Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

Discovery of a novel class of boron-based antibacterials with activity against gram-negative bacteria.

Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

Inhibition of Toll-like receptor-mediated inflammation in vitro and in vivo by a novel benzoxaborole.

Pro-inflammatory cytokines play a critical role in the development of autoimmune and inflammatory diseases. Targeting the cytokine environment has proven efficient for averting inflammation. In this study, we reported that 6-[4-(aminomethyl)-2-chlorophenoxyl]benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited TLR2-, TLR3-, TLR4-, and TLR5-mediated TNF-α, IL-1ß, and IL-6 release from human PBMCs and isolated monocytes with IC(50) values ranging from 18 to 580 nM, and the inhibition was mediated at the transcriptional level. Topical administration of AN3485 significantly reduced PMA-induced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice, indicating its capability of penetrating skin and potential topical application in skin inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPS-induced TNF-α and IL-6 production in mice with an ED(90) of 30 mg/kg. Oral AN3485, 35 mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases.

The Role of Calcium in Non-Invasively Imaging Breast Cancer: An Overview of Current and Modern Imaging Techniques.

The landscape of breast cancer diagnostics has significantly evolved over the past decade. With these changes, it is possible to provide a comprehensive assessment of both benign and malignant breast calcifications. The biochemistry of breast cancer and calcifications are thoroughly examined to describe the potential to characterize better different calcium salts composed of calcium carbonate, calcium oxalate, or calcium hydroxyapatite and their associated prognostic implications. Conventional mammographic imaging techniques are compared to available ones, including breast tomosynthesis and contrast-enhanced mammography. Additional methods in computed tomography and magnetic resonance imaging are discussed. The concept of using magnetic resonance imaging particularly magnetic susceptibility to characterize the biochemical characteristics of calcifications is described. As we know magnetic resonance imaging is safe and there is no ionization radiation. Experimental findings through magnetic resonance susceptibility imaging techniques are discussed to illustrate the potential for integrating this technique to provide a quantitative assessment of magnetic susceptibility. Under the right magnetic resonance imaging conditions, a distinct phase variability was isolated amongst different types of calcium salts.

Severe outcomes following pediatric cannabis intoxication: a prospective cohort study of an international toxicology surveillance registry.

INTRODUCTION: An increasing number of jurisdictions have legalized recreational cannabis for adult use. The subsequent availability and marketing of recreational cannabis has led to a parallel increase in rates and severity of pediatric cannabis intoxications. We explored predictors of severe outcomes in pediatric patients who presented to the emergency department with cannabis intoxication. METHODS: In this prospective cohort study, we collected data on all pediatric patients (<18 years) who presented with cannabis intoxication from August 2017 through June 2020 to participating sites in the Toxicology Investigators Consortium. In cases that involved polysubstance exposure, patients were included if cannabis was a significant contributing agent. The primary outcome was a composite severe outcome endpoint, defined as an intensive care unit admission or in-hospital death. Covariates included relevant sociodemographic and exposure characteristics. RESULTS: One hundred and thirty-eight pediatric patients (54% males, median age 14.0 years, interquartile range 3.7-16.0) presented to a participating emergency department with cannabis intoxication. Fifty-two patients (38%) were admitted to an intensive care unit, including one patient who died. In the multivariable logistic regression analysis, polysubstance ingestion (adjusted odds ratio = 16.3; 95% confidence interval: 4.6-58.3; P < 0.001)) and cannabis edibles ingestion (adjusted odds ratio = 5.5; 95% confidence interval: 1.9-15.9; P = 0.001) were strong independent predictors of severe outcome. In an age-stratified regression analysis, in children older than >10 years, only polysubstance abuse remained an independent predictor for the severe outcome (adjusted odds ratio 37.1; 95% confidence interval: 6.2-221.2; P < 0.001). As all children 10 years and younger ingested edibles, a dedicated multivariable analysis could not be performed (unadjusted odds ratio 3.3; 95% confidence interval: 1.6-6.7). CONCLUSIONS: Severe outcomes occurred for different reasons and were largely associated with the patient's age. Young children, all of whom were exposed to edibles, were at higher risk of severe outcomes. Teenagers with severe outcomes were frequently involved in polysubstance exposure, while psychosocial factors may have played a role.

Predicting pediatric esophageal wall thickness: An EUS study.

BACKGROUND AND OBJECTIVE: EUS has been shown in two small series to be capable of documenting increases in the total esophageal wall thickness (TWT) in children and adults with eosinophilic esophagitis (EoE). To apply EUS-derived TWT in clinical situations or in scientific investigations in pediatric EoE, measurements of esophageal TWT in children of differing ages and heights are required. MATERIALS AND METHODS: Thirty patients (18M: 12F, 7 months to 20 years and 10 months) with a history of esophageal symptoms, but no endoscopic or histologic criteria of EoE were studied using a through the scope 20 MHZ Olympus Ultrasound miniprobe UM-3R (Olympus America, Center Valley Pa 18034) through a GIF Q180 or 160 (Olympus) standard pediatric upper endoscope. The mucosa, the mucosa plus submucosa, and the TWT were measured in the mid- and distal esophagus immediately before taking diagnostic biopsies. RESULTS: Measurements from both sites showed a statistically significant increase in TWT as a function of age (P < 0.001) and height (P < 0.001), as did the individual layers. The width of the mucosa and the submucosa were equivalent and together, they contributed more than half of the entire TWT. There were no significant differences between the means of the mid- and distal esophageal measurements. A multiple regression equation that can predict TWT based on age, with 95% confidence limits, is presented. CONCLUSIONS: EUS has demonstrated that esophageal TWT in a cohort of control children correlates with height and with age and has provided insights into the organization of the esophageal wall. Esophageal TWT values obtained by EUS can now be interpreted to recognize esophageal wall thickening throughout childhood.

Healthcare expenditures for privately insured US patients with cystic fibrosis, 2010-2016.

OBJECTIVES: Published cost estimates for cystic fibrosis (CF) are based on older data and do not reflect increased use of specialty drugs in recent years. We assessed recent trends in healthcare expenditures for CF patients in the United States (US) with employer-sponsored health insurance. METHODS: The study is a retrospective analysis of claims data for privately insured individuals aged 0-64 years who were continuously enrolled in non-capitated plans for at least 1 calendar year during 2010-2016. Mean annual expenditures during a calendar year were calculated for individuals who met a claims-based CF case definition. Average annual growth rates were calculated through linear regression of the natural logarithm of annual expenditures. RESULTS: The annual CF prevalence was 1.1-1.4 per 10 000 adults and 2.9-3.0 per 10 000 children. Average spending adjusted for inflation nearly doubled from roughly $67 000 per patient in 2010 and 2011 to approximately $131 000 per patient in 2016. Inflation-adjusted spending on outpatient and inpatient care increased by 0.5% and 2.5% per year, respectively, whereas pharmaceutical spending increased by 20.2% per year. Virtually all of the growth in pharmaceutical spending was accounted for by spending on specialty drugs; inflation-adjusted spending on other medications increased by 1.3% per year. The annual growth rate in pharmaceutical spending rose by 33.1% during 2014-2016, the years during which lumacaftor/ivacaftor was introduced. CONCLUSIONS: Per-patient expenditures for privately-insured patients with CF almost doubled during 2010-2016; specialty drugs were largely responsible for this increase, with a major contribution from new, genotype-targeted CFTR modulator medications.

Precision Medicine In Action: The Impact Of Ivacaftor On Cystic Fibrosis-Related Hospitalizations.

Cystic fibrosis is a life-threatening genetic disease that causes severe damage to the lungs. Ivacaftor, the first drug that targeted the underlying defect of the disease caused by specific mutations, is a sterling example of the potential of precision medicine. Clinical trial and registry studies showed that ivacaftor improved outcomes and reduced hospitalizations. Our study used US administrative claims data to assess the real-world effectiveness of ivacaftor. Comparing twelve-month rates before and after starting the use of ivacaftor among people who initiated therapy during 2012-2015, we found that overall and cystic fibrosis-related inpatient admissions fell by 55 percent and 81 percent, respectively. There was a comparable reduction in inpatient spending. Ivacaftor appears to be effective for multiple mutations that cause the disease, as suggested by the fact that during the study period, ivacaftor's use was extended to nine additional mutations in 2014. Examination of evidence from clinical trial, clinical care, and administrative data sources is important for understanding the real-world effectiveness of precision medicines such as ivacaftor.

The Role of Primary Care Practices in Advancing Population Health.

Improving population health requires the contribution of many entities including state and local governments, hospitals, community organizations, health centers, and private practices. Primary care practices have the potential to play a key role in improving population health. While sporadic, primary care practices engage in a spectrum of practice- and community-based population health activities. Community-based activities are largely driven by altruistic motivations of physicians and staff. Patient and disease registries and access to comprehensive patient data are critical to improving population health. Guidance is needed for practices to engage in population health initiatives and appropriate incentives to motivate practices to address population health issues.

National trends in emergency department use, care patterns, and quality of care of older adults in the United States.

OBJECTIVES: To describe trends in use of emergency departments (EDs) of older adults, reasons for visits, resource use, and quality of care. DESIGN: Analysis of the National Hospital Ambulatory Medical Care Survey. SETTING: U.S. emergency departments from 2001 to 2009. PARTICIPANTS: Individuals aged 65 and older visiting U.S. EDs. MEASUREMENTS: Emergency departments (ED) visits by patients aged 65 and older were identified, and demographic, clinical, and resource use characteristics and outcomes were assessed. RESULTS: From 2001 to 2009, annual visits increased from 15.9 to 19.8 million, a 24.5% increase. Numbers of outpatients grew less than hospital admissions (20.2% vs 33.1%); intensive care unit admissions increased 131.3%. Reasons for visits were unchanged during the study; the top complaints were chest pain, dyspnea, and abdominal pain. Resource intensity grew dramatically: computed tomography 167.0%, urinalyses 87.1%, cardiac monitoring 79.3%, intravenous fluid administration 59.8%, blood tests 44.1%, electrocardiogram use 43.4%, procedures 38.3%, and radiographic imaging 36.4%. From 2005 to 2009, magnetic resonance imaging use grew 84.6%. The proportion receiving a potentially inappropriate medication decreased from 9.6% in 2001 to 4.9% in 2009, whereas the proportion seen in the ED, discharged, and subsequently readmitted to the hospital rose from 2.0% to 4.2%. CONCLUSION: Older adults accounted for 156 million ED visits in the United States from 2001 to 2009, with steady increases in visits and resource use across the study period. Hospital admissions grew faster than outpatient visits. If changes in primary care do not affect these trends, facilities will need to plan to accommodate increasingly greater demands for ED and hospital services.

Why do some primary care practices engage in practice improvement efforts whereas others do not?

OBJECTIVE: To understand what motivates primary care practices to engage in practice improvement, identify external and internal facilitators and barriers, and refine a conceptual framework. DATA SOURCES: In-depth interviews and structured telephone surveys with clinicians and practice staff (n = 51), observations, and document reviews. STUDY DESIGN: Comparative case study of primary care practices (n = 8) to examine aspects of the practice and environment that influence engagement in improvement activities. DATA COLLECTION METHODS: Three on-site visits, telephone interviews, and two surveys. PRINCIPAL FINDINGS: Pressures from multiple sources create conflicting forces on primary care practices' improvement efforts. Pressures include incentives and requirements, organizational relationships, and access to resources. Culture, leadership priorities, values set by the physician(s), and other factors influence whether primary care practices engage in improvement efforts. CONCLUSIONS: Most primary care practices are caught in a cross fire between two groups of pressures: a set of forces that push practices to remain with the status quo, the "15-minute per patient" approach, and another set of forces that press for major transformations. Our study illuminates the elements involved in the decision to stay with the status quo or to engage in practice improvement efforts needed for transformation.

U.S. trends in computed tomography use and diagnoses in emergency department visits by patients with symptoms suggestive of pulmonary embolism, 2001-2009.

OBJECTIVES: Using computed tomography (CT) to evaluate patients with chest symptoms is common in emergency departments (EDs). This article describes recent trends of CT use in U.S. EDs for patients presenting with symptoms common to acute pulmonary embolism (PE). METHODS: The 2001-2009 National Hospital Ambulatory Medical Care Survey (NHAMCS), a nationally representative survey of U.S. ED encounters, was used for data collection. Patients with at least one of three complaints (chest pain, dyspnea, or hemoptysis) were categorized into the chest symptom study (CSS) group. The yearly increases in CT use for the complaints were tabulated first, then linear regression analysis was used to calculate average rates of increases in CT use between 2001 and 2007, the years where CT use increased, for the overall population and among specific subgroups. The ratios of the number of visits when CT was ordered and there was a target diagnosis relative to the total number of visits with CT in the CSS group (diagnosis/CT ratio) were calculated for PE and pneumonia. RESULTS: Annual CT rates for the CSS group increased from 2.6% in 2001 to 13.2% in 2007, subsequently leveling off at approximately 12.5% in 2008 and 2009. The average growth rate of CT use for the CSS group was 28.1% (95% confidence interval [CI] = 20.9% to 35.7%) per year between 2001 and 2007. Testing rates for all subgroups increased. The lowest growth rate was among Hispanic patients, whose CT rates grew 14.2% (95% CI = 5.7% to 23.5%) per year. The highest growth rate was in nonurban hospitals, at 43.1% (95% CI = 15.2% to 77.8%) per year. Patients triaged as nonurgent received the fewest CTs, compared to those who should be seen in 2 hours or less. With regard to sources of payment, the self-pay subgroup experienced the highest rate of increase at 35.1% (95% CI = 18.6% to 53.9%). The PE diagnosis/CT ratio from 2002 to 2009 was 2.7% for the CSS group. The pneumonia diagnosis/CT ratio grew from 5.8% in 2002 to 2005 to 7.8% in 2006 to 2009. CONCLUSIONS: Computed tomography use in ED visits by patients with chest symptoms increased dramatically from 2001 to 2007 and seems to have leveled off in subsequent years. The low PE diagnosis-to-CT ratio suggests that EDs may need to promote evidence-based use of CT.

EHRs in primary care practices: benefits, challenges, and successful strategies.

OBJECTIVES: To understand the current use of electronic health records (EHRs) in small primary care practices and to explore experiences and perceptions of physicians and staff toward the benefits, challenges, and successful strategies for implementation and meaningful use of advanced EHR functions. STUDY DESIGN: Qualitative case study of 6 primary care practices in Virginia. METHODS: We performed surveys and in-depth interviews with clinicians and administrative staff (N = 38) and observed interpersonal relations and use of EHR functions over a 16-month period. Practices with an established EHR were selected based on a maximum variation of quality activities, location, and ownership. RESULTS: Physicians and staff report increased efficiency in retrieving medical records, storing patient information, coordination of care, and office operations. Costs, lack of knowledge of EHR functions, and problems transforming office operations were barriers reported for meaningful use of EHRs. Major disruption to patient care during upgrades and difficulty utilizing performance tracking and quality functions were also reported. Facilitators for adopting and using advanced EHR functions include team-based care, adequate technical support, communication and training for employees and physicians, alternative strategies for patient care during transition, and development of new processes and work flow procedures. CONCLUSIONS: Small practices experience difficulty with implementation and utilization of advanced EHR functions. Federal and state policies should continue to support practices by providing technical assistance and financial incentives, grants, and/or loans. Small practices should consider using regional extension center services and reaching out to colleagues and other healthcare organizations with similar EHR systems for advice and guidance.