A5075082768- Antibiotics Pharmacokinetics and Efficacy
- Antibiotic Resistance in Bacteria
- SARS-CoV-2 and COVID-19 Research
- Sepsis Diagnosis and Treatment
- Vaccine Coverage and Hesitancy
- Evolution and Genetic Dynamics
- Bacterial Identification and Susceptibility Testing
- COVID-19 epidemiological studies
- Immune Response and Inflammation
- Immune responses and vaccinations
- Pharmacogenetics and Drug Metabolism
- COVID-19 Clinical Research Studies
- Single-cell and spatial transcriptomics
- Nosocomial Infections in ICU
- Hemodynamic Monitoring and Therapy
- Immune cells in cancer
- Advanced biosensing and bioanalysis techniques
- Monoclonal and Polyclonal Antibodies Research
- Bacterial Infections and Vaccines
- CAR-T cell therapy research
- Trauma, Hemostasis, Coagulopathy, Resuscitation
- Malaria Research and Control
- Molecular Junctions and Nanostructures
- Travel-related health issues
- Antibiotic Use and Resistance
Massachusetts General Hospital
2017-2025
Harvard University
2024
Broad Institute
2022
Kantonsspital Aarau
2021
Emory University
2009-2014
Franklin & Marshall College
2007
Stanford University
2007
To determine the functional relationship between density of bacteria and pharmacodynamics antibiotics, potential consequences this inoculum effect on microbiological course antibiotic treatment Staphylococcus aureus infections. In vitro time–kill, MIC estimation bioassay experiments were performed with S. ATCC 25923 to ascertain rates kill MICs six classes antibiotics exposed. The observed effects are explored a mathematical model. Modest or substantial efficacy for all studied, such as...
Significance We use a mathematical model and computer simulations to explore the design evaluation of antibiotic treatment protocols for an acute, self-limiting bacterial infection. consider effect dose, dosing frequency, term on time before clearance infection likelihood resistance emerging ascending during therapy. Our analysis supports high-dose, full-term antimicrobial chemotherapy as most effective strategy maximizing rate cure minimizing de novo evolution course discuss current status...
The evolution of resistance to antimicrobial chemotherapy is a major and growing cause human mortality morbidity. Comparatively little attention has been paid how different patient treatment strategies shape the resistance. In particular, it not clear whether treating individual patients aggressively with high drug dosages long durations, or moderately low short durations can better prevent spread Here, we summarize very limited available empirical evidence across pathogens provide...
Abstract Background Immune response variation among sepsis patients leads to substantial clinical heterogeneity that makes treatment challenging. Bulk RNA-sequencing of circulating immune cells has been used in an attempt resolve heterogeneity, and facilitated classification into different subtypes, or “endotypes”. The Sepsis Response Signature (SRS) comprises 3 endotypes: SRS1 represents immunosuppressed transcriptional profile with high mortality; SRS2 a relatively immunocompetent low...
Abstract Background Though immune dysregulation often plays a key role in disease, characterizing circulating cells critical illnesses is challenging. Studies using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear (PBMCs) reveals the type and function patients' (cell substates) that could advance diagnostics therapeutics, particularly diseases defined by response heterogeneity such as sepsis. However, PBMC isolation from required for scRNA-seq, gold-standard method...
Multi-drug therapy is the standard-of-care treatment for tuberculosis. Despite this, virtually all studies of pharmacodynamics (PD) mycobacterial drugs employed design protocols are restricted to single agents. In this report, mathematical models and in vitro experiments with Mycobacterium marinum five antimycobacterial used quantitatively evaluate pharmaco-, population evolutionary dynamics two-drug antimicrobial chemotherapy regimes. Time kill pairs antibiotics estimate parameters fit...
There are both pharmacodynamic and evolutionary reasons to use multiple rather than single antibiotics treat bacterial infections; in combination can be more effective killing target bacteria as well preventing the emergence of resistance. Nevertheless, with few exceptions like tuberculosis, therapy is rarely used for infections. One reason this a relative dearth pharmaco-, population- dynamic information needed rational design multi-drug treatment protocols. Here, we vitro experiments,...
The vibrational Stark effect (VSE) has proven to be an effective method for the study of electric fields in proteins via use infrared probes. To explore VSE nucleic acids, we investigated spectroscopy nine structurally diverse nucleosides. These nucleosides contained nitrile or azide probes positions that correspond both major and minor grooves DNA. showed better characteristics exhibited absorption frequencies over a broad range; is, from 2253 cm-1 2'-O-cyanoethyl ribonucleosides 8 9 2102...
Abstract Background Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. To elucidate the kinetics and variant cross-protection of vaccine-induced antibodies in this population, we conducted a prospective longitudinal study heart lung receiving SARS-CoV-2 messenger RNA (mRNA) 3-dose vaccination series. Methods We measured serum antibody neutralization against ancestral major variants...
Abstract Background Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to COVID-19 vaccines. To better understand the immune alterations that determined poor vaccine response, we correlated quantities of circulating T and B cell subsets at baseline with longitudinal serologic SARS-CoV-2 mRNA vaccination in heart lung recipients. Methods Samples approximately 8 30 days after each dose for 22 no history COVID-19, four prior infection, 12 healthy controls...
Abstract Antimicrobial resistance is one of the most significant healthcare challenges our times. Multidrug or combination therapies are sometimes required to treat severe infections; for example, current protocols pulmonary tuberculosis combine four antibiotics. However, therapy usually based on lengthy empirical trials and it difficult predict its efficacy. We propose a new tool identify antibiotic synergy antagonism optimize therapies. Our model explicitly incorporates mechanisms...
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ABSTRACT Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) has enhanced our understanding host immune mechanisms in small cohorts, particularly diseases with complex and heterogeneous responses such as sepsis. However, PBMC isolation from requires technical expertise, training, approximately two hours onsite processing using Ficoll density gradient separation (‘Ficoll’) for scRNA-seq compatibility, precluding large-scale sample collection at most clinical...
We conducted an ecological analysis of the dynamics Delta and Omicron establishment dominance in US states. became dominant circulating variant later states with higher population-level immunity. By contrast, population immunity did not impact maximum rate takeover by or from prior variants.
Abstract Background Procalcitonin (PCT) is a biomarker that finding increasing diagnostic and prognostic utility in lower respiratory infections. It remains unclear, however, whether it can be helpful predicting the bacterial etiology of pneumonia, with view to informing antibiotic choice duration. This study examines relationship between serial PCT measurements microbial patients hospitalized for pneumonia determine changes levels provide discriminatory information on etiology. Methods We...
Abstract Background Dysregulation of the immune response to bacterial infection is an essential but poorly understood component sepsis. Kinetic changes in cell quantity during sepsis can reveal key elements immunopathogenesis, yet these data are scant. Single-cell RNA sequencing (scRNA-seq) peripheral blood mononuclear cells (PBMCs) from patients our laboratory has demonstrated a novel monocyte transcriptional state (monocyte substate 1, or MS1) enriched The gene expression profile MS1...
While well-recognized that clearance of bacterial infections occurs through a collaboration between antibiotics and the immune system, existing strategies for evaluating optimal antibiotic treatment regimens, including pharmacodynamic/pharmacokinetic assessments mathematical/computer simulation models, have been limited in their consideration response variations therein. This study develops within-host mathematical model an acute, potentially self-limiting infection utilizes it to explore...
A 66-Year-Old Man with Fever and ConfusionA 66-year-old man Parkinson's disease hypertension presented to the ED fever confusion after returning U.S. from Cambodia. He was febrile diaphoresis rigors. What diagnosis?
Abstract We conducted an ecological analysis of the dynamics Delta and Omicron establishment dominance in U.S. states. became dominant circulating variant later states with higher population-level immunity. By contrast, population immunity did not impact rates transition from prior variants to either or Omicron.
Abstract Background The relative advantage of each new variant severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) depends on its inherent transmissibility and capacity to evade pre-existing immunity. Delta Omicron are variants concern that have immune-evasive properties rapidly displaced preceded their emergence. In the United States, SARS-CoV-2 immunity varies considerably by state, which provides a natural experiment evaluate effect population-level takeover dynamics variants. We...
Abstract Background: Accurate determination of the microbial etiology pneumonia has important consequences for appropriate administration antimicrobials and antimicrobial stewardship. Procalcitonin (PCT) is a biomarker that finding increasing diagnostic prognostic utility in lower respiratory infections, however, it remains unclear whether can be helpful predicting bacterial pneumonia. In this study, we examined relationship between serial PCT measurements hospitalized patients with...