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Primary percutaneous coronary intervention (PPCI), the preferred reperfusion strategy for all acute ST-segment elevation myocardial infarction (STEMI) patients, is not universally available in clinical practice. Pharmacoinvasive strategy has been proposed as a therapeutic option in patients with STEMI when timely PPCI is not feasible. However, pharmacoinvasive strategy has potential delay between clinical patency and complete myocardial perfusion. The optimal reperfusion strategy for STEMI patients with anticipated PPCI delay according to current practice is uncertain. OPTIMAL-REPERFUSION is an investigator-initiated, prospective, multicenter, randomized, open-label, superiority trial with blinded evaluation of outcomes. A total of 632 STEMI patients presenting within 6 hours after symptom onset and with an expected time of first medical contact to percutaneous coronary intervention (PCI) ≥120 minute will be randomized to a reduced-dose facilitated PCI strategy (reduced-dose fibrinolysis combined with simultaneous transfer for immediate invasive therapy with a time interval between fibrinolysis to PCI

High‐dose ivermectin, co‐administered for 3 days with dihydroartemisinin‐piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow‐up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito‐cluster mortality rates, and 524 QTcF‐intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal‐effects throughout the 28‐day study duration, without invoking an unidentified mosquitocidal metabolite or drug‐drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF‐prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.

Background The personality trait of dependence is common in health-seeking behaviour. We therefore examined its impact in a large randomized controlled trial of psychological treatment for health anxiety. Aims To test whether dependent personality traits were positive or negative in determining the outcome of an adapted form of cognitive behaviour therapy for health anxiety (CBT-HA) over the course of 5 years and whether dependent personality dysfunction could be viewed dimensionally in a similar way to the new ICD-11 diagnostic system for general personality disorder. Method Dependent personality dysfunction was assessed using a self-rated questionnaire, the Dependent Personality Questionnaire, at baseline in a randomized controlled trial of 444 patients from medical clinics with pathological health anxiety treated with a modified form of CBT-HA or standard treatment in the medical clinics, with assessment on five occasions over 5 years. Dependent personality dysfunction was assessed using four severity groups. Results Patients with mild and moderate dependent personality disorder treated with CBT-HA showed the greatest reduction in health anxiety compared with standard care, and those with no dependent dysfunction showed the least benefit. Patients with higher dependent traits received significantly more treatment sessions (8.6) than those with low trait levels (5.4) (p

Background Electrocardiogram (ECG) variability is greatly affected by the ECG recording method. This study aims to compare Holter and standard ECG recording methods in terms of central locations and variations of ECG data. Methods We used the ECG data from a double-blinded, placebo-controlled, randomized clinical trial and used a mixed model approach to assess the agreement between two methods in central locations and variations of eight ECG parameters (Heart Rate, PR, QRS, QT, RR, QTcB, QTcF, and QTcI intervals). Results A total of 34 heathy male subjects with mean age of 25.7 ± 4.78 years were randomized to receive either active drug or placebo. Digital 12-lead ECG and digital 12-lead Holter ECG recordings were performed to assess ECG variability. There are no significant differences in least square mean between the Holter and the standard method for all ECG parameters. The total variance is consistently higher for the Holter method than the standard method for all ECG parameters except for QRS. The intraclass correlation coefficient (ICC) values for the Holter method are consistently lower than those for the standard method for all ECG parameters except for QRS, in particular, the ICC for QTcF is reduced from 0.86 for the standard method to 0.67 for the Holter method. Conclusions This study suggests that Holter ECGs recorded in a controlled environment are not significantly different but more variable than those from the standard method.

Background The wireless motility capsule (WMC) offers the ability to investigate luminal gastrointestinal (GI) physiology in a minimally invasive manner. Aim To investigate the effect of testing protocol, gender, age and study country on regional GI transit times and associated pH values using the WMC. Methods Regional GI transit times and pH values were determined in 215 healthy volunteers from USA and Sweden studied using the WMC over a 6.5-year period. The effects of test protocol, gender, age and study country were examined. Results For GI transit times, testing protocol was associated with differences in gastric emptying time (GET; shorter with protocol 2 (motility capsule ingested immediately after meal) vs. protocol 1 (motility capsule immediately before): median difference: 52 min, P = 0.0063) and colonic transit time (CTT; longer with protocol 2: median 140 min, P = 0.0189), but had no overall effect on whole gut transit time. Females had longer GET (by median 17 min, P = 0.0307), and also longer CTT by (104 min, P = 0.0285) and whole gut transit time by (263 min, P = 0.0077). Increasing age was associated with shorter small bowel transit time (P = 0.002), and study country also influenced small bowel and CTTs. Whole gut and CTTs showed clustering of data at values separated by 24 h, suggesting that describing these measures as continuous variables is invalid. Testing protocol, gender and study country also significantly influenced pH values. Conclusions Regional GI transit times and pH values, delineated using the wireless motility capsule (WMC), vary based on testing protocol, gender, age and country. Standardisation of testing is crucial for cross-referencing in clinical practice and future research.

Objective This study aims to compare ICD-10 and putative ICD-11 classifications of personality disorder in different clinical populations. Design Prospective recording of ICD-10 and ICD-11 personality disorder classifications was carried out in (1) an anxious medical population, (2) an acute psychiatric in-patient population and (3) a retrospective recording of a mixed anxiety depression cohort in which all baseline data were scored from baseline information using the ICD-11 classification and compared with the original ICD-10 assessments. Method Comparison of ICD-10 and ICD-11 prevalence of personality disorder in each population was carried out. Results Data from 722 patients were recorded. Using the ICD-10 criteria, the prevalence of generic personality disorder was 33.8% compared with 40.4% using the ICD-11 ones (χ2 = 6.7; P

As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time-matched difference between (baseline corrected) QTcF or QTcI under the supra-therapeutic dose and placebo. A study is considered negative, if the two-sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration-response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo-corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration-response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect.

Objective: Twin infants tend to have LBW and microvascular alterations but do not appear to have an increase in cardiovascular mortality later in life as singleton infants. We hypothesized that twin infants born to normotensive mothers would not have capillary rarefaction at birth. Methods: We studied 26 dizygotic twin infants and compared them with 115 consecutive singleton infants to normotensive mothers. We used orthogonal polarized spectroscopy to measure basal (i.e., functional) and maximal (i.e., structural) skin capillary density according to a well-standardized protocol. Results: Twin infants have significantly higher BCD (mean difference 4.3 capillaries/mm2, 95% CI: 0.4, 8.1, p = 0.03) and have marginally significantly higher MCD (mean difference 3.9 capillaries/mm2, 95% CI: -0.6, 8.3, p = 0.086) compared to singleton infants. Birth weight was significantly associated with BCD and MCD (p = 0.003 and 0.006). Conclusions: Twin infants with low and NBWs tend to have higher functional and structural capillary densities compared to singleton infants. Further longitudinal studies of skin capillary density and of retinal vascular parameters commencing from birth to various stages in early childhood are essential to identify the dynamics and the exact timing, if any, of the remodeling of microcirculation in these individuals. © 2013 John Wiley & Sons Ltd.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Strontium ranelate 2 g (granule form) oral suspension, is an anti-osteoporotic treatment which is available in European countries. • Repeated administration of strontium ranelate (4 g day−1) was found to be clinically and biologically well tolerated by healthy post menopausal women volunteers. • Strontium is a bivalent cation with strong affinity for bone and which in certain conditions has a metabolism similar to that of calcium. In terms of importance, calcium has a major role in the electrophysiology of cardiac muscle and ECG abnormalities are known to be due to changes in plasma calcium concentrations. • Although no signal was observed in pre-clinical or clinical studies, the safety of strontium ranelate in accordance with the ICH – E14 guidelines needed to be assessed in order to characterize the effect on QTc of repeated oral doses of strontium ranelate (4 g day−1). WHAT THIS STUDY ADDS • This thorough QT/QTc study directly compared supratherapeutic repeat doses of strontium ranelate (4 g day−1 for 15 days) with placebo on the largest time-matched mean QTc variation (from baseline to under treatment values) in healthy subjects. • The largest time-matched difference in QTcI compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). • Supratherapeutic (4 g day−1) repeated doses of strontium ranelate did not produce any clinically significant prolongation in QTc. • The findings of this study clearly indicate that administration of strontium ranelate at the therapeutic dose of 2 g will not cause prolongation of QT that is of any clinical concern. AIMS The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QTc studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day−1 for 15 days) with placebo on the largest time-matched mean QTc variation, from baseline to under treatment values, in healthy subjects. METHODS Ninety-six healthy male and female subjects (27.7 ± 7.5 years) were included to receive 1 day of placebo followed by 15 days of supratherapeutic repeated dosing of strontium ranelate (4 g day−1), in a 4 month, randomized, placebo (16 days) and positive-controlled (single dose of moxifloxacin 400 mg preceded by 15 days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers. RESULTS The largest time-matched difference in QTcI (individual QT correction for heart rate) between moxifloxacin 400 mg and placebo was observed at 2 h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4 g day−1) the largest time-matched difference in QTcI compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QTc greater than 480 ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects. CONCLUSIONS The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4 g day−1 for 15 days) does not lead to a prolongation of the QT/QTc interval above the threshold of regulatory concern.

This study assessed a targeted continuing osteoporosis educational program and investigated awareness and prevention of osteoporosis in Chinese female pre-internship nurse students. A quasi-experimental study was conducted. The program was presented to 256 nurse students. The baseline knowledge score of the nurse students was low (9.78 ± 3.13). They had inadequate osteoporosis health beliefs, self-efficacy and related behaviors. The educational program significantly augmented osteoporosis knowledge (Student's paired t = -13.42, P < 0.001), total osteoporosis health beliefs (Student's paired t = -4.46, P < 0.001), and the subscale (P < 0.001) except for the perceived barriers to exercising and calcium intake. Participants showed a significant increase in self-efficacy (Student's paired t = -6.45, P < 0.001) post intervention. Those who completed the program were better prepared to prevent and manage osteoporosis. Additionally, nurse students became more concerned about bone health of family members, subjects and themselves because of attending the program. Results of this study reinforce the need for osteoporosis-related continuing education in nurse students before clinical internship.

li x.-m., zhou k.-n., yan h., wang d.-l. & zhang y.-p. (2011) Effects of music therapy on anxiety of patients with breast cancer after radical mastectomy: a randomized clinical trial. Journal of Advanced Nursing 68(5), 1145–1155. Abstract Aim. This paper is a report of a clinical trial of the effects of music therapy on anxiety of female breast cancer patients following radical mastectomy. Background. There is insufficient evidence on the effects of music therapy on state anxiety of breast cancer patients following radical mastectomy. Methods. A Hall’s Core, Care, and Cure Model-based clinical trial was conducted in 120 female breast cancer patients from March to November 2009. A randomized controlled design was utilized. The patients were randomly allocated to the experimental group (n = 60) received music therapy in addition to routine nursing care, and the control group (n = 60) only received routine nursing care. A standardized questionnaire and the State Anxiety Inventory were applied. The primary endpoint was the state anxiety score measured at pretest (on the day before radical mastectomy) and at three post-tests (on the day before patients were discharged from hospital, the second and third time of admission to hospital for chemotherapy respectively). Results. The pretest score revealed that the majority of the patients had a moderate level (77·5%) and 15% had severe level of state anxiety. The repeated-measure ancova model analysis indicated that the mean state anxiety score was significantly lower in the experimental group than those in the control group at each of the three post-test measurements. The mean difference between the experimental and control group together with 95% confidence intervals were −4·57 (−6·33, −2·82), −8·91 (−10·75, −7·08) and −9·69 (−11·52, −7·85) at the 1st post-test, 2nd post-test and 3rd post-test respectively. Conclusion. Music therapy is found to have positive effects on decreasing state anxiety score.

Objective To explore maternal healthcare utilization in rural western China, and to analyze the socioeconomic and demographic determinants associated with use of maternal health services. Methods Between July and August 2005, 14 112 women from 45 counties in 10 western provinces of China were enrolled in a cross-sectional study by a multi-stage probability sampling method. The women completed a structured questionnaire, and a 2-level logistic regression model was used to examine the data. Results The proportion of women who had prenatal care was 95%. The average number of prenatal visits was 4.94. The proportion of women who had more than 4 prenatal visits was 52.9%, and 66.9% of these had their first prenatal visit within 12 weeks of gestation. The hospital delivery rate was 86.3%. The frequency of postnatal visits was 84.8%, and the average number of postnatal visits was 2.19. Han ethnicity, higher education, lower parity, higher wealth index, and lower altitude of county had a higher odds ratio for more than 4 prenatal visits, hospital delivery, and postnatal visits. Conclusion Maternal healthcare utilization seems to be associated with socio-economic and regional factors. The Chinese government should focus on the supply, funding, and quality of maternity services in rural areas.

Objectives. Not all patients with post-traumatic stress disorder (PTSD) respond to cognitive behavioural therapy (CBT). Literature suggests group music therapy might be beneficial in treating PTSD. However, feasibility and effectiveness have not been assessed. The study objectives were to assess whether group music therapy was feasible for patients who did not respond to CBT, and whether it has an effect on PTSD symptoms and depression. Design. The study employed mixed methods comprising of an exploratory randomized controlled trial, qualitative content analysis of therapy, and patient interviews. Method. Patients with significant PTSD symptoms (n= 17) following completion of CBT were randomly assigned to treatment (n= 9) or control groups (n= 8). The treatment group received 10 weeks of group music therapy after which exit interviews were conducted. Control group patients were offered the intervention at the end of the study. Symptoms were assessed on the Impact of Events Scale-Revised and Beck Depression Inventory II at the beginning and end of treatment. Results. Treatment-group patients experienced a significant reduction in severity of PTSD symptoms (−20.18; 95% confidence interval [CI]: [−31.23, −9.12]) and a marginally significant reduction in depression (−11.92; 95%CI: [−24.05, 0.21]) at 10 weeks from baseline compared to the control. Patients viewed music therapy as helpful and reported experiences concur with current literature. Conclusions. Group music therapy appears feasible and effective for PTSD patients who have not sufficiently responded to CBT. Limitations include the small sample size and lack of blinding. Further research should address these limitations, test sustainability, and identify specific factors that address symptoms in treatment.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • New drugs are expected to undergo rigorous clinical electrocardiographic evaluation (‘thorough QT/QTc study’) during their early clinical development in order to determine any affect on cardiac repolarization. • The fluoroquinolone antibiotic moxifloxacin (400 mg) has been used as a positive comparator for thorough QT/QTc studies due to its QT prolongation (QTcF) of between 6 and 10 ms. • Positive comparators that are able to produce mean changes close to the regulatory guidelines of 5 ms, and which can be detected by the assay in use, would enable a more rigorous evaluation of the assay conditions used in evaluating new chemical entities. WHAT THIS STUDY ADDS • This thorough QT/QTc study directly compares the effects of two doses of levofloxacin and moxifloxacin on QTc in the same healthy subjects. • Mean QTc was prolonged in subjects receiving levofloxacin compared with placebo as determined by both individual and Fridericia's heart rate correction methods. • The largest time-matched differences in QTc for two doses of levofloxacin compared with placebo suggest the potential for using levofloxacin in more rigorous QT/QTc studies, providing a robust evaluation of the assay conditions used in determining potential effects on cardiac repolarization. • There is evidence to suggest that levofloxacin moderately increases heart rate in a dose-dependent fashion. AIMS To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODS Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTS Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONS Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.

Study Type – Prognosis (case series) Level of Evidence 4 OBJECTIVE To compare 10-year overall (OS) and cancer-specific survival (CSS) of a cohort of consecutively presenting patients with bladder cancer of all pT categories from one UK institution. PATIENTS AND METHODS Data were collected on 144 patients with newly diagnosed bladder tumours presenting from 1983 to 1985 followed up for 10 years. Histological variables were reviewed by one pathologist who had no knowledge of the clinical details. Bladder muscle was present in 95% of the transurethral resection specimens. Date and causes of death were ascertained through death certificates, primary care physicians and/or hospital case notes. Data were analysed using the Kaplan–Meier method and Cox model. RESULTS There were 69 patients (48%) with pTa, 32 (22%) with pT1 and 43 (30%) with pT2/3/4 tumours. The 10-year OS was 54%, 34% and 16% and the CSS was 97%, 50% and 29%, respectively. There were only two cancer-related deaths in the pTa category whereas half the pT1 cases and half the muscle-invasive cases died within 5 and 2 years of diagnosis, respectively. CONCLUSIONS This study compared the 10-year OS and CSS of a cohort of patients with bladder cancer from the UK, where such data are lacking, and showed marked differences. The CSS was higher in all pT categories compared with OS, especially within pTa cancers in which almost all patients died of competing causes. It is important to be aware of such a significant difference between the two survival measures and to use them appropriately in the right context.

Aims The prevalence and importance of liver function test (LFT) abnormalities in a large contemporary cohort of heart failure patients have not been systematically evaluated. Methods and results We characterized the LFTs of 2679 patients with symptomatic chronic heart failure from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity program (CHARM). We used multivariable modelling to assess the relationships between baseline LFT values and long-term outcomes. Liver function test abnormalities were common in patients with chronic heart failure, ranging from alanine aminotransferase elevation in 3.1% of patients to low albumin in 18.3% of patients; total bilirubin was elevated in 13.0% of patients. In multivariable analysis, elevated total bilirubin was the strongest LFT predictor of adverse outcome for both the composite outcome of cardiovascular death or heart failure hospitalization (HR 1.21 per 1 SD increase, P < 0.0001) and all-cause mortality (HR 1.19 per 1 SD increase, P < 0.0001). Even after adjustment for other variables, elevated total bilirubin was one of the strongest independent predictors of poor prognosis (by global chi-square). Conclusion Bilirubin is independently associated with morbidity and mortality. Changes in total bilirubin may offer insight into the underlying pathophysiology of chronic heart failure.

Background Bundle branch block (BBB) is a powerful independent predictor of cardiovascular mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). The prognostic implications in HF with preserved systolic function (HF–PSF) are less well understood. Methods The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic HF to receive candesartan or placebo. The primary outcome comprised cardiovascular death or HF hospitalisation. The relative risk conveyed by BBB relative to a normal electrocardiogram was examined. Results The prevalence of BBB was significantly lower in patients with preserved compared with reduced systolic function (CHARM-Preserved 14.4%, Alternative 29.6%, Added 30.5%), p

Interdigestive human small bowel motility is characterized by the migrating motor complex (MMC). The aims of this study were to: (i) establish the normal range of variables of the nocturnal jejunal MMC and (ii) incorporate these data in a subsequent meta-analysis. Eighty-one recordings were performed by prolonged (24 h) ambulatory manometry in 51 subjects in two centres. Quantitative analysis was undertaken of 419 Phase III and 332 Phase II episodes. Adjusted mean values of seven variables were calculated using a mixed-effects model. Meta-analysis of pooled published data to generate a reliable 95% reference range was also performed. Adjusted mean values and confidence intervals are presented for all seven variables. Intrasubject variances were large in comparison with intersubject. Meta-analysis of 19 studies (356 pooled patients) meeting inclusion criteria produced wide reference ranges. At least five such ranges are useful for the detection of abnormality in the individual. This is the largest study of normal volunteers presented to date, with ranges for many variables produced using appropriate statistical methodology. A model for definition of abnormality has been proposed. We recommend that these data may be used by investigators in this field as a complement to other existing indicators of small bowel dysmotility.

Logistic regression is the standard method for assessing predictors of diseases. In logistic regression analyses, a stepwise strategy is often adopted to choose a subset of variables. Inference about the predictors is then made based on the chosen model constructed of only those variables retained in that model. This method subsequently ignores both the variables not selected by the procedure, and the uncertainty due to the variable selection procedure. This limitation may be addressed by adopting a Bayesian model averaging approach, which selects a number of all possible such models, and uses the posterior probabilities of these models to perform all inferences and predictions. This study compares the Bayesian model averaging approach with the stepwise procedures for selection of predictor variables in logistic regression using simulated data sets and the Framingham Heart Study data. The results show that in most cases Bayesian model averaging selects the correct model and out-performs stepwise approaches at predicting an event of interest.