Efficacy and safety of secukinumab administration by autoinjector in patients with psoriatic arthritis: results from a randomized, placebo-controlled trial (FUTURE 3)

Background: The study aimed to assess 52-week efficacy and safety of secukinumab self-administration by autoinjector in patients with active psoriatic arthritis (PsA) in the FUTURE 3 study (ClinicalTrials.gov NCT01989468). Methods: Patients (≥ 18 years of age; N = 414) with active PsA were randomized 1:1:1 to subcutaneous (s.c.) secukinumab 300 mg, 150 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and every 4 weeks thereafter. Per clinical response, placebo-treated patients were re-randomized to s.c. secukinumab 300 or 150 mg at week 16 (nonresponders) or week 24 (responders) and stratified at randomization by prior anti-tumor necrosis factor (TNF) therapy (anti-TNF-naïve, 68.1%; intolerant/inadequate response (anti-TNF-IR), 31.9%). The primary endpoint was the proportion of patients achieving at least 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24. Autoinjector usability was evaluated by Self-Injection Assessment Questionnaire (SIAQ). Results: Overall, 92.1% (300 mg), 91.3% (150 mg), and 93.4% (placebo) of patients completed 24 weeks, and 84.9% (300 mg) and 79.7% (150 mg) completed 52 weeks. In the overall population (combined anti-TNF-naïve and anti-TNF-IR), ACR20 response rate at week 24 was significantly higher in secukinumab groups (300 mg, 48.2% (p < 0.0001); 150 mg, 42% (p < 0.0001); placebo, 16.1%) and was sustained through 52 weeks. SIAQ results showed that more than 93% of patients were satisfied/very satisfied with autoinjector usage. Secukinumab was well tolerated with no new or unexpected safety signals reported. Conclusions: Secukinumab provided sustained improvements in signs and symptoms in active PsA patients through 52 weeks. High acceptability of autoinjector was observed. The safety profile was consistent with that reported previously

Intrapartum epidural analgesia and breastfeeding: a prospective cohort study

BACKGROUND Anecdotal reports suggest that the addition of fentanyl (an opioid) to epidural analgesia for women during childbirth results in difficulty establishing breastfeeding. The aim of this paper is to determine any association between epidural analgesia and 1) breastfeeding in the first week postpartum and 2) breastfeeding cessation during the first 24 weeks postpartum. METHODS A prospective cohort study of 1280 women aged > or = 16 years, who gave birth to a single live infant in the Australian Capital Territory in 1997 was conducted. Women completed questionnaires at weeks 1, 8, 16 and 24 postpartum. Breastfeeding information was collected in each of the four surveys and women were categorised as either fully breastfeeding, partially breastfeeding or not breastfeeding at all. Women who had stopped breastfeeding since the previous survey were asked when they stopped. RESULTS In the first week postpartum, 93% of women were either fully or partially breastfeeding their baby and 60% were continuing to breastfeed at 24 weeks. Intrapartum analgesia and type of birth were associated with partial breastfeeding and breastfeeding difficulties in the first postpartum week (p < 0.0001). Analgesia, maternal age and education were associated with breastfeeding cessation in the first 24 weeks (p < 0.0001), with women who had epidurals being more likely to stop breastfeeding than women who used non-pharmacological methods of pain relief (adjusted hazard ratio 2.02, 95% CI 1.53, 2.67). CONCLUSION Women in this cohort who had epidurals were less likely to fully breastfeed their infant in the few days after birth and more likely to stop breastfeeding in the first 24 weeks. Although this relationship may not be causal, it is important that women at higher risk of breastfeeding cessation are provided with adequate breastfeeding assistance and support.Christine Roberts is supported by a National Health and Medical Research Council (NHMRC) of Australia Public Health Practitioner Fellowship and Siranda Torvaldsen is supported by a NHMRC Australian Research Training Fellowship. The cohort study was supported by a project grant from The Canberra Hospital Private Practice Fund. Additional funding was provided by The Canberra Hospital Auxiliary, the Nurses' Board of the Australian Capital Territory, and the Australian Capital Territory Department of Health & Community Care

Interleukin-1 blockade in recently decompensated systolic heart failure: study design of the recently decompensated heart failure anakinra response trial (RED-HART)

Heart Failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, and poor exercise capacity due to impaired cardiac function. The incidence of HF is increasing and represents the leading cause of hospitalization in the United States among patients &gt; 65 years of age. Neurohormonal blockade has proven to reduce morbidity and mortality; however the persistent toll of HF demonstrates the urgent need to continue to develop novel drugs that target other pathophysiological paradigms. The presence of inflammation in cardiovascular disease has been well-established and interleukin-1 (IL-1), the prototypical proinflammatory agent, has been shown in preclinical animal models to induce cardiac dysfunction. The current study will investigate the role of IL-1 as an inflammatory mediator of HF progression and investigate whether IL-1 blockade with anakinra, recombinant human IL-1 receptor antagonist, improves aerobic exercise performance in patients with recently decompensated systolic HF. This study will be composed of 3 treatment arms (20 patients each): 1) anakinra 100mg daily for 12 weeks; 2) anakinra 100mg daily for 2 weeks followed by placebo for 10 weeks; or 3) placebo for 12 weeks. All patients will be followed for at least 24 weeks. The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) measured by Cardiopulmonary Exercise Testing (CPX) after 2 weeks of anakinra treatment. Secondary endpoints will include interval changes in 1) CPX variables at 4, 12 and 24 weeks; 2) echocardiographic measures of cardiac dimension/function; 3) quality of life assessments; 4) inflammatory biomarkers; and 5) clinical outcome including days alive outside of the hospital and survival free of re-hospitalization for HF. The RED-HART study will be the first study to address the potential benefits of IL-1 blockade on aerobic exercise performance in patients with recently decompensated HF

Iodine status during pregnancy in India and related neonatal and infant outcomes

Objective: To document iodine status in Indian pregnancies, associations with maternal diet and demographics, and offspring developmental measures. Design: Longitudinal study following mothers through pregnancy and offspring up to 24 months. Setting: Rural health-care centre (Vadu) and urban antenatal clinic (Pune) in the Maharashtra region of India. Subjects: Pregnant mothers at 17 (n 132) and 34 weeks’ (n 151) gestation and their infants from birth to the age of 24 months. Results: Median urinary iodine concentration (UIC) was 203 and 211 μg/l at 17 and 34 weeks of pregnancy, respectively (range 26–800 μg/l). Using the UIC distribution adjusted for within-person variation, extreme UIC quartiles were compared for predictors and outcomes. There was no correlation between UIC at 17 and 34 weeks, but 24 % of those with UIC in the lowest quartile at 17 weeks had UIC in the same lowest quartile at 34 weeks. Maternal educational, socio-economic status and milk products consumption (frequency) were different between the lowest and highest quartile of UIC at 34 weeks. Selected offspring developmental outcomes differed between the lowest and highest UIC quartiles (abdominal circumference at 24 months, subscapular and triceps skinfolds at 12 and 24 months). However, UIC was only a weak predictor of subscapular skinfold at 12 months and of triceps skinfold at 24 months. Conclusions: Median UIC in this pregnant population suggested adequate dietary provision at both gestational stages studied. Occasional high results found in spot samples may indicate intermittent consumption of iodine-rich foods. Maternal UIC had limited influence on offspring developmental outcomes

Spitzer 24-micron Time-Series Observations of the Eclipsing M-dwarf Binary GU Bootis

We present a set of {\it Spitzer} 24$\mu$m MIPS time series observations of the M-dwarf eclipsing binary star GU Bo\"otis. Our data cover three secondary eclipses of the system: two consecutive events and an additional eclipse six weeks later. The study's main purpose is the long wavelength (and thus limb darkening-independent) characterization of GU Boo's light curve, allowing for independent verification of the results of previous optical studies. Our results confirm previously obtained system parameters. We further compare GU Boo's measured 24$\mu$m flux density to the value predicted by spectral fitting and find no evidence for circumstellar dust. In addition to GU Boo, we characterize (and show examples of) light curves of other objects in the field of view. Analysis of these light curves serves to characterize the photometric stability and repeatability of {\it Spitzer's} MIPS 24\micron array over short (days) and long (weeks) timescales at flux densities between approximately 300--2,000$\mu$Jy. We find that the light curve root mean square about the median level falls into the 1--4% range for flux densities higher than 1mJy. Finally, we comment on the fluctuations of the 24\micron background on short and long timescales.Comment: ApJ accepted. 10 pages, 12 figure

An evaluation of the efficacy of the exercise on referral scheme in Northumberland, UK: association with physical activity and predictors of engagement. A naturalistic observation study

Objectives Exercise on referral schemes (ERS) are widely commissioned in the UK but there is little evidence of their association with physical activity levels. We sought to assess the Northumberland exercise on referral scheme in terms of increased levels of physical activity and identify predictors of engagement. Design A naturalistic observational study. Setting 9 local authority leisure sites in Northumberland. Participants 2233 patients referred from primary and secondary care between July 2009 and September 2010. Intervention A 24-week programme including motivational consultations and supervised exercise sessions for participants. Outcome measures Uptake, 12-week adherence, 24-week completion, changes in Godin Leisure-Time Exercise Questionnaire scores after 24-weeks and attendance levels at supervised exercise sessions during the scheme. Three binary logistic regressions were used to examine demographic and referral factors associated with initial uptake, 12-week adherence and 24-week completion. Results Uptake was 81% (n=1811), 12-week adherence was 53.5% (n=968) and 24-week completion was 42.9% (n=777). Participants who completed significantly increased their self-reported physical activity levels at 24-weeks t (638)=−11.55, p<0.001. Completers attended a mean of 22.87 (12.47 SD) of a target 48 supervised sessions. Increasing age, being female and leisure site were associated with uptake, increasing age, Index of Multiple Deprivation and leisure site were associated with 12-week adherence and Body Mass Index and leisure site were associated with 24-week completion. Each regression significantly increased the prediction accuracy of stage of exit (non-starters vs starters 81.5%, dropouts before 12 weeks vs 12-week adherers 66.9%, and dropouts between 13 and 24 weeks 82.2%). Conclusions Completers of the Northumberland ERS increased physical activity at 24 weeks, although the levels achieved were below the current UK guidelines of 150 min of moderate exercise per week. Leisure site was associated with uptake, adherence and completion

A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model.

Prostate cancer (PCa) has been linked to fat intake, but the effects of both different dietary fat levels and types remain inconsistent and incompletely characterised. The effects on PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model of an elevated fat (20 % of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20 % of energy as soyabean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8 % of energy as soyabean oil) diet. Mice, starting at 8 weeks of age, consumed one of the three different diets ad libitum; and prostates, livers and blood were obtained after 9, 18 or 24 weeks of feeding. No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumour weight and growth rate were reduced in the walnut diet group. Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks, while no statistically significant prostate weight differences by diet were seen at 9 or 24 weeks. Multiple metabolites in the livers differed by diet at 9 and 18 weeks. The walnut diet's beneficial effects probably represent the effects of whole walnuts' multiple constituents and not via a specific fatty acid or tocopherols. Moreover, as the two HF diets had dissimilar effects on prostate tumour growth rate and size, and yet had the same total fat and tocopherol composition and content, this suggests that these are not strongly linked to PCa growth

Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection.

BackgroundLimited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy.Methods and findingsWe prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/raltegravir/maraviroc). Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24. At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01_AE (70%). Median CD4 was 406 cells/mm(3). HIV RNA was 5.5 log(10) copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/10(6) PBMC) vs. Fiebig I (8 copy/10(6) PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008). After 24 weeks of megaHAART, HIV RNA levels of &lt;50 copies were achieved in 14/15 in blood and 13/13 in gut. Total blood HIV DNA at week 0 predicted reservoir size at week 24 (p&lt;0.001). Total HIV DNA declined significantly and was undetectable in 3 of 15 in blood and 3 of 7 in gut. Frequency of CD4+CCR5+ gut T cells increased from 41% at baseline to 64% at week 24 (p&gt;0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02).ConclusionsGut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission

Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life

Background: Older adults are the main recipients of repeat prescriptions for benzodiazepine (BZD) hypnotics. BZDs can impair cognitive function and may not aid sleep when taken continuously for years. This study therefore aimed to determine if withdrawing from BZDs leads to changes in patients' cognitive function, quality of life, mood and sleep. Method: One hundred and ninety-two long-term users of BZD hypnotics, aged [gt-or-equal, slanted]65 years, were identified in 25 general practices. One hundred and four who wished to withdraw were randomly allocated to one of two groups under double-blind, placebo controlled conditions: group A's BZD dose was tapered from week 1 of the trial; group B were given their usual dose for 12 weeks and then it was tapered. An additional group (C) of 35 patients who did not wish to withdraw from BZDs participated as ‘continuers’. All patients were assessed at 0, 12 and 24 weeks and 50% were re-assessed at 52 weeks. Results: Sixty per cent of patients had taken BZDs continuously for >10 years; 27% for >20 years. Of all patients beginning the trial, 80% had successfully withdrawn 6 months later. There was little difference between groups A and B, but these groups differed from continuers (C) in that the performance of the withdrawers on several cognitive/psychomotor tasks showed relative improvements at 24 or 52 weeks. Withdrawers and continuers did not differ in sleep or BZD withdrawal symptoms. Conclusions: These results have clear implications for clinical practice. Withdrawal from BZDs produces some subtle cognitive advantages for older people, yet little in the way of withdrawal symptoms or emergent sleep difficulties. These findings also suggest that, taken long-term, BZDs do not aid sleep