Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

IFRS 17 Insurance Contracts is a new accounting standard currently expected to come into force on 1 January 2023. It supersedes IFRS 4 Insurance Contracts. IFRS 17 establishes key principles that entities must apply in all aspects of the accounting of insurance contracts. In doing so, the Standard aims to increase the usefulness, comparability, transparency and quality of financial statements.

A fundamental concept introduced by IFRS 17 is the contractual service margin (CSM). This represents the unearned profit that an entity expects to earn as it provides services. However, as a principles-based standard, IFRS 17 results in entities having to apply significant judgement when determining the inputs, assumptions and techniques it uses to determine the CSM at each reporting period.

In general, the Standard resolves broad categories of mismatches which arise under IFRS 4. Notable examples include mismatches between assets recorded at current market value and liabilities calculated using fixed discount rates as well as inconsistencies in the timing of profit recognition over the duration of an insurance contract. However, there are requirements of IFRS 17 that may create economic or accounting mismatches of its own. For example, new mismatches could arise between the measurement of underlying contracts and the corresponding reinsurance held. Additionally, mismatches can still arise between the measurement of liabilities and the assets that support the liabilities.

This paper explores the technical, operational and commercial issues that arise across these and other areas focusing on the CSM. As a standard that is still very much in its infancy, and for which wider consensus on topics is yet to be achieved, this paper aims to provide readers with a deeper understanding of the issues and opportunities that accompany it.

Background: Since January 1, 2016 2358 people have died from opioid poisoning in Alberta. Buprenorphine/naloxone (bup/nal) is the recommended first line treatment for opioid use disorder (OUD) and this treatment can be initiated in emergency departments and urgent care centres (EDs). Aim Statement: This project aims to spread a quality improvement intervention to all 107 adult EDs in Alberta by March 31, 2020. The intervention supports clinicians to initiate bup/nal for eligible individuals and provide rapid referrals to OUD treatment clinics. Measures & Design: Local ED teams were identified (administrators, clinical nurse educators, physicians and, where available, pharmacists and social workers). Local teams were supported by a provincial project team (project manager, consultant, and five physician leads) through a multi-faceted implementation process using provincial order sets, clinician education products, and patient-facing information. We used administrative ED and pharmacy data to track the number of visits where bup/nal was given in ED, and whether discharged patients continued to fill any opioid agonist treatment (OAT) prescription 30 days after their index ED visit. OUD clinics reported the number of referrals received from EDs and the number attending their first appointment. Patient safety event reports were tracked to identify any unintended negative impacts. Evaluation/Results: We report data from May 15, 2018 (program start) to September 31, 2019. Forty-nine EDs (46% of 107) implemented the program and 22 (45% of 49) reported evaluation data. There were 5385 opioid-related visits to reporting ED sites after program adoption. Bup/nal was given during 832 ED visits (663 unique patients): 7 visits in the 1st quarter the program operated, 55 in the 2nd, 74 in the 3rd, 143 in the 4th, 294 in the 5th, and 255 in the 6th. Among 505 unique discharged patients with 30 day follow up data available 319 (63%) continued to fill any OAT prescription after receiving bup/nal in ED. 16 (70%) of 23 community clinics provided data. EDs referred patients to these clinics 440 times, and 236 referrals (54%) attended their first follow-up appointment. Available data may under-report program impact. 5 patient safety events have been reported, with no harm or minimal harm to the patient. Discussion/Impact: Results demonstrate effective spread and uptake of a standardized provincial ED based early medical intervention program for patients who live with OUD.

The theoretical investigation of shocks and solitary structures in a dense quantum plasma containing electrons at finite temperature, nondegenerate cold electrons, and stationary ions has been carried out. A linear dispersion relation is derived for the corresponding electron acoustic waves. The solitary structures of small nonlinearity have been studied by using the standard reductive perturbation method. We have considered collisions to be absent, and the shocks arise out of viscous force. Furthermore, with the help of a standard reductive perturbation technique, a KdV–Burger equation has been derived and analyzed numerically. Under limiting cases, we have also obtained the KdV solitary profiles and studied the parametric dependence. The results are important in explaining the many phenomena of the laser–plasma interaction of dense plasma showing quantum effects.

Background: Buprenorphine/naloxone (bup/nal) is a partial opioid agonist/antagonist and recommended first line treatment for opioid use disorder (OUD). Emergency departments (EDs) are a key point of contact with the healthcare system for patients living with OUD. Aim Statement: We implemented a multi-disciplinary quality improvement project to screen patients for OUD, initiate bup/nal for eligible individuals, and provide rapid next business day walk-in referrals to addiction clinics in the community. Measures & Design: From May to September 2018, our team worked with three ED sites and three addiction clinics to pilot the program. Implementation involved alignment with regulatory requirements, physician education, coordination with pharmacy to ensure in-ED medication access, and nurse education. The project is supported by a full-time project manager, data analyst, operations leaders, physician champions, provincial pharmacy, and the Emergency Strategic Clinical Network leadership team. For our pilot, our evaluation objective was to determine the degree to which our initiation and referral pathway was being utilized. We used administrative data to track the number of patients given bup/nal in ED, their demographics and whether they continued to fill bup/nal prescriptions 30 days after their ED visit. Addiction clinics reported both the number of patients referred to them and the number of patients attending their referral. Evaluation/Results: Administrative data shows 568 opioid-related visits to ED pilot sites during the pilot phase. Bup/nal was given to 60 unique patients in the ED during 66 unique visits. There were 32 (53%) male patients and 28 (47%) female patients. Median patient age was 34 (range: 21 to 79). ED visits where bup/nal was given had a median length of stay of 6 hours 57 minutes (IQR: 6 hours 20 minutes) and Canadian Triage Acuity Scores as follows: Level 1 – 1 (2%), Level 2 – 21 (32%), Level 3 – 32 (48%), Level 4 – 11 (17%), Level 5 – 1 (2%). 51 (77%) of these visits led to discharge. 24 (47%) discharged patients given bup/nal in ED continued to fill bup/nal prescriptions 30 days after their index ED visit. EDs also referred 37 patients with OUD to the 3 community clinics, and 16 of those individuals (43%) attended their first follow-up appointment. Discussion/Impact: Our pilot project demonstrates that with dedicated resources and broad institutional support, ED patients with OUD can be appropriately initiated on bup/nal and referred to community care.

By using reductive perturbation technique we have studied the linear and non-linear properties of ion-acoustic solitary structures in a three-component plasma containing non-thermal electrons and Boltzmann positrons and a comparatively cold ion which has got a streaming motion. The Korteweg–de Vries equation has been obtained and the dependence of small amplitude solitary structures on various plasma parameters such as streaming velocity (v0), non-thermal parameter (β), reciprocal of electron temperature (χ), positron density (p), Mach number (M), and ion density (δ) have been studied. The possibility of formation of enveloping soliton and its characteristic features are further investigated by deriving the non-linear Schrödinger equation.

Using reductive perturbation technique, small-amplitude ion-acoustic solitary wave has been investigated in multi-component dense plasma, in which an electron beam propagates along the general streaming motion. The electrons in plasma have the q-exponential distribution. The positive and negative ions follow a regular Maxwellian distribution. It has been found that the positive and negative ion densities as well as the beam concentration have significant effect on the formation and properties of solitary structures. The streaming velocities of corresponding particles also have pronounced effect on the features of the solitons.

Most nutritional studies on the development of children focus on mother–infant interactions. Maternal nutrition is critically involved in the growth and development of the fetus, but what about the father? The aim is to investigate the effects of paternal methyl-group donor intake (methionine, folate, betaine, choline) on paternal and offspring global DNA (hydroxy)methylation, offspring IGF2 DMR DNA methylation, and birth weight. Questionnaires, 7-day estimated dietary records, whole blood samples, and anthropometric measurements from 74 fathers were obtained. A total of 51 cord blood samples were collected and birth weight was obtained. DNA methylation status was measured using liquid chromatography-tandem mass spectrometry (global DNA (hydroxy)methylation) and pyrosequencing (IGF2 DMR methylation). Paternal betaine intake was positively associated with paternal global DNA hydroxymethylation (0.028% per 100 mg betaine increase, 95% CI: 0.003, 0.053, P=0.03) and cord blood global DNA methylation (0.679% per 100 mg betaine increase, 95% CI: 0.057, 1.302, P=0.03). Paternal methionine intake was positively associated with CpG1 (0.336% per 100 mg methionine increase, 95% CI: 0.103, 0.569, P=0.006), and mean CpG (0.201% per 100 mg methionine increase, 95% CI: 0.001, 0.402, P=0.049) methylation of the IGF2 DMR in cord blood. Further, a negative association between birth weight/birth weight-for-gestational age z-score and paternal betaine/methionine intake was found. In addition, a positive association between choline and birth weight/birth weight-for-gestational age z-score was also observed. Our data indicate a potential impact of paternal methyl-group donor intake on paternal global DNA hydroxymethylation, offspring global and IGF2 DMR DNA methylation, and prenatal growth.

Nonlinear amplitude modulation of ion-acoustic waves (IAWs) in a fully relativistic unmagnetized two-fluid plasma has been theoretically studied by using complete set of fully relativistic dynamic equations. To describe the nonlinear evolution of the wave envelope a nonlinear Schrödinger (NLS) equation is derived by using standard multiple scale perturbation technique. Using this equation it is shown that the wave becomes modulationally unstable as the wavenumber exceeds certain critical value. This critical wavenumber is found to decrease with increase in relativistic effect. The instability growth rate has also been calculated numerically for different values of plasma drift velocity. The growth rate is shown to decrease with increase in the relativistic effect.

This study developed a fast and high throughput dot-blot technique to evaluate the presence of Entamoeba in stool samples (n = 643) followed by a PCR-based method to validate and differentiate the two species E. histolytica and E. dispar. The prevalence rate of the parasite has been detected in a cross-sectional study carried out in the population of the Eastern and Northern parts of India. Of the various demographic features, prevalence was highest in the monsoon season (P = 0·017), in the <15 years age group (P = 0·015). In HIV-positive individuals, the prevalence rate was significantly high (P = 0·008) in patients with a CD4 cell count <200 as well as in patients without antiretroviral therapy (ART) (P = 0·011). Our analysis further confirmed that risk factors such as toilet facilities, living conditions, hygienic practices, drinking water source, occupation and level of education are important predictors as they were found to contribute significantly in the prevalence of the parasite.

Using high resolution powder neutron diffraction data, we show that there is a distinct anomaly in the structural noncentrosymmetry around the magnetic transition point TN for bulk and nanoscale BiFeO3. It appears that the structural noncentrosymmetry - which gives rise to the ferroelectric polarization - is suppressed anomalously by ~1% (of the average noncentrosymmetry at above the magnetic transition) in the bulk sample and by ~12% in the nanoscale sample as the magnetic transition is approached from higher temperature. This observation shows that the multiferroic coupling improves in the nanoscale sample which is expected to brighten the application prospects of nanoscale BiFeO3 in nanospintronics-based sensor devices.

PACS Nos. 75.70.Cn, 75.75.-c

X-ray powder diffraction data of BaFCl are reported for 2θ from 5° to 150° at 25 °C. Strain-free and dendrite-free single crystals of BaFCl, grown by flux method with KCl as flux, were powdered for recording this data. BaFCl is tetragonal, space group P4/nmm, with a=4.3964(1) Å and c=7.2315(3) Å.