The research included a rapid review of current literature to describe epidemiology, management, and system impact of heart valve disease (HVD) in adult populations. Key issues were identified in consultation with expert focus groups and were framed across the continuum of care and systemic policy issues. The groupings were adapted and adjusted during deliberations.

A rapid literature review was conducted on HVD key interventions and evidence of effectiveness along with expert interviews to identify high-level themes for reform. This served as the evidentiary backgrounder. Two virtual policy engagements with clinical leaders, patients, and health system managers were conducted. The focus was their collective drafting of recommendations. These workshops identified nine thematic areas and developed associated recommendations for action under each theme. The success of the process is evident as the report has been taken up as a roadmap for ongoing research and policy work.

A comprehensive grouping of recommendations for improving HVD detection, management, and treatment in Canada was produced. It was designed to be comprehensive to then allow more targeted work to proceed under an evidence-informed and clinically endorsed agenda.

Heart valve conditions are increasingly treatable, especially if detected early. Innovation in treatments as well as detection and management to address gaps in care were identified as the most urgent priorities. The key result was formation of formal working groups with a professional society to explore spoke–hub-and node models for care delivery and to launch awareness programs for early detection.

Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.

1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.

At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.

Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.

Funding Acknowledgements: This study was supported by Assurex Health, Inc.

Our aims were to estimate the prevalence of increased nuchal translucency in fetuses with a normal karyotype that were subsequently diagnosed with congenital cardiac disease on fetal echocardiography, and to assess whether there is a link between increased nuchal translucency and specific congenital cardiac malformations.

We reviewed all patients referred to King’s College Hospital and the Evelina Children’s Hospital in London for fetal echocardiography between January 1998 and December 2007. We investigated the proportion of chromosomally normal fetuses with congenitally malformed hearts in which nuchal thickness was increased, both overall and with specific defects.

We indentified 2133 fetuses with congenital cardiac disease by prenatal echocardiography. Of those, 707 were excluded due to abnormal karyotype, and 690 were excluded due to unknown karyotype. The remaining 736 were eligible for inclusion. Among 481 fetuses with documented congenital cardiac disease and normal chromosomes, making up 23% of the overall cohort, 224 had increased nuchal thickness defined as equal or greater than 2.5 millimetres, this being 0.47 of the inclusive cohort, with 95% confidence intervals from 0.42 to 0.51. These proportions were significantly higher than the expected proportion of the normal population, which was 0.05 (p < 0.001). The only diagnosis for which the proportion of fetuses with nuchal translucency measurement equal or greater than 2.5 millimetres was higher than the others was atrioventricular septal defect, with 0.62 of this cohort having abnormal values, with 95% confidence intervals from 0.47 to 0.77 (p = 0.038).

We found that nearly half of prenatally diagnosed fetuses with congenitally malformed hearts, when examined ultrasonically in the first or early-second trimester, had increased nuchal thickness. We recommend, therefore, referral of all fetuses with increased nuchal translucency for fetal echocardiography.

Early worsening of anxiety, agitation and irritability are thought to be common among people commencing antidepressants, especially for anxiety disorders. This phenomenon, which may be termed jitteriness/anxiety syndrome, is cited as an explanation for early treatment failure and caution in using selective serotonin reuptake inhibitors (SSRIs). However, we believe that it is inconsistently defined and that robust evidence to support the phenomenon is lacking.

To review systematically all evidence relating to jitteriness/ anxiety syndrome to identify: constituent symptoms; medications implicated; disorders in which it was reported; incidence; time course; management strategies; relationship of this syndrome to therapeutic response; distinction between syndrome and akathisia; relationship between syndrome and suicide; and genetic predispositions.

A systematic search identified articles and these were included in the review if they addressed one of the above aspects of jitteriness/anxiety syndrome.

Of 245 articles identified, 107 articles were included for review. No validated rating scales for jitteriness/anxiety syndrome were identified. There was no robust evidence that the incidence differed between SSRIs and tricyclic antidepressants, or that there was a higher incidence in anxiety disorders. Published incidence rates varied widely from 4 to 65% of people commencing antidepressant treatment. Common treatment strategies for this syndrome included a slower titration of antidepressant and the addition of benzodiazepines. Conclusive evidence for the efficacy of these strategies is lacking. There was conflicting and inconclusive evidence as to whether the emergence of this syndrome had a predictive value on the response to treatment. It appears to be a separate syndrome from akathisia, but evidence for this assertion was limited. The effect of jitteriness/anxiety syndrome on suicide rates has not been evaluated. Three studies examined genetic variations and side-effects from treatment, but none was specifically designed to assess jitteriness/anxiety syndrome.

Jitteriness/anxiety syndrome remains poorly characterised. Despite this, clinicians' perception of this syndrome influences prescribing and it is cited to support postulated mechanisms of drug action. We recommend systematised evaluation of side-effects at earlier time points in antidepressant trials to further elucidate this clinically important syndrome.