Curtis H. Weiss

Prompting physicians to address a daily checklist and process of care and clinical outcomes: A single-site study

RATIONALE Checklists may reduce errors of omission for critically ill patients. OBJECTIVES To determine whether prompting to use a checklist improves process of care and clinical outcomes. METHODS We conducted a cohort study in the medical intensive care unit (MICU) of a tertiary care university hospital. Patients admitted to either of two independent MICU teams were included. Intervention team physicians were prompted to address six parameters from a daily rounding checklist if overlooked during morning work rounds. The second team (control) used the identical checklist without prompting. MEASUREMENTS AND MAIN RESULTS One hundred and forty prompted group patients were compared with 125 control and 1,283 preintervention patients. Compared with control, prompting increased median ventilator-free duration, decreased empirical antibiotic and central venous catheter duration, and increased rates of deep vein thrombosis and stress ulcer prophylaxis. Prompted group patients had lower risk-adjusted ICU mortality compared with the control group (odds ratio, 0.36; 95% confidence interval, 0.13-0.96; P = 0.041) and lower hospital mortality compared with the control group (10.0 vs. 20.8%; P = 0.014), which remained significant after risk adjustment (odds ratio, 0.34; 95% confidence interval, 0.15-0.76; P = 0.008). Observed-to-predicted ICU length of stay was lower in the prompted group compared with control (0.59 vs. 0.87; P = 0.02). Checklist availability alone did not improve mortality or length of stay compared with preintervention patients. CONCLUSIONS In this single-site, preliminary study, checklist-based prompting improved multiple processes of care, and may have improved mortality and length of stay, compared with a stand-alone checklist. The manner in which checklists are implemented is of great consequence in the care of critically ill patients.

A protein kinase associated with apoptosis and tumor suppression: structure, activity and discovery of peptide substrates

Death-associated protein kinase (DAPK) has been implicated in apoptosis and tumor suppression, depending on cellular conditions, and associated with mechanisms of disease. However, DAPK has not been characterized as an enzyme due to the lack of protein or peptide substrates. Therefore, we determined the structure of DAPK catalytic domain, used a homology model of docked peptide substrate, and synthesized positional scanning substrate libraries in order to discover peptide substrates with K m values in the desired 10 μm range and to obtain knowledge about the preferences of DAPK for phosphorylation site sequences. Mutagenesis of DAPK catalytic domain at amino acids conserved among protein kinases or unique to DAPK provided a link between structure and activity. An enzyme assay for DAPK was developed and used to measure activity in adult brain and monitor protein purification based on the physical and chemical properties of the open reading frame of the DAPK cDNA. The results allow insight into substrate preferences and regulation of DAPK, provide a foundation for proteomic investigations and inhibitor discovery, and demonstrate the utility of the experimental approach, which can be extended potentially to kinase open reading frames identified by genome sequencing projects or functional genetics screens and lacking a known substrate.

Pulmonary disease caused by nontuberculous mycobacteria

The propensity of various nontuberculous mycobacteria to cause lung disease varies widely and is conditioned by host factors; infection is believed to occur from environmental sources. Nontuberculous mycobacteria pulmonary disease (PNTM) is increasing worldwide and Mycobacterium avium complex is the most common cause. PNTM usually occurs in one of three prototypical forms: hypersensitivity pneumonitis, cavitary tuberculosis-like disease or nodular bronchiectasis. PNTM has been linked in some patients to genetic variants of the cystic fibrosis transmembrane conductance regulator gene and a distinct patient phenotype. Interactions between PNTM and other comorbidities are also increasingly appreciated. Guidelines for diagnosis, emphasizing chest imaging and microbiology, have been published; speciation using molecular techniques is critical for accuracy and for treatment decisions. Clinical trials are lacking to inform treatment for many species and experience with M. avium complex and several others species serves as a guide instead. Use of multiple drugs for a period of at least 12 months following sputum conversion is the norm for most species. In vitro drug susceptibility results for many drugs may not correlate with clinical outcomes and such testing should be done on a selective basis.

A Clinical Trial Comparing Physician Prompting With an Unprompted Automated Electronic Checklist to Reduce Empirical Antibiotic Utilization

Objectives:To determine whether face-to-face prompting of critical care physicians reduces empirical antibiotic utilization compared to an unprompted electronic checklist embedded within the electronic health record. Design:Random allocation design. Setting:Medical ICU with high-intensity intensivist coverage at a tertiary care urban medical center. Patients:Two hundred ninety-six critically ill patients treated with at least 1 day of empirical antibiotics. Interventions:For one medical ICU team, face-to-face prompting of critical care physicians if they did not address empirical antibiotic utilization during a patient’s daily rounds. On a separate medical ICU team, attendings and fellows were trained once to complete an electronic health record-embedded checklist daily for each patient, including a question asking whether listed empirical antibiotics could be discontinued. Measurements and Main Results:Prompting led to a more than four-fold increase in discontinuing or narrowing of empirical antibiotics compared to use of the electronic checklist. Prompted group patients had a lower proportion of patient-days on which empirical antibiotics were administered compared to electronic checklist group patients (63.1% vs 70.0%, p = 0.002). Mean proportion of antibiotic-days on which empirical antibiotics were used was also lower in the prompted group, although not statistically significant (0.78 [0.27] vs 0.83 [0.27], p = 0.093). Each additional day of empirical antibiotics predicted higher risk-adjusted mortality (odds ratio, 1.14; 95% CI, 1.05–1.23). Risk-adjusted ICU length of stay and hospital mortality were not significantly different between the two groups. Conclusions:Face-to-face prompting was superior to an unprompted electronic health record-based checklist at reducing empirical antibiotic utilization. Sustained culture change may have contributed to the electronic checklist having similar empirical antibiotic utilization to a prompted group in the same medical ICU 2 years prior. Future studies should investigate the integration of an automated prompting mechanism with a more generalizable electronic health record-based checklist.

Analysis of the kinase‐related protein gene found at human chromosome 3q21 in a multi‐gene cluster: Organization, expression, alternative splicing, and polymorphic marker

We report the amino acid sequence, genomic organization, tissue expression, and alternative splice patterns for the human kinase related protein (KRP) gene, as well as the discovery of a new CA repeat sequence polymorphic marker in an upstream intron of the myosin light chain kinase (MLCK) gene. The KRP/MLCK genetic locus is a prototype for a recently discovered paradigm in which an independently regulated gene for a non‐enzymic protein is embedded within a larger gene for a signal transduction enzyme, and both classes of proteins are involved in the regulation of the same cellular structure. The MLCK/KRP gene cluster has been found only in higher vertebrates and is localized to human chromosome 3q21. The determination of the human KRP amino acid sequence through cDNA sequence analysis and its comparison to the exon/intron organization of the human KRP gene revealed an alternative splice pattern at the start of KRP exon 2, resulting in the insertion of a single glutamic acid in the middle of the protein. Examination of tissue distribution using Northern blot analysis revealed that the human expression pattern is more similar to the well‐characterized chicken KRP gene expression pattern than to rodent or rabbit. Unexpected differences of the human gene from other species is the apparent expression of the human gene products in adult cardiac muscle, an observation that was pursued further by the production of a site‐directed antiserum and immunohistochemistry analysis. The results reported here provide insight into the conserved and variable features of this late evolving genetic paradigm, raise new questions about the molecular aspects of cardiac muscle regulation, and provide tools needed for future clinical studies. The comparative analysis of the MLCK/KRP locus, combined with the recent discovery of a similar genomic relationship among other signal transduction proteins, suggest a diverse distribution of this theme among signal transduction systems in higher vertebrate genomes and indicate the utility of comparative genomics in revealing late evolving genetic paradigms. J. Cell. Biochem. 75:481–491, 1999.

Bronchoalveolar lavage amylase is associated with risk factors for aspiration and predicts bacterial pneumonia.

Objectives:Aspiration of oropharyngeal or gastric contents into the respiratory tract leads to a spectrum of disorders with high morbidity. Aspiration is a diagnostic dilemma, because clinical characteristics and diagnostic tests are not effective predicting or confirming aspiration. We sought to determine whether &agr;-amylase, a protein secreted by salivary glands and the pancreas, is elevated in bronchoalveolar lavage specimens in patients with clinical risk factors for aspiration and whether bronchoalveolar lavage amylase predicts bacterial pneumonia. Design:Retrospective analysis. Setting:Five adult ICUs at a tertiary care urban medical center. Patients:Mechanically ventilated patients who underwent either bronchoscopic or nonbronchoscopic bronchoalveolar lavage within 72 hrs of endotracheal intubation between August 1, 2008 and June 30, 2010. Measurements and Main Results:A total of 296 bronchoalveolar lavage amylase results from 280 patients were included in the analysis, and 155 bronchoalveolar lavage amylase specimens were obtained from patients with at least one predefined preintubation risk factor (altered consciousness, swallowing dysfunction, difficult intubation, peri-intubation vomiting, or cardiac arrest). Bronchoalveolar lavage amylase concentration increased as the number of preintubation risk factors increased (p < 0.001). In addition, bronchoalveolar lavage amylase was elevated in patients with bacterial pneumonia (cfu/mL ≥ 104) (p < 0.001). The area under the receiver operator curve for the ability of bronchoalveolar lavage amylase to differentiate between positive and negative bronchoalveolar lavage culture was 0.67 (95% confidence interval, 0.60–0.75). The lower 95% confidence interval for bronchoalveolar lavage amylase in patients with at least one preintubation risk factor for aspiration was 125.9 units/L. In multivariate analysis, bronchoalveolar lavage amylase < 125 units/L was associated with significantly lower odds of bacterial pneumonia (odds ratio 0.39, 95% confidence interval 0.21–0.71, p = 0.002). Conclusions:Elevated bronchoalveolar lavage amylase is associated with risk factors for aspiration and may predict bacterial pneumonia. Bronchoalveolar lavage amylase may be useful as an early screening tool to guide management of patients suspected of aspiration.

Low Tidal Volume Ventilation Use in Acute Respiratory Distress Syndrome

Objective:Low tidal volume ventilation lowers mortality in the acute respiratory distress syndrome. Previous studies reported poor low tidal volume ventilation implementation. We sought to determine the rate, quality, and predictors of low tidal volume ventilation use. Design:Retrospective cross-sectional study. Setting:One academic and three community hospitals in the Chicago region. Patients:A total of 362 adults meeting the Berlin Definition of acute respiratory distress syndrome consecutively admitted between June and December 2013. Measurements and Main Results:Seventy patients (19.3%) were treated with low tidal volume ventilation (tidal volume < 6.5 mL/kg predicted body weight) at some time during mechanical ventilation. In total, 22.2% of patients requiring an FIO2 greater than 40% and 37.3% of patients with FIO2 greater than 40% and plateau pressure greater than 30 cm H2O received low tidal volume ventilation. The entire cohort received low tidal volume ventilation 11.4% of the time patients had acute respiratory distress syndrome. Among patients who received low tidal volume ventilation, the mean (SD) percentage of acute respiratory distress syndrome time it was used was 59.1% (38.2%), and 34% waited more than 72 hours prior to low tidal volume ventilation initiation. Women were less likely to receive low tidal volume ventilation, whereas sepsis and FIO2 greater than 40% were associated with increased odds of low tidal volume ventilation use. Four attending physicians (6.2%) initiated low tidal volume ventilation within 1 day of acute respiratory distress syndrome onset for greater than or equal to 50% of their patients, whereas 34 physicians (52.3%) never initiated low tidal volume ventilation within 1 day of acute respiratory distress syndrome onset. In total, 54.4% of patients received a tidal volume less than 8 mL/kg predicted body weight, and the mean tidal volume during the first 72 hours after acute respiratory distress syndrome onset was never less than 8 mL/kg predicted body weight. Conclusions:More than 12 years after publication of the landmark low tidal volume ventilation study, use remains poor. Interventions that improve adoption of low tidal volume ventilation are needed.

Proteasomal Regulation of Pulmonary Fibrosis

It is estimated that, combined, 400,000 people are diagnosed with idiopathic pulmonary fibrosis (IPF) or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of IPF. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor (TGF)-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or IPF, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.

Ubiquitination and Proteolysis in Acute Lung Injury

Ubiquitination is a posttranslational modification that regulates a variety of cellular functions depending on timing, subcellular localization, and type of tagging, as well as modulators of ubiquitin binding leading to proteasomal or lysosomal degradation or nonproteolytic modifications. Ubiquitination plays an important role in the pathogenesis of acute lung injury (ALI) and other lung diseases with pathologies secondary to inflammation, mechanical ventilation, and decreased physical mobility. Particularly, ubiquitination has been shown to affect alveolar epithelial barrier function and alveolar edema clearance by targeting the Na,K-ATPase and epithelial Na(+) channels upon lung injury. Notably, the proteasomal system also exhibits distinct functions in the extracellular space, which may contribute to the pathogenesis of ALI and other pulmonary diseases. Better understanding of these mechanisms may ultimately lead to novel therapeutic modalities by targeting elements of the ubiquitination pathway.

Trends in Pathogens Among Patients Hospitalized for Pneumonia From 1993 to 2011

The Nationwide Inpatient Sample aggregated data from approximately 20% of US hospital admissions from 1993 to 2011. Prior literature found that pneumonia admissions decreased following the introduction of the pneumococcal vaccine in 2000.1 The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), codes provide information regarding pneumonia pathogens, but no studies, to our knowledge, have used these codes to analyze longitudinal trends in the pathogens documented during hospitalizations for pneumonia.