Socioeconomic Disparities and the Prevalence of Antimicrobial Resistance.

BACKGROUND: The increased prevalence of antimicrobial resistant (AMR) infections is a significant global health threat, resulting in increased morbidity, mortality, and costs. The drivers of AMR are complex and potentially impacted by socioeconomic factors. We investigated the relationships between geographic and socioeconomic factors and AMR. METHODS: We collected select patient bacterial culture results from 2015 to 2020 from electronic health records (EHR) of two expansive healthcare systems within the Dallas-Fort Worth, TX (DFW) metropolitan area. Among individuals with EHR records who resided in the four most populus counties in DFW, culture data were aggregated. Case counts for each organism studied were standardized per 1,000 persons per area population. Using residential addresses, the cultures were geocoded and linked to socioeconomic index values. Spatial autocorrelation tests identified geographic clusters of high and low AMR organism prevalence and correlations with established socioeconomic indices. RESULTS: We found significant clusters of AMR organisms in areas with high levels of deprivation, as measured by the Area Deprivation Index (ADI). We found a significant spatial autocorrelation between ADI and the prevalence of AMR organisms, particularly for AmpC and MRSA with 14% and 13%, respectively, of the variability in prevalence rates being attributable to their relationship with the ADI values of the neighboring locations. CONCLUSIONS: We found that areas with a high ADI are more likely to have higher rates of AMR organisms. Interventions that improve socioeconomic factors such as poverty, unemployment, decreased access to healthcare, crowding, and sanitation in these areas of high prevalence may reduce the spread of AMR.

Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes.

PURPOSE: An elevated number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear. PATIENTS AND METHODS: Here, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases. RESULTS: We found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype. CONCLUSIONS: Our results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation.

United States blood pricing: A cross-sectional analysis of charges and reimbursement at 200 US hospitals.

A violin plot demonstrating listed chargemaster charges for RBC transfusion at 200 hospitals based on hospital ownership. A violin plot shows the volume of the samples at each point by width and lines correspond to the 25th percentile, median, and 75th percentile.

Correction: The Association of a Geographically Wide Social Media Network on Depression: County-Level Ecological Analysis.

[This corrects the article DOI: 10.2196/43623.].

The Association of a Geographically Wide Social Media Network on Depression: County-Level Ecological Analysis.

BACKGROUND: Social connectedness decreases human mortality, improves cancer survival, cardiovascular health, and body mass, results in better-controlled glucose levels, and strengthens mental health. However, few public health studies have leveraged large social media data sets to classify user network structure and geographic reach rather than the sole use of social media platforms. OBJECTIVE: The objective of this study was to determine the association between population-level digital social connectedness and reach and depression in the population across geographies of the United States. METHODS: Our study used an ecological assessment of aggregated, cross-sectional population measures of social connectedness, and self-reported depression across all counties in the United States. This study included all 3142 counties in the contiguous United States. We used measures obtained between 2018 and 2020 for adult residents in the study area. The study's main exposure of interest is the Social Connectedness Index (SCI), a pair-wise composite index describing the "strength of connectedness between 2 geographic areas as represented by Facebook friendship ties." This measure describes the density and geographical reach of average county residents' social network using Facebook friendships and can differentiate between local and long-distance Facebook connections. The study's outcome of interest is self-reported depressive disorder as published by the Centers for Disease Control and Prevention. RESULTS: On average, 21% (21/100) of all adult residents in the United States reported a depressive disorder. Depression frequency was the lowest for counties in the Northeast (18.6%) and was highest for southern counties (22.4%). Social networks in northeastern counties involved moderately local connections (SCI 5-10 the 20th percentile for n=70, 36% of counties), whereas social networks in Midwest, southern, and western counties contained mostly local connections (SCI 1-2 the 20th percentile for n=598, 56.7%, n=401, 28.2%, and n=159, 38.4%, respectively). As the quantity and distance that social connections span (ie, SCI) increased, the prevalence of depressive disorders decreased by 0.3% (SE 0.1%) per rank. CONCLUSIONS: Social connectedness and depression showed, after adjusting for confounding factors such as income, education, cohabitation, natural resources, employment categories, accessibility, and urbanicity, that a greater social connectedness score is associated with a decreased prevalence of depression.

Using dipstick urinalysis to predict development of acute kidney injury in patients with COVID-19.

BACKGROUND: Acute kidney injury (AKI) is a common complication in patients hospitalized with COVID-19 and may require renal replacement therapy (RRT). Dipstick urinalysis is frequently obtained, but data regarding the prognostic value of hematuria and proteinuria for kidney outcomes is scarce. METHODS: Patients with positive severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) PCR, who had a urinalysis obtained on admission to one of 20 hospitals, were included. Nested models with degree of hematuria and proteinuria were used to predict AKI and RRT during admission. Presence of Chronic Kidney Disease (CKD) and baseline serum creatinine were added to test improvement in model fit. RESULTS: Of 5,980 individuals, 829 (13.9%) developed an AKI during admission, and 149 (18.0%) of those with AKI received RRT. Proteinuria and hematuria degrees significantly increased with AKI severity (P < 0.001 for both). Any degree of proteinuria and hematuria was associated with an increased risk of AKI and RRT. In predictive models for AKI, presence of CKD improved the area under the curve (AUC) (95% confidence interval) to 0.73 (0.71, 0.75), P < 0.001, and adding baseline creatinine improved the AUC to 0.85 (0.83, 0.86), P < 0.001, when compared to the base model AUC using only proteinuria and hematuria, AUC = 0.64 (0.62, 0.67). In RRT models, CKD status improved the AUC to 0.78 (0.75, 0.82), P < 0.001, and baseline creatinine improved the AUC to 0.84 (0.80, 0.88), P < 0.001, compared to the base model, AUC = 0.72 (0.68, 0.76). There was no significant improvement in model discrimination when both CKD and baseline serum creatinine were included. CONCLUSIONS: Proteinuria and hematuria values on dipstick urinalysis can be utilized to predict AKI and RRT in hospitalized patients with COVID-19. We derived formulas using these two readily available values to help prognosticate kidney outcomes in these patients. Furthermore, the incorporation of CKD or baseline creatinine increases the accuracy of these formulas.

The 21st Century Cures Act and Multiuser Electronic Health Record Access: Potential Pitfalls of Information Release.

Although the Office of The National Coordinator for Health Information Technology's (ONC) Information Blocking Provision in the Cures Act Final Rule is an important step forward in providing patients free and unfettered access to their electronic health information (EHI), in the contexts of multiuser electronic health record (EHR) access and proxy access, concerns on the potential for harm in adolescent care contexts exist. We describe how the provision could erode patients' (both adolescent and older patients alike) trust and willingness to seek care. The rule's preventing harm exception does not apply to situations where the patient is a minor and the health care provider wishes to restrict a parent's or guardian's access to the minor's EHI to avoid violating the minor's confidentiality and potentially harming patient-clinician trust. This may violate previously developed government principles in the design and implementation of EHRs for pediatric care. Creating legally acceptable workarounds by means such as duplicate "shadow charting" will be burdensome (and prohibitive) for health care providers. Under the privacy exception, patients have the opportunity to request information to not be shared; however, depending on institutional practices, providers and patients may have limited awareness of this exception. Notably, the privacy exception states that providers cannot "improperly encourage or induce a patient's request to block information." Fearing being found in violation of the information blocking provisions, providers may feel that they are unable to guide patients navigating the release of their EHI in the multiuser or proxy access setting. ONC should provide more detailed guidance on their website and targeted outreach to providers and their specialty organizations that care for adolescents and other individuals affected by the Cures Act, and researchers should carefully monitor charting habits in these multiuser or proxy access situations.

Early Crowdfunding Response to the COVID-19 Pandemic: Cross-sectional Study.

BACKGROUND: As the number of COVID-19 cases increased precipitously in the United States, policy makers and health officials marshalled their pandemic responses. As the economic impacts multiplied, anecdotal reports noted the increased use of web-based crowdfunding to defray these costs. OBJECTIVE: We examined the web-based crowdfunding response in the early stage of the COVID-19 pandemic in the United States to understand the incidence of initiation of COVID-19-related campaigns and compare them to non-COVID-19-related campaigns. METHODS: On May 16, 2020, we extracted all available data available on US campaigns that contained narratives and were created between January 1 and May 10, 2020, on GoFundMe. We identified the subset of COVID-19-related campaigns using keywords relevant to the COVID-19 pandemic. We explored the incidence of COVID-19-related campaigns by geography, by category, and over time, and we compared the characteristics of the campaigns to those of non-COVID-19-related campaigns after March 11, when the pandemic was declared. We then used a natural language processing algorithm to cluster campaigns by narrative content using overlapping keywords. RESULTS: We found that there was a substantial increase in overall GoFundMe web-based crowdfunding campaigns in March, largely attributable to COVID-19-related campaigns. However, as the COVID-19 pandemic persisted and progressed, the number of campaigns per COVID-19 case declined more than tenfold across all states. The states with the earliest disease burden had the fewest campaigns per case, indicating a lack of a case-dependent response. COVID-19-related campaigns raised more money, had a longer narrative description, and were more likely to be shared on Facebook than other campaigns in the study period. CONCLUSIONS: Web-based crowdfunding appears to be a stopgap for only a minority of campaigners. The novelty of an emergency likely impacts both campaign initiation and crowdfunding success, as it reflects the affective response of a community. Crowdfunding activity likely serves as an early signal for emerging needs and societal sentiment for communities in acute distress that could be used by governments and aid organizations to guide disaster relief and policy.

Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones.

8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

Trends in Use of Electronic Health Records in Pediatric Office Settings.

OBJECTIVES: To determine the prevalence and functionalities of electronic health records (EHRs) and pediatricians' perceptions of EHRs. STUDY DESIGN: An 8-page self-administered questionnaire sent to 1619 randomly selected nonretired US American Academy of Pediatrics members in 2016 was completed by 709 (43.8%). Responses were compared with surveys in 2009 and 2012. RESULTS: The percent of pediatricians who were using EHRs increased from 58% in 2009 and 79% in 2012 to 94% in 2016. Those with fully functional EHRs, including pediatric functionality, more than doubled from 8.2% in 2012 to 16.9% in 2016 (P = .01). Fully functional EHRs lacking pediatric functionality increased slightly from 7.8% to 11.1% (P = .3), and the percentage of pediatricians with basic EHRs remained stable (30.4% to 31.0%; P < .3). The percentage of pediatricians who lacked basic EHR functionality or who reported no EHR decreased (from 53.6% to 41.0%; P < .001). On average, pediatricians spent 3.4 hours per day documenting care. CONCLUSIONS: Although the adoption of EHRs has increased, >80% of pediatricians are working with EHRs that lack optimal functionality and 41% of pediatricians are not using EHRs with even basic functionality. EHRs lacking pediatric functionality impact the health of children through increased medical errors, missed diagnoses, lack of adherence to guidelines, and reduced availability of child-specific information. The pediatric certification outlined in the 21st Century Cures Act may result in improved EHR products for pediatricians.

The design and conduct of Project RedDE: A cluster-randomized trial to reduce diagnostic errors in pediatric primary care.

BACKGROUND: Diagnostic errors contribute to the large burden of healthcare-associated harm experienced by children. Primary care settings involve high diagnostic uncertainty and limited time and information, creating ideal conditions for diagnostic errors. We report on the design and conduct of Project RedDE, a stepped-wedge, cluster-randomized controlled trial of a virtual quality improvement collaborative aimed at reducing diagnostic errors in pediatric primary care. METHODS: Project RedDE cluster-randomized pediatric primary care practices into one of three groups. Each group participated in a quality improvement collaborative targeting the same three diagnostic errors (missed diagnoses of elevated blood pressure and adolescent depression and delayed diagnoses of abnormal laboratory studies), but in a different sequence. During the quality improvement collaborative, practices worked both independently and collaboratively, leveraging general quality improvement strategies (e.g. process mapping) in addition to error-specific content (e.g. pocket guides for blood pressure norms) delivered during the intervention phase for each error. The quality improvement collaborative intervention included interactive learning sessions and webinars, quality improvement coaching at the team level, and repeated evaluation of failures via root cause analyses. Pragmatic data were collected monthly, submitted to a centralized data aggregator, and returned to the practices in the form of run charts comparing each practice's progress over time to that of the group. The primary analysis used patients as the unit of analysis and compared diagnostic error proportions between the intervention and baseline periods, while secondary analyses evaluated the sustainability of observed reductions in diagnostic errors after the intervention period ended. RESULTS: A total of 43 practices were recruited and randomized into Project RedDE. Eleven practices withdrew before submitting any data, and one practice merged with another participating practice, leaving 31 practices that began work on Project RedDE. All but one of the diverse, national pediatric primary care practices that participated ultimately submitted complete data. Quality improvement collaborative participation was robust, with an average of 63% of practices present on quality improvement collaborative webinars and 85% of practices present for quality improvement collaborative learning sessions. Complete data included 30 months of outcome data for the first diagnostic error worked on, 24 months of outcome data for the second, and 16 months of data for the third. LESSONS LEARNED AND LIMITATIONS: Contamination across study groups was a recurring concern; concerted efforts were made to mitigate this risk. Electronic health records played a large role in teams' success. CONCLUSION: Project RedDE, a virtual quality improvement collaborative aimed at reducing diagnostic errors in pediatric primary care, successfully recruited and retained a diverse, national group of pediatric primary care practices. The stepped-wedge, cluster-randomized controlled trial design allowed for enhanced scientific efficiency.

Advance Directives and Code Status Information Exchange: A Consensus Proposal for a Minimum Set of Attributes.

Documentation of code status and advance directives for end-of-life (EOL) care improves care and quality of life, decreases cost of care, and increases the likelihood of an experience desired by the patient and his/her family. However, the use of advance directives and code status remains low and only a few organizations maintain code status in electronic form. Members of the American Medical Informatics Association's Ethics Committee identified a need for a patient's EOL care wishes to be documented correctly and communicated easily through the electronic health record (EHR) using a minimum data set for the storage and exchange of code status information. After conducting an environmental scan that produced multiple resources, Ethics Committee members used multiple conference calls and a shared document to arrive at consensus on the proposed minimum data set. Ethics Committee members developed a minimum required data set with links to the HL7 C_CDA Advance Directives Module. Data categories include information on the organization obtaining the code status information, the patient, any supporting documentation, and finally the desired code status information including mandatory, optional, and conditional elements. The "minimum set of attributes" to exchange advance directive / code status data described in this manuscript enables communication of patient wishes across multiple providers and health care settings. The data elements described serve as a starting point for a dialog among informatics professionals, physicians experienced in EOL care, and EHR vendors, with the goal of developing standards for incorporating this functionality into the EHR systems.

5-Lipoxygenase is a direct p53 target gene in humans.

The p53 tumor suppressor plays a critical role in cancer, and more than 50% of human tumors contain mutations or deletions of the TP53 gene. p53 can transactivate or repress target genes in response to diverse stress signals, such as transient growth arrest, DNA repair, cellular differentiation, senescence and apoptosis. Through an unbiased genome-wide ChIP-seq analysis, we have found that 5-lipoxygenase (ALOX5, 5-LO) which is a key enzyme of leukotriene (LT) biosynthesis, is a direct target gene of p53 and its expression is induced by genotoxic stress via actinomycin D (Act.D) or etoposide (Eto) treatment. 5-LO and LTs play a role in immunological diseases as well as in tumorigenesis and tumor growth. p53 binds to a specific binding site consisting of a complete p53 consensus-binding motif in ALOX5 intron G which is located about 64kbp downstream of the transcriptional start site. We confirmed the strong binding of p53 to the 5-LO target site in ChIP-qPCR experiments. Expression analyses by qRT-PCR and immunoblot further revealed that genotoxic stress induces the ALOX5 mRNA and protein expression in a p53-dependent manner. Knockdown of p53 in U2OS cells leads to a downregulation of 5-LO mRNA and protein expression. In addition, immunofluorescence and immunoprecipitation assays indicate the direct binding of 5-LO to p53 protein. Furthermore, we found that 5-LO can inhibit the transcriptional activity of p53 suggesting that 5-LO acts in a negative feedback loop to limit induction of p53 target genes.

Lipoxin and resolvin biosynthesis is dependent on 5-lipoxygenase activating protein.

Resolution of acute inflammation is an active process coordinated by proresolving lipid mediators (SPMs) such as lipoxins (LXs) and resolvins (Rvs), which are formed by the concerted action of 2 lipoxygenases (LOs). Because the exact molecular mechanisms of SPM biosynthesis are not completely understood, we aimed to investigate LX and D-type Rv formation in human leukocytes and HEK293T cells overexpressing leukotriene (LT) pathway enzymes. Activity assays in precursor (15-hydroxyeicosatetraenoic acids, 17-HDoHE)-treated granulocytes [polymorphonuclear leukocytes (PMNLs)] showed a strict dependence of LXA4/RvD1 biosynthesis on cell integrity, and incubation with recombinant human 5-LO did not lead to LX or Rv formation. Pharmacologic inhibition of 5-LO activating protein (FLAP) by MK-886 inhibited LXA4/RvD1 biosynthesis in precursor-treated PMNLs (drug concentration causing 50% inhibition ∼ 0.3/0.2 µM), as did knockdown of the enzyme in MM6 cells, and precursor-treated HEK293T overexpressing 5-LO produced high amounts of LXA4 only in the presence of FLAP. In addition, inhibition of cytosolic phospholipase A2α (cPLA2α) interfered with LXA4/RvD1 formation from exogenous precursors in PMNLs. Furthermore, inhibition of the LT synthases LTA4 hydrolase and LTC4 synthase in PMNL/platelet coincubations augmented LXA4 levels. These findings show that several enzymes known to be involved in the biosynthesis of proinflammatory LTs, such as FLAP and cPLA2α, also contribute to LX and Rv formation.

An Analysis of 34,218 Pediatric Outpatient Controlled Substance Prescriptions.

BACKGROUND: Prescription errors are among the most common types of iatrogenic errors. Because of a previously reported 82% error rate in handwritten discharge narcotic prescriptions, we developed a computerized, web-based, controlled substance prescription writer that includes weight-based dosing logic and alerts to reduce the error rate to (virtually) zero. Over the past 7 years, >34,000 prescriptions have been created by hospital providers using this platform. We sought to determine the ongoing efficacy of the program in prescription error reduction and the patterns with which providers prescribe controlled substances for children and young adults (ages 0-21 years) at hospital discharge. METHODS: We examined a database of 34,218 controlled substance discharge prescriptions written by our institutional providers from January 1, 2007 to February 14, 2014, for demographic information, including age and weight, type of medication prescribed based on patient age, formulation of dispensed medication, and amount of drug to be dispensed at hospital discharge. In addition, we randomly regenerated 2% (700) of prescriptions based on stored data and analyzed them for errors using previously established error criteria. Weights that were manually entered into the prescription writer by the prescriber were compared with the patient's weight in the hospital's electronic medical record. RESULTS: Patients in the database averaged 9 ± 6.1 (range, 0-21) years of age and 36.7 ± 24.9 (1-195) kg. Regardless of age, the most commonly prescribed opioid was oxycodone (73%), which was prescribed as a single agent uncombined with acetaminophen. Codeine was prescribed to 7% of patients and always in a formulation containing acetaminophen. Liquid formulations were prescribed to 98% of children <6 years of age and to 16% of children >12 years of age (the remaining 84% received tablet formulations). Regardless of opioid prescribed, the amount of liquid dispensed averaged 106 ± 125 (range, 2-3240) mL, and the number of tablets dispensed averaged 51 ± 51 (range, 1-1080). Of the subset of 700 regenerated prescriptions, all were legible (drug, amount dispensed, dose, patient demographics, and provider name) and used best prescribing practice (e.g., no trailing zero after a decimal point, leading zero for doses <1). Twenty-five of the 700 (3.6%) had incorrectly entered weights compared with the most recent weight in the chart. Of these, 14 varied by 10% or less and only 2 varied by >15%. Of these, 1 resulted in underdosing (true weight 80 kg prescribed for a weight of 50 kg) and the other in overdosing (true weight 10 kg prescribed for a weight of 30 kg). CONCLUSIONS: A computerized prescription writer eliminated most but not all the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much of the prescribed medication is actually used by patients.

Adoption of a Portal for the Primary Care Management of Pediatric Asthma: A Mixed-Methods Implementation Study.

BACKGROUND: Patient portals may improve communication between families of children with asthma and their primary care providers and improve outcomes. However, the feasibility of using portals to collect patient-reported outcomes from families and the barriers and facilitators of portal implementation across diverse pediatric primary care settings have not been established. OBJECTIVE: We evaluated the feasibility of using a patient portal for pediatric asthma in primary care, its impact on management, and barriers and facilitators of implementation success. METHODS: We conducted a mixed-methods implementation study in 20 practices (11 states). Using the portal, parents of children with asthma aged 6-12 years completed monthly surveys to communicate treatment concerns, treatment goals, symptom control, medication use, and side effects. We used logistic regression to evaluate the association of portal use with child characteristics and changes to asthma management. Ten clinician focus groups and 22 semistructured parent interviews explored barriers and facilitators of use in the context of an evidence-based implementation framework. RESULTS: We invited 9133 families to enroll and 237 (2.59%) used the portal (range by practice, 0.6%-13.6%). Children of parents or guardians who used the portal were significantly more likely than nonusers to be aged 6-9 years (vs 10-12, P=.02), have mild or moderate/severe persistent asthma (P=.009 and P=.04), have a prescription of a controller medication (P<.001), and have private insurance (P=.002). Portal users with uncontrolled asthma had significantly more medication changes and primary care asthma visits after using the portal relative to the year earlier (increases of 14% and 16%, respectively). Qualitative results revealed the importance of practice organization (coordinated workflows) as well as family (asthma severity) and innovation (facilitated communication and ease of use) characteristics for implementation success. CONCLUSIONS: Although use was associated with higher treatment engagement, our results suggest that achieving widespread portal adoption is unlikely in the short term. Implementation efforts should include workflow redesign and prioritize enrollment of symptomatic children. CLINICALTRIAL: Clinicaltrials.gov NCT01966068; https://clinicaltrials.gov/ct2/show/NCT01966068 (Archived by WebCite at http://www.webcitation.org/6i9iSQkm3).

Tandem Benzophenone Amino Pyridines, Potent and Selective Inhibitors of Human Leukotriene C4 Synthase.

Cysteinyl leukotrienes (cys-LTs) are lipid mediators of inflammation. The enzyme catalyzing synthesis of cys-LTs, leukotriene C4 synthase (LTC4S), is considered an important drug target. Here we report the synthesis and characterization of three tandem benzophenone amino pyridines as inhibitors of LTC4S in vitro and in vivo. The inhibitors were characterized in vitro using recombinant human LTC4S, MonoMac 6 cells, and a panel of peripheral human immune cells. In vivo, the compounds were tested in the Zymosan A-induced peritonitis mouse model. The molecules, denoted TK04, TK04a, and TK05, were potent and selective inhibitors of LTC4S with IC50 values of 116, 124, and 95 nM, respectively. Molecular docking revealed binding in a hydrophobic crevice between two enzyme monomers and interaction with two catalytic residues, Arg104 and Arg31. The TK compounds potently inhibited cys-LT biosynthesis in immune cells. In coincubations of platelets and polymorphonuclear leukocytes, inhibition of LTC4S led to shunting of LTA4 toward anti-inflammatory lipoxin A4, which was significantly enhanced by simultaneous inhibition of LTA4H. Finally, we found that TK05 (6 mg⋅kg(-1)⋅body weight) reduces LTE4 levels in peritoneal lavage fluid by 88% and significantly decreases vascular permeability in vivo. Our findings indicate that the TK compounds are valuable experimental tools in eicosanoid research in vitro and in vivo. Their chemical structures may serve as leads for further inhibitor design. Novel drugs depleting cys-LT production could be beneficial for treatment of inflammatory diseases associated with overexpression of LTC4S.

Eliminating Health Care Disparities With Mandatory Clinical Decision Support: The Venous Thromboembolism (VTE) Example.

BACKGROUND: All hospitalized patients should be assessed for venous thromboembolism (VTE) risk factors and prescribed appropriate prophylaxis. To improve best-practice VTE prophylaxis prescription for all hospitalized patients, we implemented a mandatory computerized clinical decision support (CCDS) tool. The tool requires completion of checklists to evaluate VTE risk factors and contraindications to pharmacological prophylaxis, and then recommends the risk-appropriate VTE prophylaxis regimen. OBJECTIVES: The objective of the study was to examine the effect of a quality improvement intervention on race-based and sex-based health care disparities across 2 distinct clinical services. RESEARCH DESIGN: This was a retrospective cohort study of a quality improvement intervention. SUBJECTS: The study included 1942 hospitalized medical patients and 1599 hospitalized adult trauma patients. MEASURES: In this study, the proportion of patients prescribed risk-appropriate, best-practice VTE prophylaxis was evaluated. RESULTS: Racial disparities existed in prescription of best-practice VTE prophylaxis in the preimplementation period between black and white patients on both the trauma (70.1% vs. 56.6%, P=0.025) and medicine (69.5% vs. 61.7%, P=0.015) services. After implementation of the CCDS tool, compliance improved for all patients, and disparities in best-practice prophylaxis prescription between black and white patients were eliminated on both services: trauma (84.5% vs. 85.5%, P=0.99) and medicine (91.8% vs. 88.0%, P=0.082). Similar findings were noted for sex disparities in the trauma cohort. CONCLUSIONS: Despite the fact that risk-appropriate prophylaxis should be prescribed equally to all hospitalized patients regardless of race and sex, practice varied widely before our quality improvement intervention. Our CCDS tool eliminated racial disparities in VTE prophylaxis prescription across 2 distinct clinical services. Health information technology approaches to care standardization are effective to eliminate health care disparities.