectively in the population. Women had significantly higher SGRQ-C scores compared to men (15.0 vs. 7.7). Wheezing or whistling in the last year and SGRQ-C scores were strongly associated with FeNO levels >50 ppb after adjusting for age, gender, BMI, and tobacco use. Conclusion: Airway disease is a significant health problem in Kenya affecting a young population who lack a significant tobacco use history.
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    Characterizing the Switching Thresholds of Magnetophoretic Transistors.
    (Adv Mater, 2015-10-28) Abedini-Nassab, Roozbeh; Joh, Daniel Y; Van Heest, Melissa A; Yi, John S; Baker, Cody; Taherifard, Zohreh; Margolis, David M; Garcia, J Victor; Chilkoti, Ashutosh; Murdoch, David M; Yellen, Benjamin B
    The switching thresholds of magnetophoretic transistors for sorting cells in microfluidic environments are characterized. The transistor operating conditions require short 20-30 mA pulses of electrical current. By demonstrating both attractive and repulsive transistor modes, a single transistor architecture is used to implement the full write cycle for importing and exporting single cells in specified array sites.
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    Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study.
    (Anesthesia and analgesia, 2019-05-03) Berger, Miles; Murdoch, David M; Staats, Janet S; Chan, Cliburn; Thomas, Jake P; Garrigues, Grant E; Browndyke, Jeffrey N; Cooter, Mary; Quinones, Quintin J; Mathew, Joseph P; Weinhold, Kent J; MADCO-PC Study Team
    Animal models suggest postoperative cognitive dysfunction may be caused by brain monocyte influx. To study this in humans, we developed a flow cytometry panel to profile cerebrospinal fluid (CSF) samples collected before and after major noncardiac surgery in 5 patients ≥60 years of age who developed postoperative cognitive dysfunction and 5 matched controls who did not. We detected 12,654 ± 4895 cells/10 mL of CSF sample (mean ± SD). Patients who developed postoperative cognitive dysfunction showed an increased CSF monocyte/lymphocyte ratio and monocyte chemoattractant protein 1 receptor downregulation on CSF monocytes 24 hours after surgery. These pilot data demonstrate that CSF flow cytometry can be used to study mechanisms of postoperative neurocognitive dysfunction.
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    Oxygen delivery systems for adults in Sub-Saharan Africa: A scoping review.
    (Journal of global health, 2021-05-08) Navuluri, Neelima; Srour, Maria L; Kussin, Peter S; Murdoch, David M; MacIntyre, Neil R; Que, Loretta G; Thielman, Nathan M; McCollum, Eric D

    Background

    Respiratory diseases are the leading cause of death and disability worldwide. Oxygen is an essential medicine used to treat hypoxemia from respiratory diseases. However, the availability and utilization of oxygen delivery systems for adults in sub-Saharan Africa is not well-described. We aim to identify and describe existing data around oxygen availability and provision for adults in sub-Saharan Africa, determine knowledge or research gaps, and make recommendations for future research and capacity building.

    Methods

    We systematically searched four databases for articles on April 22, 2020, for variations of keywords related to oxygen with a focus on countries in sub-Saharan Africa. Inclusion criteria were studies that included adults and addressed hypoxemia assessment or outcome, oxygen delivery mechanisms, oxygen availability, oxygen provision infrastructure, and oxygen therapy and outcomes.

    Results

    35 studies representing 22 countries met inclusion criteria. Availability of oxygen delivery systems ranged from 42%-94% between facilities, with wide variability in the consistency of availability. There was also wide reported prevalence of hypoxemia, with most studies focusing on specific populations. In facilities where oxygen is available, health care workers are ill-equipped to identify adult patients with hypoxemia, provide oxygen to those who need it, and titrate or discontinue oxygen appropriately. Oxygen concentrators were shown to be the most cost-effective delivery system in areas where power is readily available.

    Conclusions

    There is a substantial need for building capacity for oxygen delivery throughout sub-Saharan Africa. Addressing this critical issue will require innovation and a multi-faceted approach of developing infrastructure, better equipping facilities, and health care worker training.
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    Prevalence and phenotypic trajectories of hypoxaemia among hospitalised adults in Kenya: a single-centre, prospective cohort study.
    (BMJ open, 2023-09) Navuluri, Neelima; Lagat, David K; Birgen, Elcy; Kitur, Sylvia; Kussin, Peter S; Murdoch, David M; Thielman, Nathan M; Parish, Alice; Green, Cynthia L; MacIntyre, Neil; Egger, Joseph R; Wools-Kaloustian, Kara; Que, Loretta G

    Objective

    Global medical oxygen security is limited by knowledge gaps in hypoxaemia burden and oxygen access in low-income and middle-income countries. We examined the prevalence and phenotypic trajectories of hypoxaemia among hospitalised adults in Kenya, with a focus on chronic hypoxaemia.

    Design

    Single-centre, prospective cohort study.

    Setting

    National tertiary referral hospital in Eldoret, Kenya between September 2019 and April 2022.

    Participants

    Adults (age ≥18 years) admitted to general medicine wards.

    Primary and secondary outcome measures

    Our primary outcome was proportion of patients who were hypoxaemic (oxygen saturation, SpO2 ≤88%) on admission. Secondary outcomes were proportion of patients with hypoxaemia on admission who had hypoxaemia resolution, hospital discharge, transfer, or death among those with unresolved hypoxaemia or chronic hypoxaemia. Patients remaining hypoxaemic for ≤3 days after admission were enrolled into an additional cohort to determine chronic hypoxaemia. Chronic hypoxaemia was defined as an SpO2 ≤ 88% at either 1-month post-discharge follow-up or, for patients who died prior to follow-up, a documented SpO2 ≤88% during a previous hospital discharge or outpatient visit within the last 6 months.

    Results

    We screened 4104 patients (48.5% female, mean age 49.4±19.4 years), of whom 23.8% were hypoxaemic on admission. Hypoxaemic patients were significantly older and more predominantly female than normoxaemic patients. Among those hypoxaemic on admission, 33.9% had resolution of their hypoxaemia as inpatients, 55.6% had unresolved hypoxaemia (31.0% died before hospital discharge, 13.3% were alive on discharge and 11.4% were transferred) and 10.4% were lost to follow-up. The prevalence of chronic hypoxaemia was 2.1% in the total screened population, representing 8.8% of patients who were hypoxaemic on admission. Chronic hypoxaemia was determined at 1-month post-discharge among 59/86 patients and based on prior documentation among 27/86 patients.

    Conclusion

    Hypoxaemia is highly prevalent among adults admitted to a general medicine ward at a national referral hospital in Kenya. Nearly 1 in 11 patients who are hypoxaemic on admission are chronically hypoxaemic.
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    The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.
    (Journal of the American Geriatrics Society, 2019-01-23) Berger, Miles; Oyeyemi, Deborah; Olurinde, Mobolaji O; Whitson, Heather E; Weinhold, Kent J; Woldorff, Marty G; Lipsitz, Lewis A; Moretti, Eugene; Giattino, Charles M; Roberts, Kenneth C; Zhou, Junhong; Bunning, Thomas; Ferrandino, Michael; Scheri, Randall P; Cooter, Mary; Chan, Cliburn; Cabeza, Roberto; Browndyke, Jeffrey N; Murdoch, David M; Devinney, Michael J; Shaw, Leslie M; Cohen, Harvey Jay; Mathew, Joseph P; INTUIT Investigators
    BACKGROUND/OBJECTIVES:Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN:Observational prospective cohort. SETTING:Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS:Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS:Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION:INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae.
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    Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells.
    (Frontiers in immunology, 2020-01) Healy, Zachary R; Weinhold, Kent J; Murdoch, David M
    Previous studies suggest that the presence of antigen-specific polyfunctional T cells is correlated with improved pathogen clearance, disease control, and clinical outcomes; however, the molecular mechanisms responsible for the generation, function, and survival of polyfunctional T cells remain unknown. The study of polyfunctional T cells has been, in part, limited by the need for intracellular cytokine staining (ICS), necessitating fixation and cell membrane permeabilization that leads to unacceptable degradation of RNA. Adopting elements from prior research efforts, we developed and optimized a modified protocol for the isolation of high-quality RNA (i.e., RIN > 7) from primary human T cells following aldehyde-fixation, detergent-based permeabilization, intracellular cytokines staining, and sorting. Additionally, this method also demonstrated utility preserving RNA when staining for transcription factors. This modified protocol utilizes an optimized combination of an RNase inhibitor and high-salt buffer that is cost-effective while maintaining the ability to identify and resolve cell populations for sorting. Overall, this protocol resulted in minimal loss of RNA integrity, quality, and quantity during cytoplasmic staining of cytokines and subsequent flourescence-activated cell sorting. Using this technique, we obtained the transcriptional profiles of functional subsets (i.e., non-functional, monofunctional, bifunctional, polyfunctional) of CMV-specific CD8+T cells. Our analyses demonstrated that these functional subsets are molecularly distinct, and that polyfunctional T cells are uniquely enriched for transcripts involved in viral response, inflammation, cell survival, proliferation, and metabolism when compared to monofunctional cells. Polyfunctional T cells demonstrate reduced activation-induced cell death and increased proliferation after antigen re-challenge. Further in silico analysis of transcriptional data suggested a critical role for STAT5 transcriptional activity in polyfunctional cell activation. Pharmacologic inhibition of STAT5 was associated with a significant reduction in polyfunctional cell cytokine expression and proliferation, demonstrating the requirement of STAT5 activity not only for proliferation and cell survival, but also cytokine expression. Finally, we confirmed this association between CMV-specific CD8+ polyfunctionality with STAT5 signaling also exists in immunosuppressed transplant recipients using single cell transcriptomics, indicating that results from this study may translate to this vulnerable patient population. Collectively, these results shed light on the mechanisms governing polyfunctional T cell function and survival and may ultimately inform multiple areas of immunology, including but not limited to the development of new vaccines, CAR-T cell therapies, and adoptive T cell transfer.