A comparison of synthetic control approaches for the evaluation of policy interventions using observational data: Evaluating the impact of redesigning urgent and emergency care in Northumberland

Objective

To compare the original synthetic control (OSC) method with alternative approaches (Generalized [GSC], Micro [MSC], and Bayesian [BSC] synthetic control methods) and re-evaluate the impact of a significant restructuring of urgent and emergency care in Northeast England, which included the opening of the UK's first purpose-built specialist emergency care hospital.

Data Sources

Simulations and data from Secondary Uses Service data, a single comprehensive repository for patient-level health care data in England.

Study Design

Hospital use of individuals exposed and unexposed to the restructuring is compared. We estimate the impact using OSC, MSC, BSC, and GSC applied at the general practice level. We contrast the estimation methods' performance in a Monte Carlo simulation study.

Data Collection/Extraction Methods

Hospital activity data from Secondary Uses Service for patients aged over 18 years registered at a general practice in England from April 2011 to March 2019.

Principal Findings

None of the methods dominated all simulation scenarios. GSC was generally preferred. In contrast to an earlier evaluation that used OSC, GSC reported a smaller impact of the opening of the hospital on Accident and Emergency (A&E) department (also known as emergency department or casualty) visits and no evidence for any impact on the proportion of A&E patients seen within 4 h.

Conclusions

The simulation study highlights cases where the considered methods may lead to biased estimates in health policy evaluations. GSC was found to be the most reliable method of those considered. Considering more disaggregated data over a longer time span and applying GSC indicates that the specialist emergency care hospitals in Northumbria had less impact on A&E visits and waiting times than suggested by the original evaluation which applied OSC to more aggregated data.     

Correction to: Epilepsy related multimorbidity,polypharmacy and risks in adults with intellectual disabilities: a national study

Journal of Neurology -     

Synchrotron-based intravenous cerebral angiography in a small animal model

K-edge digital subtraction angiography (KEDSA), a recently developed synchrotron-based technique, utilizes monochromatic radiation and allows acquisition of high-quality angiography images after intravenous administration of contrast agent. We tested KEDSA for its suitability for intravenous cerebral angiography in an animal model. Adult male New Zealand rabbits were subjected to either angiography with conventional x-ray equipment or synchrotron-based intravenous KEDSA, using an iodine-based contrast agent. Angiography with conventional x-ray equipment after intra-arterial administration of contrast agent demonstrated the major intracranial vessels but no smaller branches. KEDSA was able to visualize the major intracranial vessels as well as smaller branches in both radiography mode (planar images) and tomography mode. Visualization was achieved with as little as 0.5 ml kg-1 of iodinated contrast material. We were able to obtain excellent visualization of the cerebral vasculature in an animal model using intravenous injection of contrast material, using synchrotron-based KEDSA.     

CD4+/CD56+ hematodermic neoplasm ("blastic natural killer cell lymphoma"): neoplastic cells express the immature dendritic cell marker BDCA-2 and produce interferon

CD4+/CD56+ hematodermic neoplasm ("blastic natural killer [NK]-cell lymphoma") is a rare highly aggressive neoplasm associated with cutaneous manifestations followed by dissemination to blood, bone marrow, and other tissues. Neoplastic cells exhibit a lineage-negative CD4+/CD56+/CD43+/HLA-DR+ immunophenotype, initially suggesting an NK-cell derivation. The recent discovery of CD123 antigen expression by tumor cells has provided evidence for a relationship to immature dendritic cells (DCs), a group of myeloid and lymphoid early-committed progenitors capable of differentiating into antigen-presenting DCs. Based on flow cytometric analysis, myeloid DCs represent the majority of human peripheral blood DCs and are positive for blood dendritic cell antigen (BDCA)-1 (or CD1c), CD13, CD11c(high), CD33, and CD123(low). Plasmacytoid DCs are BDCA-2+/ CD123(high)+/CD13-/CD33- and produce interferon (IFN)-alpha when triggered by antigens. IFN-alpha production may be detected in tissue sections using antibodies for myxovirus A (MxA) protein, a surrogate marker. This report describes the clinical, histologic, immunophenotypic, cytogenetic, and molecular genetic findings for 3 cases of CD4+/CD56+ hematodermic neoplasms. In all cases, neoplastic cells were reactive for CD123, BDCA-2, and MxA protein, providing strong evidence for an immature plasmacytoid DC derivation for this rare neoplasm.     

SMS-based smartphone application for disease surveillance has doubled completeness and timeliness in a limited-resource setting – evaluation of a 15-week pilot program in Central African Republic (CAR)

Background

It is a challenge in low-resource settings to ensure the availability of complete, timely disease surveillance information. Smartphone applications (apps) have the potential to enhance surveillance data transmission.

Methods

The Central African Republic (CAR) Ministry of Health and Médecins Sans Frontières (MSF) conducted a 15-week pilot project to test a disease surveillance app, Argus, for 20 conditions in 21 health centers in Mambéré Kadéi district (MK 2016). Results were compared to the usual paper-based surveillance in MK the year prior (MK 2015) and simultaneously in an adjacent health district, Nana-Mambére (NM 2016). Wilcoxon rank sum and Kaplan-Meier analyses compared report completeness and timeliness; the cost of the app, and users’ perceptions of its usability were assessed.

Results

Two hundred seventy-one weekly reports sent by app identified 3403 cases and 63 deaths; 15 alerts identified 28 cases and 4 deaths. Median completeness (IQR) for MK 2016, 81% (81–86%), was significantly higher than in MK 2015 (31% (24–36%)), and NM 2016 (52% (48–57)) (p?<?0.01). Median timeliness (IQR) for MK 2016, 50% (39–57%) was also higher than in MK 2015, 19% (19–24%), and NM 2016 29% (24–36%) (p?<?0.01). Kaplan-Meier Survival Analysis showed a significant progressive reduction in the time taken to transmit reports over the 15-week period (p?<?0.01). Users ranked the app’s usability as greater than 4/5 on all dimensions. The total cost of the 15-week pilot project was US$40,575. It is estimated that to maintain the app in the 21 health facilities of MK will cost approximately US$18,800 in communication fees per year.

Conclusions

The app-based data transmission system more than doubled the completeness and timeliness of disease surveillance reports. This simple, low-cost intervention may permit the early detection of disease outbreaks in similar low-resource settings elsewhere.

     

Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate

Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.     

Postbaccalaureate nurse residency 1-year outcomes

The authors document the 1-year outcomes of the postbaccalaureate residency program jointly developed and implemented by the University Health-System Consortium and the American Association of Colleges of Nursing. Data on 2 cohorts of residents (n = 679) in 12 sites across the country are presented. The 1-year termination rate was 12%, after those lost to the program because of National Council Licensure Examination failure, serious illness, or death were eliminated from the analysis. Additional analyses using data collected at entry to the program, 6 months, and 1 year using 3 instruments, the Casey-Fink Graduate Nurse Experience Survey, the Gerber's Control Over Nursing Practice Scale, and the McCloskey Mueller Satisfaction Scale, are presented and discussed.     

An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials,utilizing polymer‐supported reagents

Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in‐house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer‐supported reagents starting from 2‐amino‐2'‐chloro‐5‐nitrobenzophenone (clonazolam) and 2‐amino‐5‐nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4‐triazole ring moiety was performed within a gas chromatography–mass spectrometry (GC–MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by‐product profiles for both the micro and the preparative scale syntheses are also presented.     

Synthesis,analytical characterization,and monoamine transporter activity of the new psychoactive substance 4‐methylphenmetrazine (4‐MPM), with differentiation from its ortho‐ and meta‐ positional isomers

The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to 3,4‐methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace.