Continuous infusion versus bolus injection of loop diuretics for acute heart failure.

BACKGROUND: Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload. OBJECTIVES: To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults. SEARCH METHODS: We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence. MAIN RESULTS: The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I2 = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I2 = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I2 = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I2 = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics. AUTHORS' CONCLUSIONS: Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.

Peer mentorship and professional identity formation: an ecological systems perspective.

BACKGROUND: Mentoring can help shape how medical students think, feel, and act as physicians. Yet, the mechanism in which it influences this process of professional identity formation (PIF) remains poorly understood. Through the lens of the ecological systems theory, this study explores the interconnected and dynamic system of mentoring relationships and resources that support professional development and growth within the Palliative Medicine Initiative (PMI), a structured research peer mentoring program. METHODS: A secondary analysis of transcripts of semi-structured interviews with peer mentors and mentees and a review of their mentoring diaries was conducted to explore the impact of participation in a longitudinal peer mentoring program on both mentees and peer mentors on their personal and professional development through the lens of the mentoring ecosystem model. The Systematic Evidence-Based Approach was adapted to analyze the data via content and thematic analysis. RESULTS: Eighteen mentees and peer mentors participated and described a supportive community of practice within the research program, with discrete micro-, meso-, and macro-environments that are dynamic, reflexive, and interconnected to form a mentoring ecosystem. Within this ecosystem, reflection is fostered, and identity work is done-ultimately shaping and refining self-concepts of personhood and identity. CONCLUSION: This study underscores the nuances and complexities of mentorship and supports the role of the mentoring ecosystem in PIF. A deeper understanding of the multiple factors that converge to facilitate the professional development of mentees can help educators develop and implement structured peer mentorship programs that better support reflective practice and identity work.

Mentoring as a complex adaptive system - a systematic scoping review of prevailing mentoring theories in medical education.

BACKGROUND: Effective mentorship is an important component of medical education with benefits to all stakeholders. In recent years, conceptualization of mentorship has gone beyond the traditional dyadic experienced mentor-novice mentee relationship to include group and peer mentoring. Existing theories of mentorship do not recognize mentoring's personalized, evolving, goal-driven, and context-specific nature. Evidencing the limitations of traditional cause-and-effect concepts, the purpose of this review was to systematically search the literature to determine if mentoring can be viewed as a complex adaptive system (CAS). METHODS: A systematic scoping review using Krishna's Systematic Evidence-Based Approach was employed to study medical student and resident accounts of mentoring and CAS in general internal medicine and related subspecialties in articles published between 1 January 2000 and 31 December 2023 in PubMed, Embase, PsycINFO, ERIC, Google Scholar, and Scopus databases. The included articles underwent thematic and content analysis, with the themes identified and combined to create domains, which framed the discussion. RESULTS: Of 5,704 abstracts reviewed, 134 full-text articles were evaluated, and 216 articles were included. The domains described how mentoring relationships and mentoring approaches embody characteristics of CAS and that mentorship often behaves as a community of practice (CoP). Mentoring's CAS-like features are displayed through CoPs, with distinct boundaries, a spiral mentoring trajectory, and longitudinal mentoring support and assessment processes. CONCLUSION: Recognizing mentorship as a CAS demands the rethinking of the design, support, assessment, and oversight of mentorship and the role of mentors. Further study is required to better assess the mentoring process and to provide optimal training and support to mentors.

Barriers to and facilitators of physical activity in adults living with and beyond cancer, with special emphasis on head and neck cancer: a systematic review of qualitative and mixed methods studies.

PURPOSE: Physical activity can improve health outcomes for cancer patients; however, only 30% of patients are physically active. This review explored barriers to and facilitators of physical activity promotion and participation in patients living with and beyond cancer. Secondary aims were to (1) explore similarities and differences in barriers and facilitators experienced in head and neck cancer versus other cancers, and (2) identify how many studies considered the influence of socioeconomic characteristics on physical activity behaviour. METHODS: CINAHL Plus, MEDLINE, PsycINFO, Scopus and Cochrane (CDSR) were searched for qualitative and mixed methods evidence. Quality assessment was conducted using the Mixed Methods Appraisal Tool and a Critical Appraisal Skills Programme Tool. Thematic synthesis and frequency of reporting were conducted, and results were structured using the Capability-Opportunity-Motivation-Behaviour model and Theoretical Domains Framework. RESULTS: Thirty qualitative and six mixed methods studies were included. Socioeconomic characteristics were not frequently assessed across the included studies. Barriers included side effects and comorbidities (physical capability; skills) and lack of knowledge (psychological capability; knowledge). Having a dry mouth or throat and choking concerns were reported in head and neck cancer, but not across other cancers. Facilitators included improving education (psychological capability; knowledge) on the benefits and safety of physical activity. CONCLUSION: Educating patients and healthcare professionals on the benefits and safety of physical activity may facilitate promotion, uptakeand adherence. Head and neck cancer patients experienced barriers not cited across other cancers, and research exploring physical activity promotion in this patient group is required to improve physical activity engagement.

Perampanel add-on for drug-resistant focal epilepsy.

BACKGROUND: Epilepsy is one of the most common neurological disorders. Approximately 30% of people with epilepsy are considered to be drug-resistant, and usually need treatment with a combination of other antiepileptic drugs. Perampanel is a newer antiepileptic drug that has been investigated as add-on therapy for drug-resistant focal epilepsy. OBJECTIVES: To evaluate the benefits and harms of perampanel as add-on therapy for people with drug-resistant focal epilepsy. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 20 October 2022. SELECTION CRITERIA: We included randomised controlled trials comparing add-on perampanel with placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. 50% or greater reduction in seizure frequency. Our secondary outcomes were 2. seizure freedom, 3. treatment withdrawal due to any reason, 4. treatment withdrawal due to adverse effects, and 5. ADVERSE EFFECTS: We used an intention-to-treat population for all primary analyses. We presented the results as risk ratios (RR) with 95% confidence intervals (CIs), except for individual adverse effects, which we reported with 99% CIs to compensate for multiple testing. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included seven trials involving 2524 participants, all aged over 12 years. The trials were double-blind, randomised, placebo-controlled trials with treatment duration of 12 to 19 weeks. We assessed four trials at overall low risk of bias, and three trials at overall unclear risk of bias, due to risk of detection, reporting, and other biases. Compared with placebo, participants receiving perampanel were more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.67, 95% CI 1.43 to 1.95; 7 trials, 2524 participants; high-certainty evidence). Compared to placebo, perampanel increased seizure freedom (RR 2.50, 95% CI 1.38 to 4.54; 5 trials, 2323 participants; low-certainty evidence) and treatment withdrawal (RR 1.30, 95% CI 1.03 to 1.63; 7 trials, 2524 participants; low-certainty evidence). Participants treated with perampanel were more likely to withdraw from treatment due to adverse effects compared to those receiving placebo (RR 2.36, 95% CI 1.59 to 3.51; 7 trials, 2524 participants; low-certainty evidence). A higher proportion of participants receiving perampanel reported one or more adverse effects when compared to participants who received placebo (RR 1.17, 95% CI 1.10 to 1.24; 7 trials, 2524 participants; high-certainty evidence). Compared with placebo, participants receiving perampanel were more likely to experience ataxia (RR 14.32, 99% CI 1.09 to 188.31; 2 trials, 1098 participants; low-certainty evidence), dizziness (RR 2.87, 99% CI 1.45 to 5.70; 7 trials, 2524 participants; low-certainty evidence), and somnolence (RR 1.76, 99% CI 1.02 to 3.04; 7 trials, 2524 participants). Subgroup analysis indicated that a larger proportion of participants who received perampanel at a dose of 4 mg/day (RR 1.38, 95% CI 1.05 to 1.83; 2 trials, 710 participants), 8 mg/day (RR 1.83, 95% CI 1.51 to 2.22; 4 trials, 1227 participants), or 12 mg/day (RR 2.38, 95% CI 1.86 to 3.04; 3 trials, 869 participants) achieved a 50% or greater reduction in seizure frequency compared to placebo; however, treatment with perampanel 12 mg/day also increased treatment withdrawal (RR 1.77, 95% CI 1.31 to 2.40; 3 trials, 869 participants). AUTHORS' CONCLUSIONS: Add-on perampanel is effective at reducing seizure frequency and may be effective at maintaining seizure freedom for people with drug-resistant focal epilepsy. Although perampanel was well-tolerated, there was a higher proportion of treatment withdrawals with perampanel compared with placebo. Subgroup analysis suggested that 8 mg/day and 12 mg/day are the most efficacious perampanel doses; however, the use of 12 mg/day would likely increase the number of treatment withdrawals. Future research should focus on investigating the efficacy and tolerability of perampanel with longer-term follow-up, as well as exploring an optimal dose.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required. OBJECTIVES: To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child. SEARCH METHODS: For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy. DATA COLLECTION AND ANALYSIS: Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine-exposed children (> 2700). Further, a non-significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro-facial clefts. Data for all other ASMs were extremely limited. Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases. AUTHORS' CONCLUSIONS: Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.

ANTECEDENTES: La exposición prenatal a determinados fármacos anticonvulsivos (FAC) se asocia con un mayor riesgo de malformaciones congénitas graves (MCG). La mayoría de las mujeres con epilepsia continúan tomando FAC durante todo el embarazo y, por lo tanto, se requiere información sobre los riesgos potenciales asociados con el tratamiento con FAC. OBJETIVOS: Evaluar los efectos de la exposición prenatal a los FAC sobre la prevalencia de MCG en el niño. MÉTODOS DE BÚSQUEDA: Para la última actualización de esta revisión se hicieron búsquedas el 17 de febrero de 2022 en las siguientes bases de datos: Registro Cochrane de Estudios (Cochrane Register of Studies [CRS Web]), MEDLINE (Ovid, 1946 hasta el 16 de febrero de 2022), SCOPUS (1823 en adelante) y ClinicalTrials.gov , Plataforma de registros internacionales de ensayos clínicos (ICTRP). No se impusieron restricciones de idioma. CRITERIOS DE SELECCIÓN: Se incluyeron estudios prospectivos controlados de cohortes, estudios de cohortes establecidos dentro de registros de embarazos, ensayos controlados aleatorizados y estudios epidemiológicos que utilizaron datos rutinarios de los historiales médicos. Las participantes fueron mujeres con epilepsia que tomaban FAC; los dos grupos de control fueron mujeres sin epilepsia y mujeres con epilepsia que no recibían tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cinco autores seleccionaron de forma independiente los estudios para inclusión. Ocho autores completaron la extracción de los datos y las evaluaciones del riesgo de sesgo. El desenlace principal fue la presencia de una MCG. Los desenlaces secundarios incluyeron tipos específicos de MCG. Cuando no fue posible realizar un metanálisis, los estudios incluidos se examinaron de forma narrativa. RESULTADOS PRINCIPALES: De 12 296 resúmenes, se revisaron 283 publicaciones a texto completo que identificaron 49 estudios con 128 publicaciones entre ellos. Los datos de los embarazos expuestos a FAC fueron más numerosos en el caso de los estudios prospectivos de cohortes (n = 17 963), que los datos actualmente disponibles de estudios de registros sanitarios epidemiológicos (n = 7913). El riesgo de MCG en los hijos de mujeres sin epilepsia fue del 2,1% (IC del 95%: 1,5 a 3,0) en los estudios de cohortes y del 3,3% (IC del 95%: 1,5 a 7,1) en los estudios de registros sanitarios. El riesgo conocido asociado con la exposición al valproato de sodio fue evidente en todas las comparaciones, con una prevalencia agrupada del 9,8% (IC del 95%: 8,1 a 11,9) a partir de los datos de los estudios de cohortes y del 9,7% (IC del 95%: 7,1 a 13,4) a partir de los estudios con datos rutinarios de los historiales médicos. Este fue elevado en casi todas las comparaciones con otros FAC como monoterapia, con diferencias absolutas de riesgo que variaron entre el 5% y el 9%. Múltiples estudios han constatado que el riesgo de MCG depende de la dosis. Los niños expuestos a la carbamazepina tuvieron una mayor prevalencia de MCG tanto en los estudios de cohortes (4,7%; IC del 95%: 3,7 a 5,9) como en los estudios con datos rutinarios de los historiales médicos (4,0%; IC del 95%: 2,9 a 5,4), que fue significativamente superior a la de los niños nacidos de mujeres sin epilepsia tanto en los estudios de cohortes (RR 2,30; IC del 95%: 1,47 a 3,59) como en los estudios de historias clínicas habituales (RR 1,14; IC del 95%: 0,80 a 1,64), con resultados significativos similares en comparación con los hijos de mujeres con epilepsia que no reciben tratamiento tanto en los estudios de cohortes (RR 1,44; IC del 95%: 1,05 a 1,96) como en los estudios con datos rutinarios de los historiales médicos (RR 1,42; IC del 95%: 1,10 a 1,83). Para la exposición al fenobarbital, la prevalencia fue del 6,3% (IC del 95%: 4,8 a 8,3) y del 8,8% IC del 95%: 0,0 a 9277,0) a partir de los datos de estudios de cohortes y los datos de estudios con datos rutinarios de los historiales médicos, respectivamente. Este aumento del riesgo fue significativo en comparación con los hijos de mujeres sin epilepsia (RR 3,22; IC del 95%: 1,84 a 5,65) y los nacidos de mujeres con epilepsia que no reciben tratamiento (RR 1,64; IC del 95%: 0,94 a 2,83) en estudios de cohortes; los datos procedentes de estudios con datos rutinarios de los historiales médicos fueron limitados. En cuanto a la exposición a la fenitoína, la prevalencia de MCG fue elevada en los datos de los estudios de cohortes (5,4%; IC del 95%: 3,6 a 8,1) y en los datos rutinarios de los historiales médicos (6,8%; IC del 95%: 0,1 a 701,2). La prevalencia de MCG fue mayor en los niños expuestos a la fenitoína en comparación con los hijos de mujeres sin epilepsia (RR 3,81; IC del 95%: 1,91 a 7,57) y los hijos de mujeres con epilepsia que no reciben tratamiento (RR 2,01; IC del 95%: 1,29 a 3,12); no hubo datos procedentes de estudios con datos rutinarios de los historiales médicos. Los datos agrupados de los estudios de cohortes indicaron un riesgo significativamente mayor de MCG en los niños expuestos a lamotrigina en comparación con los niños nacidos de mujeres sin epilepsia (RR 1,99; IC del 95%: 1,16 a 3,39); con una diferencia de riesgos (DR) que indica un riesgo 1% mayor de MCG (DR 0,01. IC del 95%: 0,00 a 0,03). Esto no se repitió en la comparación con los hijos de las mujeres con epilepsia que no reciben tratamiento (RR 1,04; IC del 95%: 0,66 a 1,63), que contenía el mayor grupo de niños expuestos a la lamotrigina (> 2700). Además, también se encontró una diferencia no significativa tanto en comparación con los hijos de mujeres sin epilepsia (RR 1,19; IC del 95%: 0,86 a 1,64) como con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,00; IC del 95%: 0,79 a 1,28) a partir de los estudios con datos rutinarios. Para la exposición al levetiracetam, los datos agrupados proporcionaron razones de riesgos similares a las de las mujeres sin epilepsia en los estudios de cohortes (RR 2,20; IC del 95%: 0,98 a 4,93) y en los estudios con datos rutinarios de los historiales médicos (RR 0,67; IC del 95%: 0,17 a 2,66). Los resultados agrupados de los estudios de cohortes (RR: 0,71; IC del 95%: 0,39 a 1,28) y de los estudios con datos rutinarios de los historiales médicos (RR: 0,82; IC del 95%: 0,39 a 1,71) respaldan esta afirmación cuando se comparan con los hijos de las mujeres con epilepsia que no reciben tratamiento. En el caso del topiramato, la prevalencia de MCG fue del 3,9% (IC del 95%: 2,3 a 6,5) a partir de los datos de los estudios de cohortes y del 4,1% (0,0 a 27.050,1) a partir de los estudios con datos rutinarios de los historiales médicos. Las razones de riesgos fueron significativamente más altas para los niños expuestos al topiramato en comparación con los hijos de mujeres sin epilepsia en estudios de cohortes (RR 4,07; IC del 95%: 1,64 a 10,14), pero no en una comparación más pequeña con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,37; IC del 95%: 0,57 a 3,27); actualmente se dispone de pocos datos a partir de estudios con datos rutinarios de los historiales médicos. La exposición en el útero al topiramato también se asoció con RR significativamente mayores en comparación con otros FAC para las hendiduras orofaciales. Los datos de todos las demás FAC fueron extremadamente limitados. Debido a los diseños observacionales, todos los estudios presentaron un alto riesgo de ciertos sesgos, pero los sesgos observados en los estudios de obtención de datos primarios y el uso secundario de historiales médicos rutinarios fueron diferentes y, en parte, complementarios. Los sesgos estaban equilibrados entre los FAC investigados, y es poco probable que los resultados diferenciales observados entre los FAC se expliquen únicamente por estos sesgos. CONCLUSIONES DE LOS AUTORES: La exposición en el útero a ciertos FAC se asoció con un mayor riesgo de ciertos MCG que, para muchos, depende de la dosis.

Professional identity formation amongst peer-mentors in a research-based mentoring programme.

BACKGROUND: Mentoring plays a pivotal yet poorly understood role in shaping a physician's professional identity formation (PIF) or how they see, feel and act as professionals. New theories posit that mentoring nurtures PIF by functioning as a community of practice through its structured approach and its support of a socialisation process made possible by its assessment-directed personalized support. To test this theory and reshape the design, employ and support of mentoring programs, we evaluate peer-mentor experiences within the Palliative Medicine Initiative's structured research mentoring program. METHODS: Semi-structured interviews with peer mentors under the Palliative Medicine Initiative (PMI) at National Cancer Centre Singapore were conducted and triangulated against mentoring diaries to capture longitudinal data of their PMI experiences. The Systematic Evidence-Based Approach (SEBA) was adopted to enhance the trustworthiness of the data. SEBA employed concurrent content and thematic analysis of the data to ensure a comprehensive review. The Jigsaw Perspective merged complementary themes and categories identified to create themes/categories. The themes/categories were compared with prevailing studies on mentoring in the Funnelling Process to reaffirm their accuracy. RESULTS: Twelve peer-mentors participated in the interviews and eight peer-mentors completed the mentoring diaries. The domains identified were community of practice and identity work. CONCLUSIONS: The PMI's structured mentoring program functions as a community of practice supporting the socialisation process which shapes the peer-mentor's belief system. Guided by a structured mentoring approach, stage-based assessments, and longitudinal mentoring and peer support, peer-mentors enhance their detection and evaluation of threats to their regnant belief system and adapt their self-concepts of identity and personhood to suit their context. These insights will help structure and support mentoring programs as they nurture PIF beyond Palliative Medicine.

Assessing the effects of a mentoring program on professional identity formation.

BACKGROUND: Medical education has enjoyed mixed fortunes nurturing professional identity formation (PIF), or how medical students think, feel and act as physicians. New data suggests that structured mentoring programs like the Palliative Medicine Initiative (PMI) may offer a means of developing PIF in a consistent manner. To better understand how a well-established structured research mentoring program shapes PIF, a study of the experiences of PMI mentees is proposed. METHODOLOGY: Acknowledging PIF as a sociocultural construct, a Constructivist approach and Relativist lens were adopted for this study. In the absence of an effective tool, the Ring Theory of Personhood (RToP) and Krishna-Pisupati Model (KPM) model were used to direct this dual Systematic Evidence-Based Approach (Dual-SEBA) study in designing, employing and analysing semi-structured interviews with PMI mentees and mentoring diaries. These served to capture changes in PIF over the course of the PMI's mentoring stages. Transcripts of the interviews and mentoring diaries were concurrently analysed using content and thematic analysis. Complementary themes and categories identified from the Split Approach were combined using the Jigsaw Approach and subsequently compared with mentoring diaries in the Funnelling Process. The domains created framed the discussion. RESULTS: A total of 12 mentee interviews and 17 mentoring diaries were analysed, revealing two domains-PMI as a Community of Practice (CoP) and Identity Formation. The domains confirmed the centrality of a structured CoP capable of facilitating longitudinal mentoring support and supporting the Socialisation Process along the mentoring trajectory whilst cultivating personalised and enduring mentoring relationships. CONCLUSION: The provision of a consistent mentoring approach and personalised, longitudinal mentoring support guided along the mentoring trajectory by structured mentoring assessments lay the foundations for more effective mentoring programs. The onus must now be on developing assessment tools, such as a KPM-based tool, to guide support and oversight of mentoring relationships.

Optimising a person-centred approach to stopping medicines in older people with multimorbidity and polypharmacy using the DExTruS framework: a realist review.

BACKGROUND: Tackling problematic polypharmacy requires tailoring the use of medicines to individual circumstances and may involve the process of deprescribing. Deprescribing can cause anxiety and concern for clinicians and patients. Tailoring medication decisions often entails beyond protocol decision-making, a complex process involving emotional and cognitive work for healthcare professionals and patients. We undertook realist review to highlight and understand the interactions between different factors involved in deprescribing and to develop a final programme theory that identifies and explains components of good practice that support a person-centred approach to deprescribing in older patients with multimorbidity and polypharmacy. METHODS: The realist approach involves identifying underlying causal mechanisms and exploring how, and under what conditions they work. We conducted a search of electronic databases which were supplemented by citation checking and consultation with stakeholders to identify other key documents. The review followed the key steps outlined by Pawson et al. and followed the RAMESES standards for realist syntheses. RESULTS: We included 119 included documents from which data were extracted to produce context-mechanism-outcome configurations (CMOCs) and a final programme theory. Our programme theory recognises that deprescribing is a complex intervention influenced by a multitude of factors. The components of our final programme theory include the following: a supportive infrastructure that provides clear guidance around professional responsibilities and that enables multidisciplinary working and continuity of care, consistent access to high-quality relevant patient contextual data, the need to support the creation of a shared explanation and understanding of the meaning and purpose of medicines and a trial and learn approach that provides space for monitoring and continuity. These components may support the development of trust which may be key to managing the uncertainty and in turn optimise outcomes. These components are summarised in the novel DExTruS framework. CONCLUSION: Our findings recognise the complex interpretive practice and decision-making involved in medication management and identify key components needed to support best practice. Our findings have implications for how we design medication review consultations, professional training and for patient records/data management. Our review also highlights the role that trust plays both as a central element of tailored prescribing and a potential outcome of good practice in this area.

Management of new onset atrial fibrillation in critically unwell adult patients: a systematic review and narrative synthesis.

BACKGROUND: New onset atrial fibrillation (NOAF) is the most common arrhythmia affecting critically unwell patients. NOAF can lead to worsening haemodynamic compromise, heart failure, thromboembolic events, and increased mortality. The aim of this systematic review and narrative synthesis is to evaluate the non-pharmacological and pharmacological management strategies for NOAF in critically unwell patients. METHODS: Of 1782 studies, 30 were eligible for inclusion, including 4 RCTs and 26 observational studies. Efficacy of direct current cardioversion, amiodarone, ß-adrenergic receptor antagonists, calcium channel blockers, digoxin, magnesium, and less commonly used agents such as ibutilide are reported. RESULTS: Cardioversion rates of 48% were reported for direct current cardioversion; however, re-initiation of NOAF was as high as 23.4%. Amiodarone was the most commonly reported intervention with cardioversion rates ranging from 18% to 96% followed by ß-antagonists with cardioversion rates from 40% to 92%. Amiodarone was more effective than diltiazem (odds ratio [OR]=1.91, P=0.32) at cardioversion. Short-acting ß-antagonists esmolol and landiolol were more effective compared with diltiazem for cardioversion (OR=3.55, P=0.04) and HR control (OR=3.2, P<0.001). CONCLUSION: There was significant variation between studies with regard to the definition of successful cardioversion and heart rate control, making comparisons between studies and interventions difficult. Future RCTs comparing individual anti-arrhythmic agents, in particular magnesium, amiodarone, and ß-antagonists, and studying the role of anticoagulation in critically unwell patients are required. There is also an urgent need for a core outcome dataset for studies of new onset atrial fibrillation to allow comparisons between different anti-arrhythmic strategies. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42019121739.

Mindfulness-based cognitive therapy for prevention and time to depressive relapse: Systematic review and network meta-analysis.

OBJECTIVE: To perform a network meta-analysis (NMA) to compare the long-term effectiveness of mindfulness-based cognitive therapy (MBCT) with available strategies for prevention and time to depressive relapse. METHODS: Seven electronic databases were searched up to June 2019. Studies evaluated MBCT for the management of depression-related outcomes and follow-up assessments occurred at 12 months or longer. RESULTS: Twenty-three publications were included, 17 of which were randomised controlled trials (RCTs). Data from 14 RCTs including 2077 participants contributed to meta-analysis (MA) and NMA to assess relapse of depression and 13 RCTs with 2017 participants contributed to MA and NMA for time to relapse of depression. NMAs showed statistically significant advantages for MBCT over treatment as usual (TAU) for relapse of depression (RR = 0.73, 95% CI 0.54 to 0.98) and for MBCT over TAU and placebo for time to relapse of depression (MBCT vs TAU: HR = 0.57, 95% CI 0.37 to 0.88; MBCT vs placebo: HR = 0.23, 95% CI 0.08 to 0.67). Subgroup meta-analysis of relapse of depression by previous number of depressive episodes showed similar results between subgroups. Subgroup meta-analysis by the use or not of booster sessions suggests these may lead to improved effectiveness. CONCLUSIONS: MBCT is more effective than TAU in the long-term in preventing relapse of depression and has statistically significant advantages over TAU and placebo for time to relapse of depression. No statistically significant differences were observed between MBCT and active treatment strategies for rate of relapse or time to relapse of depression.

What interventions are effective in reducing development of hypertension and other cardiovascular complications in women who have had hypertensive disorders of pregnancy? A systematic review.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) affect approximately 10-15% of pregnancies and pre-eclampsia affects 3-5% of pregnancies. Women with previous pre-eclampsia or HDP are at increased risk of hypertension (2 to 5 times) and major cardiovascular disease (1.5 to 3 times). There is little guidance on how to reduce this risk. AIM: To establish if there are interventions in women with previous HDP or pre-eclampsia that reduce the risk of developing adverse cardiovascular outcomes. METHOD: A protocol was submitted to PROSPERO; inclusion and exclusion criteria were determined and a search strategy implemented. Primary outcomes were: development of hypertension or change in blood pressure and development of other cardiovascular complications. Records and full texts were screened independently by two reviewers. The Cochrane Risk of Bias tool was used for quality assessment. RESULTS: 3593 articles were screened. Nine articles were included. There were seven randomised-controlled trials and two quasi-experimental studies. One study trialled antihypertensive use, two studies looked at blood pressure monitoring and six studies focused on lifestyle interventions. Three trials reported significant reductions in diastolic blood pressure in the experimental group. No studies looked at the optimal time of intervention or the impact of interventions on the development of other long-term cardiovascular complications. Five studies reported participant feedback. The majority of studies were of low quality. CONCLUSION: Further research needs to explore potential interventions and optimal timing of interventions to reduce cardiovascular risk. Women also need to be consulted about their preferences for discussions about cardiovascular risk and potential interventions.

Development of Core Outcome Sets for trials on the management of Atrial fiBrillAtion in Critically Unwell patientS (COS-ABACUS): a protocol.

INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia in critically unwell patients. New-onset AF (NOAF) affects 5%-11% of all admissions and up to 46% admitted with septic shock. NOAF is associated with increased morbidity, mortality and healthcare costs. Existing trials into the prevention and management of NOAF suffer from significant heterogeneity making comparisons and inferences limited. Core outcome sets (COS) aim to standardise outcome reporting, reduce inconsistency between trials and reduce outcome reporting bias. We aim to develop an internationally agreed COS for trials of interventions on the management of NOAF during critical illness. METHODS AND ANALYSIS: Stakeholders including intensive care physicians, cardiologists and patients will be recruited from national and international critical care organisations. COS development will occur in five stages: (1) Outcomes included in trials, recent systematic reviews and surveys of clinician practice and patient focus groups will be extracted. (2) Extracted outcomes will inform a two-stage e-Delphi process and consensus meeting using Grading of Recommendations Assessment, Development and Evaluation methodology. (3) Outcome measurement instruments (OMIs) will be identified from the literature and a consensus meeting held to agree OMI for core outcomes. (4) Nominal group technique will be used in a final consensus meeting to the COS. (5) The findings of our COS will be published in peer-reviewed journals and implemented in future guidelines and intervention trials. ETHICS AND DISSEMINATION: The study has been approved by the University of Liverpool ethics committee (Ref: 11 256, 21 June 2022), with a formal consent waiver and assumed consent. We will disseminate the finalised COS via national and international critical care organisations and publication in peer-reviewed journals.

Efficacy and Safety of Anticoagulants in Patients with Atrial Fibrillation and History of Falls or Risk of Falls: A Systematic Review and Multilevel Meta-Analysis.

INTRODUCTION: Atrial fibrillation (AF) is a major cause of stroke. Anticoagulants substantially reduce risk of stroke but are also associated with an increased risk of bleeding. Because of that, many patients do not receive anticoagulants, particularly patients at risk of falls. This systematic review and meta-analysis aims to compare anticoagulant treatment options for the management of atrial fibrillation patients at risk of falls or with a history of falls. METHODS: We conducted a PRISMA systematic review (until March 2022), including studies evaluating safety and efficacy of different anticoagulants (vitamin K antagonist [VKA] versus non-vitamin K antagonist oral anticoagulant [NOAC]). Outcomes were ischemic stroke, major bleeding, intracranial hemorrhage, hemorrhagic stroke, myocardial infarction, gastrointestinal bleeding, cardiovascular and all-cause mortality. A multilevel meta-analysis was conducted adjusting for clustering effects within studies examining more than one effect size. RESULTS: A total of 919 articles were identified, 848 after removing duplicates. The full text of 155 were screened and 10 articles were retained for final quantitative synthesis. Risk of bias was moderate to serious for the included studies. In meta-analysis, NOACs were associated with superior effectiveness compared with VKA for ischemic stroke/systemic embolism (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.69-0.98; p < 0.05) and safety (HR 0.53, 95% CI 0.40-0.71; p < 0.05) for intracranial hemorrhage. There were no differences in other outcomes. CONCLUSION: NOACs were associated with less intracranial hemorrhages and ischemic strokes/systemic embolisms than VKAs in AF patients at risk of falls. These findings suggesting preferred use of NOACs over VKAs have clinical implications for physicians, patients and policy makers.

The management of anticoagulants in patients with atrial fibrillation and history of falls or risk of falls: protocol for a systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation affects an estimated 33 million individuals worldwide and is a major cause of stroke, heart failure, and death. Anticoagulants substantially reduce the risk of stroke but are also associated with an increased risk of bleeding and especially intracranial hemorrhage which is the most concerning complication. Because of this, many patients are not offered anticoagulants, particularly patients at risk of falls or with a history of falls. It is unclear what anticoagulant treatment these patients should be offered. The Liverpool AF-Falls project aims to investigate this area, and this protocol for a systematic review and meta-analysis aims to define what is the most appropriate anticoagulant treatment option for the management of atrial fibrillation patients at risk of falls or with a history of falls. METHODS: This systematic review and meta-analysis will include randomized and non-randomized studies evaluating the safety and efficacy of different anticoagulant treatments (vitamin K antagonist and non-vitamin K antagonist oral anti-coagulant). Bibliographic databases (Cochrane Central Register of Controlled Trials, CINAHL, ClinicalTrials.gov , Embase, MEDLINE, Scopus and Web of Science) will be searched according to a pre-specified search strategy. Titles, abstracts, and full texts will be assessed by two independent reviewers and disagreements resolved with a third independent reviewer. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias in randomized trials, and the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool will be used for non-randomized studies. A pairwise meta-analysis based on the fixed and random-effects models will be conducted. Publication bias will be evaluated with a funnel plot and Egger's test. Heterogeneity will be assessed with the I2 statistic. If conditions for indirect comparison are met and sufficient data are available, a network meta-analysis will be conducted using frequentist and Bayesian methodologies. DISCUSSION: This review will be the first to summarize direct and indirect evidence on the safety and efficacy of anticoagulant treatments in atrial fibrillation patients at risk of falls or with a history of falls. The findings will be important to patients, clinicians, and health policy-makers to inform best practices in the use of these treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number: CRD42020201086.

Deprescribing medicines in older people living with multimorbidity and polypharmacy: the TAILOR evidence synthesis.

BACKGROUND: Tackling problematic polypharmacy requires tailoring the use of medicines to individual needs and circumstances. This may involve stopping medicines (deprescribing) but patients and clinicians report uncertainty on how best to do this. The TAILOR medication synthesis sought to help understand how best to support deprescribing in older people living with multimorbidity and polypharmacy. OBJECTIVES: We identified two research questions: (1) what evidence exists to support the safe, effective and acceptable stopping of medication in this patient group, and (2) how, for whom and in what contexts can safe and effective tailoring of clinical decisions related to medication use work to produce desired outcomes? We thus described three objectives: (1) to undertake a robust scoping review of the literature on stopping medicines in this group to describe what is being done, where and for what effect; (2) to undertake a realist synthesis review to construct a programme theory that describes 'best practice' and helps explain the heterogeneity of deprescribing approaches; and (3) to translate findings into resources to support tailored prescribing in clinical practice. DATA SOURCES: Experienced information specialists conducted comprehensive searches in MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Google (Google Inc., Mountain View, CA, USA) and Google Scholar (targeted searches). REVIEW METHODS: The scoping review followed the five steps described by the Joanna Briggs Institute methodology for conducting a scoping review. The realist review followed the methodological and publication standards for realist reviews described by the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) group. Patient and public involvement partners ensured that our analysis retained a patient-centred focus. RESULTS: Our scoping review identified 9528 abstracts: 8847 were removed at screening and 662 were removed at full-text review. This left 20 studies (published between 2009 and 2020) that examined the effectiveness, safety and acceptability of deprescribing in adults (aged ≥ 50 years) with polypharmacy (five or more prescribed medications) and multimorbidity (two or more conditions). Our analysis revealed that deprescribing under research conditions mapped well to expert guidance on the steps needed for good clinical practice. Our findings offer evidence-informed support to clinicians regarding the safety, clinician acceptability and potential effectiveness of clinical decision-making that demonstrates a structured approach to deprescribing decisions. Our realist review identified 2602 studies with 119 included in the final analysis. The analysis outlined 34 context-mechanism-outcome configurations describing the knowledge work of tailored prescribing under eight headings related to organisational, health-care professional and patient factors, and interventions to improve deprescribing. We conclude that robust tailored deprescribing requires attention to providing an enabling infrastructure, access to data, tailored explanations and trust. LIMITATIONS: Strict application of our definition of multimorbidity during the scoping review may have had an impact on the relevance of the review to clinical practice. The realist review was limited by the data (evidence) available. CONCLUSIONS: Our combined reviews recognise deprescribing as a complex intervention and provide support for the safety of structured approaches to deprescribing, but also highlight the need to integrate patient-centred and contextual factors into best practice models. FUTURE WORK: The TAILOR study has informed new funded research tackling deprescribing in sleep management, and professional education. Further research is being developed to implement tailored prescribing into routine primary care practice. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018107544 and PROSPERO CRD42018104176. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 32. See the NIHR Journals Library website for further project information.

Many patients take multiple medicines, every day, on a long-term basis. Some feel overloaded by their medicines. However, both doctors and patients have told us that they feel anxious about knowing when and how to safely stop medicines. TAILOR aimed to help by providing the information that doctors and patients need to make individual (tailored) decisions about whether or not to stop (deprescribe) medicines. We had two research questions and so used a different research method to answer each. Both methods involved us first finding all the published research looking at deprescribing for older people living with long-term conditions and using five or more medicines a day. Our first (scoping) review produced a map of what we know about deprescribing: how it is done and if it is safe. We found evidence that structured deprescribing can be safe and acceptable to clinicians, but specific effects were very varied and patient views were often not reported. Our team's patient partners continuously reminded us that medicines mean more to individuals than just a medical effect (e.g. a 'tablet for my blood pressure'), meaning that our research needed to describe good person-centred deprescribing. Our second (realist) review focused on this by looking at if and how tailored deprescribing decisions happen. Our results showed that health-care services need to give clinicians the permission and resources they need to work with patients to develop a joint understanding of the value of medicines, to guide decisions about using/changing medicines, and so to build and maintain trust. Our findings remind us that decisions about medicines are personal. We need to remember that any changes in medicines affect not just an individual's disease, but also their understanding of their health and health care. Our work makes recommendations on how future practice and research can be more person centred. We are now working with patients and health-care professionals to share our findings with a wide audience.

Potential approaches for the pricing of cancer medicines across Europe to enhance the sustainability of healthcare systems and the implications.

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems.Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines.Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments.

Mapping of Current Obstacles for Rationalizing Use of Medicines (CORUM) in Europe: Current Situation and Potential Solutions.

INTRODUCTION: There are increasing concerns regarding the inappropriate use of medicines with expenditure continuing to grow driven by increasing sales in oncology and orphan diseases, enhanced by their emotive nature. As a result, even high income countries are struggling to fund new premium priced medicines. These concerns have resulted in initiatives to better manage the entry of new medicines and enhance the rational use of medicines (RUM). However, there is a need to ascertain the current situation. We sought to address this by developing the Current Obstacles for Rationalizing Use of Medicines in Europe (CORUM) mapping tool to qualitatively investigate the current situation and provide analysis of current views on RUM and interventions among key European payers and their advisers. The findings will be used to provide future guidance. METHODOLOGY: Descriptive study exploring and identifying perceived gaps to achieving optimal RUM. The CORUM tool was based on the WHO 12 key interventions to promote RUM. RESULTS: 62 participants took part with most respondents believing their country could improve RUM capacity. This included educational initiatives on the use of clinical guidelines (90%) and the inclusion of problem-based pharmacotherapy in undergraduate curricula and for Continued Professional Development. Key challenges included a lack of regular updates of guidelines, exacerbated by limited funding and a lack of follow-up to monitor adherence to agreed guidelines. RUM could also be enhanced by the development of regional formularies as well as implementing Drug and Therapeutic Committees where these are currently limited. There also needs to be greater co-ordination between RUM and Health Technology Assessment activities, with countries learning from each other. CONCLUSION: There is an urgent need to improve RUM through improved educational and other activities among European countries, with countries learning from each other. This will involve addressing current challenges and we will be following this up.

Barriers and facilitators to deprescribing in primary care: a systematic review.

BACKGROUND: Managing polypharmacy is a challenge for healthcare systems globally. It is also a health inequality concern as it can expose some of the most vulnerable in society to unnecessary medications and adverse drug-related events. Care for most patients with multimorbidity and polypharmacy occurs in primary care. Safe deprescribing interventions can reduce exposure to inappropriate polypharmacy. However, these are not fully accepted or routinely implemented. AIM: To identify barriers and facilitators to safe deprescribing interventions for adults with multimorbidity and polypharmacy in primary care. DESIGN & SETTING: A systematic review of studies published from 2000, examining safe deprescribing interventions for adults with multimorbidity and polypharmacy. METHOD: A search of electronic databases: MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature (CINHAL), Cochrane, and Health Management Information Consortium (HMIC) from inception to 26 Feb 2019, using an agreed search strategy. This was supplemented by handsearching of relevant journals, and screening of reference lists and citations of included studies. RESULTS: In total, 40 studies from 14 countries were identified. Cultural and organisational barriers included: a culture of diagnosing and prescribing; evidence-based guidance focused on single diseases; a lack of evidence-based guidance for the care of older people with multimorbidities; and a lack of shared communication, decision-making systems, tools, and resources. Interpersonal and individual-level barriers included: professional etiquette; fragmented care; prescribers' and patients' uncertainties; and gaps in tailored support. Facilitators included: prudent prescribing; greater availability and acceptability of non-pharmacological alternatives; resources; improved communication, collaboration, knowledge, and understanding; patient-centred care; and shared decision-making. CONCLUSION: A whole systems, patient-centred approach to safe deprescribing interventions is required, involving key decision-makers, healthcare professionals, patients, and carers.