Faculty Bibliography

Carotid Doppler ultrasound is used as a measure of fluid responsiveness, however, assessing change with statistical confidence requires an adequate beat sample size. The coefficient of variation helps quantify the number of cardiac cycles needed to adequately detect change during functional hemodynamic monitoring.

INTRODUCTION/BACKGROUND:Professionalism is a core concept in medicine. The extent to which knowledge about professionalism is anchored in empirical research is unknown. Understanding the current state of research is necessary to identify significant gaps and create a road map for future professionalism efforts. The authors conducted an exploratory literature review to characterize professionalism research published in widely read medical journals, identify knowledge gaps, and describe the sources of funding for the identified studies. METHODS:The authors focused on Medline's Abridged Index Medicus and 4 core Medline education-oriented journal and developed a search filter using text words found in the article title or abstract addressing professionalism. Articles were further filtered to include those indicating a research focus. RESULTS:The search strategy resulted in 461 professionalism research articles for analysis. Articles were divided into themes of education (n = 212, 45.9%), performance (n = 83, 18%), measurement development (n = 13, 2.8%), remediation (n = 53, 11.5%), and well-being (n = 100, 21.6%). There were 36 studies from 1980 to 2002 (Era 1: before publication of Accreditation Council for Graduate Medical Education competencies) and 425 from 2003 to 17 (Era 2: after Accreditation Council for Graduate Medical Education publication of competencies). Professionalism education was the most common topic area, and most studies were from single institutions with results based on convenience samples. Most studies received no funding or were funded by the authors' own institution. DISCUSSION/CONCLUSIONS:Little empirical research is available on professionalism in widely read medical journals. There has been limited external research funding available to study this topic. CONCLUSION/CONCLUSIONS:More investment in high quality professionalism research is justified and should be encouraged.

BACKGROUND:Serum creatinine concentrations (SCr) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the ICU. Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults. METHODS:We collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured seven endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all seven solutes, and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death. RESULTS:The urine/plasma ratio of six of seven secretory solutes were lower in critically ill patients compared with normal individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = -0.51 and r = -0.53, respectively). Each standard deviation higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% - 38% lower) independent of severity of illness, SCr and tubular injury markers. Higher urine to plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing. CONCLUSIONS:Among critically ill adults, tubular secretory clearance is associated with adverse outcomes and measurement could improve assessment of kidney function and dosing of essential ICU medications. TRIAL REGISTRATION/BACKGROUND:None. FUNDING/BACKGROUND:PKB was supported by grants from the Digestive and Kidney Diseases K23DK116967, the University of Washington Diabetes Research Center P30DK017047, and an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers. EDS was supported by the Vanderbilt O'Brien Kidney Center (NIDDK 5P30 DK114809-03) The funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

We compared the in vitro susceptibility of multidrug-resistant Pseudomonas aeruginosa isolates collected before and after treatment-emergent resistance to ceftolozane-tazobactam. Median baseline and post-exposure ceftolozane-tazobactam MICs were 2 and 64 μg/mL, respectively. Whole-genome sequencing identified treatment-emergent mutations in ampC among 79% (11/14) of paired isolates. AmpC mutations were associated with cross-resistance to ceftazidime-avibactam, but increased susceptibility to piperacillin-tazobactam and imipenem. Eighty-one percent (12/16) of ceftolozane-tazobactam resistant isolates with ampC mutations were susceptible to imipenem-relebactam.

The emergence of the plasmid-mediated high-level tigecycline resistance mechanism Tet(X) threatens the role of tigecycline as the "last-resort" antibiotic in the treatment of infections caused by carbapenem-resistant Gram-negative bacteria. Compared with that of the prototypical Tet(X), the enzymatic activities of Tet(X3) and Tet(X4) were significantly enhanced, correlating with high-level tigecycline resistance, but the underlying mechanisms remain unclear. In this study, we probed the key amino acid changes leading to the enhancement of Tet(X) function and clarified the structural characteristics and evolutionary path of Tet(X) based upon the key residue changes. Through domain exchange and site-directed mutagenesis experiments, we successfully identified five candidate residues mutations (L282S, A339T, D340N, V350I, and K351E), involved in Tet(X2) activity enhancement. Importantly, these 5 residue changes were 100% conserved among all reported high-activity Tet(X) orthologs, Tet(X3) to Tet(X7), suggesting the important role of these residue changes in the molecular evolution of Tet(X). Structural analysis suggested that the mutant residues did not directly participate in the substrate and flavin adenine dinucleotide (FAD) recognition or binding, but indirectly altered the conformational dynamics of the enzyme through the interaction with adjacent residues. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and UV full-wavelength scanning experiments confirmed that each mutation led to an increase in activity without changing the biochemical properties of the Tet(X) enzyme. Further phylogenetic analysis suggested that Riemerella anatipestifer served as an important incubator and a main bridge vector for the resistance enhancement and spread of Tet(X). This study expands the knowledge of the structure and function of Tet(X) and provides insights into the evolutionary relationship between Tet(X) orthologs.IMPORTANCE The newly emerged tigecycline-inactivating enzymes Tet(X3) and Tet(X4), which are associated with high-level tigecycline resistance, demonstrated significantly higher activities in comparison to that of the prototypical Tet(X) enzyme, threatening the clinical efficacy of tigecycline as a last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections. However, the molecular mechanisms leading to high-level tigecycline resistance remain elusive. Here, we identified 5 key residue changes that lead to enhanced Tet(X) activity through domain swapping and site-directed mutagenesis. Instead of direct involvement with substrate binding or catalysis, these residue changes indirectly alter the conformational dynamics and allosterically affect enzyme activities. These findings further broaden the understanding of the structural characteristics and functional evolution of Tet(X) and provide a basis for the subsequent screening of specific inhibitors and the development of novel tetracycline antibiotics.

Ceftazidime/Avibactam (CAZ/AVI) is a β-lactam/β-lactamase inhibitor combination with activity against type A and C β-lactamases. Resistance emergence has been seen with multiple mechanisms accounting for the resistance. We performed four experiments in the dynamic Hollow Fiber Infection Model, delineating the linkage between drug exposure and both rate of bacterial kill and resistance emergence by all mechanisms. The P. aeruginosa isolate had an MIC of 1.0 mg/L (CAZ)/4 mg/L (AVI). We demonstrated that Time>4.0 mg/L AVI was linked to rate of bacterial kill. Linkage to resistance emergence/suppression was more complex. In one experiment where CAZ/AVI administration was intermittent/continuous and where AVI was given in unitary steps from 1-8 mg/L, AVI up to 3 mg/L allowed resistance emergence, whereas higher values did not. The threshold value was 3.72 mg/L as a continuous infusion to counterselect resistance (AUC of 89.3 mg*h/L AVI). The mechanism was by a 7 amino acid deletion in the Ω-loop region of the PDC β-lactamase. Further experiments, where CAZ/AVI were both administered intermittently with regimens above and below the AUC of 89.3 mg*hr/L resulted in resistance in the lower exposure groups. Deletion mutants were not identified. Finally, an experiment where paired exposures both as continuous and intermittent infusions were performed, the lower value of 25 mg*hr/L by both profiles allowed selection of deletion mutants. Of the five instances where these mutants were recovered, 4/5 were by the continuous infusion profile. Both continuous infusion administration and low avibactam AUC exposures have a role in selection of this mutation.

During the coronavirus disease 2019 (COVID-19) pandemic, rapid and accurate triage of patients at the emergency department is critical to inform decision-making. We propose a data-driven approach for automatic prediction of deterioration risk using a deep neural network that learns from chest X-ray images and a gradient boosting model that learns from routine clinical variables. Our AI prognosis system, trained using data from 3661 patients, achieves an area under the receiver operating characteristic curve (AUC) of 0.786 (95% CI: 0.745-0.830) when predicting deterioration within 96 hours. The deep neural network extracts informative areas of chest X-ray images to assist clinicians in interpreting the predictions and performs comparably to two radiologists in a reader study. In order to verify performance in a real clinical setting, we silently deployed a preliminary version of the deep neural network at New York University Langone Health during the first wave of the pandemic, which produced accurate predictions in real-time. In summary, our findings demonstrate the potential of the proposed system for assisting front-line physicians in the triage of COVID-19 patients.

OBJECTIVE:To estimate population health outcomes with delayed second dose versus standard schedule of SARS-CoV-2 mRNA vaccination. DESIGN:Simulation agent based modeling study. SETTING:Simulated population based on real world US county. PARTICIPANTS:The simulation included 100 000 agents, with a representative distribution of demographics and occupations. Networks of contacts were established to simulate potentially infectious interactions though occupation, household, and random interactions. INTERVENTIONS:Simulation of standard covid-19 vaccination versus delayed second dose vaccination prioritizing the first dose. The simulation runs were replicated 10 times. Sensitivity analyses included first dose vaccine efficacy of 50%, 60%, 70%, 80%, and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread (that is, non-sterilizing vaccine); and an alternative vaccination strategy that implements delayed second dose for people under 65 years of age, but not until all those above this age have been vaccinated. MAIN OUTCOME MEASURES:Cumulative covid-19 mortality, cumulative SARS-CoV-2 infections, and cumulative hospital admissions due to covid-19 over 180 days. RESULTS:236 for 90%, 80%, and 70% first dose efficacy, respectively. The delayed second dose strategy was optimal for vaccine efficacies at or above 80% and vaccination rates at or below 0.3% of the population per day, under both sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100 000. The delayed second dose strategy for people under 65 performed consistently well under all vaccination rates tested. CONCLUSIONS:A delayed second dose vaccination strategy, at least for people aged under 65, could result in reduced cumulative mortality under certain conditions.

Spike protein mutations E484K and N501Y carried by SARS-CoV-2 variants have been associated with concerning changes of the virus, including resistance to neutralizing antibodies and increased transmissibility. While the concerning variants are fast spreading in various geographical areas, identification and monitoring of these variants is lagging far behind, due in large part to the slow speed and insufficient capacity of viral sequencing. In response to the unmet need for a fast and efficient screening tool, we developed a single-tube duplex molecular assay for rapid and simultaneous identification of E484K and N501Y mutations from nasopharyngeal swab (NS) samples within 2.5 h from sample preparation to report. Using this tool, we screened a total of 1135 clinical NS samples collected from COVID patients at 8 hospitals within the Hackensack Meridian Health network in New Jersey between late December 2020 and March 2021. Our data revealed dramatic increases in the frequencies of both E484K and N501Y over time, underscoring the need for continuous epidemiological monitoring.