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Abstract Background Between 25 and 75% of people with persistent post-acute sequelae of SARS-CoV-2 infection (PASC) experience cognitive difficulties, compromising functional ability, quality of life, and activities of daily living, including work. Despite this significant morbidity, there is a paucity of interventions for this disorder that have undergone evaluation within a formal trial setting. Therefore, we have developed a cognitive rehabilitation programme, specifically designed to address the cognitive symptoms of PASC, notably impaired attention and processing speed, while also accounting for other PASC symptoms (fatigue, post-exertional malaise) that may aggravate the cognitive impairment. This study protocol outlines a randomised controlled trial (RCT) designed to evaluate the effectiveness of this programme compared to standard clinical care. Methods This is a multi-centre, parallel-group, individually randomised controlled trial, comparing standard clinical care with and without cognitive rehabilitation. We will recruit 120 non-hospitalised adults (aged 30–60 years) from three NHS sites in England with a history of COVID-19 infection and cognitive impairment persisting more than 3 months after the acute infection. Participants will be randomised (1:1) to the intervention or control groups, with the latter represented as a provision of standard clinical care without cognitive rehabilitation. The cognitive rehabilitation programme consists of ten 1-hour sessions, delivered weekly. Outcomes will be collected at baseline, 3, and 6 months, with participant-defined goal-attainment scores, relating to functional goals, at 3 months as the primary outcome measure. Secondary outcomes will be cognitive function, measures of quality of life, social functioning, mental health, fatigue, sleep, post-exertional malaise, and social and health care service use. We will also evaluate the health-economic benefits of cognitive rehabilitation in this population. Discussion Cognitive impairment in PASC is a major cause of functional disability with no effective treatment. Accordingly, we will undertake an RCT of cognitive rehabilitation, the protocol of which is published here. If this trial is successful in delivering improvements in trial outcomes, it will address a major unmet need relating to this emergent disorder, with a significant impact on affected individuals and the wider health economy. Trial registration ClinicalTrials.gov NCT05731570. Registered on February 16, 2023

Abstract Background Māori are over-represented in Aotearoa New Zealand morbidity and mortality statistics. Other populations with high health needs include Pacific peoples and those living with material deprivation. General practice has evolved into seven models of primary care: Traditional, Corporate, Health Care Home, Māori, Pacific, Trusts / Non-governmental organisations (Trust/NGOs) and District Health Board / Primary Care Organisations (DHB/PHO). We describe nurse work in relation to these models of care, populations with high health need and patient health outcomes. Methods We conducted a cross-sectional study (at 30 September 2018) of data from national datasets and practices at patient level. Six primary outcome measures were selected because they could be improved by primary care: polypharmacy (≥ 65 years), glucose control testing in adults with diabetes, immunisations (at 6 months), ambulatory sensitive hospitalisations (0–14, 45–64 years) and emergency department attendances. Analysis adjusted for patient and practice characteristics. Results Nurse clinical time, and combined nurse, nurse practitioner and general practitioner clinical time, were substantially higher in Trust/NGO, Māori, and Pacific practices than in other models. Increased patient clinical complexity was associated with more clinical input and higher scores on all outcome measures. The highest rates of preventative care by nurses (cervical screening, cardiovascular risk assessment, depression screening, glucose control testing) were in Māori, Trust/NGO and Pacific practices. There was an eightfold difference, across models of care, in percentage of depression screening undertaken by nurses and a fivefold difference in cervical screening and glucose control testing. The highest rates of nurse consultations afterhours and with unenrolled patients, improving access, were in PHO/DHB, Pacific, Trust/NGO and Māori practices. Work not attributed to nurses in the practice records meant nurse work was underestimated to an unknown degree. Conclusions Transferring work to nurses in Traditional, Health Care Home, and Corporate practices, would release general practitioner clinical time for other work. Worse patient health outcomes were associated with higher patient need and higher clinical input. It is plausible that there is insufficient clinical input to meet the degree of patient need. More practitioner clinical time is required, especially in practices with high volumes of complex patients.

Abstract Background Polygenic risk scores (PRS) and subjective cognitive decline (SCD) are associated with the risk of developing dementia. It remains to examine whether they can improve the established cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare. Methods The CAIDE model was applied to a sub-sample of a large, population-based cohort study (n = 5,360; aged 50–75) and evaluated for the outcomes of all-cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) by calculating Akaike’s information criterion (AIC) and the area under the curve (AUC). The improvement of the CAIDE model by PRS and SCD was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). Results During 17 years of follow-up, 410 participants were diagnosed with dementia, including 139 AD and 152 VD diagnoses. Overall, the CAIDE model showed high discriminative ability for all outcomes, reaching AUCs of 0.785, 0.793, and 0.789 for all-cause dementia, AD, and VD, respectively. Adding information on SCD significantly increased NRI for all-cause dementia (4.4%, p = 0.04) and VD (7.7%, p = 0.01). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.03). When APOE ε4 carrier status was included (CAIDE Model 2), AUCs increased, but PRS and SCD did not further improve the prediction. Conclusions Unlike PRS, information on SCD can be assessed more efficiently, and thus, the model including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.

Abstract Background Glycolytic flux is regulated by the energy demands of the cell. Upregulated glycolysis in cancer cells may therefore result from increased demand for adenosine triphosphate (ATP), however it is unknown what this extra ATP turnover is used for. We hypothesise that an important contribution to the increased glycolytic flux in cancer cells results from the ATP demand of Na+/K+-ATPase (NKA) due to altered sodium ion homeostasis in cancer cells. Methods Live whole-cell measurements of intracellular sodium [Na+]i were performed in three human breast cancer cells (MDA-MB-231, HCC1954, MCF-7), in murine breast cancer cells (4T1), and control human epithelial cells MCF-10A using triple quantum filtered 23Na nuclear magnetic resonance (NMR) spectroscopy. Glycolytic flux was measured by 2H NMR to monitor conversion of [6,6-2H2]d-glucose to [2H]-labelled l-lactate at baseline and in response to NKA inhibition with ouabain. Intracellular [Na+]i was titrated using isotonic buffers with varying [Na+] and [K+] and introducing an artificial Na+ plasma membrane leak using the ionophore gramicidin-A. Experiments were carried out in parallel with cell viability assays, 1H NMR metabolomics of intracellular and extracellular metabolites, extracellular flux analyses and in vivo measurements in a MDA-MB-231 human-xenograft mouse model using 2-deoxy-2-[18F]fluoroglucose (18F-FDG) positron emission tomography (PET). Results Intracellular [Na+]i was elevated in human and murine breast cancer cells compared to control MCF-10A cells. Acute inhibition of NKA by ouabain resulted in elevated [Na+]i and inhibition of glycolytic flux in all three human cancer cells which are ouabain sensitive, but not in the murine cells which are ouabain resistant. Permeabilization of cell membranes with gramicidin-A led to a titratable increase of [Na+]i in MDA-MB-231 and 4T1 cells and a Na+-dependent increase in glycolytic flux. This was attenuated with ouabain in the human cells but not in the murine cells. 18FDG PET imaging in an MDA-MB-231 human-xenograft mouse model recorded lower 18FDG tumour uptake when treated with ouabain while murine tissue uptake was unaffected. Conclusions Glycolytic flux correlates with Na+-driven NKA activity in breast cancer cells, providing evidence for the ‘centrality of the [Na+]i-NKA nexus’ in the mechanistic basis of the Warburg effect.

Abstract Background Depression ranks as the foremost mental health concern among childbearing women. Within low- and middle-income countries (LMICs), between 20 and 25% of women encounter depression during pregnancy or soon after delivery. This condition impacts not only the mothers but also their offspring. Offspring of women suffering from postnatal depression (PND) exhibit suboptimal cognitive development and increased emotional and behavioural issues throughout their growth. This scenario becomes more pronounced in LMICs, where numerous adversities further jeopardise children’s developmental progress. Despite antenatal services providing a pivotal platform to address women’s mental health needs, PND treatment remains inaccessible in many LMICs. The World Health Organization advocates interpersonal psychotherapy (IPT) for treating depression. While research from high-income countries has established the efficacy of IPT and group-IPT (g-IPT) for PND, its effectiveness within the LMIC context and its potential benefits for child development remain uncharted. This study seeks to gauge the potency of g-IPT for women with PND in two LMICs. Methods This multi-site randomised controlled trial is a continuation of two preceding phases—conceptual mapping and a feasibility study executed in Lebanon and Kenya. Insights gleaned from these phases underpin this comprehensive RCT, which contrasts the efficacy and cost-effectiveness of high-quality standard care (HQ-SC) augmented with g-IPT against HQ-SC in isolation. The trial, characterised as an individually randomised superiority assessment, targets women with postnatal depression in Beirut, Lebanon, and Nairobi, Kenya. It aims to determine if culturally tailored g-IPT, administered within community settings in both countries, outperforms HQ-SC in influencing child developmental outcomes, maternal depression, and the quality of the mother–child bond. Discussion The SUMMIT trial, designed with pragmatism, possesses the magnitude to evaluate g-IPT within two LMIC frameworks. It seeks to enlighten policymakers, service commissioners, professionals, and users about g-IPT’s potential to alleviate maternal PND and bolster child developmental outcomes in LMICs. Additionally, the trial will generate valuable data on the clinical and economic merits of high-quality standard care. Trial registration ISRCTN, ISRCTN15154316. Registered on 27 September 2023, https://doi.org/10.1186/ISRCTN15154316

Abstract Background We need to preserve the lessons of the COVID-19 pandemic in caring for the mental health of clinicians, of shared experiences, interdependence, team cohesion and vulnerability, among others. We need reform in the way that clinicians are cared for, and a resistance to the idea of a post-pandemic ‘return to normal’. Main text To build connected and optimally functioning clinical teams, we need to create an inclusive culture in which difficult conversations and caring are the expectation. If we are to be better at solving problems and better at serving our patients, we should be vigilant about creating a psychologically safe medical culture in which colleagues feel safe, seen, heard, and respected. Conclusion Going forward, each of us, regardless of seniority, needs to take responsibility for this culture change. We need to create and participate in weekly collegial peer support sessions that feel nurturing and safe, that allow us to reveal parts of ourselves, to be vulnerable with each other in a way that reduces loneliness, and encourages and maintains social connections and a sense of belonging within clinical teams, improves clinician well-being and reduces the risk of burnout. “Care is a practice of informed responsive actions on behalf of the one cared for and authentically aimed toward their growth and flourishing.” Care Ethics in the Age of Precarity; Maurice Hamington and Michael Flower.

Abstract Background Non-memory-led dementias such as posterior cortical atrophy (PCA), primary progressive aphasia (PPA) and behavioural variant frontotemporal dementia (bvFTD) are low prevalent and often affect individuals under the age of 65. Tailored educational and support resources for caregivers of people living with these dementia phenotypes are scarce and unevenly distributed geographically. Web-based educational programmes are emerging as promising alternatives to improve caregiver self-efficacy and well-being. Here, we present the protocol of a study aiming to assess the feasibility of a co-produced online educational programme for caregivers of people living PCA, PPA and bvFTD: the Better Living with Non-memory-led Dementia programme. Methods A randomised controlled feasibility trial will be conducted on a sample of 30 caregivers of people living with PCA, PPA and bvFTD. Participants will be recruited among members of the support organisation Rare Dementia Support (based at UCL in the UK). The intervention group will be given access to an 8-week co-produced web-based educational programme consisting of 6 modules addressing education about PCA, PPA and bvFTD and support strategies for the person with dementia and for the caregiver. The control group will receive treatment as usual (TAU). Feasibility will be measured through feasibility of recruitment, clinical measurement tools and acceptability. Clinical measures will be used to assess preliminary efficacy and data on completion rates, missing data and variability used to decide on measures to be included in a full-scale trial. Allocation ratio will be 2:1 (intervention:control) stratified by diagnosis. Feasibility of recruitment and acceptability will be assessed. Clinical measures will be administered at baseline and 8-week and 3-month post-randomisation. The control group will be offered access to the intervention at the completion of data collection. Participants will be unblinded, and all measures will be self-reported online. Discussion Online-delivered educational programmes show potential for improving care competency of caregivers and may contribute to overcoming geographical inequalities in local provision of support services. This pilot study will inform a fully powered international trial to determine the effectiveness of Better Living with Non-memory-led Dementia. Trial registration This trial has been registered prospectively on the Clinical Trials Registry on 1st September 2022, registration number NCT05525377.

Abstract Background To analyze the influence of the COVID-19 pandemic on the process of diagnosis and monitoring of drug-resistant pulmonary tuberculosis (TB) cases reported in the state of Paraná, Brazil, from 2015 to 2020. Methods Ecological study with quantitative approach. This study was based on diagnosed cases of pulmonary TB reported in the Notifiable Disease Information System in residents of Paraná; as well as through the number of confirmed cases of COVID-19 in the state epidemiological bulletin for the year 2020. The study data were analyzed using descriptive statistics. Results It was found that, although the number of reported pulmonary TB cases (drug-resistant and general) increased between 2015 and 2019, there was a drop in notification in 2020, the first year of the COVID-19 pandemic. The notification of TB cases was also influenced monthly during the year according to the increase in the number of COVID-19 cases. For cases of drug-resistant pulmonary TB, the provision of diagnostic tests and Directly Observed Treatment decreased by more than half in 2020, especially when compared to 2019. Conclusions In view of these findings, the influence of COVID-19 on the diagnosis and monitoring of drug-resistant and general pulmonary TB cases is evident, showing that the pandemic has compromised the advances of recent decades in achieving the goals established for its eradication by 2035.

Abstract Background Alzheimer’s disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers. Main body To address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p

Abstract Background The public health measures imposed in many countries to contain the spread of COVID-19 resulted in significant suspensions in the provision of support and care for people with dementia. The negative effects of these measures have been extensively reported. However, little is known about the specific impact on people with young onset, non-memory-led and inherited dementias. This group may have experienced different challenges compared to those with late onset dementia given their non-memory phenotypes and younger age. We explored the impact of the first COVID-19 lockdown on people living with familial Alzheimer’s disease, behavioural variant frontotemporal dementia, familial frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy and primary progressive aphasia and their carers in the UK and their self-reported strategies for coping. Methods This was a mixed methods study. An online survey was administered to people with dementia and family carers recruited via Rare Dementia Support. Free-text responses were analysed using framework analysis to identify key issues and themes. Results 184 carers and 24 people with dementia completed the survey. Overall, people with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%), well-being (57%) and changes to medication (26%) during lockdown. Carers reported a reduction in the support they received (55%) which impacted their own mental health negatively. Qualitative analysis of free-text responses shed light on how the disruption to routines, changes to roles and responsibilities, and widespread disconnection from friends, family and health and social care support varied according to phenotype. These impacts were exacerbated by a more general sense that precious time was being lost, given the progressive nature of dementia. Despite significant challenges, respondents demonstrated resilience and resourcefulness in reporting unexpected positives and strategies for adapting to confinement. Conclusions This study has highlighted the specific impacts of the COVID-19 restrictions on people with young onset, non-memory-led and inherited dementias, including behavioural variant frontotemporal dementia, primary progressive aphasia and posterior cortical atrophy, and their carers. The specific challenges faced according to diagnosis and the self-reported strategies speak to the importance of – and may inform the development of – tailored support for these underrepresented groups more generally. Visual abstract

Abstract Background Metformin, a medication for type 2 diabetes, has been linked to many non-diabetes health benefits including increasing healthy lifespan. Previous work has only examined the benefits of metformin over periods of less than ten years, which may not be long enough to capture the true effect of this medication on longevity. Methods We searched medical records for Wales, UK, using the Secure Anonymised Information Linkage dataset for type 2 diabetes patients treated with metformin (N = 129,140) and sulphonylurea (N = 68,563). Non-diabetic controls were matched on sex, age, smoking, and history of cancer and cardiovascular disease. Survival analysis was performed to examine survival time after first treatment, using a range of simulated study periods. Findings Using the full twenty-year period, we found that type 2 diabetes patients treated with metformin had shorter survival time than matched controls, as did sulphonylurea patients. Metformin patients had better survival than sulphonylurea patients, controlling for age. Within the first three years, metformin therapy showed a benefit over matched controls, but this reversed after five years of treatment. Interpretation While metformin does appear to confer benefits to longevity in the short term, these initial benefits are outweighed by the effects of type 2 diabetes when patients are observed over a period of up to twenty years. Longer study periods are therefore recommended for studying longevity and healthy lifespan. Evidence before this study Work examining the non-diabetes outcomes of metformin therapy has suggested that there metformin has a beneficial effect on longevity and healthy lifespan. Both clinical trials and observational studies broadly support this hypothesis, but tend to be limited in the length of time over which they can study patients or participants. Added value of this study By using medical records we are able to study individuals with Type 2 diabetes over a period of two decades. We are also able to account for the effects of cancer, cardiovascular disease, hypertension, deprivation, and smoking on longevity and survival time following treatment. Implications of all the available evidence We confirm that there is an initial benefit to longevity of metformin therapy, but this benefit does not outweigh the negative effect on longevity of diabetes. Therefore, we suggest that longer study periods are required for inference to be made about longevity in future research.

Abstract Background Capturing changes in health and wellbeing within randomised controlled trials (RCTs) can be complex. The precision and accuracy of outcome scales to measure change is crucial, and therefore, consideration needs to be given to potential measurement errors when collecting these outcomes. Many RCTs use multiple researchers to collect data, which has the potential to introduce variation in measurements. This study aimed to identify if there was a measurable effect of using different researchers to collect repeated assessments of quality of life (QoL) at different time points. Methods A previously conducted study assessing the impact of reminiscence therapy on participants with dementia and carer (PwD-carer) dyads, ‘REMCARE’ (Reminiscence groups for people with dementia and their family caregivers), provided the platform for this exploratory secondary analysis. Data was categorised into two broad groups: those where the same researcher attended all assessments and those where different researchers undertook the assessments. ANCOVA (analysis of covariance) models used in the original REMCARE analysis with the addition of the ‘researcher-continuity’ variable were run on two QoL measures, the QoL-AD (Quality of Life in Alzheimer’s Disease) and QCPR (Quality of the Caregiving Relationship). Results Three hundred thirty PwD-carer dyads were included in the analysis. For the PwD, a statistically significant effect was found on the researcher continuity variable for the QoL-AD and QCPR outcome measures at follow-up 1 but not at follow-up 2 signifying an impact of researcher attendance at the first follow-up but not follow-up 2. For the carer data, analyses revealed no statistically significant effects at follow-up 1; however, the QoL-AD measure at follow-up 2 was found to be statistically significant. Conclusions These exploratory results indicate the possible impact of researcher continuity on QoL outcomes in dementia studies. Further research is required to explore this further and establish causality. If demonstrated, this would have implications for the planning of future empirical studies in dementia, in order to reduce this potential source of bias.

Abstract Background Tinnitus is the awareness of a sound in the ear or head in the absence of an external source. It affects around 10–15% of people and current treatment options are limited. Experimental treatments include various forms of electrical stimulation of the brain. Currently, there is no consensus on the outcomes that should be measured when investigating the efficacy of this type of intervention for tinnitus. This study seeks to address this by establishing a Core Domain Set: a common standard of what specific tinnitus-related complaints are critical and important to assess in all clinical trials of electrical stimulation-based interventions for tinnitus. Methods A two-round online survey will be conducted, followed by a stakeholder consensus meeting to identify a Core Domain Set. Participants will belong to one of two stakeholder groups: healthcare users with lived experience of tinnitus, and professionals with relevant clinical, commercial, or research experience. Discussion This study will establish a Core Domain Set for the evaluation of electrical stimulation-based interventions for tinnitus via an e-Delphi study. The resulting Core Domain Set will act as a minimum standard for reporting in future clinical trials of electrical stimulation interventions for tinnitus. Standardisation will facilitate comparability of research findings.

Abstract Background Single-sided deafness (SSD) has functional, psychological, and social consequences. Interventions for adults with SSD include hearing aids and auditory implants. Benefits and harms (outcome domains) of these interventions are until now reported inconsistently in clinical trials. Inconsistency in reporting outcome measures prevents meaningful comparisons or syntheses of trial results. The Core Rehabilitation Outcome Set for Single-Sided Deafness (CROSSSD) international initiative used structured communication techniques to achieve consensus among healthcare users and professionals working in the field of SSD. The novel contribution is a set of core outcome domains that experts agree are critically important to assess in all clinical trials of SSD interventions. Methods A long list of candidate outcome domains compiled from a systematic review and published qualitative data, informed the content of a two-round online Delphi survey. Overall, 308 participants from 29 countries were enrolled. Of those, 233 participants completed both rounds of the survey and scored each outcome domain on a 9-point scale. The set of core outcome domains was finalised via a web-based consensus meeting with 12 participants. Votes involved all stakeholder groups, with an approximate 2:1 ratio of professionals to healthcare users participating in the Delphi survey, and a 1:1 ratio participating in the consensus meeting. Results The first round of the survey listed 44 potential outcome domains, organised thematically. A further five outcome domains were included in Round 2 based on participant feedback. The structured voting at round 2 identified 17 candidate outcome domains which were voted on at the consensus meeting. Consensus was reached for a core outcome domain set including three outcome domains: spatial orientation, group conversations in noisy social situations, and impact on social situations. Seventy-seven percent of the remaining Delphi participants agreed with this core outcome domain set. Conclusions Adoption of the internationally agreed core outcome domain set would promote consistent assessment and reporting of outcomes that are meaningful and important to all relevant stakeholders. This consistency will in turn enable comparison of outcomes reported across clinical trials comparing SSD interventions in adults and reduce research waste. Further research will determine how those outcome domains should best be measured.

Abstract Background Dental service provision in the care home sector is poor, with little emphasis on prevention. Emerging evidence suggests that the use of Dental Care Professionals (dental therapists and dental nurses) as an alternative to dentists has the potential to improve preventive advice, the provision of care and access to services within care homes. However, robust empirical evidence from definitive trials on how to successfully implement and sustain these interventions within care homes is currently lacking. The aim of the study is to determine whether Dental Care Professionals could reduce plaque levels of dentate older adults (65 + years) residing in care homes. Methods This protocol describes a two-arm cluster-randomised controlled trial that will be undertaken in care homes across Wales, Northern Ireland and England. In the intervention arm, the dental therapists will visit the care homes every 6 months to assess and then treat eligible residents, where necessary. All treatment will be conducted within their Scope of Practice. Dental nurses will visit the care homes every month for the first 3 months and then three-monthly afterwards to promulgate advice to improve the day-to-day prevention offered to residents by carers. The control arm will be ‘treatment as usual’. Eligible care homes (n = 40) will be randomised based on a 1:1 ratio (20 intervention and 20 control), with an average of seven residents recruited in each home resulting in an estimated sample of 280. Assessments will be undertaken at baseline, 6 months and 12 months and will include a dental examination and quality of life questionnaires. Care home staff will collect weekly information on the residents’ oral health (e.g. episodes of pain and unscheduled care). The primary outcome will be a binary classification of the mean reduction in Silness-Löe Plaque Index at 6 months. A parallel process evaluation will be undertaken to explore the intervention’s acceptability and how it could be embedded in standard practice (described in a separate paper), whilst a cost-effectiveness analysis will examine the potential long-term costs and benefits of the intervention. Discussion This trial will provide evidence on how to successfully implement and sustain a Dental Care Professional-led intervention within care homes to promote access and prevention. Trial registration ISRCTN16332897 . Registered on 3 December 2021.

Abstract Background Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness — monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated. Methods This is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2–24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards. Discussion This pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere. Trial registration EU Clinical Trials register 2018-004460-63.

Abstract Background The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Methods Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. Results Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. Conclusions Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.

Abstract Background Cognitive problems affect up to 70% of people with multiple sclerosis (MS), which can negatively impact mood, ability to work, and quality of life. Addressing cognitive problems is a top 10 research priority for people with MS. Our ongoing research has systematically developed a cognitive screening and management pathway (NEuRoMS) tailored for people with MS, involving a brief cognitive evaluation and rehabilitation intervention. The present study aims to assess the feasibility of delivering the pathway and will inform the design of a definitive randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of the intervention and eventually guide its clinical implementation. Methods The feasibility study is in three parts. Part 1 involves an observational study of those who receive screening and support for cognitive problems, using routinely collected clinical data. Part 2 is a two-arm, parallel group, multicentre, feasibility RCT with a nested fidelity evaluation. This part will evaluate the feasibility of undertaking a definitive trial comparing the NEuRoMS intervention plus usual care to usual care only, amongst people with MS with mild cognitive problems (n = 60). In part 3, semi-structured interviews will be undertaken with participants from part 2 (n = 25), clinicians (n = 9), and intervention providers (n = 3) involved in delivering the NEuRoMS cognitive screening and management pathway. MS participants will be recruited from outpatient clinics at three UK National Health Service hospitals. Discussion Timely screening and effective management of cognitive problems in MS are urgently needed due to the detrimental consequences of cognitive problems on people with MS, the healthcare system, and wider society. The NEuRoMS intervention is based on previous and extant literature and has been co-constructed with relevant stakeholders. If effective, the NEuRoMS pathway will facilitate timely identification and management of cognitive problems in people with MS. Trial registration ISRCTN11203922 . Prospectively registered on 09.02.2021.

Abstract Qualitative research can enhance the design, conduct and interpretation of trials. Despite this, few trials incorporate qualitative methods, and those that do may not realise their full potential. In this commentary, we highlight how qualitative research can contribute to the design, conduct and day-to-day running of a trial, outlining the working arrangements and relationships that facilitate these contributions. In doing so, we draw on (i) existing frameworks on the role of qualitative research alongside trials and (ii) our experience of integrated qualitative research conducted as part of the feasibility study of the SAFER trial (Screening for Atrial Fibrillation with ECG to Reduce stroke), a cluster randomised controlled trial of screening people aged 70 and above for atrial fibrillation in primary care in England. The activities and presence of the qualitative team contributed to important changes in the design, conduct and day-to-day running of the SAFER feasibility study, and the subsequent main trial, informing diverse decisions concerning trial documentation, trial delivery, timing and content of measures and the information given to participating patients and practices. These included asking practices to give screening results to all participants and not just to ‘screen positive’ participants, and greater recognition of the contribution of practice reception staff to trial delivery. These changes were facilitated by a ‘one research team’ approach that underpinned all formal and informal working processes from the outset and maximised the value of both qualitative and trial coordination expertise. The challenging problems facing health services require a combination of research methods and data types. Our experience and the literature show that the benefits of embedding qualitative research in trials are more likely to be realised if attention is given to both structural factors and relationships from the outset. These include sustained and sufficient funding for qualitative research, embedding qualitative research fully within the trial programme, providing shared infrastructure and resources and committing to relationships based on mutual recognition of and respect for the value of different methods and perspectives. We outline key learning for the planning of future trials. Trial registration: Screening for atrial fibrillation with ECG to reduce stroke ISRCTN16939438 (feasibility study); Screening for atrial fibrillation with ECG to reduce stroke – a randomised controlled trial ISRCTN72104369 .

Abstract Background Literature on factors influencing medication adherence within paediatric clinical trials is sparse. The Paracetamol and Ibuprofen in the Primary Prevention of Asthma in Tamariki (PIPPA Tamariki) trial is an open-label, randomised controlled trial aiming to determine whether paracetamol treatment, compared with ibuprofen treatment, as required for fever and pain in the first year of life, increases the risk of asthma at age six years. To inform strategies for reducing trial medication crossovers, understanding factors influencing the observed ibuprofen-to-paracetamol crossovers (non-protocol adherence) is vital. The aim of this study was to investigate the factors influencing the decision-making process when administering or prescribing ibuprofen to infants that may contribute to the crossover events in the PIPPA Tamariki trial. Methods Constructivist grounded theory methods were employed. We conducted semi-structured interviews of caregivers of enrolled PIPPA Tamariki infants and healthcare professionals in various healthcare settings. Increasing theoretical sensitivity of the interviewers led to theoretical sampling of participants who could expand on the teams’ early constructed codes. Transcribed interviews were coded and analysed using the constant comparative method of concurrent data collection and analysis. Results Between September and December 2020, 20 participants (12 caregivers; 8 healthcare professionals) were interviewed. We constructed a grounded theory of prioritising infant welfare that represents a basic social process when caregivers and healthcare professionals medicate feverish infants. This process comprises three categories: historical, trusting relationships and being discerning; and is modified by one condition: being conflicted. Participants bring with them historical ideas. Trusting relationships with researchers, treating clinicians and family play a central role in enabling participants to challenge historical ideas and be discerning. Trial medication crossovers occur when participants become conflicted, and they revert to historical practices that feel familiar and safer. Conclusions We identified factors and a basic social process influencing ibuprofen use in infants and trial medication crossover events, which can inform strategies for promoting adherence in the PIPPA Tamariki trial. Future studies should explore the role of trusting relationships between researchers and treating clinicians when conducting research.

Abstract Background Up to 20% of UK children experience socio-emotional difficulties which can have serious implications for themselves, their families and society. Stark socioeconomic and ethnic inequalities in children’s well-being exist. Supporting parents to develop effective parenting skills is an important preventive strategy in reducing inequalities. Parenting interventions have been developed, which aim to reduce the severity and impact of these difficulties. However, most parenting interventions in the UK focus on early childhood (0–10 years) and often fail to engage families from ethnic minority groups and those living in poverty. Strengthening Families, Strengthening Communities (SFSC) is a parenting programme designed by the Race Equality Foundation, which aims to address this gap. Evidence from preliminary studies is encouraging, but no randomised controlled trials have been undertaken so far. Methods/design The TOGETHER study is a multi-centre, waiting list controlled, randomised trial, which aims to test the effectiveness of SFSC in families with children aged 3–18 across seven urban areas in England with ethnically and socially diverse populations. The primary outcome is parental mental well-being (assessed by the Warwick-Edinburgh Mental Well-Being Scale). Secondary outcomes include child socio-emotional well-being, parenting practices, family relationships, self-efficacy, quality of life, and community engagement. Outcomes are assessed at baseline, post intervention, three- and six-months post intervention. Cost effectiveness will be estimated using a cost-utility analysis and cost-consequences analysis. The study is conducted in two stages. Stage 1 comprised a 6-month internal pilot to determine the feasibility of the trial. A set of progression criteria were developed to determine whether the stage 2 main trial should proceed. An embedded process evaluation will assess the fidelity and acceptability of the intervention. Discussion In this paper we provide details of the study protocol for this trial. We also describe challenges to implementing the protocol and how these were addressed. Once completed, if beneficial effects on both parental and child outcomes are found, the impact, both immediate and longer term, are potentially significant. As the intervention focuses on supporting families living in poverty and those from minority ethnic communities, the intervention should also ultimately have a beneficial impact on reducing health inequalities. Trial registration Prospectively registered Randomised Controlled Trial ISRCTN15194500 .

Abstract Background Evidence for interventions promoting oral health amongst care home residents is weak. The National Institute for Health and Care Excellence (NICE) guideline NG48 aims to maintain and improve the oral health of care home residents. A co-design process that worked with residents and care home staff to understand how the NG48 guideline could be best implemented in practice has been undertaken to refine a complex intervention. The aim of this study is to assess the feasibility of the intervention to inform a future larger scale definitive trial. Methods This is a protocol for a pragmatic cluster randomised controlled trial with a 12-month follow-up that will be undertaken in 12 care homes across two sites (six in London, six in Northern Ireland). Care homes randomised to the intervention arm (n = 6) will receive the complex intervention based on the NG48 guideline, whilst care homes randomised to the control arm (n = 6) will continue with routine practice. The intervention will include a training package for care home staff to promote knowledge and skills in oral health promotion, the use of the Oral Health Assessment Tool on residents by trained care home staff, and a ‘support worker assisted’ daily tooth-brushing regime with toothpaste containing 1500 ppm fluoride. An average of ten residents, aged 65 years or over who have at least one natural tooth, will be recruited in each care home resulting in a recruited sample of 120 participants. Assessments will be undertaken at baseline, 6 months and 12 months, and will include a dental examination and questionnaires on general health and oral health administered by a research assistant. A parallel process evaluation involving semi-structured interviews will be undertaken to explore how the intervention could be embedded in standard practice. Rates of recruitment and retention, and intervention fidelity will also be recorded. A cost-consequence model will determine the relevance of different outcome measures in the decision-making context. Discussion The study will provide valuable information for trialists, policymakers, clinicians and care home staff on the feasibility and associated costs of oral health promotion in UK care homes. Trial registration ISRCTN10276613. Registered on 17th April 2020. http://www.isrctn.com/ISRCTN10276613 .

Abstract Background Compared to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing COVID-19 pandemic and its major impact on cancer referrals. The ThinkCancer! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! intervention for a future definitive randomised controlled trial. Methods The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect primary care intervals (PCI), 2-week wait (2WW) referral rates, conversion rates and detection rates at baseline and 6 months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. Discussion This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. Trial registration ClinicalTrials.gov NCT04823559 .

Abstract Background Hyperacusis is a chronic condition commonly defined as a lowered tolerance or increased sensitivity to everyday environmental sounds. It has been viewed as a paediatric disorder which can cause significant impairment to a child’s normal functioning. Although clinical guidance highlights the importance of identifying whether the child has intolerance to loud sounds and managing this appropriately, there are currently no assessment or treatment methods that have been designed and tested for use with children with hyperacusis. A review is therefore indicated to consider the profile of children with hyperacusis as a basis for future research into their assessment and treatment. Method A scoping review methodology was followed with literature searches conducted in Embase, PsychINFO, PubMed CENTRAL, Scopus, Web of Science and Google Scholar. Research articles were included if they reported on research studies describing children diagnosed with hyperacusis, providing clinical profile information, and/or reporting on an assessment or management method for children with a primary complaint of hyperacusis. Data were charted on Excel and verified by a second researcher. Twenty-one research articles were included. Results Children with hyperacusis are typically described in terms of age at presentation, troublesome sounds, physical sensation, behavioural reactions, coping strategies, comorbid conditions and impact on daily life. Methods of assessing the children include semi-structured interviews, questionnaires, neurological assessment, observation and uncomfortable loudness levels. Management methods include psychological therapy, sound therapy, tinnitus retraining therapy, medication and neuro-rehabilitation. Conclusion The information we catalogued on various elements of clinical profile, assessment and management can serve as a stepping stone in future research developing questionnaires for clinical measurement of the impact of hyperacusis on children, and the measurement of treatment related change in clinic and in trials. Positive outcomes were noted by the authors following all of the above treatments; future research must compare these and specify the parameters for optimal results.

Abstract Background Whilst evidence indicates many children experience troublesome tinnitus, specialist services for children are far less established than those available for adults. To date, there is limited understanding of how paediatric tinnitus is managed in the UK, and to what extent current practice reflects what is recommended. This service evaluation aimed to 1) profile how tinnitus in children is managed in UK clinical practice, and assess to what extent care provided by services reflects advice included in the British Society of Audiology (BSA) Tinnitus in Children Practice Guidance, 2) collate clinician opinions on how services may be optimised, and 3) identify common problems experienced by children who present with bothersome tinnitus in clinic. Methods As part of a larger survey, eight questions regarding services for paediatric tinnitus were distributed to UK NHS audiology services via email and social media. Representatives from eighty-seven services responded between July and September 2017. Results Fifty-three percent of respondents reported that their department provided a paediatric tinnitus service. Among these services, there was widespread use of most BSA recommended assessments and treatments. Less widely used practices were the assessment of mental health (42%), and the use of psychological treatment approaches; cognitive behavioural therapy (CBT) (28%), mindfulness (28%), and narrative therapy (14%). There was varied use of measurement tools to assess tinnitus in children, and a minority of respondents reported using adult tinnitus questionnaires with children. Frequently reported tinnitus-related problems presented by children were sleep difficulties, concentration difficulties at school, situation-specific concentration difficulties, and emotional distress. Conclusions Approaches used to manage children with troublesome tinnitus in UK NHS services are largely consistent and reflective of the current practice guidance. However, findings from this study indicate specialist staff training, access to child-specific tools, and the treatment and referral of children with tinnitus-related psychological problems represent key areas in need of optimisation.

Abstract Background We tested the feasibility of delivering and evaluating a complex therapy intervention which aimed to promote activity and independence for people with early dementia (PrAISED). Feasibility questions were on: recruitment, randomisation, intervention delivery, adherence and withdrawals, level of supervision required, adverse events, data collection and sample size assumptions. Methods We conducted a three-arm, multi-site, single-blind, randomised controlled feasibility trial. Eligibility criteria were aged 65 years or older, diagnosed mild dementia or mild cognitive impairment, able to walk without human help, and communicate in English, no co-morbidities that prevented participation in cognitive assessment and capacity to give consent. Participants were recruited from Memory Assessment Service clinics and the ‘Join Dementia Research’ register. Patient participants were randomised 1:1:1 to a high intensity supervision PrAISED intervention, moderate intensity supervision PrAISED intervention or brief falls prevention assessment and advice (control). The PrAISED intervention aimed for participants to complete three hours of PrAISED exercises a week for 12 months. It included individualised activity and exercise plans and supervised exercises with regular re-assessment and progression, and was delivered by occupational therapists, physiotherapists and rehabilitation support workers. Primary efficacy outcome was the Disability Assessment for Dementia (DAD), measured after 12 months. Secondary outcomes included physical activity, quality of life, mood, cognition, strength, balance, rate of falls, frailty and carer strain. Falls and activity were ascertained by monthly diary. Results Between September 2016 and March 2017 we recruited 60 patient participants and 54 carer participants from two sites. Forty-nine patient participants completed a follow-up interview. Feasibility outcomes were mostly satisfactory, including recruitment and retention, intervention delivery and data completeness for most scales used. We could not maintain blinding of researchers at follow-up and experienced difficulties collecting data using some questionnaires and devices. Participants only completed a mean 77 (moderate supervision) and 71 (high supervision) minutes per week of PrAISED exercises over 12 months. We recorded 19 adverse events, none serious and related to the intervention. Conclusion We conclude that with some adjustments to the trial protocol, it is feasible to deliver the PrAISED intervention and conduct a trial. Trial registration ClinicalTrials.gov: NCT02874300 (first posted 22nd August 2016), ISRCTN: 10550694 (date assigned 31st August 2016).

Abstract Background People with dementia progressively lose cognitive and functional abilities. Interventions promoting exercise and activity may slow decline. We developed a novel intervention to promote activity and independence and prevent falls in people with mild cognitive impairment (MCI) or early dementia. We successfully undertook a feasibility randomised controlled trial (RCT) to refine the intervention and research delivery. We are now delivering a multi-centred RCT to evaluate its clinical and cost-effectiveness. Methods We will recruit 368 people with MCI or early dementia (Montreal Cognitive Assessment score 13–25) and a family member or carer from memory assessment clinics, other community health or social care venues or an online register (the National Institute for Health Research Join Dementia Research). Participants will be randomised to an individually tailored activity and exercise programme delivered using motivational theory to promote adherence and continued engagement, with up to 50 supervised sessions over one year, or a brief falls prevention assessment (control). The intervention will be delivered in participants’ homes by trained physiotherapists, occupational therapists and therapy assistants. We will measure disabilities in activities of daily living, physical activity, balance, cognition, mood, quality of life, falls, carer strain and healthcare and social care use. We will use a mixed methods approach to conduct a process evaluation to assess staff training and delivery of the intervention, and to identify individual- and context-level mechanisms affecting intervention engagement and activity maintenance. We will undertake a health economic evaluation to determine if the intervention is cost-effective. Discussion We describe the protocol for a multi-centre RCT that will evaluate the clinical and cost-effectiveness of a therapy programme designed to promote activity and independence amongst people living with dementia. Trial registration ISRCTN, ISRCTN15320670. Registered on 4 September 2018.

Abstract Background The sensitivity of endoscopic ultrasound (EUS) in staging gastro-oesophageal cancers (GOCs) has been widely studied. However, the economic evidence of EUS staging in the management of patients with GOCs is scarce. This review aimed to examine all economic evidence (not limited to randomised controlled trials) of the use of EUS staging in the management of GOCs patients, and to offer a review of economic evidence on the costs, benefits (in terms of GOCs patients’ health-related quality of life), and economic implications of the use of EUS in staging GOCs patients. Methods The protocol was registered prospectively with PROSPERO (CRD42016043700; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016043700). MEDLINE (ovid), EMBASE (ovid), The Cochrane Collaboration Register and Library (including the British National Health Service Economic Evaluation Database), CINAHL (EBSCOhost) and Web of Science (Core Collection) as well as reference lists were systematically searched for studies conducted between 1996 and 2018 (search update 28/04/2018). Two authors independently screened the identified articles, assessed study quality, and extracted data. Study characteristics of the included articles, including incremental cost-effectiveness ratios, when available, were summarised narratively. Results Of the 197 articles retrieved, six studies met the inclusion criteria: three economic studies and three economic modelling studies. Of the three economic studies, one was a cost-effectiveness analysis and two were cost analyses. Of the three economic modelling studies, one was a cost-effectiveness analysis and two were cost-minimisation analyses. Both of the cost-effectiveness analyses reported that use of EUS as an additional staging technique provided, on average, more QALYs (0.0019–0.1969 more QALYs) and saved costs (by £1969–£3364 per patient, 2017 price year) compared to staging strategy without EUS. Of the six studies, only one included GOCs participants and the other five included oesophageal cancer participants. Conclusions The data available suggest use of EUS as a complementary staging technique to other staging techniques for GOCs appears to be cost saving and offers greater QALYs. Nevertheless, future studies are necessary because the economic evidence around this EUS staging intervention for GOCs is far from robust. More health economic research and good quality data are needed to judge the economic benefits of EUS staging for GOCs. PROSPERO Registration Number CRD42016043700.

Abstract Background War in Syria has lasted for more than eight years, causing population displacement, collapse of medical and public health services, extensive violence and countless deaths. Since November 2016, military operations in Northeast Syria intensified. In October 2017 a large influx of internally displaced persons (IDPs) arrived to Ein Issa camp, Raqqa governate. Médecins Sans Frontières (MSF) assessed the health status of recently arrived IDPs in Ein Issa camp. Methods MSF carried out a cross-sectional survey using simple random sampling between 8 and 18 November 2017, enrolling households who had arrived to Ein Issa camp since 1 October 2017. A questionnaire collected data on demographics, history of displacement, retrospective one-year mortality, two-week morbidities, non-communicable diseases, exposure to violence in the last year and two-week psychological distress symptoms among all household members as well as vaccination status in children aged 6 to 59 months. The latter were also screened for malnutrition. Prevalence estimates and mortality rates were calculated with their 95% confidence interval. Mortality rates were calculated as the number of deaths/10,000 persons/day using the individual person-day contribution of all household members. Results MSF surveyed 257 households (1482 participants). They reported 31 deaths in the previous year, resulting in a crude mortality rate of 0.56 deaths/10,000 persons/day (95%CI: 0.39–0.80). Conflict-related violence was the most frequently reported cause of death (64.5%). In the previous year, 31.7% (95%CI: 29.4–34.2) of the participants experienced at least one violent episode. The most frequent type of violence reported was witnessing atrocities (floggings, executions or public body displays); 18.9% (95%CI: 17.0–21.0) of the population and 9.8% (95%CI: 7.9–12.0) of the children under 15 years had witnessed such atrocities. In men over 14 years, 15.8% (95%CI: 11.9–20.8) were detained/kidnapped and 11.3% (95%CI: 8.0–15.8) tortured/beaten/attacked. In the two weeks prior to interview, 14.4% (95%CI: 10.6–19.3) of the respondents felt so hopeless that they did not want to carry on living most of the time. Conclusions High levels of mortality, exposure to violence and psychological distress were reported. These survey results increase understanding of the impact of the conflict on the IDP population in Northeast Syria.

Abstract Background While the majority of seriously ill people wish to die at home, only half achieve this. The likelihood of someone dying at home often depends on the availability of able and willing lay carers to support them. Dying people are usually unable to take oral medication. When top-up symptom relief medication is required, a clinician travels to the home to administer injectable medication, with attendant delays. The administration of subcutaneous injections by lay carers, though not widespread practice in the UK, has proven key in achieving home deaths in other countries. Our aim is to determine if carer-administration of as-needed subcutaneous medication for four frequent breakthrough symptoms (pain, nausea, restlessness and noisy breathing) in home-based dying patients is feasible and acceptable in the UK. Methods This paper describes a randomised pilot trial across three UK sites, with an embedded qualitative study. Dyads of adult patients/carers are eligible, where patients are in the last weeks of life and wish to die at home, and lay carers who are willing to be trained to give subcutaneous medication. Dyads who do not meet strict risk assessment criteria (including known history of substance abuse or carer ability to be trained to competency) will not be approached. Carers in the intervention arm will receive a manualised training package delivered by their local nursing team. Dyads in the control arm will receive usual care. The main outcomes of interest are feasibility, acceptability, recruitment rates, attrition and selection of the most appropriate outcome measures. Interviews with carers and healthcare professionals will explore attitudes to, experiences of and preferences for giving subcutaneous medication and experience of trial processes. The study has obtained full ethical approval. Discussion This study will rehearse the procedures and logistics which will be undertaken in a future definitive randomised controlled trial and will inform the design of such a study. Findings will illuminate methodological and ethical issues pertaining to researching last days of life care. The study is funded by the National Institute for Health Research (Health Technology Assessment [HTA] project 15/10/37). Trial registration ISRCTN, ISRCTN 11211024. Registered on 27 September 2016.

Abstract Introduction Health related quality of life is a multi-dimensional construct of particular interest in determining the consequences of illness and disease. This study aimed to determine the relationships between overweight/obesity, and associated obesogenic risk behaviours with health related quality of life and physical, social, emotional and school sub-domains, among a large cohort of Australian primary school children. Methods The data were derived from the Goulburn Valley Health Behaviours Monitoring study whereby a census-styled school recruitment process and high participatory opt-out (passive) procedure was employed. All primary schools in three Local Government Areas were invited to participate between July-September 2016 with 39/62 (62%) of schools participating and 1606/2034 (79%) students in Grade 2 (aged approx. 7-8 years), Grade 4 (aged approx. 9-10 years) and Grade 6 (aged approx. 11-12 years) participating. Measured height and weight were collected among participating students and older children (Grade 4 and 6) who also completed a self-report behavioural questionnaire, including the paediatric quality of life inventory. Results Among 809 children aged 9 to 12 years, there were 219 (27.1%) classified as overweight/obese. Male children classified as overweight/obese reported significantly lower health related quality of life in the physical functioning and global functioning scores, compared to normal weight males. Significantly higher quality of life scores were observed among all children who met the physical activity recommendations on five out of the seven previous days. Significantly higher scores were observed among males adhering to the daily screen time recommendations, and among those meeting daily recommendations for fruit consumption. Among male school children, soft drink consumption was associated to lower health related quality of life. Conclusion Although cross-sectional, these findings highlight children with overweight/obesity and some underlying lifestyle behavioural risk factors, had significantly lower healthy-related quality of life, although this was observed most consistently among male school children. These findings have not previously been identified in young children and highlights the need to consider mental and emotional health in public health efforts to prevent obesity. Trial Registration ANZCTR Trial Registry: ACTRN12616000980437 retrospectively registered 26 July 2016

Abstract Background Adalimumab, a biological treatment targeting tumour necrosis factor α, might be useful in sciatica. This paper describes the challenges faced when developing a new treatment pathway for a randomised controlled trial of adalimumab for people with sciatica, as well as the reasons why the trial discussed was stopped early. Methods A pragmatic, parallel group, randomised controlled trial with blinded (masked) participants, clinicians, outcome assessment and statistical analysis was conducted in six UK sites. Participants were identified and recruited from general practices, musculoskeletal services and outpatient physiotherapy clinics. They were adults with persistent symptoms of sciatica of 1 to 6 months’ duration with moderate to high level of disability. Eligibility was assessed by research physiotherapists according to clinical criteria, and participants were randomised to receive two doses of adalimumab (80 mg then 40 mg 2 weeks later) or saline placebo subcutaneous injections in the posterior lateral thigh. Both groups were referred for a course of physiotherapy. Outcomes were measured at baseline, 6-week, 6-month and 12-month follow-up. The main outcome measure was disability measured using the Oswestry Disability Index. The planned sample size was 332, with the first 50 in an internal pilot phase. Results The internal pilot phase was discontinued after 10 months from opening owing to low recruitment (two of the six sites active, eight participants recruited). There were several challenges: contractual delays; one site did not complete contract negotiations, and two sites signed contracts shortly before trial closure; site withdrawal owing to patient safety concerns; difficulties obtaining excess treatment costs; and in the two sites that did recruit, recruitment was slower than planned because of operational issues and low uptake by potential participants. Conclusions Improved patient care requires robust clinical research within contexts in which treatments can realistically be provided. Step changes in treatment, such as the introduction of biologic treatments for severe sciatica, raise complex issues that can delay trial initiation and retard recruitment. Additional preparatory work might be required before testing novel treatments. A randomised controlled trial of tumour necrosis factor-α blockade is still needed to determine its cost-effectiveness in severe sciatica. Trial registration Current Controlled Trials, ISRCTN14569274. Registered on 15 December 2014.

Abstract Background Health economic evaluations rely on the accurate measurement of health service resource use in order to calculate costs. These are usually measured with patient completed questionnaires using instruments such as the Client Service Receipt Inventory (CSRI). These rely on participants’ recall and can be burdensome to complete. Health service activity data are routinely captured by electronic databases. The aim was to test methods for obtaining these data and compare with those data collected using the CSRI, within a feasibility study of an enhanced rehabilitation intervention following hip fracture (Fracture in the Elderly Multidisciplinary Rehabilitation: FEMuR). Methods Primary care activity including prescribing data was obtained from the Secure Anonymised Information Linkage (SAIL) Databank and secondary care activity (Emergency Department attendances, out-patient visits and in-patient days) directly from Betsi Cadwaladr University Health Board (BCUHB), North Wales, UK. These data were compared with patient responses from the CSRI using descriptive statistics and the intraclass correlation coefficient (ICC). Results It was possible to compare health service resource use data for 49 out of 61 participants in the FEMuR study. For emergency department (ED) attendances, records matched in 23 (47%) cases, 21 (43%) over-reported on electronic records compared with CSRI and five participants (10%) under-reported, with an overall ICC of 0.42. For out-patient episodes, records matched in only six cases, 28 participants over-reported on electronic records compared with CSRI and 15 (12%) under-reported, with an overall ICC of only 0.27. For in-patient days, records matched exactly in only five cases (10%), but if an error margin of 7 days was allowed, then agreement rose to 39 (66%) cases, and the overall ICC for all data was 0.88. It was only possible to compare prescribing data for 12 participants. For prescribing data, the SAIL data reported 117 out of 118 items (99%) and the CSRI only 89 (79%) items. Conclusions The use of routinely collected data has the potential to improve the efficiency of trials and other studies. Although the methodology to make the data available has been demonstrated, the data obtained was incomplete and the validity of using this method remains to be demonstrated. Trial registration Trial registration: ISRCTN22464643 Registered 21 July 2014.

Abstract Background Motor outcomes of children with unilateral cerebral palsy are clearly documented and well understood, yet few studies describe the cognitive functioning in this population, and the associations between the two is poorly understood. Using two hands together in daily life involves complex motor and cognitive processes. Impairment in either domain may contribute to difficulties with bimanual performance. Research is yet to derive whether, and how, cognition affects a child’s ability to use their two hands to perform bimanual tasks. Methods/Design This study will use a prospective, cross-sectional multi-centre observational design. Children (aged 6–12 years) with unilateral cerebral palsy will be recruited from one of five Australian treatment centres. We will examine associations between cognition, bimanual performance and brain neuropathology (lesion type and severity) in a sample of 131 children. The primary outcomes are: Motor - the Assisting Hand Assessment; Cognitive - Executive Function; and Brain – lesion location on structural MRI. Secondary data collected will include: Motor - Box and Blocks, ABILHAND- Kids, Sword Test; Cognitive – standard neuropsychological measures of intelligence. We will use generalized linear modelling and structural equation modelling techniques to investigate relationships between bimanual performance, executive function and brain lesion location. Discussion This large multi-centre study will examine how cognition affects bimanual performance in children with unilateral cerebral palsy. First, it is anticipated that distinct relationships between bimanual performance and cognition (executive function) will be identified. Second, it is anticipated that interrelationships between bimanual performance and cognition will be associated with common underlying neuropathology. Findings have the potential to improve the specificity of existing upper limb interventions by providing more targeted treatments and influence the development of novel methods to improve both cognitive and motor outcomes in children with unilateral cerebral palsy. Trial registration ACTRN12614000631606; Date of retrospective registration 29/05/2014.

Abstract Objectives Currently, there is no consensus protocols regarding the combination of glycerol (GLY), gelatin or foetal bovine serum (FBS) with dimethyl sulphoxide (DMSO) as cryoprotectants for Mycoplasma bovis in bovine milk samples. This study aimed to compare different cryopreservation compounds and storage temperatures for M. bovis. Results There were significant differences in the survival of M. bovis on different media. Differences were also observed between different storage conditions. All additives improved the survival of M. bovis in comparison to control (CON). The combination of GLY and DMSO was shown to be significantly different to CON with 57.1% (95% CI = 21.43–133.34) and 19.1% (95% CI = 11.73–60.27), respectively at week 16, and its use should be encouraged as a cryoprotectant for M. bovis at − 20 and − 80 °C. GEL/DMSO showed the highest survival rate for M. bovis with 57.14% (95% CI = 21.43–133.34) at 4 °C in comparison with CON 14.29% (95% CI = 9.60–50.39). FBS/DMSO showed the highest survival rate for the short-term preservation similarly to other additives. The evaluated cryopreservative compounds would improve survivability of M. bovis in milk for both transport and long-term storage. Hence, it is recommended to use the mentioned methods for routine transportation or storage purposes for suspicious M. bovis milk samples.

Abstract Objectives This study aimed to provide a rapid, accurate and cost-effective diagnostic real time polymerase chain reaction-high resolution melting curve assay (PCR-HRM) to identify and distinguish between four different mycoplasmas and Acholeplasma laidlawii isolated at cow-level from a single commercial dairy farm in South Australia. One set of genus-level universal primers was designed targeting the 16S ribosomal RNA gene. Results Real time PCR-HRM analysis was able to identify and distinguish between five different mollicutes, namely A. laidlawii, M. arginini, M. bovirhinis, M. bovis and uncultured Mycoplasma. Results were confirmed through sequencing. Our developed assay provides rapid and accurate screening for Mycoplasma mastitis detection.

Abstract Background Tinnitus service provision in the United Kingdom has been investigated from the healthcare provider’s perspective demonstrating considerable regional variation particularly regarding availability of psychological treatments. An audiological-based tinnitus service, however, was reportedly available for all tinnitus patients in the UK. The aim of the current study was to define and evaluate nationwide tinnitus healthcare services from the patients’ viewpoint. Methods Secondary analyses were performed on data from a 33-item questionnaire provided by the British Tinnitus Association. The questionnaire had been distributed via email and social media. Results Responses from 937 participants who had or had previously experienced tinnitus were analysed. All but one person had at some time consulted their GP. About one in five received medication in primary care. The majority were referred to secondary care, generally an ENT surgeon or audiovestibular physician; some were referred directly to audiological services. In secondary care the majority underwent audiometric testing and over half underwent MRI scanning. Drugs were prescribed less frequently in secondary care. About one third of patients were referred onwards from diagnostic services in secondary care to receive therapeutic interventions for tinnitus. Therapy was generally delivered by an audiologist or hearing therapist. Just under two fifths of people discharged from secondary care returned to their GP, with most returning within one year. Over a third of this group were re-referred to secondary care. Few patients saw a psychologist (2.6%) though some psychological treatments were delivered by appropriately trained audiologists. Negative counselling from healthcare professionals in both primary and secondary care settings was reported. Conclusions Although the UK has developed a national service for patients with tinnitus many people find it difficult to access, being blocked at the primary care level or after secondary care diagnostic services. Many of those discharged from secondary care return to their GP within a short space of time and are re-referred to secondary care creating an unsatisfactory and expensive revolving-door pattern of healthcare. Despite psychological treatment modalities having the best evidence base for successful tinnitus management, only a minority of tinnitus patients ever get to meet a psychologist.

Abstract Background Numerous studies have detailed the physical health benefits of children’s participation in sport and a growing body of research also highlights the benefits for mental health. Children who participate in sport have also been shown to be advantaged academically. However, despite the benefits there is evidence that children are leading increasingly sedentary lifestyles and are at greater risk of chronic disease than those with active lifestyles. Sport provides an important means for children to achieve their recommended amount of daily physical activity. This systematic review asks ‘what are those barriers to children’s participation in sport?’ Methods Literature searches were carried out in June 2015 using; EMBASE, Medline, CINAHL and SportDiscus using the search terms barrier*, stop*, prevent*, participat*, taking part, Sports/, sport*, “physical education”, PE, child*, young person*, adolescen*. These were supplemented with hand searches. A total of 3434 records were identified of which 22 were suitable for inclusion in the review, two additional studies were identified from Google Scholar in November 2016. Both qualitative and quantitative studies were included. Study’s included in the review assessed children up to 18 years of age. Study quality was assessed using Critical Appraisal Skills Programme (CASP) tools. Results Studies took place in the school environment (n = 14), sports club (n = 1), community setting (n = 8) and adolescent care setting (n = 1). Frequently reported barriers across quantitative studies were ‘time’ (n = 4), ‘cost’ (n = 3), ‘opportunity/accessibility’ (n = 3) and ‘friends’ (n = 2). Frequently reported barriers across qualitative studies were ‘time’ (n = 6), 'cost' (n = 5), 'not being good at sport' (n = 6) and ‘fear of being judged/embarrassed’ (n = 6). Conclusion Policy makers, parents and teachers should all be aware that ‘cost’ and ‘time’ are key barriers to participation in sport. More local sports opportunities are needed where costs are reduced. Schools and local clubs could better work together to provide more affordable local opportunities to increase children’s participation in sport.

Abstract Background People with dementia progressively lose abilities and are prone to falling. Exercise- and activity-based interventions hold the prospect of increasing abilities, reducing falls, and slowing decline in cognition. Current falls prevention approaches are poorly suited to people with dementia, however, and are of uncertain effectiveness. We used multiple sources, and a co-production approach, to develop a new intervention, which we will evaluate in a feasibility randomised controlled trial (RCT), with embedded adherence, process and economic analyses. Methods We will recruit people with mild cognitive impairment or mild dementia from memory assessment clinics, and a family member or carer. We will randomise participants between a therapy programme with high intensity supervision over 12 months, a therapy programme with moderate intensity supervision over 3 months, and brief falls assessment and advice as a control intervention. The therapy programmes will be delivered at home by mental health specialist therapists and therapy assistants. We will measure activities of daily living, falls and a battery of intermediate and distal health status outcomes, including activity, balance, cognition, mood and quality of life. The main aim is to test recruitment and retention, intervention delivery, data collection and other trial processes in advance of a planned definitive RCT. We will also study motivation and adherence, and conduct a process evaluation to help understand why results occurred using mixed methods, including a qualitative interview study and scales measuring psychological, motivation and communication variables. We will undertake an economic study, including modelling of future impact and cost to end-of-life, and a social return on investment analysis. Discussion In this study, we aim to better understand the practicalities of both intervention and research delivery, and to generate substantial new knowledge on motivation, adherence and the approach to economic analysis. This will enable us to refine a novel intervention to promote activity and safety after a diagnosis of dementia, which will be evaluated in a definitive randomised controlled trial. Trial registration ClinicalTrials.gov: NCT02874300; ISRCTN 10550694.

Abstract Background Mycoplasma mastitis is increasingly posing significant impact on dairy industry. Although the effects of major conventional mastitis pathogens on milk components has been widely addressed in the literature, limited data on the effects of different Mycoplasma and Acholeplasma spp. on milk quality and quantity is available. The aim of this study was to determine the casual relationship of Mycoplasma spp. and A. laidlawii to mastitis and compare them to subclinical mastitis caused by conventional mastitis pathogens from a single dairy herd in South Australia; Mycoplasma spp. and A. laidlawii were detected using PCR applied directly to milk samples. The herd had mastitis problem with high somatic cell count and low response rate to conventional antimicrobial therapy. A total of 288 cow-level milk samples were collected aseptically and used in this study. Results Conventional culture showed a predominance of coagulase-negative staphylococci, followed by coagulase-positive staphylococci, Streptococcus spp., Enterococcus spp., E. coli, and Klebsiella spp. PCR results showed a high prevalence of mycoplasmas (76.7%), including A. laidlawii (10.8%), M. bovis (6.2%), M. bovirhinis (5.6%), M. arginini (2%), and (52.1%) of cows were co-infected with two or more Mycoplasma and Acholeplasma species. Mycoplasma co-infection significantly increased somatic cell counts (SCC) similar to conventional mastitis pathogens and compared to non-infected cows with 389.3, 550.3 and 67.3 respectively; and decreased the milk yield with 29.0, 29.9 and 34.4 l, respectively. Mycoplasma co-infection caused significant increase in protein percentage, and significant decrease in fat percentage and total milk solids, similar to other conventional mastitis pathogens. In contrast, changes in milk composition and yield caused by various individual Mycoplasma species were non-significant. Conclusions Mycoplasma mastitis had on-farm economic consequences similar to common conventional mastitis pathogens. Results of our study indicate that co-infection Mycoplasma mastitis caused similar effect on milk composition to other mastitis pathogens and we hope these findings raise the awareness of the importance of their detection on routine diagnostic panels.

Abstract Rainbow trout fry syndrome (RTFS) is a disease caused by the Gram-negative bacterium Flavobacterium psychrophilum, responsible for significant economic losses in salmonid aquaculture worldwide. The diversity of F. psychrophilum isolates and the inherent difficulties in vaccinating juvenile fish has hampered the development of a vaccine for RTFS. Disease episodes tend to occur between 10–14 °C with necrotic lesions often seen on the skin surrounding the dorsal fin and tail. At present no commercial vaccines are available for RTFS in the UK, leaving antibiotics as the only course of action to control disease outbreaks. The current work was performed as a pilot study to assess the efficacy of a polyvalent, whole cell vaccine containing formalin-inactivated F. psychrophilum, to induce protective immunity in rainbow trout fry. Duplicate groups of 30 trout (5 g) were immersed in 1 L of the vaccine for 30 s. Samples were taken 4 h, day 2 and 7 post-vaccination (pv) of skin mucus, tissues for histology and gene expression analysis; serum and histology samples were taken 6 weeks pv. A booster vaccination was given at 315 degree days (dd) also by immersion. Challenge was by immersion with a heterologous isolate of F. psychrophilum 630 dd post primary vaccination. The vaccine provided significant protection to the trout fry with a RPS of 84% (p

Abstract Background Chronic tinnitus is a common incurable condition often associated with depression, anxiety, insomnia and reduced quality of life. Within National Health Service (NHS) audiology in the United Kingdom (UK), no standard protocol currently exists for the treatment of tinnitus. Counselling is only available in less than half of audiology departments, and there is no agreed standard for what constitutes tinnitus counselling. There is substantial evidence from systematic reviews for the clinical benefit of cognitive behaviour therapy (CBT) for tinnitus delivered by clinical psychologists or psychiatrists, but no studies have sufficiently evidenced the NHS model of tinnitus care where management is increasingly being delivered by audiology professionals. In a pilot randomised controlled trial (RCT), this study aims to evaluate the feasibility of comparing a psychologically informed guidance manual developed to support audiologist management of tinnitus with usual treatment. Methods/design Phase 1 consisted of three development stages: (1) a scoping review to generate a comprehensive set of tinnitus counselling components, (2) a Delphi survey involving expert patients (n = 18) and clinicians (n = 21) to establish consensus on the essential core attributes of tinnitus counselling, and (3) incorporation of these elements into a manualised care protocol. In phase 2, following training in a dedicated workshop, the manualised intervention will be delivered by three experienced audiologists across three different sites. Patients (n = 30) will be randomly allocated to receive either (1) psychologically informed management from an audiologist trained to deliver the manualised intervention or (2) treatment as usual (TAU) from an audiologist who has not received this training. Quantitative outcome measures will be administered at baseline, discharge and 6-month follow-up. Qualitative interviews with participating patients and clinicians will be conducted to gather perspectives on the feasibility and acceptability of the manualised intervention. Discussion The feasibility of proceeding to a definitive RCT will be assessed via compliance with the manual, willingness to be randomised, number of eligible participants, rate of recruitment, retention and collection of quantitative outcome measures. This research offers an important first step to an evidence-based, standardised and accessible approach to tinnitus care. Trial registration ISRCTN13059163 . Date of registration: 6 May 2016

Abstract Background There has been rapid increase in time spent using Internet as a platform for entertainment, socialising and information sourcing. This study aimed to evaluate the relationship between duration of time spent using Internet for leisure, depressive symptoms, and psychological distress among Australian adolescents. Methods Depressive symptoms were indicated by the youth self-report module from the Diagnostic and Statistical Manual of Mental Disorders Version IV criteria, and psychological distress was measured by Kessler Psychological Distress scale. Internet use was self-reported based on use on an average weekday, and an average weekend day. Multivariate logistic regression models were used to examine the relationship between Internet use and mental health outcomes. Models were adjusted for potential confounders: age; relative level of socio-economic disadvantage, and body mass index. Results Adolescents were aged 11–17 years (M = 14.5 years, SD = 2.04 years). Greatest time spent using internet (≥7 h a day) was significantly associated with experiencing depressive symptoms among females (OR = 2.09, 95% CI = 1.16, 3.76, p

Abstract Background Learning to undertake intimate female and male examinations is an important part of medical student training but opportunities to participate in practical, supervised learning in a safe environment can be limited. A collaborative, integrated training programme to provide such learning was developed by two university teaching departments and a specialist sexual health service, utilising teaching associates trained for intimate examinations in a simulated clinical educational setting. The objective of this research was to determine changes in senior medical students’ self- reported experience and confidence in performing male and female genital examinations, before and after participating in a new clinical teaching programme. Methods A quasi-experimental mixed methods design, using pre and post programme questionnaires and focus groups, was used to assess the effectiveness of the programme. Results The students reported greatly improved skill, confidence and comfort levels for both male and female genital examination following the teaching programme. Skill, confidence and comfort regarding male examinations were rated particularly low on the pre-teaching programme self- assessment, but post-programme was rated at similar levels to the female examination. Conclusions This integrated female–male teaching programme (utilising trained teaching associates as simulated patients in a supervised clinical teaching environment) was successful in increasing senior medical students’ skills and levels of confidence in performing genital examinations. There were differences between female and male medical students in their learning. Suggestions for improvement included providing more detailed instruction to some clinical supervisors about their facilitation role in the session.

Shigella flexneri causes bacillary dysentery in humans. Essential to the establishment of the disease is the invasion of the colonic epithelial cells. Here we investigated the role of the lipopolysaccharide (LPS) O antigen in the ability of S. flexneri to adhere to and invade polarized Caco-2 cells. The S. flexneri 2a O antigen has two preferred chain lengths: a short O antigen (S-OAg) regulated by the WzzB protein and a very long O antigen (VL-OAg) regulated by Wzz pHS2. Mutants with defined deletions of the genes required for O-antigen assembly and polymerization were constructed and assayed for their abilities to adhere to and enter cultured epithelial cells. The results show that both VL- and S-OAg are required for invasion through the basolateral cell membrane. In contrast, the absence of O antigen does not impair adhesion. Purified LPS does not act as a competitor for the invasion of Caco-2 cells by the wild-type strain, suggesting that LPS is not directly involved in the internalization process by epithelial cells.

Abstract Background Ideally clinical trials should use some form of randomization for allocating participants to the treatment groups under trial. As an integral part of the process of assessing the effectiveness of these treatment groups, randomization performed well can reduce, if not eliminate, some forms of bias that can be evident in non-randomized trials. Given the vast set of possible randomization methods to choose from we demonstrate a method that incorporates many of the advantages of these other methods. Methods A step-by-step introduction of how to use the adaptive randomization algorithm for conducting a clinical trial is given. Results The implications, effects and capabilities of using the adaptive randomization algorithm are fully demonstrated and explained using simulated data and examples from actual trials. Conclusions This paper provides an introduction to a dynamic type of treatment allocation, which fulfills the CONSORT requirements of participants being randomly allocated whilst maintaining a level of control of the balances overall, within the stratification variables and within the strata simultaneously. Maintaining control of the imbalances within the groups is vital particularly if interim analyses are planned. Trial registration Current controlled trials ISRCTN17551624, ISRCTN37558856, ISRCTN97185214.

Abstract Background Improving the quality of care for people with dementia and their carers has become a national priority in many countries. Cognitive Stimulation Therapy (CST) groups can be beneficial in improving cognition and quality of life for people with dementia. The aim of the current study is to develop and evaluate a home-based individual Cognitive Stimulation Therapy (iCST) programme for people with dementia which can be delivered by their family carer. Methods This multi-centre, pragmatic randomised controlled trial (RCT) will compare the effectiveness and cost-effectiveness of iCST for people with dementia with a treatment as usual control group. The intervention consists of iCST sessions delivered by a carer for 30 minutes, 3 times a week over 25 weeks. For people with dementia the primary outcome measures are cognition assessed by the ADAS-Cog, and quality of life assessed by QoL-AD. For carers, quality of life using the SF-12 is the primary outcome measure. Using a 5% significance level, comparison of 306 participants will yield 80% power to detect an effect size of 0.35 for cognition as measured by the ADAS-Cog, and quality of life as measured by the QoL-AD. Quality of life for the carer will be measured using the SF-12. The trial will include a cost-effectiveness analysis from a public sector perspective. Discussion The UK Department of Health has recently stressed that improving access to psychological therapies is a national priority, but many people with dementia are unable to access psychological interventions. The development of a home-based individual version of CST will provide an easy to use, widely available therapy package that will be evaluated for effectiveness and cost-effectiveness in a multi centre RCT.

Abstract Background Tinnitus is a prevalent and complex medical complaint often co-morbid with stress, anxiety, insomnia, depression, and cognitive or communication difficulties. Its chronicity places a major burden on primary and secondary healthcare services. In our recent national survey of General Practitioners (GPs) from across England, many reported that their awareness of tinnitus was limited and as a result were dissatisfied with the service they currently provide. GPs identified 10 online sources of information they currently use in clinical practice, but welcomed further concise and accurate information on tinnitus assessment and management. The purpose of this study was to assess the content, reliability, and quality of the information related to primary care tinnitus assessment and management on these 10 websites. Methods Tinnitus related content on each website was assessed using a summative content analysis approach. Reliability and quality of the information was assessed using the DISCERN questionnaire. Results Quality of information was rated using the validated DISCERN questionnaire. Significant inter-rater reliability was confirmed by Kendall’s coefficient of concordance (Wt) which ranged from 0.48 to 0.92 across websites. The website Map of Medicine achieved the highest overall DISCERN score. However, for information on treatment choice, the British Tinnitus Association was rated best. Content analysis revealed that all websites lacked a number of details relating to either tinnitus assessment or management options. Conclusions No single website provides comprehensive information for GPs on tinnitus assessment and management and so GPs may need to refer to more than one if they want to maximise their coverage of the topic. From those preferred by GPs we recommend several specific websites as the current ‘best’ sources. Our findings should guide healthcare website providers to improve the quality and inclusiveness of the information they publish on tinnitus. In the case of one website, our preliminary findings are already doing so. Such developments will in turn help facilitate best practice in primary care.