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Background Global Public Health Days (GPHD) are public health interventions which serve to improve public awareness of specific health conditions. Google Trends is a publicly available tool that allows the user to view the popularity of a searched keyword during a specified time period and across a predetermined region. Our objective was to use Google Trends to assess the impact of four GPHD (World Heart Day, World Mental Health Day, World Diabetes Day and World Hypertension Day) on online health information-seeking behaviour (OHISB), 4 weeks before and a week after the GPHD, across six countries of the Arabian Peninsula (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates). Methods Relative Search Volume (RSV) was extracted for the aforementioned countries from 28 days before the GPHD and 7 days afterwards. Statistical analysis, undertaken using joinpoint regression software, showed that GPHD have significant changes for Saudi Arabia (Diabetes, Mental Health and Heart day) and UAE (Mental Health day) but were short-lived with a fall in RSV of up to 80% after peak interest. Conclusion GPHD appears to be effective in some countries while further research is needed to investigate the reason of its limitations.

To examine the risk of self-harm in rheumatic conditions.We conducted a retrospective cohort study using data from the Clinical Practice Research Datalink. Patients with ankylosing spondylitis, fibromyalgia, osteoarthritis, or rheumatoid arthritis were identified from 1990 to 2016 and matched to patients without these conditions. Incident self-harm was defined by medical record codes following a rheumatic diagnosis. Incidence rates (per 10,000 person-years) were reported for each condition, both overall and year-on-year (2000-2016). Cox regression analysis determined risk (hazard ratio [HR] and 95% confidence interval [95% CI]) of self-harm for each rheumatic cohort compared to the matched unexposed cohort. Initial crude analysis was subsequently adjusted and stratified by age and sex. Due to nonproportionality over time, osteoarthritis was also stratified by disease duration (1 year, ≥1 to5 years, ≥5 to10 years, and ≥10 years).The incidence of self-harm was highest in patients with fibromyalgia (HR 25.12 [95% CI 22.45-28.11] per 10,000 person-years) and lowest for osteoarthritis (HR 6.48 [95% CI 6.20-6.76]). There was a crude association with each rheumatic condition and self-harm, except for ankylosing spondylitis. Although attenuated, these associations remained after adjustment for fibromyalgia (HR 2.06 [95% CI 1.60-2.65]), rheumatoid arthritis (HR 1.59 [95% CI 1.20-2.11]), and osteoarthritis (1 to5 years HR 1.12 [95% CI 1.01-1.24]; ≥5 to10 years HR 1.35 [95% CI 1.18-1.54]). Age and sex were weak effect modifiers for these associations.Primary care patients with fibromyalgia, osteoarthritis, or rheumatoid arthritis (but not ankylosing spondylitis) are at increased risk of self-harm compared to people without these rheumatic conditions. Clinicians need to be aware of the potential for self-harm in patients with rheumatic conditions (particularly fibromyalgia), explore mood and risk with them, and offer appropriate support and management.

International audience; Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias isinherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mmbiopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB butlow clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Background\ud Public health awareness can help prevent illness and result in earlier intervention when it does occur. For this reason, health promotion and disease awareness campaigns have great potential to alleviate the global burden of disease. Global Public Health Days (GPHD) are frequently implemented with this intent, but research evaluating their effectiveness, especially in the developing world setting, is scant.\ud \ud Objectives\ud We aimed to evaluate the impact of four GPHDs (World Cancer Day, World Diabetes Day, World Mental Health Day, World AIDS Day) on online health information seeking behaviour (OHISB) in five Central and South American (CSA) countries which differ in their stage of economic development and epidemiological transition (Uruguay, Chile, Brazil, Colombia, Nicaragua).\ud \ud Methods\ud Google Trends data was used as a ‘surrogate’ of OHISB. This was measured on the 28 days leading up to the GPHD, on the date of the GPHD, and on the seven days following it. The Joinpoint regression programme was used to perform a time trend analysis on the Google Trends data. This allowed us to identify statistically significant time points of a change in trend, which reflect significant ‘changes’ to OHISB.\ud \ud Results\ud GPHDs were inconsistently effective at influencing internet search query activity in the studied countries. In situations where an effect was significant, this impact was consistently short-term, with Relative Search Volume level returning to precampaign levels within 7 days of the GPHD.\ud \ud Conclusions\ud Our findings imply the need to revise GPHDs or create alternative health awareness campaigns, perhaps with a more long-term approach and tailored to the specific health needs of the CSA population. Developing effective preventive strategies is vital in helping combat the rising threat of NCDs in this region.

Purpose: This article presents data challenging the widely held but untested view that concurrently playing mid-week Union of European Football Associations (UEFA) Europa League matches adversely affects domestic league performance. Method: Over 16 seasons we compared next-season domestic league performance of the two highest finishing UEFA Europa League qualifying clubs with the two highest finishing non-qualifiers in England and Spain. Results: Clubs concurrently playing UEFA Europa League football showed significantly superior domestic league performance including wins, losses, goals, goal difference and points tally. The number of European matches played was not related to domestic league performance. Conclusions: The absence of prior rigorous analysis including appropriate comparison data has led to the proliferation of a widespread confirmatory bias, defined as the tendency to seek out evidence that backs one&rsquo, s hunches and to ignore evidence that contradicts them. Based on our evidence, football professionals, journalists, pundits, and fans should consider the UEFA Europa League competition more favorably.

Background Depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. The number of prescriptions for antidepressants has risen dramatically in recent years yet up to 50% of patients who are treated for depression with antidepressants do not report feeling better as a result of treatment, and do not show the desired improvement on depression measures. We report a qualitative study embedded in a trial of second antidepressant for people who had not responded to one antidepressant, exploring the acceptability of a combination of antidepressants from the perspectives of both patients and practitioners, together with experiences of participating in a clinical trial. Methods A qualitative study embedded in a randomized controlled trial investigating the effectiveness and cost-effectiveness of combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants versus SNRI or SSRI therapy alone (the MIR trial). 59 interviews were conducted with people who declined to participate in the trial, people who completed the study and people who withdrew from the intervention, and 16 general practitioners. Results Across the data-sets, four main themes were identified: the hard work of managing depression, uncertainties over the value of a second antidepressant, help-seeking at a point of crisis, and attainment and maintenance of a hard-won equilibrium. Conclusions Exploring reasons for declining to participate in a trial of a second antidepressant in people who had not responded to one antidepressant suggests that people who are already taking one antidepressant may be reluctant to take a second, being wary of possible side-effects, but also being unconvinced of the logic behind such a combination. In addition, people describe being in a state of equilibrium and reluctant to make a change, reflecting that this equilibrium is ‘hard-won’ and they are unwilling to risk disturbing this. This makes some people reluctant to enrol in a clinical trial. Understanding a patient’s view on medication is important for GPs when discussing antidepressants. Trial registration MIR Trial Registration: ISRCTN 06653773.

ObjectiveTo investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care.DesignTwo parallel group multicentre phase III randomised placebo controlled trial.Setting106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015.Participants480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up.Main outcome measuresDepressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks.ResultsBeck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.ConclusionThis study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited.Trial registrationCurrent Controlled TrialsISRCTN06653773.

Background Anxiety and depression are common among older people, with up to 20% reporting such symptoms, and the prevalence increases with co-morbid chronic physical health problems. Access to treatment for anxiety and depression in this population is poor due to a combination of factors at the level of patient, practitioner and healthcare system. There is evidence to suggest that older people with anxiety and/or depression may benefit both from one-to-one interventions and group social or educational activities, which reduce loneliness, are participatory and offer some activity. Non-traditional providers (support workers) working within third-sector (voluntary) organisations are a valuable source of expertise within the community but are under-utilised by primary care practitioners. Such a resource could increase access to care, and be less stigmatising and more acceptable for older people. Methods The study is in three phases and this paper describes the protocol for phase III, which will evaluate the feasibility of recruiting general practices and patients into the study, and determine whether support workers can deliver the intervention to older people with sufficient fidelity and whether this approach is acceptable to patients, general practitioners and the third-sector providers. Phase III of the NOTEPAD study is a randomised controlled trial (RCT) that is individually randomised. It recruited participants from approximately six general practices in the UK. In total, 100 participants aged 65 years and over who score 10 or more on PHQ9 or GAD7 for anxiety or depression will be recruited and randomised to the intervention or usual general practice care. A mixed methods approach will be used and follow-up will be conducted 12 weeks post-randomisation. Discussion This study will inform the design and methods of a future full-scale RCT. Trial registration ISRCTN, ID: ISRCTN16318986. Registered 10 November 2016. The ISRCTN registration is in line with the World Health Organization Trial Registration Data Set. The present paper represents the original version of the protocol. Any changes to the protocol will be communicated to ISRCTN. Electronic supplementary material The online version of this article (10.1186/s13063-018-2550-6) contains supplementary material, which is available to authorized users.

Monozygotic (MZ) and dizygotic (DZ) twins participate in research that partitions variance in health, disease, and behavior into genetic and environmental components. However, there are other innovative roles for twins in medical research. One such way is involving MZ and/or DZ twins in co-twin control-designed randomized controlled trials (RCTs). To our knowledge, no reviews have been conducted that summarizes the involvement of twins in RCTs. Therefore, we conducted a systematic literature search using the U.S. Clinical Trials Database, NHS electronic databases, MEDLINE, EMBASE, and PsychINFO for RCTs on publications involving MZ and/or DZ twins as RCT participants. Out of the 186,027 clinical trials registered in the U.S. clinical trial register ClinicaTrails.gov, only six RCTs used twins as participants. From 1,598 articles identified in our search, 50 peer-reviewed English language publications met our pre-defined inclusion criteria. Sample sizes for RCTs have ranged from a total number of participants from 2 to 1,162; however, 32 (64%) studies had a sample size of 100 or less, and of those, 12 (24%) had fewer than 10. Both MZ and DZ twins have been recruited to the RCTs. In most instances (33/50) each twin from a pair were assigned to different study arms. Most of those studies included MZ twins only. Despite the methodological advantages, the use of MZ and DZ twins as participants in interventional RCTs appeared limited. The continuous development of innovative twin designs, especially RCTs, indicates that twin research can extend beyond the more widely recognized heritability estimates.

Background One-in-five people in the UK experience anxiety and/or depression in later life. However, anxiety and depression remain poorly detected in older people, particularly in those with chronic physical ill health. In the UK, a stepped care approach, to manage common mental health problems, is advocated which includes service provision from non-statutory organisations (including third/voluntary sector). However, evidence to support such provision, including the most effective interventions, is limited. The qualitative study reported here constitutes the first phase of a feasibility study which aims to assess whether third sector workers can deliver a psychosocial intervention to older people with anxiety and/or depression. The aim of this qualitative study is to explore the views of older people and third sector workers about anxiety and depression among older people in order to refine an intervention to be delivered by third sector workers. Methods Semi-structured interviews with participants recruited through purposive sampling from third sector groups in North Staffordshire. Interviews were digitally recorded with consent, transcribed and analysed using principles of constant comparison. Results Nineteen older people and 9 third sector workers were interviewed. Key themes included: multiple forms of loss, mental health as a personal burden to bear, having courage and providing/receiving encouragement, self-worth and the value of group activities, and tensions in existing service provision, including barriers and gaps. Conclusions The experience of loss was seen as central to feelings of anxiety and depression among community-dwelling older people. This study contributes to the evidence pointing to the scale and severity of mental health needs for some older people which can arise from multiple forms of loss, and which present a significant challenge to health, social care and third sector services. The findings informed development of a psychosocial intervention and training for third sector workers to deliver the intervention.

Background The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson’s disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. Methods Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. Results A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON–OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. Conclusions This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. Trial registration EudraCT 2012-000801-64

Bodily symptoms are common in community samples, but not all people consult for medical advice about such symptoms. Medically unexplained symptoms (MUS) refer to persistent bodily complaints for which adequate examination (including investigation) does not reveal sufficiently explanatory structural or other specified pathology.1 MUS are common, with a spectrum of severity, and patients are found everywhere within the healthcare system.2 It has been estimated that MUS account for up to 45% of all general practice consultations,3 while a study based in secondary care indicated that about 50% of patients had no clear diagnosis at 3 months.2 The annual NHS cost for MUS in adults of working age in England was estimated to be £2.89 billion in 2008/2009 (approximately 10% of total NHS expenditure on these services for the working age population), while sickness absence and decreased quality of life for people with MUS was estimated as costing over £14 billion per annum to the UK economy.4 Although the costs to the NHS and the economy are important considerations, the personal cost to the patient can also be significant. Patients often experience stress, distress, and anxiety because of their unexplained symptoms. They report feeling that their concerns are not taken seriously by their doctor, which can exacerbate the presentation of somatic symptoms. The suggestion that ‘negative test results means that nothing is wrong’ is cited as the most common explanation given by doctors,5 but patients can feel that their symptoms are not believed, and may disengage from health care (including for other …

The catechin, epigallocatechin gallate (eGCG), found in green tea, has inhibitory activity against a number of protein toxins and was investigated in relation to its impact upon ricin toxin (RT) in vitro. The IC50 for RT was 0.08 ± 0.004 ng/mL whereas the IC50 for RT + 100 μM eGCG was 3.02 ± 0.572 ng/mL, indicating that eGCG mediated a significant (p