Health care professional barriers and facilitators to discontinuing antidepressant use: A systematic review and thematic synthesis.

INTRODUCTION: Long-term antidepressant (AD) use, much longer than recommended, is very common and can lead to potential harms. OBJECTIVE: To investigate the existing literature on perspectives of health professionals (HPs) regarding long-term AD treatment, focusing on barriers and facilitators to discontinuation. METHODS: A systematic review with thematic synthesis. Eight electronic databases were searched until August 2023 including MEDLINE, PubMed, Embase, PsycINFO, CINAHL, AMED, Health Management Information Consortium, and the Networked Digital Library of Theses and Dissertation. RESULTS: Thirteen studies were included in the review. Of these, nine focused on general practitioner perspectives, one on psychiatrist perspectives, and three on a mix of HPs perspectives. Barriers and facilitators to discontinuing long-term ADs emerged within eight themes, ordered chronologically based on HP considerations during an AD review: perception of AD use, fears, HP role and responsibility, HPs' perception of AD discontinuation, HPs' confidence regarding their ability to manage discontinuation, perceived patient readiness to stop, support from patient's trusted people, and support from other HPs. LIMITATIONS: Coding and development of subthemes and themes was performed by one researcher and further developed through discussion within the research team. CONCLUSION: Deprescribing long-term ADs is a challenging concept for HPs. The review found evidence that the barriers far outweigh the facilitators with fear of relapse as a main barrier. HP education, reassurance and confidence-building is essential to increase the initiation of the discontinuation process. Further research into the perspectives of pharmacists and mental health workers is needed as well as exploring the role of trusted people.

Correction: Internet Tool to Support Self-Assessment and Self-Swabbing of Sore Throat: Development and Feasibility Study.

[This corrects the article DOI: 10.2196/39791.].

Pharmacists' perspectives on recommending herbal medicines for acute infections: a qualitative study.

BACKGROUND: Community pharmacists have an essential role in antimicrobial stewardship by providing self-care advice for self-limiting infections. AIM: To explore community pharmacists' perceptions and experiences of advising patients on management of acute respiratory tract infections (RTIs) and urinary tract infections (UTIs), and to explore issues regarding use of over-the-counter (OTC) medicines, including herbal medicines. DESIGN & SETTING: A qualitative study using semi-structured interviews with community pharmacists in England. METHOD: Qualitative interviews with community pharmacists were carried out face to face and by telephone between November 2019 and March 2020. Data were collected through in-depth, semi-structured interviews, recorded and transcribed. A reflexive thematic analysis was undertaken. RESULTS: In total, 18 community pharmacists were interviewed. Three main themes were identified. Theme 1 was self-management recommendations. Community pharmacists considered patients' preferences when recommending self-management strategies. Some believed that conventional OTC medications had quicker and stronger effects, while others preferred herbal OTCs as a more natural approach, particularly for less severe symptoms. Theme 2 was factors influencing pharmacists' recommendations for acute infections. This included pharmacists' perceptions of patient preferences, nature or severity of illness, research evidence, training, commercial pressures, and patient concerns about medication cost. Theme 3 was pharmacist-patient communication. Pharmacists sometimes experienced challenges with language barriers and patients' expectations of receiving antibiotics. Pharmacists emphasised the importance of being trusted by their patients. There was widespread acceptance of their role in self-management advice for acute illness and interest in the role of herbal medicines, but pharmacists did not feel confident in recommending these. CONCLUSION: Pharmacists are central to the management of self-limiting infections. There is a need to educate the public about appropriate use of antibiotics and provide training and support for pharmacists on self-management strategies including herbal medicine.

Internet Tool to Support Self-Assessment and Self-Swabbing of Sore Throat: Development and Feasibility Study.

BACKGROUND: Sore throat is a common problem and a common reason for the overuse of antibiotics. A web-based tool that helps people assess their sore throat, through the use of clinical prediction rules, taking throat swabs or saliva samples, and taking throat photographs, has the potential to improve self-management and help identify those who are the most and least likely to benefit from antibiotics. OBJECTIVE: We aimed to develop a web-based tool to help patients and parents or carers self-assess sore throat symptoms and take throat photographs, swabs, and saliva samples for diagnostic testing. We then explored the acceptability and feasibility of using the tool in adults and children with sore throats. METHODS: We used the Person-Based Approach to develop a web-based tool and then recruited adults and children with sore throats who participated in this study by attending general practices or through social media advertising. Participants self-assessed the presence of FeverPAIN and Centor score criteria and attempted to photograph their throat and take throat swabs and saliva tests. Study processes were observed via video call, and participants were interviewed about their views on using the web-based tool. Self-assessed throat inflammation and pus were compared to clinician evaluation of patients' throat photographs. RESULTS: A total of 45 participants (33 adults and 12 children) were recruited. Of these, 35 (78%) and 32 (71%) participants completed all scoring elements for FeverPAIN and Centor scores, respectively, and most (30/45, 67%) of them reported finding self-assessment relatively easy. No valid response was provided for swollen lymph nodes, throat inflammation, and pus on the throat by 11 (24%), 9 (20%), and 13 (29%) participants respectively. A total of 18 (40%) participants provided a throat photograph of adequate quality for clinical assessment. Patient assessment of inflammation had a sensitivity of 100% (3/3) and specificity of 47% (7/15) compared with the clinician-assessed photographs. For pus on the throat, the sensitivity was 100% (3/3) and the specificity was 71% (10/14). A total of 89% (40/45), 93% (42/45), 89% (40/45), and 80% (30/45) of participants provided analyzable bacterial swabs, viral swabs, saliva sponges, and saliva drool samples, respectively. Participants were generally happy and confident in providing samples, with saliva samples rated as slightly more acceptable than swab samples. CONCLUSIONS: Most adult and parent participants were able to use a web-based intervention to assess the clinical features of throat infections and generate scores using clinical prediction rules. However, some had difficulties assessing clinical signs, such as lymph nodes, throat pus, and inflammation, and scores were assessed as sensitive but not specific. Many participants had problems taking photographs of adequate quality, but most were able to take throat swabs and saliva samples.

Parental perceptions and experiences of infant crying: A systematic review and synthesis of qualitative research.

BACKGROUND: Excessive infant crying is common and can have a huge impact on families and well-being. Systematically reviewing qualitative studies on infant crying can provide a greater understanding of parental perceptions and experiences. AIM: This study sought to systematically review and thematically synthesize qualitative studies exploring parents/carers' views and experiences of infant crying. DESIGN: A systematic review and synthesis of qualitative research. DATA SOURCES: Electronic databases MEDLINE, EMBASE, PsycINFO and CINAHL were searched from the earliest date available to January 2022. We selected papers focussing on parents/carers' experiences, views, attitudes and beliefs about infant crying. We excluded papers focussing on health professionals' views and children older than 12 months. REVIEW METHODS: Thematic synthesis was followed for the analysis of included studies and quality appraisal was conducted. RESULTS: We synthesized 22 papers, reporting data from 376 participants in eight countries. Four analytical themes were developed: (1) Experiences and impact of crying; (2) parental management strategies; (3) the role of the health professional; (4) the role of infant feeding and maternal diet. Our findings suggest that infant crying has a substantial emotional impact on parents/carers that often impacts relationships. Parents/carers reported using a range of soothing techniques and coping strategies but were desperate to find effective treatment or cure. Support was often perceived as lacking. Excessive crying and beliefs about the role of maternal diet on breastmilk were reported to undermine parents' confidence in breastfeeding by making them feel their milk is insufficient or harmful, or through pressure from others to stop breastfeeding. CONCLUSION: Parents/carers use a range of strategies to interpret and deal with the challenges of infant crying, but there is a need for more information and support. IMPACT: Findings can be used to inform future research and interventions to support families experiencing excessive infant crying.

Self-sampling to identify pathogens and inflammatory markers in patients with acute sore throat: Feasibility study.

Introduction: Sore throat is a common reason for overuse of antibiotics. The value of inflammatory or biomarkers in throat swab or saliva samples in predicting benefit from antibiotics is unknown. Methods: We used the 'person-based approach' to develop an online tool to support self-swabbing and recruited adults and children with sore throats through participating general practices and social media. Participants took bacterial and viral swabs and a saliva sponge swab and passive drool sample. Bacterial swabs were cultured for streptococcus (Group A, B, C, F and G). The viral swab and saliva samples were tested using a routine respiratory panel PCR and Covid-19 PCR testing. We used remaining viral swab and saliva sample volume for biomarker analysis using a panel of 13 biomarkers. Results: We recruited 11 asymptomatic participants and 45 symptomatic participants. From 45 symptomatic participants, bacterial throat swab, viral throat swab, saliva sponge and saliva drool samples were returned by 41/45 (91.1%), 43/45 (95.6%), 43/45 (95.6%) and 43/45 (95.6%) participants respectively. Three saliva sponge and 6 saliva drool samples were of insufficient quantity. Two adult participants had positive bacterial swabs. Six participants had a virus detected from at least one sample (swab or saliva). All of the biomarkers assessed were detectable from all samples where there was sufficient volume for testing. For most biomarkers we found higher concentrations in the saliva samples. Due to low numbers, we were not able to compare biomarker concentrations in those who did and did not have a bacterial pathogen detected. We found no evidence of a difference between biomarker concentrations between the symptomatic and asymptomatic participants but the distributions were wide. Conclusions: We have demonstrated that it is feasible for patients with sore throat to self-swab and provide saliva samples for pathogen and biomarker analysis. Typical bacterial and viral pathogens were detected but at low prevalence rates. Further work is needed to determine if measuring biomarkers using oropharyngeal samples can help to differentiate between viral and bacterial pathogens in patients classified as medium or high risk using clinical scores, in order to better guide antibiotic prescribing and reduce inappropriate prescriptions.

Self-management for chronic widespread pain including fibromyalgia: A systematic review and meta-analysis.

BACKGROUND: Chronic widespread pain (CWP) including fibromyalgia has a prevalence of up to 15% and is associated with substantial morbidity. Supporting psychosocial and behavioural self-management is increasingly important for CWP, as pharmacological interventions show limited benefit. We systematically reviewed the effectiveness of interventions applying self-management principles for CWP including fibromyalgia. METHODS: MEDLINE, Embase, PsycINFO, The Cochrane Central Register of Controlled Trials and the WHO International Clinical Trials Registry were searched for studies reporting randomised controlled trials of interventions adhering to self-management principles for CWP including fibromyalgia. Primary outcomes included physical function and pain intensity. Where data were sufficient, meta-analysis was conducted using a random effects model. Studies were narratively reviewed where meta-analysis could not be conducted Evidence quality was rated using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (PROSPERO-CRD42018099212). RESULTS: Thirty-nine completed studies were included. Despite some variability in studies narratively reviewed, in studies meta-analysed self-management interventions improved physical function in the short-term, post-treatment to 3 months (SMD 0.42, 95% CI 0.20, 0.64) and long-term, post 6 months (SMD 0.36, 95% CI 0.20, 0.53), compared to no treatment/usual care controls. Studies reporting on pain narratively had greater variability, however, those studies meta-analysed showed self-management interventions reduced pain in the short-term (SMD -0.49, 95% CI -0.70, -0.27) and long-term (SMD -0.38, 95% CI -0.58, -0.19) compared to no treatment/usual care. There were few differences in physical function and pain when self-management interventions were compared to active interventions. The quality of the evidence was rated as low. CONCLUSION: Reviewed studies suggest self-management interventions can be effective in improving physical function and reducing pain in the short and long-term for CWP including fibromyalgia. However, the quality of evidence was low. Future research should address quality issues whilst making greater use of theory and patient involvement to understand reported variability.

Helping people discontinue long-term antidepressants: views of health professionals in UK primary care.

OBJECTIVE: The aims of this paper were to identify, characterise and explain clinician factors that shape decision-making around antidepressant discontinuation in UK primary care. DESIGN: Four focus groups and three interviews were conducted and analysed using thematic analysis. PARTICIPANTS: Twenty-one general practitioners (GPs), four GP assistants, seven nurses and six community mental health team workers and psychotherapists took part in focus groups and interviews. SETTING: Participants were recruited from seven primary care regions and two National Health Service Trusts providing community mental health services in the South of England. RESULTS: Participants highlighted a number of barriers and enablers to discussing discontinuation with patients. They held a range of views around responsibility, with some suggesting it was the responsibility of the health professional (HP) to broach the subject, and others suggesting responsibility rested with the patients. HPs were concerned about destabilising the current situation, discussed how continuity and knowing the patient facilitated discontinuation talks, and discussed how confidence in their professional skills and knowledge affected whether they elected to raise discontinuation in consultations. CONCLUSIONS: Findings indicate a need to consider support for HPs in the management of antidepressant medication and discussions of discontinuation in particular. They may also benefit from support around their fears of patient relapse and awareness of when and how to initiate discussions about discontinuation with their patients.

Managing Antidepressant Discontinuation: A Systematic Review.

PURPOSE: We aimed to determine the effectiveness of interventions to manage antidepressant discontinuation, and the outcomes for patients. METHODS: We conducted a systematic review with narrative synthesis and meta-analysis of studies published to March 2017. Studies were eligible for inclusion if they were randomized controlled trials, quasi-experimental studies, or observational studies assessing interventions to facilitate discontinuation of antidepressants for depression in adults. Our primary outcomes were antidepressant discontinuation and discontinuation symptoms. Secondary outcomes were relapse/recurrence; quality of life; antidepressant reduction; and sexual, social, and occupational function. RESULTS: Of 15 included studies, 12 studies (8 randomized controlled trials, 2 single-arm trials, 2 retrospective cohort studies) were included in the synthesis. None were rated as having high risk for selection or detection bias. Two studies prompting primary care clinician discontinuation with antidepressant tapering guidance found 6% and 7% of patients discontinued, vs 8% for usual care. Six studies of psychological or psychiatric treatment plus tapering reported cessation rates of 40% to 95%. Two studies reported a higher risk of discontinuation symptoms with abrupt termination. At 2 years, risk of relapse/recurrence was lower with cognitive behavioral therapy plus taper vs clinical management plus taper (15% to 25% vs 35% to 80%: risk ratio = 0.34; 95% CI, 0.18-0.67; 2 studies). Relapse/recurrence rates were similar for mindfulness-based cognitive therapy with tapering and maintenance antidepressants (44% to 48% vs 47% to 60%; 2 studies). CONCLUSIONS: Cognitive behavioral therapy or mindfulness-based cognitive therapy can help patients discontinue antidepressants without increasing the risk of relapse/recurrence, but are resource intensive. More scalable interventions incorporating psychological support are needed.

Barriers and facilitators to discontinuing antidepressant use: A systematic review and thematic synthesis.

OBJECTIVE: To explore patient and health professional views and experiences of antidepressant treatment with particular focus on barriers and facilitators to discontinuing use. DESIGN: Systematic review with thematic synthesis DATA SOURCES: MEDLINE, PubMed, Embase, PsycINFO, CINAHL, AMED, Health Management Information Consortium, OpenGrey, and the Networked Digital Library of Theses and Dissertations from inception until February 2017. Updated searches were carried out in July 2018. ELIGIBILITY CRITERIA: Primary studies, published in English, that used qualitative data collection and analysis, and had data on attitudes, beliefs, feelings, perceptions on continuing or discontinuing antidepressant use, of patients (aged 18 or above, who received treatment with antidepressants for at least 6 months) or any health professionals. DATA EXTRACTION: One reviewer extracted data and assessed study quality, which was checked by a second reviewer. FINDINGS: Twenty two papers were included in the review. A thematic synthesis was performed for patient perspectives only, due to insufficient data from a health professional perspective. The thematic synthesis yielded nine themes: (1) psychological and physical capabilities; (2) perception of antidepressants; (3) fears; (4) intrinsic motivators and goals; (5) the Doctor as a navigator to maintenance or discontinuation; (6) perceived cause of depression; (7) aspects of information that support decision-making; (8) significant others - a help or a hindrance; and (9) support from other health professionals. LIMITATIONS: Coding and development of subthemes and themes was performed by one researcher and further developed through discussion between two researchers. CONCLUSIONS: Barriers and facilitators to discontinuing antidepressant use are numerous and complex, and likely to require detailed conversations between patients and their general practitioners (GPs). These conversations are more likely to happen if GPs raise the issue of discontinuation. Further research from a health professional perspective including, but not limited to GPs, is needed.

Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports.

BACKGROUND: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence. METHODS: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]). RESULTS: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted. INTERPRETATION: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.

Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications.

OBJECTIVE: To determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources (journal articles and trial registries), and within clinical study reports themselves, with respect to benefits and major harms. DESIGN: Data on primary efficacy analysis and major harms extracted from each data source and compared. SETTING: Nine randomised placebo controlled trials of duloxetine (total 2878 patients) submitted to the European Medicines Agency (EMA) for marketing approval for major depressive disorder. DATA SOURCES: Clinical study reports, including protocols as appendices (total 13,729 pages), were obtained from the EMA in May 2011. Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly. Clinicaltrials.gov and the manufacturer's online clinical trial registry were searched for trial results. RESULTS: Clinical study reports fully described the primary efficacy analysis and major harms (deaths (including suicides), suicide attempts, serious adverse events, and discontinuations because of adverse events). There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 (range 177-645) and 166 (100-241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects. CONCLUSION: Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports. There were inconsistencies between protocols and clinical study reports and within clinical study reports. Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency.

Coding of adverse events of suicidality in clinical study reports of duloxetine for the treatment of major depressive disorder: descriptive study.

OBJECTIVE: To assess the effects of coding and coding conventions on summaries and tabulations of adverse events data on suicidality within clinical study reports. DESIGN: Systematic electronic search for adverse events of suicidality in tables, narratives, and listings of adverse events in individual patients within clinical study reports. Where possible, for each event we extracted the original term reported by the investigator, the term as coded by the medical coding dictionary, medical coding dictionary used, and the patient's trial identification number. Using the patient's trial identification number, we attempted to reconcile data on the same event between the different formats for presenting data on adverse events within the clinical study report. SETTING: 9 randomised placebo controlled trials of duloxetine for major depressive disorder submitted to the European Medicines Agency for marketing approval. DATA SOURCES: Clinical study reports obtained from the EMA in 2011. RESULTS: Six trials used the medical coding dictionary COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) and three used MedDRA (Medical Dictionary for Regulatory Activities). Suicides were clearly identifiable in all formats of adverse event data in clinical study reports. Suicide attempts presented in tables included both definitive and provisional diagnoses. Suicidal ideation and preparatory behaviour were obscured in some tables owing to the lack of specificity of the medical coding dictionary, especially COSTART. Furthermore, we found one event of suicidal ideation described in narrative text that was absent from tables and adverse event listings of individual patients. The reason for this is unclear, but may be due to the coding conventions used. CONCLUSION: Data on adverse events in tables in clinical study reports may not accurately represent the underlying patient data because of the medical dictionaries and coding conventions used. In clinical study reports, the listings of adverse events for individual patients and narratives of adverse events can provide additional information, including original investigator reported adverse event terms, which can enable a more accurate estimate of harms.

Exploring the outcomes in studies of primary frozen shoulder: is there a need for a core outcome set?

PURPOSE: In our study we explored the need to define a core outcome set for primary frozen shoulder. METHODS: We investigated the outcomes used by studies included in a systematic review of the management of primary frozen shoulder; surveyed which primary outcome measures health care professionals considered important; and re-examined papers previously obtained for a systematic review of patients' views of interventions for frozen shoulder to investigate their views on outcomes. RESULTS: Thirty-one studies investigated the outcomes range of movement (28 studies), pain (22), function and disability (22), adverse events (13), quality of life (7) and other outcomes (5). Many different types of pain and ranges of movement were measured. Function and disability was measured using fifteen instruments, the content of which varied considerably. Function and disability, pain and range of movement (132, 108 and 104 respondents, respectively) were most often cited by health care professionals as the primary outcome measure that should be used. Searches identified one paper that included patients' views. Outcomes of importance to patients were pain at night, general pain, reduced mobility (resulting in modification of activities) and the emotional impact of frozen shoulder. CONCLUSIONS: We identified a diverse range of outcomes that have been used or are considered to be important. The development of a core outcome set would improve the design and reporting of studies and availability of data for evidence synthesis. Methods used to develop a core outcome set should be robust, transparent and reflect the views of all stakeholders.

Challenges in coding adverse events in clinical trials: a systematic review.

BACKGROUND: Misclassification of adverse events in clinical trials can sometimes have serious consequences. Therefore, each of the many steps involved, from a patient's adverse experience to presentation in tables in publications, should be as standardised as possible, minimising the scope for interpretation. Adverse events are categorised by a predefined dictionary, e.g. MedDRA, which is updated biannually with many new categories. The objective of this paper is to study interobserver variation and other challenges of coding. METHODS: Systematic review using PRISMA. We searched PubMed, EMBASE and The Cochrane Library. All studies were screened for eligibility by two authors. RESULTS: Our search returned 520 unique studies of which 12 were included. Only one study investigated interobserver variation. It reported that 12% of the codes were evaluated differently by two coders. Independent physicians found that 8% of all the codes deviated from the original description. Other studies found that product summaries could be greatly affected by the choice of dictionary. With the introduction of MedDRA, it seems to have become harder to identify adverse events statistically because each code is divided in subgroups. To account for this, lumping techniques have been developed but are rarely used, and guidance on when to use them is vague. An additional challenge is that adverse events are censored if they already occurred in the run-in period of a trial. As there are more than 26 ways of determining whether an event has already occurred, this can lead to bias, particularly because data analysis is rarely performed blindly. CONCLUSION: There is a lack of evidence that coding of adverse events is a reliable, unbiased and reproducible process. The increase in categories has made detecting adverse events harder, potentially compromising safety. It is crucial that readers of medical publications are aware of these challenges. Comprehensive interobserver studies are needed.

Dronedarone for the treatment of atrial fibrillation: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF: amiodarone, sotalol and class 1c agents (flecainide and propafenone). The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.

Native American Y chromosomes in Polynesia: the genetic impact of the Polynesian slave trade.

Since Thor Heyerdahl asserted that Polynesia was first colonized from the Americas (Heyerdahl 1950), geneticists have sought--but have not found--any evidence to support his theories. Here, Native American Y chromosomes are detected on the Polynesian island of Rapa. However, this, together with other odd features of the island's Y-chromosomal gene pool, is best explained as the genetic impact of a 19th century Peruvian slave trade in Polynesia. These findings underscore the need to account for history before turning to prehistory and the value of archival research to understanding modern genetic diversity. Although the impact of the Atlantic slave trade on the distribution of modern genetic diversity has been well appreciated, this represents the first study investigating the impact of this underappreciated episode on genetic diversity in the Pacific.