SummaryBackgroundHigh-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome.MethodsIn this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6–12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123.FindingsBetween June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620).InterpretationUse of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our finding...

Background: The ''hygiene hypothesis'' postulates that infections during infancy may protect against asthma and atopy. There is also some evidence that antibiotic and/or paracetamol use may increase the risk of asthma. Methods: The study measured the association between infections, and medication use early in life and the risk of asthma at age 6-7 years. It involved 1584 children who had been notified to public health services with serious infections at age 0-4 years, and 2539 children sampled from the general population. For both groups, postal questionnaires were completed by parents. Results: There was little difference in the prevalence of current wheezing between the childhood infections group (prevalence = 23.5%) and the general population group (prevalence = 24.3%). There was also little difference whether the major site of infection was gastrointestinal (prevalence = 24.1%), invasive (prevalence = 24.6%) or respiratory (prevalence = 21.1%). However, in both groups, there were associations with antibiotic (OR = 1.78, 95% CI 1.49 to 2.14) or paracetamol (OR = 1.38, 95% CI 1.04 to 1.83) use in the first year of life or recent paracetamol use (OR = 2.10, 95% CI 1.78 to 2.49) and current wheezing. There was a weak protective effect of childhood infections in children who had not used antibiotics in the first year of life (OR = 0.78, 95% CI 0.55 to 1.10). Conclusions: These findings are consistent with other evidence that antibiotic use early in life may increase the risk of asthma. They are also consistent with some preliminary evidence associating paracetamol use with an increased risk of asthma. Any protective effect of notifiable childhood infections was weak.

BackgroundFalls cause fear, anxiety and loss of confidence, resulting in activity avoidance, social isolation and increasing frailty. The umbrella term for these problems is ‘fear of falling’, seen in up to 85% of older adults who fall. Evidence of effectiveness of physical and psychological interventions is limited, with no previous studies examining the role of an individually delivered cognitive–behavioural therapy (CBT) approach.ObjectivesPrimary objective To develop and then determine the effectiveness of a new CBT intervention (CBTi) delivered by health-care assistants (HCAs) plus usual care compared with usual care alone in reducing fear of falling.Secondary objectives To measure the impact of the intervention on falls, injuries, functional abilities, anxiety/depression, quality of life, social participation and loneliness; investigate the acceptability of the intervention for patients, family members and professionals and factors that promote or inhibit its implementation; and measure the costs and benefits of the intervention.DesignPhase I CBTi development.Phase II Parallel-group patient randomised controlled trial (RCT) of the new CBTi plus usual care compared with usual care alone.SettingMultidisciplinary falls services.ParticipantsConsecutive community-dwelling older adults, both sexes, aged ≥ 60 years, with excessive or undue fear of falling per Falls Efficacy Scale–International (FES-I) score of > 23.InterventionsPhase I Development of the CBTi. The CBTi was developed following patient interviews and taught to HCAs to maximise the potential for uptake and generalisability to a UK NHS setting.Phase II RCT. The CBTi was delivered by HCAs weekly for 8 weeks, with a 6-month booster session plus usual care.Main outcome measuresThese were assessed at baseline, 8 weeks, 6 months and 12 months.Primary outcome measure Fear of falling measured by change in FES-I scores at 12 months.Secondary outcome measures These comprised falls, injuries, anxiety/depression [Hospital Anxiety and Depression Scale (HADS)], quality of life, social participation, loneliness and measures of physical function. There were process and health-economic evaluations alongside the trial.ResultsFour hundred and fifteen patients were recruited, with 210 patients randomised to CBTi group and 205 to the control group. There were significant reductions in mean FES-I [–4.02; 95% confidence interval (CI) –5.95 to –2.1], single-item numerical fear of falling scale (–1.42; 95% CI –1.87 to 1.07) and HADS (–1; 95% CI –1.6 to –0.3) scores at 12 months in the CBTi group compared with the usual care group. There were no differences in the other secondary outcome measures. Most patients found the CBTi acceptable. Factors affecting the delivery of the CBTi as part of routine practice were identified. There was no evidence that the intervention was cost-effective.ConclusionsOur new CBTi delivered by HCAs significantly improved fear of falling and depression scores in older adults who were attending falls services. There was no impact on other measures.Further workFurther work should focus on a joint CBTi and physical training approach to fear of falling, more rational targeting of CBTi, the possibility of mixed group and individual CBTi, and the cost-effectiveness of provision of CBTi by non-specialists.Trial registrationCurrent Controlled Trials ISRCTN78396615.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 56. See the NIHR Journals Library website for further project information.

Purpose: Estrogen receptor (ER) ␣-positive breast cancer is often treated with endocrine therapy using either antiestrogens or aromatase inhibitors. However, 30% of patients who receive endocrine therapy will derive no benefit from such treatments and may indeed suffer adverse effects. Currently, there are no ways to predict response to such treatments. ER␤cx, a variant of ER␤, has a dominantnegative effect over ER␣, and its expression thought to modulate response to endocrine treatment may represent a predictor of response to endocrine therapy.Experimental Design: We investigated the expression of the ER␤cx in 82 frozen breast samples (8 benign, 1 ductal carcinoma in situ, and 73 malignant) by Western blot analysis. The relationship between the expression of ER␤cx variants with prognosis and outcome of endocrine therapy was examined.Results: There was a statistically significant association between the presence of ER␤cx and the response to endocrine therapy (Fisher's exact test, P ‫؍‬ 0.04). We also examined the influence of the ER␤cx status of a tumor on time to progression and death. There was a relationship between the presence of ER␤cx and survival, with patients whose tumors express ER␤cx having a longer survival rate (P ‫؍‬ 0.05).Cell-type specificity of expression was assessed by immunohistochemistry on a selection of histological samples.Conclusions: On the basis of this small group of patients, we conclude that the expression of ER␤cx correlated with favorable response to endocrine therapy. A larger study involving the staining of archival material is currently underway to confirm these preliminary results.

In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.