Health expenditures by services and providers for 195 countries, 2000-2017.

INTRODUCTION: National Health Accounts are a significant source of health expenditure data, designed to be comprehensive and comparable across countries. However, there is currently no single repository of this data and even when compiled major gaps persist. This research aims to provide policymakers and researchers with a single repository of available national health expenditures by healthcare functions (ie, services) and providers of such services. Leveraging these data within statistical methods, a complete set of detailed health expenditures is estimated. METHODS: A methodical compilation and synthesis of all available national health expenditure reports including disaggregation by healthcare functions and providers was conducted. Using these data, a Bayesian multivariate regression analysis was implemented to estimate national-level health expenditures by the cross-classification of functions and providers for 195 countries, from 2000 to 2017. RESULTS: This research used 1662 country-years and 110 070 data points of health expenditures from existing National Health Accounts. The most detailed country-year had 52% of the categories of interest reported. Of all health functions, curative care and medical goods were estimated to make up 51.4% (uncertainty interval (UI) 33.2% to 59.4%) and 17.5% (UI 13.0% to 26.9%) of total global health expenditures in 2017, respectively. Three-quarters of the global health expenditures are allocated to three categories of providers: hospital providers (35.4%, UI 30.3% to 38.9%), providers of ambulatory care (25.5%, UI 21.1% to 28.8%) and retailers of medical goods (14.4%, UI 12.4% to 16.3%). As gross domestic product increases, countries spend more on long-term care and less on preventive care. CONCLUSION: Disaggregated estimates of health expenditures are often unavailable and unable to provide policymakers and researchers a holistic understanding of how expenditures are used. This research aggregates reported data and provides a complete time-series of estimates, with uncertainty, of health expenditures by health functions and providers between 2000 and 2017 for 195 countries.

Mining of high throughput screening database reveals AP-1 and autophagy pathways as potential targets for COVID-19 therapeutics.

The recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.

Biological activity-based modeling identifies antiviral leads against SARS-CoV-2.

Computational approaches for drug discovery, such as quantitative structure-activity relationship, rely on structural similarities of small molecules to infer biological activity but are often limited to identifying new drug candidates in the chemical spaces close to known ligands. Here we report a biological activity-based modeling (BABM) approach, in which compound activity profiles established across multiple assays are used as signatures to predict compound activity in other assays or against a new target. This approach was validated by identifying candidate antivirals for Zika and Ebola viruses based on high-throughput screening data. BABM models were then applied to predict 311 compounds with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the predicted compounds, 32% had antiviral activity in a cell culture live virus assay, the most potent compounds showing a half-maximal inhibitory concentration in the nanomolar range. Most of the confirmed anti-SARS-CoV-2 compounds were found to be viral entry inhibitors and/or autophagy modulators. The confirmed compounds have the potential to be further developed into anti-SARS-CoV-2 therapies.

Cell-Based No-Wash Fluorescence Assays for Compound Screens Using a Fluorescence Cytometry Plate Reader.

High-throughput cell-based fluorescent imaging assays often require removal of background fluorescent signal to obtain robust measurements. Processing high-density microplates to remove background signal is challenging because of equipment requirements and increasing variation after multiple plate wash steps. Here, we present the development of a wash-free cell-based fluorescence assay method for high-throughput screening using a laser scanning fluorescence plate cytometer. The cytometry data consisted of cell count and fluorescent intensity measurements for phenotypic screening. We obtained robust screening results by applying this assay methodology to the lysosomal storage disease Niemann-Pick disease type A. We further demonstrated that this cytometry method can be applied to the detection of cholesterol in Niemann-Pick disease type C. Lastly, we used the Mirrorball method to obtain preliminary results for the detection of Zika and Dengue viral envelope protein. The advantages of this assay format include 1) no plate washing, 2) 4-fold faster plate scan and analysis time, 3) high throughput, and 4) >10-fold smaller direct data files. In contrast, traditional imaging assays require multiple plate washes to remove the background signal, long plate scan and data analysis times, and large data files. Therefore, this versatile and broadly applicable Mirrorball-based method greatly improves the throughput and data quality of image-based screening by increasing sensitivity and efficiency while reducing assay artifacts. SIGNIFICANCE STATEMENT: This work has resulted in the development of broadly applicable cell-based fluorescence imaging assays without the requirement of washing out reagents to reduce background signal, which effectively decreases the need for extensive plate processing by the researcher. We demonstrate this high-throughput method for drug screening against lysosomal storage diseases and a commonly used viral titer assay.

A cell-based, infectious-free, platform to identify inhibitors of lassa virus ribonucleoprotein (vRNP) activity.

The mammarenavirus Lassa (LASV) is highly prevalent in West Africa where it infects several hundred thousand individuals annually resulting in a high number of Lassa fever (LF) cases, a febrile disease associated with high morbidity and significant mortality. Mounting evidence indicates that the worldwide-distributed prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. There are not Food and Drug Administration (FDA) licensed vaccines and current anti-mammarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective and can cause significant side effects. Therefore, there is an unmet need for novel antiviral drugs to combat LASV. This task would be facilitated by the implementation of high throughput screens (HTS) to identify inhibitors of the activity of the virus ribonucleoprotein (vRNP) responsible for directing virus RNA genome replication and gene transcription. The use of live LASV for this purpose is jeopardized by the requirement of biosafety level 4 (BSL4) containment. We have developed a virus-free cell platform, where expression levels of reporter genes serve as accurate surrogates of vRNP activity, to develop cell-based assays compatible with HTS to identify inhibitors of LASV and LCMV mammarenavirus vRNP activities.

Development and Implementation of a Surgical Quality Improvement Pathway for Pediatric Intussusception Patients.

Children with intussusception can be admitted or discharged from the emergency department (ED) following enema reduction, but little is known about best practices for surgical follow-up and the need for a return to care. METHODS: We developed a standardized clinical assessment and management plan (SCAMP) for ileocolic intussusception to enable the discharge from the ED of successfully reduced patients meeting certain criteria with 2 planned follow-up phone calls by surgical personnel after discharge. Outcomes included incidence of complications in discharged patients, bacteremia, the success of follow-up phone calls, rates of recurrent intussusception, and return to care. RESULTS: Of the 118 patient encounters treated through the SCAMP in 2 pilot studies from February 2013 to December 2017, 76% met discharge criteria, of whom 88% underwent outpatient management. There were no instances of bowel perforation, necrosis, or death in the discharged group. No patients developed bacteremia despite withholding antibiotics for the indication of intussusception. Sixty-two percent and 59% of patients received 24-hour follow-up phone calls, and 28% and 55% of patients received second follow-up phone calls in pilots 1 and 2, respectively. Of those successfully discharged, 74% did not return to care, 19% returned for recurrent intussusception, and 7% returned for unrelated symptoms. Nearly all patients who returned to care did so through the ED and not the clinic. CONCLUSIONS: Implementation of the SCAMP demonstrated that patients meeting certain criteria could be safely discharged from the ED, avoid antibiotics, and safely undergo phone-based follow-up for concerns of recurrent intussusception.

Advancing precision medicine with personalized drug screening.

Personalized drug screening (PDS) of approved drug libraries enables rapid development of specific small-molecule therapies for individual patients. With a multidisciplinary team including clinicians, researchers, ethicists, informaticians and regulatory professionals, patient treatment can be optimized with greater efficacy and fewer adverse effects by using PDS as an approach to find remedies. In addition, PDS has the potential to rapidly identify therapeutics for a patient suffering from a disease without an existing therapy. From cancer to bacterial infections, we review specific maladies addressed with PDS campaigns. We predict that PDS combined with personal genomic analyses will contribute to the development of future precision medicine endeavors.

Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1.

The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation.

Ultrasonography-guided bilateral rectus sheath block vs local anesthetic infiltration after pediatric umbilical hernia repair: a prospective randomized clinical trial.

IMPORTANCE: Regional anesthetic techniques can be used to alleviate postoperative pain in children undergoing pediatric surgical procedures. Use of ultrasonographic guidance for bilateral rectus sheath block (BRSB) has been shown to improve immediate pain scores and reduce use of postoperative analgesia in the postanesthesia care unit (PACU). OBJECTIVE: To compare efficacy of ultrasonography-guided BRSB and local anesthetic infiltration (LAI) in providing postoperative analgesia after pediatric umbilical hernia repair. DESIGN: Prospective, observer-blinded, randomized clinical trial. SETTING: Tertiary-referral urban children's hospital. PARTICIPANTS: Eligible children 3 to 12 years of age undergoing elective umbilical hernia repair from November 16, 2009, through May 31, 2011. INTERVENTIONS: Ropivacaine hydrochloride administered at the conclusion of surgery as LAI by the surgeon (n = 25) or as ultrasonography-guided BRSB by the anesthesiologist (n = 27). MAIN OUTCOMES AND MEASURES: Scores on the FACES Pain Rating Scale measured at 10-minute intervals and all use of analgesic medications in the PACU. RESULTS: Median FACES scores in the PACU were lower in the BRSB group compared with the LAI group at 10 minutes (0 vs 1; P = .04), 30 minutes (0 vs 1; P = .01), and 40 minutes or later (0 vs 1; P = .03). Fewer doses of opioid and nonopioid medications were given to the BRSB group compared with the LAI group (5 vs 11 doses for opioids; 5 vs 10 for nonopioids). CONCLUSIONS AND RELEVANCE: In the PACU, ultrasonography-guided BRSB after umbilical hernia repair in children is associated with lower median FACES scores and decreased use of opioid and nonopioid medications compared with LAI. Future studies could examine the use of longer-acting anesthetic agents with ultrasonography-guided BRSB. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01015053.

An alternative direct compound dispensing method using the HP D300 digital dispenser.

Evaluation of compound activity in vitro is crucial to drug discovery efforts and require that the compounds be accurately and reliably titrated and dispensed to the assay wells. The HP D300 dispenser uses inkjet technology to achieve small-volume dispensing that allows concentration-response testing using the direct dilution paradigm. Although inkjet technology has been long in existence, it is new to the field of screening and drug development. We have evaluated the D300 dispenser in a biochemical assay, a cell-based reporter gene assay, and a cytotoxicity assay. The software for this instrument is user friendly, and the compound-dispensing process is streamlined. However, a limitation is that this dispenser is currently applicable to only 96-well and 384-well plate formats and not to 1536-well high-density plates. Our results indicate that the D300 generates clean and reproducible results that correlate with those produced with more commonly used instruments such as the pin tool. We found that the instrument is useful and can improve the throughput of compound dispensing in 96-well and 384-well plates.

Variation in practice patterns and resource utilization surrounding management of intussusception at freestanding Children's Hospitals.

PURPOSE: To characterize variation in practice patterns and resource utilization associated with the management of intussusception at Children's Hospitals. METHODS: A retrospective cohort study (1/1/09-6/30/11) of 27 Children's Hospitals participating in the Pediatric Health Information System database was performed. Hospitals were compared with regard to their rates of operative management following attempted enema reduction, prophylactic antibiotic utilization, same-day discharge for those successfully managed non-operatively, 48-h readmission rates, and case-related cost and charges. RESULTS: 2544 patients were identified (median: 93 cases/center) with a median age of 17 months. The rate of operation following attempted enema reduction varied significantly across hospitals (overall rate: 21.1%: range: 11%-62.8%; p<0.0001). For patients managed non-operatively, significant variability was found for prophylactic antibiotic utilization (overall rate: 23.3%; range: 1.4%-93.2%; p<0.0001), same-day discharge (overall rate: 15.2%; range: 0%-83.8%; p<0.0001), readmission rates (overall rate: 17.5%; range: 5.3%-32.1%; p<0.0001), treatment-related costs (overall median: $2490; range: $829-$5905; p<0.0001), and charges (overall median: $6350; range: $2497-$10,306; p<0.0001). Variability in costs and charges was even greater when analyzing all patients (operative and non-operative) with intussusception (overall cost median: $2865; range: $1574-$6763; p<0.0001; overall charge median: $7110; range: $3544-$22,097; p<0.0001). CONCLUSION: Significant variation in practice patterns and resource utilization exists between Children's Hospitals in the management of intussusception. Prospective analysis of practice variation and appropriately risk-adjusted outcomes through a collaborative quality-improvement platform could accelerate the dissemination of best-practice guidelines for optimizing cost-effective care.

The Kaiser Permanente Electronic Health Record: transforming and streamlining modalities of care.

We examined the impact of implementing a comprehensive electronic health record (EHR) system on ambulatory care use in an integrated health care delivery system with more than 225,000 members. Between 2004 and 2007, the annual age/sex-adjusted total office visit rate decreased 26.2 percent, the adjusted primary care office visit rate decreased 25.3 percent, and the adjusted specialty care office visit rate decreased 21.5 percent. Scheduled telephone visits increased more than eightfold, and secure e-mail messaging, which began in late 2005, increased nearly sixfold by 2007. Introducing an EHR creates operational efficiencies by offering nontraditional, patient-centered ways of providing care.