Dusan Hanidziar

Bio: Dusan Hanidziar is an academic researcher from Harvard University. The author has contributed to research in topics: Sedation & ARDS. The author has an hindex of 13, co-authored 29 publications receiving 918 citations. Previous affiliations of Dusan Hanidziar include Brigham and Women's Hospital & Beth Israel Deaconess Medical Center.

SARS-CoV-2 viral load is associated with increased disease severity and mortality.

Abstract: The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). Here, we quantify SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. We detected SARS-CoV-2 plasma RNA in 27% of hospitalized participants, and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, we report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, are associated with increased risk of mortality. Our data show that SARS-CoV-2 viral loads may aid in the risk stratification of patients with COVID-19, and therefore its role in disease pathogenesis should be further explored.

SARS-CoV-2 Viral Load is Associated with Increased Disease Severity and Mortality

Abstract: The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). We quantified SARS-CoV-2 viral load from participants with a diverse range of COVID-19 severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. SARS-CoV-2 plasma RNA was detected in 27% of hospitalized participants and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, higher prevalence of detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, were associated with increased risk of mortality. SARS-CoV-2 viral load may aid in the risk stratification of patients with COVID-19 and its role in disease pathogenesis should be further explored.

Sedation of Mechanically Ventilated COVID-19 Patients: Challenges and Special Considerations.

Abstract: To the Editor Management of patient sedation and analgesia to alleviate anxiety and pain and facilitate mechanical ventilation is one of the key roles of every intensivist. During the Coronavirus Disease 2019 (COVID-19) pandemic, unprecedented numbers of patients require sedation in intensive care units (ICUs) and other hospital locations due to their ventilator dependence. However, pharmacologic sedation in mechanically ventilated patients with COVID-19 has thus far received very little attention in the critical care literature, with minimal mention in the Society of Critical Care Medicine’s COVID-19 guidelines or clinical reviews.1,2 We propose that sedation of mechanically ventilated patients with COVID-19 poses unique challenges and has multiple important implications that we would like to briefly outline: Unusually high sedation requirements in a large proportion of COVID-19 patients are observed in current clinical experience. These high sedation requirements are likely related to younger age and good health of many patients before the onset of COVID19, high respiratory drive, and intense inflammatory responses previously linked to tolerance.3 This translates into the need to administer combinations of multiple agents (eg, propofol, ketamine, hydromorphone, dexmedetomidine, and midazolam), increasing potential risks of side effects (eg, QT interval prolongation, hypertriglyceridemia, hypotension, and delirium) and requiring vigilance of the ICU staff. When these are administered in combinations, the typical requirements to ensure patient comfort and ventilator synchrony in adult patients range between 25 and 50 μg/kg/min for propofol, 10 and 20 μg/kg/min for ketamine, 2 and 4 mg/h for hydromorphone, and 2 and 5 mg/h for midazolam. There are currently no sedation guidelines specific for this patient population requiring high doses and prolonged drug administrations. Deeper sedation levels may be required to facilitate ventilator synchrony in patients with severe acute respiratory distress syndrome (ARDS) and may also be favored by ICU staff to reduce risk of patient selfextubation, which is particularly problematic in this population given the need for emergent reintubation and risk of exposure to coronavirus. Subsequent tolerance to sedatives (eg, dexmedetomidine) from their use early in the course of illness and high doses will also limit the effectiveness of these drugs during ventilator weaning. Intermittent administration of certain drugs (eg, narcotics) tailored to individual needs of each patient may not always be feasible in situations of overwhelmed health care systems (eg, when one nurse is required to attend to multiple critically ill patients). In these situations, continuous infusions of sedative drugs are favored for their practicality, but this practice further increases the risks of side effects. A subset of patients with severe ARDS is likely to require prolonged sedation (often >2 weeks)4 to facilitate lung-protective mechanical ventilation or extracorporeal membrane oxygenation (ECMO) therapy and subsequent weaning. These prolonged periods of time may lead to drug accumulation (midazolam), tolerance and tachyphylaxis (dexmedetomidine), hypertriglyceridemia (propofol), QT interval prolongation (haloperidol), psychomimetic effects (ketamine), hyperalgesia or opioid dependence (fentanyl and/or hydromorphone), and delirium (midazolam). Increased precision in monitoring the depth of sedation (eg, processed electroencephalogram [EEG]) is required in patients with high sedation requirements who also require neuromuscular blockade to improve respiratory system compliance. While these neuromonitoring technologies exist,5 they may not be widely available given the number of patients who would benefit. Patient awareness under these conditions (eg, paralysis or prone position) may result in significant psychological trauma. Prolonged infusions of opioids that are often required to facilitate strict lung-protective ventilation are known to result in gut hypomotility, leading to intolerance to feeding, interruptions in feeding, and malnutrition during prolonged ICU stay. These gastrointestinal side effects of opioids may also result in abdominal distension, which can impair ventilation and/or contribute to nausea/vomiting, increasing the risk of aspiration. High doses of opioids, sometimes required to facilitate lung-protective ventilation in patients with ventilator dyssynchrony, may paradoxically complicate ventilation management by inducing breathing patterns with large tidal volumes that may further injure lungs. Prolonged infusions of high doses of sedatives and analgesics in large numbers of patients have already resulted in drug shortages at hospital, regional, and state levels. In these situations, providing sedation with less commonly used agents (barbiturates, methadone, clonidine, chlorpromazine, and propranolol) Sedation of Mechanically Ventilated COVID-19 Patients: Challenges and Special Considerations

Inflammation and the balance of Treg and Th17 cells in transplant rejection and tolerance.

Abstract: Purpose of reviewInflammation of the allograft, occurring as a consequence of hypoxia and ischemia/reperfusion injury, adversely influences short-term and long-term transplant outcomes. Thus far, imbalance of tissue-protective Treg and tissue-destructive Th17 cells has been confirmed in a number of

Cell Biology of Ischemia/Reperfusion Injury

Abstract: Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Beta cell dysfunction and insulin resistance.

Abstract: Beta cell dysfunction and insulin resistance are inherently complex with their interrelation for triggering the pathogenesis of diabetes also somewhat undefined. Both pathogenic states induce hyperglycemia and therefore increase insulin demand. Beta cell dysfunction results from inadequate glucose sensing to stimulate insulin secretion therefore elevated glucose concentrations prevail. Persistently elevated glucose concentrations above the physiological range result in the manifestation of hyperglycemia. With systemic insulin resistance, insulin signaling within glucose recipient tissues is defective therefore hyperglycemia perseveres. Beta cell dysfunction supersedes insulin resistance in inducing diabetes. Both pathological states influence each other and presumably synergistically exacerbate diabetes. Preserving beta cell function and insulin signaling in beta cells and insulin signaling in the glucose recipient tissues will maintain glucose homeostasis.