Allocation Sequence Research Articles

Effect of remote ischemic preconditioning on cerebral vasospasm and biomarkers of cerebral ischemia in aneurysmal subarachnoid hemorrhage (ERVAS): A protocol for a randomized, controlled pilot trial.

INTRODUCTION:Cerebral vasospasm is a dreaded complication of aneurysmal subarachnoid hemorrhage (aSAH) predisposing to delayed cerebral ischemia. We intend to study the cerebroprotective effects of remote ischemic preconditioning (RIPC) in patients with aSAH.MATERIALS AND METHODS:This is a single-center, prospective, parallel group, randomized, pilot trial, approved by the Institutional Ethics Committee. Patients with aSAH admitted to our hospital for surgical clipping; fulfilling the trial inclusion criteria will be randomized to true RIPC (n = 12) (inflating upper extremity blood pressure cuff thrice for 5 min to 30 mmHg above systolic blood pressure) or sham RIPC (n = 12) (inflating blood pressure cuff thrice for 5 min to 30 mmHg) in 1:1 allocation ratio using a computerized random allocation sequence and block randomization.RESULTS:Our primary outcome measure is vasospasm on cerebral angiography and transcranial Doppler study, and concentration of serum S100B and neuron-specific enolase at 24 h after RIPC and on day 7 of ictus. Our secondary outcomes are safety of RIPC, cerebral oxygen saturation, and Glasgow coma score, and extended Glasgow outcome scale scores at discharge and at 1, 3, and 6 months following discharge. Outcome measures will be assessed by an observer blinded to the study intervention.CONCLUSION:If our preliminary results demonstrate a beneficial effect of RIPC, this would serve as a clinically applicable and safe preemptive method of protection against cerebral ischemia.

Comparison of Maternal Stress Response to Midazolam/Fentanyl and Propofol During Cesarean Delivery Under Spinal Anesthesia: A Double-Blinded Randomized Controlled Trial

Background: This research evaluated the effects of propofol and midazolam/fentanyl on maternal blood pressure, heart rate, recall, and full satisfaction with spinal anesthesia. A double-blinded randomized controlled trial was designed. Methods: The sample size was calculated as 100 patients (a type I error of 5% and statistical power of 80%) who were scheduled for elective cesarean delivery under spinal anesthesia. These patients were randomized into two equal groups by block randomization used for allocation sequence: midazolam/fentanyl and propofol groups. We measured the maternal heart rate (HR), systolic, and diastolic blood pressure (SBP and DBP) before induction, every three minutes in the operating room, and every five minutes until discharge from the recovery room. Data were analyzed by SPSS 18.0 and P value < 0.05 was considered as the significance level. Results: 100 women (mean age: 29.7 ± 5.1 years and gestational age: 37.2 ± 1.2 weeks) were enrolled. The SBP and HR decreased during the study in both groups, but it was significant only in the midazolam/fentanyl group (SBP: from 120.0 ± 10.3 to 113.9 ± 4.8, P = 0.025; and HR: from 75.0 ± 7.6 to 65.3 ± 5.5, P = 0.046). DBP reduced in both groups, but it was only significant in the propofol group (from 68.5 ± 7.2 to 56.9 ± 2.1, P = 0.039). The maternal recall of the birth time, child weight, and full satisfaction were significantly better in the propofol group than in the midazolam/fentanyl group (P = 0.046, P = 0.009, and P = 0.039, respectively). Conclusions: Propofol and midazolam/fentanyl could be useful in cesarean sections under spinal anesthesia thought propofol may induce more effective sedation with higher satisfaction. Accordingly, the propofol use during caesarian sections under spinal anesthesia is suggested due to its anti-stress effects, good delivery recall, and good sedation satisfaction.

Gait parameters in children with bilateral spastic cerebral palsy: a systematic review of randomized controlled trials.

To identify the gait parameters used to assess gait disorders in children with bilateral spastic cerebral palsy (CP) and evaluate their responsiveness to treatments. A systematic search within PubMed, Web of Science, and Scopus (in English, 2000-2016) for randomized controlled trials of children with bilateral spastic CP who were assessed by instrumented gait analysis (IGA) was performed. Data related to participants and study characteristics, risk of bias, and outcome measures were collected. A list of gait parameters responsive to clinical interventions was obtained. Twenty-one articles met the inclusion criteria. Eighty-nine gait parameters were identified, 56 of which showed responsiveness to treatments. Spatiotemporal and kinematic parameters were widely used compared to kinetic and surface electromyography data. The majority of responsive gait parameters were joint angles at the sagittal plane (flexion-extension). The IGA yields responsive outcome measures for the gait assessment of children with bilateral spastic CP. Spatiotemporal and kinematic (at sagittal plane) parameters are the gait parameters used most frequently. Further research is needed to establish the relevant gait parameters for each clinical problem. Fifty-six responsive gait parameters for children with bilateral spastic cerebral palsy were identified. Most responsive gait parameters belong to joint angles time-series at sagittal plane. Spatiotemporal and kinematic parameters are widely used compared to kinetic and surface electromyography parameters.

Smartphone problem-solving and behavioural activation therapy to reduce fear of recurrence among patients with breast cancer (SMartphone Intervention to LEssen fear of cancer recurrence: SMILE project): protocol for a randomised controlled trial

IntroductionOne of the most common distressing conditions experienced by breast cancer survivors is fear of cancer recurrence (FCR). There is, however, no standard intervention for ameliorating FCR. Our clinical experience...

Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial

Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5). R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death. National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt–chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomised non-inferiority trial

During the past decade, many patients had zotarolimus-eluting stents implanted, which had circular shape cobalt-chromium struts with limited radiographic visibility. The Resolute Onyx stent was developed to improve visibility while reducing strut thickness, which was achieved by using a novel composite wire with a dense platinum-iridium core and an outer cobalt-chromium layer. We did the first randomised clinical trial to assess the safety and efficacy of this often-used stent compared with the Orsiro stent, which consists of ultrathin cobalt-chromium struts. We did an investigator-initiated, assessor-blinded and patient-blinded, randomised non-inferiority trial in an allcomers population at seven independently monitored centres in Belgium, Israel, and the Netherlands. Eligible participants were aged 18 years or older and required percutaneous coronary intervention with drug-eluting stents. After guide wire passage with or without predilation, members of the catheterisation laboratory team used web-based computer-generated allocation sequences to randomly assign patients (1:1) to either the Resolute Onyx or the Orsiro stent. Randomisation was stratified by sex and diabetes status. Patients and assessors were masked to allocated stents, but treating clinicians were not. The primary endpoint was target vessel failure at 1 year, a composite of cardiac death, target-vessel-related myocardial infarction, and target vessel revascularisation, and was assessed by intention to treat (non-inferiority margin 2·5%) on the basis of outcomes adjudicated by an independent event committee. This trial is registered with ClinicalTrials.gov, number NCT02508714. Between Oct 7, 2015, and Dec 23, 2016, 2516 patients were enrolled, 2488 of whom were included in the intention-to-treat analysis (28 withdrawals or screening failures). 1243 participants were assigned to the Resolute Onyx group, and 1245 to the Orsiro group. Overall, 1765 (70·9%) participants presented with acute coronary syndromes and 1275 (51·2%) had myocardial infarctions. 1-year follow-up was available for 2478 (99·6%) patients. The primary endpoint was met by 55 (4·5%) patients in the Resolute Onyx group and 58 (4·7%) in the Orsiro group. Non-inferiority of Resolute Onyx to Orsiro was thus established (absolute risk difference -0·2% [95% CI -1·9 to 1·4]; upper limit of the one-sided 95% CI 1·1%; pnon-inferiority=0·0005). Definite or probable stent thrombosis occurred in one (0·1%) participant in the Resolute Onyx group and nine (0·7%) in the Orsiro group (hazard ratio 0·11 [95% CI 0·01-0·87]; p=0·0112). The Resolute Onyx stent was non-inferior to Orsiro for a combined safety and efficacy endpoint at 1-year follow-up in allcomers. The low event rate in both groups suggests that both stents are safe, and the very low rate of stent thrombosis in the Resolute Onyx group warrants further clinical investigation. Biotronik and Medtronic.

Exercise interventions to improve balance for young people with intellectual disabilities: a systematic review and meta-analysis.

To conduct a systematic review and meta-analysis of the effects of exercise interventions designed to improve balance in young people with intellectual disabilities. A systematic literature search was performed on 10 databases. Studies in press or published in English in a peer-reviewed journal were included if: (1) participants were young people with intellectual disabilities; (2) exercise interventions were designed to improve balance; and (3) they used quasi-experimental or experimental designs. Studies focusing only on a specific subpopulation of young people with intellectual disabilities or having a specific physical characteristic were excluded. Risk of bias was assessed for randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. The search strategy identified 937 articles and 15 studies, published between 1991 and 2017, that met the inclusion criteria. Exercise intervention groups showed a significant and larger improvement in static (pooled effect size, Hedges' g=0.98) and dynamic (g=1.34) balance compared with the control groups. However, although the pooled improvement of static-dynamic balance was large (g=2.80), the result was non-significant. None of the subgroup analyses were significant, except for the improvement in: (1) static balance (higher in quasi-experimental than in experimental studies); and (2) dynamic balance (higher in young people with a mild vs a mild-moderate intellectual disability). The reviewed exercise interventions seem to represent an effective means for improving the static and dynamic balance of young people with intellectual disabilities. However, the present findings should be considered as preliminary given the small number of studies and their limitations. Exercise intervention results in large and significant improvements in static and dynamic balance in young people with intellectual disabilities. Exercise intervention results in a large but non-significant improvement in static-dynamic balance. Static balance improvement was significantly higher in quasi-experimental versus experimental studies. Dynamic balance improvement was significantly higher in young people with mild versus mild-moderate intellectual disability. No significant differences related to age group, balance measures, and components of exercise intervention were found.

Lower mortality after early supervised pulmonary rehabilitation following COPD-exacerbations: a systematic review and meta-analysis

BackgroundPulmonary rehabilitation (PR), delivered as a supervised multidisciplinary program including exercise training, is one of the cornerstones in the chronic obstructive pulmonary disease (COPD) management. We performed a systematic review and meta-analysis to assess the effect on mortality of a supervised early PR program, initiated during or within 4 weeks after hospitalization with an acute exacerbation of COPD compared with usual post-exacerbation care or no PR program. Secondary outcomes were days in hospital, COPD related readmissions, health-related quality of life (HRQoL), exercise capacity (walking distance), activities of daily living (ADL), fall risk and drop-out rate.MethodsWe identified randomized trials through a systematic search using MEDLINE, EMBASE and Cocharne Library and other sources through October 2017. Risk of bias was assessed regarding randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases using the Cochrane Risk of Bias tool.ResultsWe included 13 randomized trials (801 participants). Our meta-analyses showed a clinically relevant reduction in mortality after early PR (4 trials, 319 patients; RR = 0.58 (95% CI: [0.35 to 0.98])) and at the longest follow-up (3 trials, 127 patients; RR = 0.55 (95% CI: [0.12 to 2.57])). Early PR reduced number of days in hospital by 4.27 days (1 trial, 180 patients; 95% CI: [− 6.85 to − 1.69]) and hospital readmissions (6 trials, 319 patients; RR = 0.47 (95% CI: [0.29 to 0.75])). Moreover, early PR improved HRQoL and walking distance, and did not affect drop-out rate. Several of the trials had unclear risk of bias in regard to the randomization and blinding, for some outcome there was also a lack of power.ConclusionModerate quality of evidence showed reductions in mortality, number of days in hospital and number of readmissions after early PR in patients hospitalized with a COPD exacerbation. Long-term effects on mortality were not statistically significant, but improvements in HRQoL and exercise capacity appeared to be maintained for at least 12 months. Therefore, we recommend early supervised PR to patients with COPD-related exacerbations. PR should be initiated during hospital admission or within 4 weeks after hospital discharge.

Effects of Vitamin E on Transfusion Requirements in TransfusionDependent Beta-Thalassemia Patients

Objective: To evaluate the volume of blood transfusion requirements as well as hemolytic and oxidative biochemical variables in transfusion-dependent β-thalassemia patients supplemented with vitamin E.Material and Methods: A prospective, double-blind, randomized, placebo-controlled, crossover study was undertaken between December, 2012 and September, 2014 in the Pediatric Clinic of Songklanagarind Hospital. The participants were β-thalassemia major and Hb E/β-thalassemia patients aged between 5 and 18 years. A random allocation sequence was generated to receiving either 6 months of vitamin E or placebo followed by a 3-month washout period and then switching to another drug for 6 months. The outcome variable measurements were the volumes of the transfused packed red cells, and the hemolytic and oxidative biochemical variables.Results: Thirty-nine patients were enrolled into the study. All of them had significantly low levels of vitamin E and reduced glutathione levels, as well as high levels of oxidative stress shown by significantly high levels of malondialdehyde, superoxide dismutase, and glutathione peroxidase. The vitamin E levels became normal after the 6-month period of 200-400 milligram per day of oral vitamin E intake. All of the measured oxidative stress parameters did not improve except for the glutathione peroxidase level. Moreover, there was no difference in the volumes of transfused packed red cell requirements as well as hemolytic parameters like aspartate transaminase, lactate dehydrogenase, reticulocyte count and total bilirubin levels. Finally, no adverse reactions to oral vitamin E were found.Conclusion: Vitamin E supplementation normalized the vitamin E level and possibly partially reduced oxidative stress, but there was no difference in the volume of transfusion requirements or the hemolytic parameters in transfusion-dependent β-thalassemia patients.

The use of a risk assessment and decision support tool (CRISP) compared with usual care in general practice to increase risk-stratified colorectal cancer screening: study protocol for a randomised controlled trial

BackgroundAustralia and New Zealand have the highest incidence rates of colorectal cancer worldwide. In Australia there is significant unwarranted variation in colorectal cancer screening due to low uptake of the immunochemical faecal occult blood test, poor identification of individuals at increased risk of colorectal cancer, and over-referral of individuals at average risk for colonoscopy. Our pre-trial research has developed a novel Colorectal cancer RISk Prediction (CRISP) tool, which could be used to implement precision screening in primary care. This paper describes the protocol for a phase II multi-site individually randomised controlled trial of the CRISP tool in primary care.MethodsThis trial aims to test whether a standardised consultation using the CRISP tool in general practice (the CRISP intervention) increases risk-appropriate colorectal cancer screening compared to control participants who receive standardised information on cancer prevention. Patients between 50 and 74 years old, attending an appointment with their general practitioner for any reason, will be invited into the trial. A total of 732 participants will be randomised to intervention or control arms using a computer-generated allocation sequence stratified by general practice. The primary outcome (risk-appropriate screening at 12 months) will be measured using baseline data for colorectal cancer risk and objective health service data to measure screening behaviour. Secondary outcomes will include participant cancer risk perception, anxiety, cancer worry, screening intentions and health service utilisation measured at 1, 6 and 12 months post randomisation.DiscussionThis trial tests a systematic approach to implementing risk-stratified colorectal cancer screening in primary care, based on an individual’s absolute risk, using a state-of-the-art risk assessment tool. Trial results will be reported in 2020.Trial registrationAustralian and New Zealand Clinical Trial Registry, ACTRN12616001573448p. Registered on 14 November 2016.

Remote ischaemic conditioning for preventing and treating ischaemic stroke.

Remote ischaemic conditioning (RIC) has been developed as a neuroprotective strategy to prevent and treat ischaemic stroke. It usually involves restricting blood flow to limbs and then releasing the ischaemic blood to promote a neuroprotective effect. Preclinical studies have suggested that RIC may have beneficial effects in ischaemic stroke patients and those at risk of ischaemic stroke. However, existing evidence is insufficient to demonstrate the efficacy and safety of RIC in preventing and treating ischaemic stroke. To assess the benefits and harms of RIC for preventing ischaemic stroke and for treating people with ischaemic stroke and those at risk for ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (16 January 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (January 2018), MEDLINE Ovid (1946 to January 2018), Embase Ovid (1974 to January 2018), Web of Science Core Collection (1950 to January 2018) and three Chinese databases (January 2018). We also searched four ongoing trials registers, reference lists, and conference proceedings. We included randomised controlled trials (RCTs) comparing RIC with sham RIC or medical management in people with ischaemic stroke or at risk of ischaemic stroke. Two review authors independently selected studies, assessed trial quality and risk of bias, and extracted data. We used the GRADE approach to assess the quality of the evidence. We included seven trials, involving 735 participants, in this review. We analysed the effects of RIC on preventing and treating ischaemic stroke respectively.We evaluated risk of bias and judged it to be low for generation of allocation sequence in six studies and unclear in one study; unclear for allocation concealment in four studies and low in three studies; high for incomplete outcome data (attrition bias) in five studies and low in two studies; high for blinding in three studies and low in four studies; low for selective reporting; and high for other sources of bias in six studies and low in one study.We included three trials (involving 371 participants) in the analysis of the effects of RIC on ischaemic stroke prevention. In people with symptomatic intracerebral artery stenosis, recurrent stroke was significantly reduced by RIC (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.83; 2 trials, 182 participants, low-quality evidence). In people with carotid stenosis undergoing carotid stenting, there was no significant difference in the incidence of ischaemic stroke between participants treated with RIC and non-RIC (RR 0.22, 95% CI 0.01 to 4.03; 1 trial, 189 participants, low-quality evidence); however the stroke severity (assessed by infarct volume) was significantly lower in participants treated with RIC (mean difference (MD) -0.17 mL, 95% CI -0.23 to -0.11; 1 trial, 189 participants, low-quality evidence). Adverse events associated with RIC were significantly higher in participants treated with RIC (RR 10.91; 95% CI 2.01 to 59.28; 3 trials, 371 participants, low-quality evidence), but no severe adverse event was attributable to RIC treatment. No participants experienced death or cardiovascular events during the period of the studies; and no trial reported haemorrhagic stroke or improvement in neurological, phycological or cognitive impairment.We included four trials (involving 364 participants) in the analysis of the effects of RIC on ischaemic stroke treatment. In acute ischaemic stroke, for people receiving intravenous thrombolysis, the rate of death or dependency was significantly increased by RIC treatment compared with non-RIC treatment (RR 2.34; 95% 1.19 to 4.61; 1 trial, 285 participants, low-quality evidence). In people with acute ischaemic stroke, there was no significant difference between RIC and non-RIC for reducing stroke severity as assessed by the National Institutes of Health Stroke Scale score and the final infarct volume (standardised mean difference (SMD) -0.24 mL, 95% CI -1.02 to 0.54; 2 trials, 175 participants, very low quality evidence). There was no significant difference between RIC and non-RIC for improving the psychological impairment (SMD -0.37 points, 95% CI -1.15 to 0.41; 1 trial, 26 participants, very low quality evidence) and the cognitive impairment (SMD -0.26 points; 95% CI -0.72 to 0.21; 3 trials, 79 participants, low-quality evidence) in people with acute ischaemic stroke and cerebral small vessel disease. No trial reported ischaemic stroke, recurrent ischaemic stroke, improvement in neurological impairment, hemorrhagic stroke, cardiovascular events, and RIC associated adverse events. We found low-quality evidence that RIC may reduce the risk of recurrent stroke in participants with intracerebral artery stenosis and reduce stroke severity in participants undergoing carotid stenting, but it may increase death or dependence in participants with acute ischaemic stroke who are undergoing intravenous thrombolysis. However, there is considerable uncertainty about these conclusions because of the small number of studies and low quality of the evidence.

Treatment with volanesorsen (VLN) reduced triglycerides and pancreatitis in patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG) vs placebo: Results of the approach and compass studies

Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome.The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed).Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI −79·3 to −63·2) from baseline to 3 months compared with 0·9% (−13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI −1018 to −720; 9·82 mmol/L [–11·51 to −8·14]) in volanesorsen compared with an increase in placebo of 74 mg/dL (−138 to 285; 0·83 mmol/L [–1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events.Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients.Ionis Pharmaceuticals and Akcea Therapeutics.

Parenting Resilient Kids (PaRK), an online parenting program to prevent anxiety and depression problems in primary school-aged children: Study protocol for a randomised controlled trial

BackgroundPreventive efforts targeting childhood anxiety and depression symptoms have the potential to alter the developmental trajectory of depression and anxiety disorders across the lifespan. Substantial previous research suggests that modifiable parenting factors such as parental aversiveness and over-involvement are associated with childhood anxiety, depressive and internalising symptoms, indicating that parents can play a critical role in prevention. The Parenting Resilient Kids study is a new evidence-based online parenting program designed to prevent anxiety and depression problems in primary school-aged children by reducing family-based risk factors and enhancing protective factors through increased positive interactions between parent and child.Methods/designThe current study is a parallel group superiority randomised controlled trial with parent-child dyads randomised to the intervention or active-control group in a 1:1 ratio. The intervention group will receive the Parenting Resilient Kids program consisting of a feedback report on parenting behaviours and up to 12 interactive online modules personalised based on responses to the parent survey. The active-control group will receive a standardised package of online educational materials about child development and wellbeing. The trial website is programmed to run a stratified random allocation sequence (based on parent gender) to determine group membership. We aim to recruit 340 parent-child dyads (170 dyads per group). We hypothesise that the intervention group will show greater improvement in parenting risk and protective factors from baseline to 3-month follow-up (primary outcome), which will in turn mediate changes in child depressive and anxiety symptoms from baseline to 12 and 24 months (co-primary outcomes). We also hypothesise that the intervention group will show greater benefits from baseline to 3-, 12- and 24-month follow-up, with regard to: child depressive and anxiety symptoms (co-primary outcomes); and child and parent health-related quality of life, and overall family functioning (secondary outcomes).DiscussionThis randomised controlled trial will examine the efficacy of the Parenting Resilient Kids program as a preventive intervention for anxiety and depression symptoms in primary school-aged children, as well as changes in child and parent health-related quality of life. Findings from this study will examine design features that render web-based prevention programs effective and the extent to which parents can be engaged and motivated to change through a minimally guided parenting program.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR): Trial ID ACTRN12616000621415 Registered on 13 May 2016. Updated on 3 March 2017.

Hard-to-place kidney offers: Donor- and system-level predictors of discard.

Understanding risk factors for deceased-donor kidney nontransplantation is important since discard rates remain high. We analyzed DonorNet® data of consecutive deceased-donor nonmandatory share primary kidney-only offers to adult candidates at our center and beyond between July 1, 2015 and March 31, 2016 for donor- and system-level risk factors of discard, defined as nontransplantation at our or subsequent transplant centers. Exclusions were hepatitis C virus/hepatitis B virus core antibody status, blood type AB, and donor <1year based on low candidate waitlist size. Of 456 individual kidney offers, from 296 donors, 73% were discarded. Most were national (93%) offers from Kidney Donor Profile Index 35-85% (n=233) or >85% (n=208) donors late in the allocation sequence with prior refusals logged for numerous candidates. On multivariate regression, factors significantly associated with discard were donor cerebrovascular accident (adjusted odds ratio [aOR]: 3.32), cancer transmission concern (aOR: 6.5), renal artery luminal compromise (aOR: 3.97), biopsy score ≥3 (aOR: 5.09), 2-hour pump resistive index >0.4 (aOR: 3.27), absence of pump (aOR: 2.58), nonspecific kidney abnormality (aOR: 2.76), increasing offer cold ischemia time category 11-15, 16-20, and >21hours (aOR: 2.07, 2.33, 2.82), nighttime notification (aOR: 2.19), and neither kidney placed at time of offer (aOR: 2.74). Many traditional determinants of discard lack discriminatory value when granular factors are assessed. System-level factors also influence discard and warrant further study.

Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial

Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246. Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3·0%, 95% CI -8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Gilead Sciences Inc.

Effectiveness of Family Integrated Care in neonatal intensive care units on infant and parent outcomes: a multicentre, multinational, cluster-randomised controlled trial

Despite evidence suggesting that parent involvement was beneficial for infant and parent outcomes, the Family Integrated Care (FICare) programme was one of the first pragmatic approaches to enable parents to become primary caregivers in the neonatal intensive care unit (NICU). We aimed to analyse the effect of FICare on infant and parent outcomes, safety, and resource use. In this multicentre, cluster-randomised controlled trial, we stratified 26 tertiary NICUs from Canada, Australia, and New Zealand by country and size, and assigned them, using a computer-generated random allocation sequence, to provide FICare or standard NICU care. Eligible infants were born at 33 weeks' gestation or earlier, and had no or low-level respiratory support; parents gave written informed consent for enrolment. To be eligible, parents in the FICare group had to commit to be present for at least 6 h a day, attend educational sessions, and actively care for their infant. The primary outcome, analysed at the individual level, was infant weight gain at day 21 after enrolment. Secondary outcomes were weight gain velocity, high frequency breastfeeding (≥6 times a day) at hospital discharge, parental stress and anxiety at enrolment and day 21, NICU mortality and major neonatal morbidities, safety, and resource use (including duration of oxygen therapy and hospital stay). This trial is registered with ClinicalTrials.gov, number NCT01852695. From Oct 1, 2012, 26 sites were randomly assigned to provide FICare (n=14) or standard care (n=12). One site assigned to FICare discontinued because of poor site enrolment. Parents and infants were enrolled between April 1, 2013, and Aug 31, 2015, with 895 infants being eligible in the FICare group and 891 in the standard care group. At day 21, weight gain was greater in the FICare group than in the standard care group (mean change in Z scores -0·071 [SD 0·42] vs -0·155 [0·42]; p<0·0002). Average daily weight gain was significantly higher in infants receiving FICare than those receiving standard care (mean daily weight gain 26·7 g [SD 9·4] vs 24·8 g [9·5]; p<0·0001). The high-frequency exclusive breastmilk feeding rate at discharge was higher for infants in the FICare group (279 [70%] of 396) than those in the standard care group (394 [63%] of 624; p=0·016). At day 21, parents in the FICare group had lower mean stress scores than did parents in the standard care group (2·3 [SD 0·8] vs 2·5 [0·8]; p<0·00043), and lower mean anxiety scores (70·8 [20·1] vs 74·2 [19·9]; p=0·0045). There were no significant differences between groups in the rates of the secondary outcomes of mortality, major morbidity, duration of oxygen therapy, and duration of hospital stay. Although the safety assessment was not completed, there were no adverse events. FICare improved infant weight gain, decreased parent stress and anxiety, and increased high-frequency exclusive breastmilk feeding at discharge, which together suggest that FICare is an important advancement in neonatal care. Further research is required to examine if these results translate into better long-term outcomes for families. Canadian Institutes of Health Research Partnerships for Health System Improvement, and Ontario Ministry of Health and Long-Term Care.

Morphine versus fentanyl for spinal post-caesarean analgesia: a randomised controlled trial

BackgroundFinding appropriate analgesics is important for a mother's recovery after a caesarean section. The aim of this study was to compare the analgesic effect of spinal morphine and fentanyl for women undergoing a caesarean section. MethodsIn this randomised, unmasked, parallel-group, controlled trial, eligible participants were women undergoing caesarean section with spinal anaesthetic at the Al-Helal Al-Emirati Hospital, Rafah, Gaza Strip, occupied Palestinian territory. Using a manually generated allocation sequence that was independently managed by medical staff, we randomly assigned women (1:1) to receive either 0·2 mg preservative-free morphine or 20 μg fentanyl, spinally, combined with 2 mL of 0·5% hyperbaric bupivacaine for spinal anaesthesia. Pain was recorded by visual analogue scales (VAS; range 0–10, where 0 means no pain and 10 means pain is intolerable) at 1 h, 6 h, 12 h, 18 h, and 24 h after the caesarean section. Time and amount of other analgesics needed were recorded (primary outcome). Secondary outcomes were nausea-vomiting scores (NVS 0–3, where 0 means no nausea or vomiting and 3 means severe nausea or vomiting that is unresponsive to antiemetics), and pruritus scores (PS 0–2, where 0 means no pruritus and 2 means severe pruritus). Data were analysed with SPSS. We compared outcomes using Mann-Whitney U-test, student's t-test, OR, or χ2 test. The study was approved by the ministry of health and the Helsinki Committee, Gaza Strip. Women provided verbal informed consent before participation. FindingsWe enrolled 121 women (mean age 28·43 years [SD 5·62]). 59 women were randomly assigned to the morphine group, and 62 women were randomly assigned to the fentanyl group. Pain was reduced with morphine compared with fentanyl at 1 h (VAS score: 1·81 for morphine vs 2·57 for fentanyl; p<0·039), at 6 h (1·84 vs 5·08; p<0·0001), at 12 h (1·45 vs 3·30; p<0·0001), at 18 h (1·62 vs 3·18; p<0·0001), and at 24 h (1·61 vs 2·68; p=0.0001). The time to needing other analgesic drug was longer in the morphine group than in the fentanyl group (9·03 h vs 2·46 h; p<0·0001). 20 (34%) women in the morphine group did not need analgesics, whereas all (100%) women with fentanyl needed additional analgesics (odds ratio [OR] 2·59, 95% CI 2·03–3·31). Mild nausea and drowsiness were seen more in the morphine group than in the fentanyl group at 6 h and 12 h, respectively (p=0·010). Nine (15%) women in the morphine group had pruritus and needed treatment compared with one (2%) woman in the fentanyl group (OR 10·98, 95% CI 1·35–89·62). InterpretationSpinal morphine was more effective than spinal fentanyl for caesarean analgesia. Morphine was associated with more side-effects than fentayl, but these were treatable and did not pose any danger to women. FundingNone.

Factors affecting sequential sex allocation in the parasitoid wasp Gryon japonicum

AbstractFemale wasps of the solitary egg parasitoid Gryon japonicum (Hymenoptera: Platygastridae) allocate male and female offspring in a particular sequence to successive hosts. Male eggs are typically laid in the second host, and the sex allocation sequence is reset after a certain period of time. The present study aimed to examine the underlying mechanism to hold information and reset the sequence by using eggs of Riptortus pedestris (Heteroptera: Alydidae) as hosts. After completion of initial oviposition, a female wasp was treated by cold anesthesia for 1 h, exposure to a parasitized host for 3 h, or being kept at 15°C in darkness for 24 h, and then presented with three host eggs. Cold‐anesthetized females did not reset the sex allocation sequence, indicating that cold anesthesia did not block the mechanism of holding information about oviposition order. Frequent encounters with parasitized hosts were also insufficient to reset the sequence. However, being kept in cool, dark conditions significantly affected resetting, suggesting that low temperature lengthened the time required to reset the sequence. This implies that it is probable that the mechanism to hold information and reset sex allocation sequence in G. japonicum involves metabolism.

Protocol for a systematic review: Interventions to improve mathematics achievement in primary school-aged children: a systematic review.

Protocol for a systematic review: Interventions to improve mathematics achievement in primary school-aged children: a systematic review.

Performance of Self-adhering Flowable Composite in Class V Restorations: 18 Months Clinical Study

The present randomized clinical study compared the 18 months performance of self-adhering flowable composite with a conventional flowable composite in anterior Class V restorations. Totally, 20 patients, each with two moderate cervical carious lesions, participated in this single-center study. Forty restorations were allocated on a random basis by one examiner not involved in the restoration or the evaluation procedures, In each patient, one lesion was allocated to be restored using self-adhering flowable composite [Fusio liquid dentin (FL)] and the other to be restored using conventional flowable composite [Tetric Flow (FF)]. The allocation sequence of the restorations was concealed from the operator in sequentially numbered, opaque, sealed, and stapled envelopes. An operator restored all the preparations in accordance to the manufacturer's instructions. Finishing and polishing of the restorations were done immediately after placement. Evaluation of the restorations was done in accordance to the United States Public Health Services (USPHS), modified Ryge criteria. Statistical analysis was completed with Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM Product, Chicago, USA). One case could not be reassessed at 18 months follow-up in both groups. No significant differences were detected between the tested materials from baseline to those of 18 months using the modified USPHS criteria. Self-adhering flowable composite exhibited acceptable clinical performance comparable with the conventional flow-able composite in anterior Class V restorations over an 18-month period. Nevertheless, the findings of this study must be validated by a longer clinical study. Self-adhering flowable composite exhibited clinical performance comparable with the conventional flowable composite in Class V restoration.