This analysis challenges a tendency in public health and the social sciences to associate India's medical pluralism with a distinction between biomedicine, as a homogeneous entity, and its non‐biomedical ‘others’. We argue that this overdrawn dichotomy obscures the important part played by ‘informal’ biomedical practice, an issue with salience well beyond India. Based on a qualitative study in rural Andhra Pradesh, South India, we focus on a figure little discussed in the academic literature – the Registered Medical Practitioner (RMP) – who occupies a niche in the medical market‐place as an informal exponent of biomedical treatment. We explore the significance of these practitioners by tracking diagnosis and treatment of one increasingly prominent medical ‘condition’, namely diabetes. The RMP, who despite the title is rarely registered, sheds light on the supposed formal‐informal sector divide in India's healthcare system, and its permeability in practice. We develop our analysis by contrasting two distinctive conceptualisations of ‘informality’ in relation to the state in India – one Sarah Pinto's, the other Ananya Roy's.

Objectives We present a national evaluation of the impact of independent verification visits (IVVs) performed by National Health Service (NHS) England as part of quality assuring medical revalidation. Organisational visits are central to NHS quality assurance. They are costly, yet little empirical research evidence exists concerning their impact, and what does exist is conflicting.

Setting The focus was on healthcare providers in the NHS (in secondary care) and private sector across England, who were designated bodies (DBs). DBs are healthcare organisations that have a statutory responsibility, via the lead clinician, the responsible officer (RO), to implement medical revalidation.

Participants All ROs who had undergone an IVV in England in 2014 and 2015 were invited to participate. 46 ROs were interviewed. Ethnographic data were gathered at 18 observations of the IVVs and 20 IVV post visit reports underwent documentary analysis.

Primary and secondary outcome measures Primary outcomes were the findings pertaining to the effectiveness of the IVV system in supporting the revalidation processes at the DBs. Secondary outcomes were methodological, relating to the Model for Understanding Success in Quality (MUSIQ) and how its application to the IVV reveals the relevance of contextual factors described in the model.

Results The impact of the IVVs varied by DB according to three major themes: the personal context of the RO; the organisational context of the DB; and the visit and its impact. ROs were largely satisfied with visits which raised the status of appraisal within their organisations. Inadequate or untimely feedback was associated with dissatisfaction.

Conclusions Influencing teams whose prime responsibility is establishing processes and evaluating progress was crucial for internal quality improvement. Visits acted as a nudge, generating internal quality review, which was reinforced by visit teams with relevant expertise. Diverse team membership, knowledge transfer and timely feedback made visits more impactful.

Introduction Core outcome sets are standardised lists of outcomes, which should be measured and reported in all clinical studies of a specific condition. This study aims to develop core outcome sets for economic evaluations in asthma studies. Economic outcomes include items such as costs, resource use or quality-adjusted life years. The starting point in developing core outcome sets will be conducting a systematic literature review to establish a preliminary list of reporting items to be considered for inclusion in the core outcome set.

Methods and analysis We will conduct literature searches of peer-reviewed studies published from January 1990 to January 2017. These will include any comparative or observational studies (including economic models) and systematic reviews reporting economic outcomes. All identified economic outcomes will be tabulated together with the major study characteristics, such as population, study design, the nature and intensity of the intervention, mode of data collection and instrument(s) used to derive an outcome. We will undertake a ‘realist synthesis review’ to analyse the identified economic outcomes. The outcomes will be summarised in the context of evaluation perspectives, types of economic evaluation and methodological approaches. Parallel to undertaking a systematic review, we will conduct semistructured interviews with stakeholders (including people with personal experience of asthma, health professionals, researchers and decision makers) in order to explore additional outcomes which have not been considered, or used, in published studies. The list of outcomes generated from the systematic review and interviews with stakeholders will form the basis of a Delphi survey to refine the identified outcomes into a core outcome set.

Ethics and dissemination The review will not involve access to individual-level data. Findings from our systematic review will be communicated to a broad range of stakeholders including clinical guideline developers, research funders, trial registries, ethics committees and other regulators.

Background: Neurocognitive and functional outcome deficits have long been acknowledged in schizophrenia and neurocognition has been found to account for functional disability to a greater extent than psychopathology. Much of the variance in functional outcome however still remains unexplained and metacognition may mediate the relationship between neurocognition, functional capacity, and self-reported social and occupational function. Method: 80 first-episode psychosis participants were recruited and completed measures of neurocognition (memory, executive function and IQ), metacognition (Beck Cognitive Insight Scale, Metacognitive Awareness Interview), psychopathology (PANSS), and both functional capacity (UPSA) and real-life social and occupational function (The Time Use Survey). Path analyses investigated the relationships between variables through Structural Equation Modelling. Results: A series of path models demonstrated that metacognition partially mediates the relationship between neurocognition and functional capacity, and fully mediates the relationship between functional capacity and social and occupational function. Conclusion: The present study findings identify that metacognition may be critical to translating cognitive and functional skills into real-world contexts, and this relationship is found at early stages of illness. Understanding how individuals translate cognitive and functional skills into the real-world (the competence-performance gap) may offer valuable guidance to intervention programmes. This finding is important to models of recovery as it suggests that intervention programmes that focus on enhancing metacognition abilities may have a greater impact than traditional rehabilitation programmes focusing on cognitive abilities, on social and occupational outcomes.

Jaiswal et al. report the results of four case–control studies that confirm a near doubling in the risk of coronary heart disease in patients with CHIP,1 a finding that was first reported in the Journal in 2014.2 The authors postulate that two mechanisms may be involved: the promotion of inflammatory responses, as supported in a study involving Tet2 knockout mice, and an increase in the number of myeloid cells, a finding that appears to be more relevant for patients with JAK2 mutations, which confer a much larger risk than the more common DNMT3A, TET2, and ASXL1 mutations, in which blood counts remain normal. However, the authors do not provide data relating to red-cell distribution width, which is the only blood-cell index that has been shown to have a significant association with CHIP2 and which has been associated with an unexplained increase in all-cause mortality in an aging population. 3,4 In understanding how CHIP promotes atherosclerosis, it is important to explore the causal relationship between clonal hematopoiesis and red-cell anisocytosis to determine whether these are independent or associated risk factors for cardiovascular disease.

Objectives: Vascular compliance is emerging as a useful cardiovascular risk factor. The aim of this study was to investigate the association between arterial stiffness and stroke severity at presentation and at three weeks.

Methods: From an initial sample of 73 patients, 42 were included (55% male, mean age 71 years) with acute ischaemic stroke, over a 15 month period. Stroke subtypes were classified into LACI, PACI and POCI. Arterial stiffness was measured by QKD using 24-hour ambulatory blood pressure and ECG monitoring. The measured QKD values were then corrected for a heart rate of 60bpm and a systolic blood pressure (SBP) of 100 mmHg (QKD100-60). Stroke severity was assessed on admission and after 3 weeks, using the National Institute of Health Stroke Scale (NIHSS).

Results: There was a non-significant weak correlation between initial stroke severity and QKD100-60 (r= -0.3, p = 0.08). This correlation was weaker at 3 weeks (r= ¬0.125, p=0.47). There was no difference in NIHSS at week 0 and 3, or QKD100-60, between the different stroke types (LACI, PACI and POCI) or dipper versus non-dippers and reverse dippers.

Conclusions: This study highlights the need for further research into the association between QKD and initial stroke severity.

Small open reading frames (smORFs) of 100 codons or fewer are usually - if arbitrarily - excluded from proteome annotations. Despite this, the genomes of many metazoans, including humans, contain millions of smORFs, some of which fulfil key physiological functions. Recently, the transcriptome of Drosophila melanogaster was shown to contain thousands of smORFs of different classes that actively undergo translation, which produces peptides of mostly unknown function. Here, we present a comprehensive analysis of smORFs in flies, mice and humans. We propose the existence of several functional classes of smORFs, ranging from inert DNA sequences to transcribed and translated cis-regulators of translation and peptides with a propensity to function as regulators of membrane-associated proteins, or as components of ancient protein complexes in the cytoplasm. We suggest that the different smORF classes could represent steps in gene, peptide and protein evolution. Our analysis introduces a distinction between different peptide-coding classes of smORFs in animal genomes, and highlights the role of model organisms for the study of small peptide biology in the context of development, physiology and human disease.

For much of the twentieth Century, vulnerability to deprivations of health has often been defined by geographical and economic factors. Those in wealthy, usually ‘Northern’ and ‘Western’, parts of the world have benefited from infrastructures, and accidents of geography and climate, which insulate them from many serious threats to health. Conversely, poorer people are typically exposed to more threats to health, and have lesser access to the infrastructures needed to safeguard them against the worst consequences of such exposure. However, in recent years the increasingly globalised nature of the world’s economy, society, and culture, combined with anthropogenic climate change and the evolution of antibiotic resistance, has begun to shift the boundaries that previously defined the categories of person threatened by many exogenous threats to health. In doing so, these factors expose both new, and forgotten, similarities between persons, and highlight the need for global cooperative responses to the existential threats posed by climate change and the evolution of antimicrobial resistance. In this paper, we argue that these emerging health threats, in demonstrating the similarities that exist between even distant persons, provides a catalyst for global solidarity, which justifies, and provides motivation for, the establishment of solidaristic, cooperative global health infrastructures.

Background/Aims: Use of placebo is the ideal for comparison in clinical trials to reduce biases. With digital technology being used more frequently in healthcare interventions, how do we determine the placebo effect where interventions exploit technology? If placebo in medicine is traditionally defined by a lack of pharmacological agents, how might we begin to move towards controlling for effects of digital technology?

Method: This paper explores the traditional placebo effect and discusses its impact in healthcare contexts with digital technology with reference to a particular trial. Different meanings of placebo in the context of evaluating technology suggest new challenges and positive consequences.

Results: Methodological considerations are discussed, which enabled the development of a placebo-controlled evaluation of a digital technology in healthcare and rehabilitation.

Conclusion: Digital placebo was controlled in our trial by employing technology across all groups in the absence of evidence-based practice and shows how to control for unknown and hidden effects of technology.

A 14mer peptide (T14) derived from the C-terminus of acetylcholinesterase (AChE) selectively activates metastatic breast cancer cells via the alpha-7 nicotinic receptor (α7 nAChR). This naturally occurring peptide is also present in brain, is elevated in Alzheimer’s disease, and is antagonised by a cyclized variant (NBP-14). Here we investigated the effects of NBP-14 in six different cancer cell lines, primary leukemia B-cells and normal B-cells. All cells tested expressed α7 nAChR, intracellular and extracellular T14. However, NBP-14 showed low toxicity and weak antiproliferative effects in the majority of the cell lines and was even less toxic in normal B-cells when compared to primary chronic lymphocytic leukemia cells (P < 0.001). Given the potential role of T14 peptide in metastasis, we next investigated the effects of NBP-14 on tumor cell migration, where it caused a dose-dependent reduction. The extent of NBP-14 inhibition positively correlated with the migration of the cells (r2 = 0.45; P = 0.06). Furthermore, NBP-14 preferentially inhibited the migration of primary leukemia cells when compared with normal B-cells (P = 0.0002); when the normal B-cell data was excluded, this correlation was strengthened (r2 = 0.80; P = 0.006). Importantly, the constitutive α7 nAChR expression positively correlated with intracellular T14 levels (r2 = 0.91; P = 0.0003) and inversely correlated with extracellular T14 levels in the cell culture supernatants (r2 = −0.79; P = 0.034). However, in the presence of NBP-14, α7 nAChR expression was reduced (P = 0.04) and the most migratory cells showed the largest reduction in expression. In conclusion, NBP-14-mediated antagonism of the α7 nAChR offers a novel therapeutic strategy with the potential to inhibit tumor cell migration.

Background: In 2011, the World Health Organization recognized podoconiosis as one of the neglected tropical diseases. Nonetheless, the number of people with podoconiosis and the geographical distribution of the disease is poorly understood. Based on a nationwide mapping survey and geostatistical modelling, we predict the prevalence of podoconiosis and estimate the number of cases across Ethiopia.

Methods: We used nationwide data collected in Ethiopia between 2008 and 2013. Data were available for 141,238 individuals from 1,442 villages in 775 districts from all nine regional states and two city administrations. We developed a geostatistical model of podoconiosis prevalence among adults (individuals aged 15 years or above), by combining environmental factors. The number of people with podoconiosis was then estimated using a gridded map of adult population density for 2015.

Results: Podoconiosis is endemic in 345 districts in Ethiopia: 144 in Oromia, 128 in Southern Nations, Nationalities and People’s [SNNP], 64 in Amhara, 4 in Benishangul Gumuz, 4 in Tigray and 1 in Somali Regional State. Nationally, our estimates suggest that 1,537,963 adults (95% confidence intervals, 290,923-4,577,031 adults) were living with podoconiosis in 2015. Three regions (SNNP, Oromia and Amhara) contributed 99% of the cases. The highest proportion of individuals with podoconiosis resided in the SNNP (39%), while 32% and 29% of people with podoconiosis resided in Oromia and Amhara Regional States, respectively. Tigray and Benishangul Gumuz Regional States bore lower burdens, and in the remaining regions, podoconiosis was almost non-existent.

Discussion: The estimates of podoconiosis cases presented here based upon the combination of currently available epidemiological data and a robust modelling approach clearly show that podoconiosis is highly endemic in Ethiopia. Given the presence of low cost prevention, and morbidity management and disability prevention services, it is our collective responsibility to scale-up interventions rapidly.

The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.

Mycobacterium tuberculosis has the ability to survive inside macrophages under acid-nitrosative stress. M. tuberculosis Rv1685c and its ortholog in M. smegmatis, MSMEG_3765, are induced on exposure to acid-nitrosative stress. Both genes are annotated as TetR transcriptional regulators, a family of proteins that regulate a wide range of cellular activities, including multidrug resistance, carbon catabolism and virulence. Here, we demonstrate that MSMEG_3765 is co-transcribed with the upstream genes MSMEG_3762 and MSMEG_3763, encoding efflux pump components. RTq-PCR and GFP-reporter assays showed that the MSMEG_3762/63/65 gene cluster, and the orthologous region in M. tuberculosis (Rv1687c/86c/85c), was up-regulated in a MSMEG_3765 null mutant, suggesting that MSMEG_3765 acts as a repressor, typical of this family of regulators. We further defined the MSMEG_3765 regulon using genome-wide transcriptional profiling and used reporter assays to confirm that the MSMEG_3762/63/65 promoter was induced under acid-nitrosative stress. A putative 36 bp regulatory motif was identified upstream of the gene clusters in both M. smegmatis and M. tuberculosis and purified recombinant MSMEG_3765 protein was found to bind to DNA fragments containing this motif from both M. smegmatis and M. tuberculosis upstream regulatory regions. These results suggest that the TetR repressor MSMEG_3765/Rv1685c controls expression of an efflux pump with an, as yet, undefined role in the mycobacterial response to acid-nitrosative stress.

Since the 1600s, physicians have been fascinated by the ageing process and have attempted to find biological markers which correlate with chronological age. Vascular stiffness has long been linked with ageing and is increasingly important in cardiovascular assessment. Carotid-femoral pulse wave velocity (cfPWV) is a ‘gold standard’ measure of arterial stiffness, predicting cardiovascular events1 and mortality2 independently of blood pressure (BP). The cardio-ankle vascular index (CAVI), performed using a 4 limb-cuff device including long muscular arterial paths, estimates overall vascular compliance, purportedly also BP-independent3.
The relationship between arterial compliance and age differs across international patient samples. The Helius study4 compared arterial stiffness in South Asian, African and Dutch patient samples, finding an increase in PWV in South Asian groups which was not entirely explained by conventional CV risk factors. CAVI in Japanese, Chinese and Korean groups5-7 increases with age, variably associated with risk factors. A recent Czech population study8 suggested reference ranges for CAVI in a Caucasian patient group but only up to the age of 65y.
Here, we compare CAVI and PWV against age in a UK Caucasian population, looking at the correlation between these measurements with age, and their interaction with other biological factors. We suggest ‘usual’ values for CAVI in a Caucasian population, as has been done in a large-scale international study of PWV9. We make initial comparisons of the change in CAVI with age between our study and published data from Japanese and Korean patient groups.
Background
1 – Brighton and Sussex University Hospital Trust, East Sussex, UK 2 – Brighton and Sussex Medical School, University of Sussex, UK 3 – Guy’s and St Thomas’ Hospital, King’s College and King’s Health Partners
Results

The hippocampus and amygdala are essential brain regions responsible for contextual fear conditioning (CFC). The autophosphorylation of alpha calciumcalmodulin kinase II (αCaMKII) at threonine-286 (T286) is a critical step 3 implicated in long-term potentiation (LTP), learning and memory. However, the changes in αCaMKII levels with aging and training in associated brain regions are not fully understood. Here, we studied how aging and training affect the levels of phosphorylated (T286) and proportion of phosphorylated:total αCaMKII in the hippocampus and amygdala. Young and aged mice, naïve (untrained) and trained in CFC, were analysed by immunohistochemistry for the levels of total and phosphorylated αCaMKII in the hippocampus and amygdala. We found that two hours after CFC training, young mice exhibited a higher level of phosphorylated and increased ratio of phosphorylated:total αCaMKII in hippocampal CA3 stratum radiatum. Furthermore, aged untrained mice showed a higher ratio of phosphorylated:total αCaMKII in the CA3 region of the hippocampus when compared to the young untrained group. No effect of training or aging were seen in the central, lateral and basolateral amygdala regions, for both phosphorylated and ratio of phosphorylated:total αCaMKII. These results show that aging impairs the training-induced upregulation of autophosphorylated (T286) αCaMKII in the CA3 stratum radiatum of the hippocampus. This indicates that distinct age-related mechanisms underlie CFC that may rely more heavily on NMDA receptor-dependent plasticity in young age.

Brain and body are coupled by the autonomic nervous system. Emotions evoke “top-down” autonomic responses and are shaped by “bottom-up” afferent somatic feedback. This psychophysiological integration is supported by shared autonomic and emotional neuroanatomical pathways. Emotional stress disrupts normative autonomic function, typically through sympathoexcitation. Conversely, in dissociative disorders, emotional stress may suppress sympathoexcitation despite subjective emotional distress. Psychophysiological decoupling is further observed in forms of dysautonomia defined by autonomic overexcitation, resulting in emotional symptoms via interoception of dysautonomic symptoms. The study of these disorders elucidates mechanisms of psychophysiological integration and improves our pathophysiological understanding of affective, autonomic and dissociative disorders.

Introduction: Shared decision making (SDM) is a goal of modern medicine; however, it is not currently embedded in routine care. Barriers include clinicians’ attitudes, lack of knowledge and training and time constraints. Our goal is to support the development and delivery of a robust SDM curriculum in medical education. Our objective is to assess undergraduate medical students’ knowledge of and attitudes towards SDM in four countries.

Methods and analysis: The first phase of the study involves a web-based cross-sectional survey of undergraduate medical students from all years in selected schools across the United States (US), Canada and undergraduate and graduate students in the Netherlands. In the United Kingdom (UK), the survey will be circulated to all medical schools through the UK Medical School Council. We will sample students equally in all years of training and assess attitudes towards SDM, knowledge of SDM and participation in related training. Medical students of ages 18 years and older in the four countries will be eligible. The second phase of the study will involve semistructured interviews with a subset of students from phase 1 and a convenience sample of medical school curriculum experts or stakeholders. Data will be analysed using multivariable analysis in phase 1 and thematic content analysis in phase 2. Method, data source and investigator triangulation will be performed. Online survey data will be reported according to the Checklist for Reporting the Results of Internet E-Surveys. We will use the COnsolidated criteria for REporting Qualitative research for all qualitative data.

Ethics and dissemination: The study has been approved for dissemination in the US, the Netherlands, Canada and the UK. The study is voluntary with an informed consent process. The results will be published in a peer-reviewed journal and will help inform the inclusion of SDM-specific curriculum in medical education worldwide.

Whilst breast cancer outcomes are improving steadily in younger women due to advances in screening and improved therapies, there has been little change in outcomes among the older age group. It is inevitable that co-morbidities/frailty rates are higher, which may increase the risks of some breast cancer treatments such as surgery and chemotherapy, many older women are healthy and may benefit from their use. Adjusting treatment regimens appropriately for age/co-morbidity/frailty is variable and largely non-evidence based, specifically with regard to rates of surgery for operable oestrogen receptor (ER) positive disease and rates of chemotherapy for high-risk disease.

Aim: To assess the safety and tolerability of switching between subcutaneous (SC) and intravenous (IV) trastuzumab in the PrefHer study (NCT01401166).

Patients and methods: Patients with HER2-positive early breast cancer completed (neo)adjuvant chemotherapy and were randomised to receive four cycles of SC trastuzumab, via single-use injection device (SID; Cohort 1) or hand-held syringe (Cohort 2), followed by four cycles of IV, or vice versa (the crossover period presented here) as part of their 18 standard cycles of adjuvant trastuzumab treatment. Adverse events (AEs) were reported using standard criteria.

Results: Overall, fewer AEs were reported during the IV treatment periods, regardless of administration sequence (IV→SC or SC→IV). Differences in AEs between the SC and IV periods were partly due to variances in grade 1 and 2 local injection site reactions (ISRs) and systemic administration-related reactions (ARRs) and these occurred mainly during SC treatment, as expected. When ISRs and ARRs were excluded, rates of AEs were higher during the first treatment period, compared with the second, in both treatment sequences; otherwise there was no clear pattern in the type of AEs reported. Rates of clinically important events, including grade ≥3 AEs, serious AEs, AEs leading to study drug discontinuation and cardiac AEs, were low and similar between treatment arms (<5%). There were no grade 4 or 5 AEs. No new safety signals for trastuzumab were observed.

Conclusions: PrefHer revealed that switching from IV to SC trastuzumab (hand-held syringe or SID) or vice versa did not impact the known safety profile of trastuzumab.

Genomic analysis has found that the transcriptome in both humans and Drosophila melanogaster features large numbers of long non-coding RNA transcripts (lncRNAs). This recently discovered class of RNAs regulates gene expression in diverse ways and has been involved in a large variety of important biological functions. Importantly, an increasing number of lncRNAs have also been associated with a range of human diseases, including cancer. Comparative analyses of their functions among these organisms suggest that some of their modes of action appear to be conserved. This highlights the importance of model organisms such as Drosophila, which shares many gene regulatory networks with humans, in understanding lncRNA function and its possible impact in human health. This review discusses some known functions and mechanisms of action of lncRNAs and their implication in human diseases, together with their functional conservation and relevance in Drosophila development.

The idea that antioxidant supplements can prevent or cure many diseases is extremely popular. To study the public understanding of antioxidants on the Web, we searched the term “antioxidants” in http://Google.com and analyzed 200 websites in terms of typology (news, commercial, professional, health portal, no-profit or government organization, scientific journals), disease or biological process mentioned (aging, immunity, neurological disease, diabetes, arthritis, etc.), and stance toward antioxidants, whether neutral, positive, or negative. Commercial and news websites were prevalent (over half of the total) but not in the top 10 returned by Google, where the most frequent were health portals, government, and professional websites. Among the diseases mentioned, cancer was the first, followed by vascular and eye diseases. A negative stance toward supplements was prevalent in the whole search, and this was even more evident for cancer. Information on aging or immunity had the largest proportion of pro-supplement and commercial websites. This study shows that some diseases are highly associated with antioxidants on the Internet and that information on antioxidants in aging and immunity is more likely to describe the positive effects of antioxidant supplements.

Objectives: To establish older women's (≥75 years) information preferences regarding two breast cancer treatment options: surgery plus adjuvant endocrine therapy versus primary endocrine therapy (PET). To quantify women's preferences for the mode of information presentation and decision making (DM) style.

Methods: This was a UK multi-centre survey of women, ≥75 years, who had been offered a choice between PET and surgery at diagnosis of breast cancer. A questionnaire was developed including two validated scales of decision regret and DM preferences.

Results: Questionnaires were sent to 247 women and 101 were returned (response rate 41%). The median age of participants was 82 (range 75 to 99), with 58 having had surgery and 37 having PET. Practical details about the impact, safety and efficacy of treatment were of most interest to participants. Of least interest were cosmetic outcomes after surgery. Information provided verbally by doctors and nurses, supported by booklets, was preferred. There was little interest in technology based sources of information. There was equal preference for a patient-centred or doctor-centred DM style and lower preference for a shared DM style. The majority (74%) experienced their preferred DM style. Levels of decision regret were low (15.73, scale 0-100).

Conclusions: Women strongly preferred face to face information. Written formats were also helpful, but not computer based resources. Information that was found helpful to women in the DM process was identified. The study demonstrates many women achieved their preferred DM style, with a preference for involvement, and expressed low levels of decision regret.

As a result of the successful treatment of HIV over the last four decades, people living with HIV (PLWH) can now expect a near normal life expectancy1. This change in demographic alongside later life acquisition of HIV2, has resulted in clinical services now seeing an older HIV cohort, with patients experiencing many of the problems of an older HIV-negative cohort such as multiple medical diagnoses, polypharmacy and frailty.

A large proportion of cardiovascular pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4+ T-cells characterized by loss of CD28 (‘CD4+CD28− T-cells’ or ‘CD4+CD28null cells’) are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4+CD28− T-cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1-2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in cardiovascular disease, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4+CD28− T-cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV-infection. They are likely to be responsible for the excess cardiovascular mortality observed in these situations. The CD4+CD28− phenotype convincingly links CMV infection to cardiovascular mortality based on a direct cellular-pathological mechanism rather than epidemiological association.

Objective: To identify the features and effects of a pathway for emergency assessment and referral of patients with suspected transient ischaemic attack (TIA) in order to avoid admission to hospital.

Design: Scoping review.

Data sources: PubMed, CINAHL Web of Science, Scopus.

Study: selection Reports of primary research on referral of patients with suspected TIA directly to specialist outpatient services.

Data extraction: We screened studies for eligibility and extracted data from relevant studies. Data were analysed to describe setting, assessment and referral processes, treatment, implementation and outcomes.

Results: 8 international studies were identified, mostly cohort designs. 4 pathways were used by family doctors and 3 pathways by emergency department physicians. No pathways used by paramedics were found. Referrals were made to specialist clinic either directly or via a 24-hour helpline. Practitioners identified TIA symptoms and risk of further events using a checklist including the ABCD2 tool or clinical assessment. Antiplatelet medication was often given, usually aspirin unless contraindicated. Some patients underwent tests before referral and discharge. 5 studies reported reduced incident of stroke at 90 days, from 6–10% predicted rate to 1.3–2.1% actual rate. Between 44% and 83% of suspected TIA cases in these studies were referred through the pathways.

Conclusions: Research literature has focused on assessment and referral by family doctors and ED physicians to reduce hospitalisation of patients with TIA. No pathways for paramedical use were reported. We will use results of this scoping review to inform development of a paramedical referral pathway to be tested in a feasibility trial.

Trial registration number ISRCTN85516498. Stage: pre-results.

Cytomegalovirus (CMV) infection sometimes causes large expansions of CMV-specific T-cells, particularly in older people. This is believed to undermine immunity to other pathogens and to accelerate immunosenescence. While multiple different CMV proteins are recognized, most publications on age-related T-cell expansions have focused on dominant target proteins, UL83 or UL123, and the T-cell activation marker, IFN-γ. We were concerned that this narrow approach might have skewed our understanding of CMV-specific immunity at older ages. We have, therefore, widened the scope of analysis to include in vitro-induced T-cell responses to 19 frequently recognized CMV proteins in young and older healthy volunteers and a group of oldest old, long-term survivors (>85 years of age). Polychromatic flow-cytometry was used to analyze T-cell activation markers (CD107, CD154, IL-2, TNF, IFN-γ) and memory phenotype (CD27, CD45RA). The older had on average larger T-cell responses than the young, but, interestingly, response size differences were relatively smaller when all activation markers were considered rather than IFN-γ or TNF alone. The oldest old recognized more proteins on average than the other groups and had even bigger T-cell responses than the older with a significantly larger central memory CD4 T-cell component.

Background: Rural populations in low-income countries commonly suffer from the co-morbidity of neglected tropical diseases (NTDs). Podoconiosis, trachomatous trichiasis (both NTDs) and cataract are common causes of morbidity among subsistence farmers in the highlands of northern Ethiopia. We explored whether podoconiosis was associated with cataract or trachomatous trichiasis (TT) among this population.

Methods: A comparative cross-sectional study was conducted in East Gojam region, Amhara, Ethiopia in May 2016 . Data were collected from patients previously identified as having podoconiosis and from matched healthy neighbourhood controls. Information on socio- demographic factors, clinical factors and past medical history were collected by an interview-administered questionnaire. Clinical examination involved grading of podoconiosis by examination of both legs, measurement of visual acuity, direct ophthalmoscopy of dilated pupils to grade cataract, and eyelid and corneal examination to grade trachoma. Multiple logistic regression was conducted to estimate independent association and correlates of podoconiosis, TT and cataract.

Findings: A total of 700 participants were included in this study; 350 podoconiosis patients and 350 healthy neighbourhood controls. The prevalence of TT was higher among podoconiosis patients than controls (65 (18.6%) vs 43 (12.3%)) with an adjusted odds ratio (OR) 1.55 (95% Confidence Interval (CI) 1.12 - 2.11), p=0.05. There was no significant difference in 3 prevalence of cataract between the two populations with an adjusted OR 0.83 (95% CI 0.55-1.38), p=0.37. Mean best visual acuity was 0.59 (SD +/- 0.06) in podoconiosis cases compared to 0.44 (SD +/- 0.04) in controls, p=< 0.001. The proportion of patients classified as blind was higher in podoconiosis cases compared with healthy controls; 5.6% vs 2.0%; adjusted OR 2.63 (1.08-6.39), P = 0.03.

Conclusions Individuals with podoconiosis have a higher burden of TT and worse visual acuity than their matched healthy neighbourhood controls. Further research into the environmental and biological reasons for this co-morbidity is required. A shared approach to managing these two NTDs within the same population could be beneficial.

Objective: The package of care to reduce HIV mother to child transmission (MTCT) has evolved significantly since trials of ante and intrapartum antiretroviral therapy (ART) in 1994. In the UK MTCT rate has fallen from 25.6% in the 1990s to 0.46%. We review the management of HIV in pregnancy in Brighton in the context of evolving guidelines.

Study design: HIV, obstetric and neonatal notes of all HIV positive women, pregnant between 2003 and 2014, were reviewed.

Results: 97 pregnancies in 75 women were identified, resulting in 79 live births. Antenatal HIV diagnosis was made in 22 (28%). The proportion of pregnancies in those with known HIV at conception increased over the time period. At conception 58 (60%) were on ART, 33 (57%) of who continued on their original regimen. 34 (35%) initiated ART following conception: 14 known to be HIV positive, 20 diagnosed during pregnancy. Two did not start ART (1 due to miscarriage, 1 as diagnosed post-delivery) and in three cases ART history was unavailable due to transfer to alternative centres. ART was initiated on average at 22 weeks gestation (range 6–34). 4(5%) received Zidovudine (AZT) monotherapy, all before 2006. Choice of combination ART (cART) varied with time reflecting changing guidelines. Prior to 2008 an AZT containing regimen was used in 83% versus 8% after. Planned mode of delivery was documented in 73: 30(41%) planned a normal vaginal delivery (NVD), 43(59%) a caesarean section (CS).

The viral load (VL) was <50 copies/mL in 58(76%) at 36 weeks and 64(84%) at delivery. 90% with a detectable VL at 36 weeks delivered via CS. 100% received neonatal post-exposure prophylaxis (PEP): 68(88%) AZT monotherapy, 9(12%) cART. 84% initiated PEP within four hours. 90% completed 28 days. 8(10%) babies experienced side effects. In the 10-year review period, one infant (1.3%) was diagnosed HIV positive. Both mother and infant received care in accordance with guidelines, including neonatal PEP within 4 hours.

Conclusion: Care of the HIV positive pregnant woman in Brighton has been successful with overall transmission consistent with that seen nationally. Despite effective preventative strategies MTCT remains a risk and women should be counselled accordingly.

Cancer clinicians frequently deal with emotionally challenging situations such as discussing the diagnosis or prognosis and transitions to palliative care with patients and their families. The doctor/patient relationship may be short and intensive or one lasting for many years. Until fairly recently, a formal paternalistic relationship was the norm in medicine; this has now been replaced by a more patient-centred approach. An unintended consequence of the move towards less formal relationships may be the loss of the emotional protection to the doctor.

Hypertension is the leading cause of cardiovascular (CV) morbidity and mortality in adults over the age of 65. The first part of this paper is an overview, summarizing the current guidelines on the pharmacological management of hypertension in older adults in Europe and the USA, and evidence from key trials that contributed to the guidelines. In the second part of the paper, we will discuss the major challenges of managing hypertension in the context of multimorbidity, including frailty, orthostatic hypotension (OH), falls and cognitive impairment that are associated with ageing. A novel ‘BEGIN’ algorithm is proposed for use by prescribers prior to initiating antihypertensive therapy to guide safe medication use in older adults. Practical suggestions are highlighted to aid practitioners in making rational decisions to treat and monitor hypertension, and for considering withdrawal of antihypertensive drugs in the complex older person.

Introduction: Family carers of people with dementia are their most important support in practical, personal and economic terms. Carers are vital to maintaining the quality of life (QOL) of people with dementia. This review aims to identify factors related to the QOL of family carers of people with dementia.

Methods: Searches on terms including ‘carers’, ‘dementia’, ‘family’ and ‘quality of life’ in research databases. Findings were synthesised inductively, grouping factors associated with carer QOL into themes.

Results: 909 abstracts were identified. Following screening, lateral searches and quality appraisal, 41 studies (n=5,539) were included for synthesis. Ten themes were identified: demographics; carer-patient relationship; dementia characteristics; demands of caring; carer health; carer emotional wellbeing; support received; carer independence; carer self-efficacy; and future.

Discussion: The quality and level of evidence supporting each theme varied. We need further research on what factors predict carer QOL in dementia and how to measure it.

Aim: This study aimed to assess the quality of the information available on the Web on gum disease.

Methods: The term ‘gum disease’ was searched in Google and in MedlinePlus. The first 200 websites were analysed by the Journal of the American Medical Association (JAMA) criteria and the Health On the Net Foundation (HONCode) certification, instruments for assessing quality of health information. Data was analysed through the Mann-Whitney test or KruskalWallis test, followed by the Dunn’s test, using the GraphPad Prism Software version 6.

Results: MedlinePlus presented a significantly higher JAMA score than Google. Google’s first ten results had a higher JAMA score than the remaining websites. Journalism and health portals are the most reliable affiliations, while commercial and dental practices had low JAMA scores. JAMA score was significantly higher in websites with the HONCode certification compared to the ones without it.

Conclusion: There are current concerns regarding patients’ use of the Internet for accessing health information. However, the conclusion we can make is that Google seems to favour websites with high quality information, at least in terms of JAMA score or HONCode accreditation. The JAMA score of dental practices’ websites could be improved by providing basic information such as authorship and date.

Background: Health-care workers have been implicated in nosocomial outbreaks of Staphylococcus aureus, but the dearth of evidence from non-outbreak situations means that routine health-care worker screening and S aureus eradication are controversial. We aimed to determine how often S aureus is transmitted from health-care workers or the environment to patients in an intensive care unit (ICU) and a high-dependency unit (HDU) where standard infection control measures were in place.

Methods: In this longitudinal cohort study, we systematically sampled health-care workers, the environment, and patients over 14 months at the ICU and HDU of the Royal Sussex County Hospital, Brighton, England. Nasal swabs were taken from health-care workers every 4 weeks, bed spaces were sampled monthly, and screening swabs were obtained from patients at admission to the ICU or HDU, weekly thereafter, and at discharge. Isolates were cultured and their whole genome sequenced, and we used the threshold of 40 single-nucleotide variants (SNVs) or fewer to define subtypes and infer recent transmission.

Findings: Between Oct 31, 2011, and Dec 23, 2012, we sampled 198 health-care workers, 40 environmental locations, and 1854 patients; 1819 isolates were sequenced. Median nasal carriage rate of S aureus in health-care workers at 4-weekly timepoints was 36·9% (IQR 35·7–37·3), and 115 (58%) health-care workers had S aureus detected at least once during the study. S aureus was identified in 8–50% of environmental samples. 605 genetically distinct subtypes were identified (median SNV difference 273, IQR 162–399) at a rate of 38 (IQR 34–42) per 4-weekly cycle. Only 25 instances of transmission to patients (seven from health-care workers, two from the environment, and 16 from other patients) were detected.

Interpretation: In the presence of standard infection control measures, health-care workers were infrequently sources of transmission to patients. S aureus epidemiology in the ICU and HDU is characterised by continuous ingress of distinct subtypes rather than transmission of genetically related strains.

Funding: UK Medical Research Council, Wellcome Trust, Biotechnology and Biological Sciences Research Council, UK National Institute for Health Research, and Public Health England.

Introduction: Peripheral nerves slide and stretch during limb movements. Changes in nerve stiffness associated with such movements have not been examined in detail but may be important in understanding movement-evoked pain in patients with a variety of different musculoskeletal conditions.

Methods: Shear-wave elastography was used to examine stiffness in the median and tibial nerves of healthy individuals during postures used clinically to stretch these nerves.

Results: Shear-wave velocity increased when limbs were moved into postures that are thought to increase nerve stiffness (mean increase: median nerve = 208% in arm, 236% in forearm; tibial nerve = 136%). There was a trend toward a negative correlation between age and shear-wave velocity (r = 0.58 for tibial nerve).

Conclusions: Shear-wave elastography provides a tool for examining nerve biomechanics in healthy individuals and patients. However, limb position, age, and effects of nerve tension on neural architecture should be taken into consideration.

This report discusses the findings of the first ever study dedicated to the qualitative exploration of mirror-touch synaesthesia from a first-person perspective. As part of a project investigating the cross-disciplinary resonances of mirror-touch in the context of the broader social trait of empathy, this study aimed to document the lived experiences of people with this form of synaesthesia in order to offer insights into existing and new theoretical models for mirror-touch. Through examination of quotes drawn from first-hand accounts given by participating mirror-touch synaesthetes concerning their unique perceptual, interpersonal, and social experiences, this report demonstrates the value of experimental research, in particular first-person reporting, to enhancing the understanding of the way mirror-touch relates to empathy and social functioning beyond its quantitiavely measurable characteristics. The descriptions point to mirror-touch synaesthetes' automatic feeling into the emotional lives of others and their deliberate attempts to regulate this.

Objective: To carry out a prospective evaluation of tranexamic acid (TXA) use in trauma patients. Patients and methods: TXA was introduced to all emergency ambulances and emergency departments in the South West, UK, on 1 December 2011. We carried out a prospective evaluation of TXA use in trauma patients in the South West Peninsula between December 2011 and December 2012. We collected prehospital and hospital data on TXA administration using the Trauma Audit Research Network database. Data on prehospital administration of TXA were cross-checked with the South Western Ambulance Service Trust. Data were analysed using SPSS (version 20).

Results: Altogether, 82 patients were administered TXA during the study period. The median age of the patients was 49 years (IQR 30, 66), and 72% were men. One-third of the patients arrived at hospital by air ambulance. During the first 3 months, administration of TXA was limited to one patient each month receiving the drug. However, an upward trend was observed after June until October 2012, with the increment being more than 10 fold in July, September and October 2012.

Conclusion: This is the first study to evaluate the use of TXA in civilian practice in the UK. Our study shows that ambulance service personnel and emergency departments can effectively administer TXA.

Infectious disease outbreaks in residential care are complex to manage and difficult to control. Research in this setting that includes individuals who lack capacity must conform to national legislation (specifically in England and Wales, the Mental Capacity Act 2005). We report here on our study that is investigating outbreaks of scabies, an itchy skin infection, in the residential care setting in the southeast of England. There appears to be a gap in legislative advice regarding the inclusion of people who lack capacity in research that takes place during time-limited acute scenarios such as outbreaks. We received inconsistent advice from experts regarding, in particular, the role of nominated consultees. There is a potential inequality for vulnerable populations who cannot themselves provide informed consent in terms of their access to participation in a range of health-related research.