Search

Background This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. It affects approximately 2% of the general population. Up to 70% of patients with fibromyalgia meet the criteria for a depressive or anxiety disorder. People often report high disability levels and poor health-related quality of life. Drug therapy focuses on reducing key symptoms and disability, and improving health-related quality of life. Antipsychotics might reduce fibromyalgia and associated mental health symptoms. Objectives To assess the efficacy, tolerability and safety of antipsychotics in fibromyalgia in adults. Search methods We searched CENTRAL (2016, Issue 4), MEDLINE and EMBASE to 20 May 2016, together with reference lists of retrieved papers and reviews and two clinical trial registries. We also contacted trial authors. Selection criteria We selected controlled trials of at least four weeks duration of any formulation of antipsychotics used for the treatment of fibromyalgia in adults. Data collection and analysis We extracted the data from all included studies and two review authors independently assessed study risks of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. We derived first tier evidence from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs, at least 200 participants in the comparison, eight to 12 weeks duration, parallel design), second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with adequate numbers in the comparison, and third tier evidence from data involving small numbers of participants that we considered very likely to be biased or used outcomes of limited clinical utility, or both. We rated the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Main results We included a total of four studies with 296 participants. Three studies with 206 participants compared quetiapine, an atypical (second-generation) antipsychotic, with placebo. One study used a cross-over design and two studies a parallel-group design. Study duration was eight or 12 weeks. Quetiapine was used in all studies with a bedtime dosage between 50 and 300 mg/day. All studies had one or more sources of potential major bias and we judged them to be at moderate risk of bias overall. The primary outcomes in this review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Second tier evidence indicated that quetiapine was not statistically superior to placebo in the number of participants with a 50% or more pain reduction (very low quality evidence). No study reported data on PGIC. A greater proportion of participants on quetiapine reported a 30% or more pain reduction (risk difference (RD) 0.12, 95% confidence interval (CI) 0.00 to 0.23; number needed to treat for an additional benefit (NNTB) 8, 95% CI 5 to 100) (very low quality evidence). A greater proportion of participants on quetiapine reported a clinically relevant improvement of health-related quality of life compared to placebo ( RD 0.18, 95% CI 0.05 to 0.31; NNTB 5, 95% CI 3 to 20) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing sleep problems (standardised mean difference (SMD) -0.67, 95% CI -1.10 to -0.23), depression (SMD -0.39, 95% CI -0.74 to -0.04) and anxiety (SMD -0.40, 95% CI -0.69 to -0.11) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing the risk of withdrawing from the study due to a lack of efficacy (RD -0.14, 95% CI -0.23 to -0.05) (very low quality evidence). There was no statistically significant difference between quetiapine and placebo in the proportion of participants withdrawing due to adverse events (tolerability) (very low quality evidence), in the frequency of serious adverse events (safety) (very low quality evidence) and in the proportion of participants reporting dizziness and somnolence as an adverse event (very low quality evidence). In more participants in the quetiapine group a substantial weight gain was noted (RD 0.08, 95% CI 0.02 to 0.15; number needed to treat for an additional harm (NNTH) 12, 95% CI 6 to 50) (very low quality evidence). We downgraded the quality of evidence by three levels to a very low quality rating because of limitations of study design, indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed). One parallel design study with 90 participants compared quetiapine (50 to 300 mg/day flexible at bedtime) to amitriptyline (10 to 75 mg/day flexible at bedtime). The study had three major risks of bias and we judged it to be at moderate risk of bias overall. We downgraded the quality of evidence by two levels to a low quality rating because of indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed). Third tier evidence indicated no statistically significant differences between the two drugs. Both drugs did not statistically significantly differ in the reduction of average scores for pain, fatigue, sleep problems, depression, anxiety and for limitations of health-related quality of life and in the proportion of participants reporting dizziness, somnolence and weight gain as a side effect (low quality evidence). Compared to amitriptyline, more participants left the study due to adverse events (low quality evidence). No serious adverse events were reported (low quality evidence). We found no relevant study with other antipsychotics than quetiapine in fibromyalgia. Authors' conclusions Very low quality evidence suggests that quetiapine may be considered for a time-limited trial (4 to 12 weeks) to reduce pain, sleep problems, depression and anxiety in fibromyalgia patients with major depression. Potential side effects such as weight gain should be balanced against the potential benefits in shared decision making with the patient.

The aim was to evaluate the design parameters of dental implants shape, diameter and length on stress distribution by finite element analysis (FEA).The objectives of the study was to compare the influence of stress distribution in the implants of screw-vent tapered and parallel design by varying the implant diameter with a standard implant length. Six dental implant models have been simulated three-dimensionally. The influence of diameter and length on stress distribution was evaluated by Group I: for screw-vent tapered design (Zimmer Dental Implant Carlsbad, CA, USA) (1) Dental implant model with diameter 3.7 mm and length 13 mm. (2) Dental implant model with diameter 4.1 mm and length 13 mm. (3) Dental implant model with diameter 4.7 mm and length 13 mm. Group II: for parallel design (Zimmer Dental Implant Carlsbad, CA, USA) (4) Dental implant model with diameter 3.7 mm and length 13 mm. (5) Dental implant model with diameter 4.1 mm and length 13 mm. (6) Dental implant model with diameter 4.7 mm and length 13 mm. The 3-D model of the implant was created in the pro-e wildfire 4.0 software by giving various commands. This model was imported to the ANSYS software through IGES (initial graphic exchange specification) file for further analysis. All six models were loaded with a force of 17.1, 114.6 and 23.4 N in a lingual, an axial and disto-mesial direction respectively, simulating average masticatory force in a natural oblique direction, to analyze the stress distribution on these implants. The increase in implant diameter in Group I and Group II from 3.7 to 4.1 mm and from 4.1 to 4.7 mm with constant 13 mm length for screw-vent tapered and parallel design implant resulted in a reduction in maximum value of Von Mises stress in the bone surrounding the implant was statistically significant at 5% level done by student “t” test. The overall maximum value of Von Mises stress was decreased in parallel design implant diameter of 4.7 mm with constant length of 13 mm when compared to screw-vent tapered design implant samples. The results of the FEA computation depend on many individual factors including material properties, boundary conditions interface definition and also on the overall approach to the model. The results depicted that the tapered shape implant design exhibited higher stress levels in bone than the parallel shaped implant design which seemed to be distributing stresses more evenly. The application of a 3-D model simulation with the non-symmetric loading by the masticatory force on a dental implant resulted in a more satisfactory modeling of “clinical reality” than that achieved with 2-D models used in other studies.

AIMS/HYPOTHESIS: The aim of this study was to measure the efficacy of motivational interviewing (MI) compared with usual care on changes in glycaemic control and competence of diabetes self-management in patients with diabetes mellitus. METHODS: Patients were eligible if they had type 1 or 2 diabetes mellitus, were over 18 years of age and had participated in a 4 day group education programme offered at a diabetes clinic at a university hospital in Denmark. Exclusion criteria included pregnancy, severe debilitating disease and cognitive deficit. Out of 469 patients who attended the group education programme, 349 patients were randomised to either a usual care control group or an intervention group, which received up to five individual counselling sessions in 1 year based on MI, in addition to usual care. A randomised parallel design was used and open-label allocation was done by random permuted blocks, with allocation concealment by sequentially numbered, sealed, opaque envelopes. The primary outcome was glycated haemoglobin (HbA(1c)). Analysis regarding measurements of glycated haemoglobin (HbA(1c)) and competence of self-management (using the Problem Areas in Diabetes Scale [PAID] and Perceived Competence for Diabetes Scale [PCDS]) was based on 298 participants followed for a 24 month period. Data were collected at the Department of Endocrinology at Odense University Hospital. Our hypotheses were that MI could: (1) reduce HbA(1c) levels; (2) increase self-efficacy; and (3) increase diabetes self-care, compared with usual care. RESULTS: Out of the 176 included in the control group and 173 in the intervention group, 153 and 145 were analysed in the groups, respectively. When using the baseline value as covariate there were no significant differences in change score between the two study groups with regard to mean level of HbA(1c) (0.131, p = 0.221), PAID scores (-1.793, p = 0.191) or PCDS scores (0.017, p = 0.903) at the 24 month follow-up, using a mixed effects regression model. The patients in the intervention group showed significantly higher levels of perceived competence in dealing with diabetes compared with the control group (mean change score = -0.387, p = 0.002) following 1 year of intervention. CONCLUSION/INTERPRETATION: We were unable to demonstrate any benefit, over or above usual care, of MI in patients with diabetes who have just completed a diabetes education programme, and who have well-regulated diabetes. AIMS/HYPOTHESIS: The aim of this study was to measure the efficacy of motivational interviewing (MI) compared with usual care on changes in glycaemic control and competence of diabetes self-management in patients with diabetes mellitus. METHODS: Patients were eligible if they had type 1 or 2 diabetes mellitus, were over 18 years of age and had participated in a 4 day group education programme offered at a diabetes clinic at a university hospital in Denmark. Exclusion criteria included pregnancy, severe debilitating disease and cognitive deficit. Out of 469 patients who attended the group education programme, 349 patients were randomised to either a usual care control group or an intervention group, which received up to five individual counselling sessions in 1 year based on MI, in addition to usual care. A randomised parallel design was used and open-label allocation was done by random permuted blocks, with allocation concealment by sequentially numbered, sealed, opaque envelopes. The primary outcome was glycated haemoglobin (HbA(1c)). Analysis regarding measurements of glycated haemoglobin (HbA(1c)) and competence of self-management (using the Problem Areas in Diabetes Scale [PAID] and Perceived Competence for Diabetes Scale [PCDS]) was based on 298 participants followed for a 24 month period. Data were collected at the Department of Endocrinology at Odense University Hospital. Our hypotheses were that MI could: (1) reduce HbA(1c) levels; (2) increase self-efficacy; and (3) increase diabetes self-care, compared with usual care. RESULTS: Out of the 176 included in the control group and 173 in the intervention group, 153 and 145 were analysed in the groups, respectively. When using the baseline value as covariate there were no significant differences in change score between the two study groups with regard to mean level of HbA(1c) (0.131, p = 0.221), PAID scores (-1.793, p = 0.191) or PCDS scores (0.017, p = 0.903) at the 24 month follow-up, using a mixed effects regression model. The patients in the intervention group showed significantly higher levels of perceived competence in dealing with diabetes compared with the control group (mean change score = -0.387, p = 0.002) following 1 year of intervention. CONCLUSION/INTERPRETATION: We were unable to demonstrate any benefit, over or above usual care, of MI in patients with diabetes who have just completed a diabetes education programme, and who have well-regulated diabetes. TRIAL REGISTRATION: Clinical Trials NCT00555854. FUNDING: The National Board of Health, Funen County, Danish Association of Diabetes, Odense University Hospital, University of Southern Denmark and TRYG Fonden.

The high efficiency is demanded in aerospace field. In the design of the control system, adopting single processor can hardly meet the demand of efficiency required. However processor array's hardware size and off-chip bus delay cannot be ignored. In order to solve the above mentioned problems, this paper is intended to study multi-task collaborative parallel design based on multi-core SOC (system on chip). Firstly, multi-core architecture based on SOC is achieved, which includes constructing two MicroBlaze cores, two ARM (advanced RISC machines) cores and designing inter-core communication, as well as designing external data collection and hardware acceleration unit based on FPGA (field programmable gate array). Secondly, collaborative parallel design in missile control system is studied. Finally, a verification platform is developed. By comparing with single core processor, it is proved that the approaches proposed have advantages over enhancing the efficiency.

High placebo response is widely believed to be one major reason why many psychiatric clinical trials fail to demonstrate drug efficacy. In order to alleviate this problem, research has developed several enrichment designs, including the parallel design with a placebo lead-in phase, the sequential parallel design, and a recently proposed two-way enriched design. While these designs have been evaluated and discussed individually, their effectiveness against each other has not been rigorously compared. The current study examines the various enrichment designs simultaneously. Building on their strengths, we introduce a new improved design named' sequential enriched design' (SED) aimed at removing not only patients with high placebo response but also patients who do not respond to any treatment from the study. The SED begins with a double-blind placebo lead-in phase followed by a traditional parallel design in the first stage. Only patients who respond to the drug in the first stage are re-randomized to the drug or placebo at the second stage. We simulate data for a mixed population composed of four subgroups of patients who are predetermined as to whether they respond to drug or not as well as to placebo or not. By focusing on the target patients whose responses reflect the drug's efficacy,we evaluate the bias, mean squared error, and power for different designs. We demonstrate that the SED produces a less biased estimate for the target treatment effect and yields reasonably high power in general compared with the other designs.

Context The type of dietary protein may modulate markers of diabetic kidney disease; however, no attempt to summarize the evidence from randomized controlled trials (RCTs) has been performed to date. Objective To assess the effects of different types of dietary protein on urinary albumin excretion and glomerular filtration rate in individuals with diabetes. Data sources MEDLINE, EMBASE, and Scopus were searched for all published RCTs, with no language restriction, up to July 2020. Data Extraction Study selection and data extraction were performed independently by 3 authors. Risk of bias was assessed independently by 2 authors, and the GRADE approach was used to assess the quality of the evidence. Results Twelve RCTs were included, of which 11 (involving 228 participants) were compiled in meta-analyses of random-effects models. Interventions consisted of diets emphasizing plant or white meat protein, with reduced intake of animal or red meat protein. Pooled data from crossover trials (n = 8) favored intervention diets for urinary albumin excretion (ratio of means, 0.86; 95% confidence interval 0.80 to 0.94; I2 = 4%) and glomerular filtration rate (ratio of means, 0.90; 95% confidence interval 0.87 to 0.94; I2 = 45%), compared with control diets. Results from parallel-design studies (n = 3), however, were not statistically significant for any outcome. The quality of the evidence ranged from very low to moderate, and most studies were judged with at least some concerns in terms of risk of bias. Conclusion This meta-analysis found weak evidence for small to moderate improvements in markers of kidney function in favor of interventions with lower animal protein (or red meat protein) compared with usual diets in short-term crossover trials. These findings require confirmation in well-designed randomized controlled trials.

OBJECTIVE The primary objective of this trial was to determine if shunt entry site affects the risk of shunt failure. METHODS The authors performed a parallel-design randomized controlled trial with an equal allocation of patients who received shunt placement via the anterior entry site and patients who received shunt placement via the posterior entry site. All patients were children with symptoms or signs of hydrocephalus and ventriculomegaly. Patients were ineligible if they had a prior history of shunt insertion. Patients received a ventriculoperitoneal shunt after randomization; randomization was stratified by surgeon. The primary outcome was shunt failure. The planned minimum follow-up was 18 months. The trial was designed to achieve high power to detect a 10% or greater absolute difference in the shunt failure rate at 1 year. An independent, blinded adjudication committee determined eligibility and the primary outcome. The study was conducted by the Hydrocephalus Clinical Research Network. RESULTS The study randomized 467 pediatric patients at 14 tertiary care pediatric hospitals in North America from April 2015 to January 2019. The adjudication committee, blinded to intervention, excluded 7 patients in each group for not meeting the study inclusion criteria. For the primary analysis, there were 229 patients in the posterior group and 224 patients in the anterior group. The median patient age was 1.3 months, and the most common etiologies of hydrocephalus were postintraventricular hemorrhage secondary to prematurity (32.7%), myelomeningocele (16.8%), and aqueductal stenosis (10.8%). There was no significant difference in the time to shunt failure between the entry sites (log-rank test, stratified by age < 6 months and ≥ 6 months; p = 0.061). The hazard ratio (HR) of a posterior shunt relative to an anterior shunt was calculated using a univariable Cox regression model and was nonsignificant (HR 1.35, 95% CI, 0.98–1.85; p = 0.062). No significant difference was found between entry sites for the surgery duration, number of ventricular catheter passes, ventricular catheter location, and hospital length of stay. There were no significant differences between entry sites for intraoperative complications, postoperative CSF leaks, pseudomeningoceles, shunt infections, skull fractures, postoperative seizures, new-onset epilepsy, or intracranial hemorrhages. CONCLUSIONS This randomized controlled trial comparing the anterior and posterior shunt entry sites has demonstrated no significant difference in the time to shunt failure. Anterior and posterior entry site surgeries were found to have similar outcomes and similar complication rates.

Background: Quinoa (Chenopodium quinoa) is a pseudo-cereal originally cultivated in the Andean region. The popularity of its seeds has increased in recent years due to the claims of health benefits and superfood qualities. Studies to date on the health benefits of quinoa have been restricted to animal models, and the results provide weak to moderate evidence to support improved plasma lipid profiles. Clinical trials in humans to examine the claims of health benefits of quinoa are limited to a few prospective studies and one randomized trial carried out in postmenopausal women. To our knowledge, no studies have been conducted in the general population. Objective: The objective of this randomized clinical trial was to investigate the effect of different quinoa doses (25 and 50 g/d) on body composition, serum lipids and hormones, and nutrient intakes in overweight and obese humans. Methods: This was a dose-response randomized, controlled, single-blind trial with a parallel design (1 control and 2 treatment groups) that compared the effect of 25 and 50 g quinoa/d in 50 overweight and obese participants over a 12-wk intervention period. Results: Body composition, nutrient intake, and total, LDL, and HDL cholesterol were not significantly altered by quinoa consumption (P > 0.05). Mean serum triglyceride (TG) concentration was reduced significantly in the 50-g quinoa group from 1.14 to 0.72 mmol/L at 12 wk (P < 0.05). The prevalence of metabolic syndrome (MetS) was also reduced in this group by 70%. No significant changes in TGs were observed in the control and 25-g quinoa groups. The prevalence of MetS was reduced by 40% (from n = 7 at baseline to n = 4 at 12 wk) in the 25-g group. Conclusions: The consumption of 50 g quinoa/d lowers serum TGs in overweight and obese participants and reduces the prevalence of MetS. This trial was registered at clinicaltrials.gov as UTN U1111-1175-470.

Background: Observational studies and crossover feeding studies suggest that moderate alcohol use may benefit cardiovascular risk, but we know of no long-term randomized trials that have tested this hypothesis. Objective: We evaluated the feasibility of an efficacy study of daily ethanol use in a 6-mo randomized pilot study in adults at higher cardiovascular risk. Methods: In a double-blind, randomized, controlled parallel-design trial, we screened 67 adults aged ≥55 y and randomly assigned 45 participants to consume 150 mL of an artificially sweetened beverage with or without 10% grain alcohol daily for 6 mo. Participants were asked to consume no other alcohol and returned monthly to receive the beverage and undergo measurement of HDL cholesterol, liver function tests, and complete blood counts. Results: Of the 45 randomly assigned participants, 39 completed the trial; the primary reason cited for attrition was inconvenience. None of the participants reported problem drinking or developed any serious adverse events or abnormal biochemical findings. However, we observed no differences in concentrations of HDL cholesterol, HDL lipoprotein subclasses, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, mean corpuscular volume, or adiponectin between the alcohol and control arms, suggesting that adherence was poor. Every participant accurately identified their assigned beverage, most with great certainty. Conclusions: In this parallel-design pilot study of daily alcohol use, we observed none of the expected changes in markers of alcohol intake, which suggests poor adherence to this pure alcohol intervention. Our results suggest that long-term trials of alcohol consumption, if they are conducted in light drinkers similar to these, must use pragmatic designs for maximal feasibility. This study was registered at clinicaltrials.gov as NCT01377727.

Background Cerebral palsy (CP) and brain injury (BI) are common conditions that have devastating effects on a child’s ability to use their hands. Hand splinting and task-specific training are two interventions that are often used to address deficits in upper limb skills, both in isolation or concurrently. The aim of this paper is to describe the method to be used to conduct two randomised controlled trials (RCT) investigating (a) the immediate effect of functional hand splints, and (b) the effect of functional hand splints used concurrently with task-specific training compared to functional hand splints alone, and to task-specific training alone in children with CP and BI. The Cognitive Orientation to Occupational Performance (CO-OP) approach will be the task-specific training approach used. Methods/Design Two concurrent trials; a two group, parallel design, RCT with a sample size of 30 participants (15 per group); and a three group, parallel design, assessor blinded, RCT with a sample size of 45 participants (15 per group). Inclusion criteria: age 4-15 years; diagnosis of CP or BI; Manual Abilities Classification System (MACS) level I – IV; hand function goals; impaired hand function; the cognitive, language and behavioural ability to participate in CO-OP. Participants will be randomly allocated to one of 3 groups; (1) functional hand splint only (n=15); (2) functional hand splint combined with task-specific training (n=15); (3) task-specific training only (n=15). Allocation concealment will be achieved using sequentially numbered, sealed opaque envelopes opened by an off-site officer after baseline measures. Treatment will be provided for a period of 2 weeks, with outcome measures taken at baseline, 1 hour after randomisation, 2 weeks and 10 weeks. The functional hand splint will be a wrist cock-up splint (+/- thumb support or supination strap). Task-specific training will involve 10 sessions of CO-OP provided in a group of 2-4 children. Primary outcome measures will be the Canadian Occupational Performance Measure (COPM) and the Goal Attainment Scale (GAS). Analysis will be conducted on an intention-to-treat basis. Discussion This paper outlines the protocol for two randomised controlled trials investigating functional hand splints and CO-OP for children with CP and BI.

Background The low utilisation of modern contraceptives in many low- and middle-income countries remains a challenge. Patent medicine vendors (PMVs) that operate in the informal health sector, have the potential to address this challenge. Between 2015 and 2018, the Population Council, in collaboration with the Federal and State Ministries of Health and the Pharmacy Council of Nigeria, trained PMVs in six states to deliver injectable contraceptive services. Outcome evaluation demonstrated increased client uptake of injectable contraceptive services; however, there is limited information on how and why the intervention influenced outcomes. This study was conducted to elucidate the processes and mechanism through which the previous intervention influenced women’s utilisation of injectable contraceptive services. Methods The study utilised a mixed methods, convergent parallel design guided by the UK Medical Research Council framework. Quantitative data were obtained from 140 trained PMVs and 145 of their clients in three states and 27 in-depth interviews were conducted among relevant stakeholders. The quantitative data were analysed descriptively, while the qualitative data were analysed thematically. Results The results revealed that even after the completion of the PMV study which had a time-bound government waiver for injectable contraceptive service provision by PMVs, they continued to stock and provide injectables in response to the needs of their clients contrary to the current legislation which prohibits this. The causal mechanism that influenced women’s utilisation of injectable contraceptives were the initial training that the PMV received; the favourable regulatory environment as demonstrated in the approval provided by government for PMVs to provide injectable contraceptives for the duration of the study; and the satisfaction and the confidence the female clients had developed in the ability of the PMVs to serve them. However, there were gaps with regards to the consistent supply of quality injectable contraceptive commodities and in PMVs use of job aids. Referral and linkages to government or private-owned facilities were also sub-optimal. Conclusion PMVs continue to play important roles in family planning service provision; this underscores the need to formalize and scale-up this intervention to aid their integral roles coupled with multi-faceted initiatives to enhance the quality of their services.

AIMS To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS This was a two-part, randomized, double-blind Phase 1b study. Part A used a six-period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal. RESULTS URLi increased the insulin exposure within the first 30 minutes postdose by 2.2-fold and reduced the time to the early half-maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal-to-dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%-105% for all three dose timings (-15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing. CONCLUSIONS URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal-to-dose timings compared with Humalog and was well tolerated in patients with T2D.

Aim This study compared the pharmacokinetics (PK), glucodynamics (GD), and tolerability following single and multiple daily subcutaneous (SC) doses of ultra rapid lispro (URLi) and Humalog in patients with type 1 diabetes mellitus (T1D). Materials and methods This was a 2-part, randomized, double-blind, Phase 1b study. Part A used a 6-period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, and 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2-weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2-weeks when insulins were administered immediately before the start of the meal. Results URLi increased the insulin exposure within the first 30-minutes post-dose by 2.2-fold and reduced the time to early half-maximal drug concentration by 37% compared to Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal compared to Humalog. In comparing the same meal-to-dose timing between the insulins, the postprandial glucose excursion over 5 hours was reduced by 40-44% for all 3 dose timings (-15 minutes, 0 minutes, and +15 minutes) with URLi, achieving statistical significance for the 0- and +15-minute timings. The PK and GD profiles were sustained after daily SC dosing for 2-weeks in patients with T1D. The number of documented hypoglycaemic events was similar between URLi and Humalog during the postprandial period of the MMTTs and outpatient period. Conclusions URLi demonstrated an accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal-to-dose timings compared to Humalog and was well tolerated in patients with T1D. This article is protected by copyright. All rights reserved.

Background Yoga nidra is practised by sages for sleep. The practice is simple to use and has been clearly laid out, but its role in the treatment of chronic insomnia has not been well studied. Methods In this randomized parallel-design study conducted during 2012–16, we enrolled 41 patients with chronic insomnia to receive conventional intervention of cognitive behavioural therapy for insomnia (n=20) or yoga nidra (n=21). Outcome measures were both subjective using a sleep diary and objective using polysomnography (PSG). Salivary cortisol levels were also measured. PSG was done before the intervention in all patients and repeated only in those who volunteered for the same. Results Both interventions showed an improvement in subjective total sleep time (TST), sleep efficiency, wake after sleep onset, reduction in total wake duration and enhancement in subjective sleep quality. Objectively, both the interventions improved TST and total wake duration and increased N1% of TST. Yoga nidra showed marked improvement in N2% and N3% in TST. Salivary cortisol reduced statistically significantly after yoga nidra (p=0.041). Conclusion Improvement of N3 sleep, total wake duration and subjective sleep quality occurred following yoga nidra practice. Yoga nidra practice can be used for treatment of chronic insomnia after supervised practice sessions.

The design and conduct of a 9-month multi-center clinical trial to evaluate the safety and efficacy of subgingivally delivered 5% sanguinarium chloride (SC) and 10% doxycycline hyclate (DH) from a biodegradable drug delivery system in the treatment of adult periodontitis is described. The 3-group randomized study of 180 adults with moderate to severe periodontitis was a modified double-blind parallel design. One group received DH, one group received SC, and the other group received the vehicle control (VC). Patients selected had two quadrants with a minimum of four periodontal pockets > or = 5 mm in depth with two sites > or = 7 mm. All qualifying sites exhibited bleeding on gentle probing. Qualifying sites were treated at baseline and again at 4 months. Clinical response was assessed by measuring attachment level, probing depth, and bleeding on probing at monthly examinations at qualifying sites and the entire dentition. The plaque index was measured monthly to verify oral hygiene status. The parallel design afforded the opportunity to distinguish between treatment effectiveness of SC, DH, and VC independent of possible crossover effects. Also the effectiveness of oral hygiene in untreated sites of the mouth could be evaluated. Finally, treatment effects in moderate (5 to 6 mm) and deep (> or = 7 mm) pockets in both treated and untreated sites could be compared. The design was capable of simulating a periodontal practice maintenance program and assessing the response according to maintenance and treatment history. Study management procedures that emphasized center examiner and therapist training and adherence to protocol and procedures to reduce variability are described.

The importance of safety standards of software systems is increasing as the use of software grows because of its convenience and flexibility. Software safety standards are very important in aircraft, military, automotive or medical devices. We are developing parallel code generating and refactoring system for safety standards compliance, which increases reliability of existing codes by refactoring of existing parallel source code, introducing parallel design patterns into this code. This paper describes the current status of these software safety standards, points out the common requirements of all these standards, specially the requirement for reliability. Reliability can be easily achieved using design patterns with verified reliable source code modules. In our research, we propose system for implementation of concurrency and synchronization design patterns into existing code. We have created parallel source code search API, which is planned to be used in our parallel code refactoring system for safety standards compliance. This API enables us to define appropriate places in source codes for introduction of parallel design patterns into existing parallel source codes. In next design iteration, the proposed system will provide suggestions of refactoring operations of found source codes, based on static code analysis and formal description of parallel design patterns.

With the development of high-performance computing and big data applications, the scale of data transmitted, stored, and processed by high-performance computing cluster systems is increasing explosively. Efficient compression of large-scale data and reducing the space required for data storage and transmission is one of the keys to improving the performance of high-performance computing cluster systems. In this paper, we present SW-LZMA, a parallel design and optimization of LZMA based on the Sunway 26010 heterogeneous many-core processor. Combined with the characteristics of SW26010 processors, we analyse the storage space requirements, memory access characteristics, and hotspot functions of the LZMA algorithm and implement the thread-level parallelism of the LZMA algorithm based on Athread interface. Furthermore, we make a fine-grained layout of LDM address space to achieve DMA double buffer cyclic sliding window algorithm, which optimizes the performance of SW-LZMA. The experimental results show that compared with the serial baseline implementation of LZMA, the parallel LZMA algorithm obtains a maximum speedup ratio of 4.1 times using the Silesia corpus benchmark, while on the large-scale data set, speedup is 5.3 times.

Rabies vaccines are lifesaving in human post animal exposure. However, the compliance to the complete course of vaccine is found to be only 60%. Hence, there is a need for safe and immunogenic, shorter course vaccine that can enhance the compliance and effectively prevent the disease.To establish a noninferiority of a novel three-dose recombinant rabies G protein vaccine to be administered as simulated postexposure prophylaxis when compared to five-dose WHO prequalified vaccine for better safety and immunogenicity.A multi-centric, open label, assessor blind, center-specific block randomized, parallel design, phase III clinical study was conducted among 800 subjects. The eligible subjects were randomized in 2:1 ratio for recombinant rabies G protein vaccine and the reference vaccine. Subjects in recombinant rabies G protein vaccine arm received three doses of vaccine on days 0, 3, and 7, while subjects in reference vaccine arm received five doses of WHO prequalified vaccine on days 0, 3, 7, 14, and 28.The socio-demographic characteristics of the two arms were comparable. About 9.9% subjects in recombinant rabies G protein vaccine arm and 17.2% subjects in reference arm reported adverse events. The sero-protection on day 14 was found to be 99.24% and 97.72% in recombinant rabies G protein vaccine arm and reference vaccine arm respectively and the difference was statistically nonsignificant.The novel three-dose recombinant rabies G protein vaccine administered as simulated postexposure prophylaxis was noninferior to five dose WHO prequalified vaccine in terms of safety and immunogenicity.

Background Stroke is the leading cause of death worldwide. China faces a similar risk of stroke as developed countries because of considerable changes in lifestyle, such as overeating and smoking. Tai Chi is a traditional form of mind-body exercise that has been widely practiced in China for thousands of years. However, there are few studies on the effect of Tai Chi on the cardiopulmonary function of stroke patients in the recovery phase. Therefore, it is necessary to observe the effect of Tai Chi on the cardiorespiratory fitness of patients after stroke. Methods This is a parallel-design, two-arm, analyst assessor-blinded, randomized controlled trial. A total of 226 stroke patients in the recovery phase will be recruited and assigned randomly to a control group or Tai Chi group at a 1:1 ratio. The patients in the Tai Chi group will perform the Tai Chi exercise. The patients in the control group will perform walking exercises. Patients in both groups will receive conventional treatments and healthy education. The primary outcomes will be VO2peak and scores on the MOS item short form health survey (SF-36) scale. Secondary outcomes will include vital capacity (VC), ejection fractions (EF), and cardiac output (CO). The assessments of the tests will be performed at three time points (before exercise, at the end of exercise, and 6 weeks after exercise). Adverse events will be recorded faithfully during the study. Discussion If the results are positive, this study will contribute to the establishment of further guided Tai Chi rehabilitation programs. Trial registration Chinese Clinical Trial Registry ChiCTR2000034719. Registered on 16 July 2020.

Background High-molecular-weight (MW) oat β-glucan (OBG), consumed at 3-4 g/d, in solid foods reduces LDL cholesterol by a median of ∼6.5%. Objectives We evaluated the effect of a beverage providing 3 g/d high-MW OBG on reduction of LDL cholesterol (primary endpoint) when compared with placebo. Methods We performed a parallel-design, randomized clinical trial at a contract research organization; participants, caregivers, and outcome assessors were blinded to treatment allocation. Participants with LDL cholesterol between 3.0 and 5.0 mmol/L, inclusive [n = 538 screened, n = 260 ineligible, n = 23 lost, n = 48 withdrawn (product safety); n = 207 randomly assigned, n = 7 dropped out, n = 9 withdrawn (protocol violation); n = 191 analyzed; n = 72 (37.7%) male, mean ± SD age: 43.3 ± 14.3 y, BMI: 29.7 ± 5.2 kg/m2], were randomly assigned to consume, 3 times daily for 4 wk, 1 g OBG (n = 104, n = 96 analyzed) or rice powder (Control, n = 103, n = 95 analyzed) mixed into 250 mL water. Treatment effects were assessed as change from baseline and differences analyzed using a 2-sided t test via ANOVA with baseline characteristics as covariates. Results After 4 wk, change from baseline least-squares-mean LDL cholesterol on OBG (-0.195 mmol/L) was less than on Control (0.012 mmol/L) by mean: 0.207 mmol/L (95% CI: 0.318, 0.096 mmol/L; P = 0.0003); the following secondary endpoints were also reduced as follows: total cholesterol (TC) (0.226 mmol/L; 95% CI: 0.361, 0.091 mmol/L; P = 0.001), TC:HDL cholesterol ratio (0.147; 95% CI: 0.284, 0.010; P = 0.036), non-HDL cholesterol (0.194 mmol/L; 95% CI: 0.314, 0.073 mmol/L; P = 0.002), and Framingham cardiovascular disease (CVD) risk (0.474; 95% CI: 0.900, 0.049, P = 0.029). Changes in HDL cholesterol, triglycerides, glucose, and insulin did not differ between treatment groups (P > 0.05). Lipid treatment effects were not significantly modified by age, sex, BMI, or hypertension treatment. There were no major adverse events, but both treatments transiently increased gastrointestinal symptoms. Conclusions Consuming a beverage containing 1 g high-MW OBG 3 times daily for 4 wk significantly reduced LDL cholesterol by ∼6% and CVD risk by ∼8% in healthy adults with LDL cholesterol between 3 and 5 mmol/L.This trial was registered at clinicaltrials.gov as NCT03911427.

Bempedoic acid is an inhibitor of adenosine triphosphate–citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether‐a‐go‐go–related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double‐blind, parallel‐design clinical study assessed the effects of steady‐state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half‐maximal inhibition (IC50) estimated at greater than 1000 μM (>1670‐fold the bempedoic acid 180 mg/day steady‐state unbound maximum concentration). In monkeys, individual rate‐corrected QT intervals showed no time‐ or dose‐dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia’s formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration‐QTcF analysis showed that maximum bempedoic acid concentration at steady‐state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was −0.5 (−5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady‐state bempedoic acid at a supratherapeutic dose of 240 mg was generally well‐tolerated and not associated with QTc prolongation in healthy subjects.

Teverelix trifluoroacetate is a decapeptide, gonadotropin-releasing hormone antagonist that binds competitively and reversibly to gonadotropin-releasing hormone receptors in the pituitary gland, resulting in immediate suppression of luteinizing hormone and follicle-stimulating hormone, which in turn causes a very rapid decrease in testosterone production in the Leydig cells of the testes in men and in estradiol in the ovaries in women. This phase 1 clinical study was an open-label, parallel-design, single-center, single-dose study in older, healthy male subjects. Following injection, teverelix is released into the systemic circulation in a biphasic manner. An initial rapid phase is followed by a slow-release phase thought to be due to the formation of a depot, which limits the diffusion of teverelix into the blood. The release characteristics differ significantly for the subcutaneous (SC) and intramuscular (IM) routes. Teverelix maximum concentration and exposure increased in an approximately dose-proportional manner across the 60 to 120 mg SC doses. All 3 pharmacodynamic end points (luteinizing hormone, follicle-stimulating hormone, and total testosterone) showed reductions that were more prolonged following the 90 mg IM administration compared to 90 mg SC administration.

Purpose To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. Methods A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. Results Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. Conclusions In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. ClinicalTrials.gov Identifier NCT03466203

Background Globally, has been an increase in the use of silver fluoride products to arrest carious lesions and a variety of products are available. Objectives To examine differences in caries arrest and lesion colour of primary tooth carious lesions. Material and methods A four-armed, parallel-design cluster-randomised controlled trial which investigated four protocols for caries arrest at 6m and 12m. Children in Group 1 and Group 2 received Rivastar Silver Diammine Fluoride (SDF), and children in Group 3 and Group 4 received a stabilised aqueous silver fluoride solution (AgF). Children in Group 2 and Group 4 received an additional application of KI immediately after the fluoride. Differences in caries arrest and lesion appearance were examined at 6m and 12m using two level logistic regression modelling. Results The arrest rate varied by group membership; group 1 and group 3 had higher arrest rates (77.3% and 75.3% respectively) than group 2 and group 4 (65.4% and 51.2% respectively). The use of KI was also associated with lower odds of arrest (12m OR 0.25; CI 0.19, 0.34) and higher odds of avoiding black discolouration (12m OR 6.08; 2.36, 15.67). Conclusions Globally, has been an increase in the use of silver fluoride products to arrest carious lesions and a variety of products are available. This study demonstrated that both AgF and SDF can effectively arrest carious lesions on primary teeth. The use of KI is associated with poorer caries control but better aesthetic outcomes.

BackgroundSleep-wake disorders occur in most persons living with dementia and include late afternoon or evening agitation, irregular sleep-wake rhythms such as daytime hypersomnia, frequent night awakenings, and poor sleep efficiency. Sleep-wake disorders pose a great burden to family caregivers, and are the principal causes of distress, poor quality of life, and institutionalization. Regulating the sleep-wake cycle through the use of light and activity has been shown to alter core clock processes and suggests that a combination of cognitive, physical, and sensory-based activities, delivered at strategic times, may be an effective mechanism through which to reduce sleep-wake disorders.MethodsA definitive Phase III efficacy trial of the Healthy Patterns intervention, a home-based activity intervention designed to improve sleep-wake disorders and quality of life, is being conducted using a randomized two-group parallel design of 200 people living with dementia and their caregivers (dyads). Specific components of this one-month, home-based intervention involve 4 in-home visits and includes: 1) assessing individuals’ functional status and interests; 2) educating caregivers on environmental cues to promote activity and sleep; and 3) training caregivers in using timed morning, afternoon, and evening activities based on circadian needs across the day. The patient focused outcomes of interest are quality of life, measures of sleep assessed by objective and subjective indicators including actigraphy, subjective sleep quality, and the presence of neuropsychiatric symptoms. Caregiver outcomes of interest are quality of life, burden, confidence using activities, and sleep disruption. Salivary measures of cortisol and melatonin are collected to assess potential intervention mechanisms.DiscussionThe results from the ongoing study will provide fundamental new knowledge regarding the effects of timing activity participation based on diurnal needs and the mechanisms underlying timed interventions which can lead to a structured, replicable treatment protocol for use with this growing population of persons living with dementia.Clinical trial registrationClinicaltrials.gov# NCT03682185 athttps://clinicaltrials.gov/; Date of clinical trial registration: 24 September 2018.

Dynamic treatment strategies are designed to change treatments over time in response to intermediate outcomes. They can be deployed for primary treatment as well as for the introduction of adjuvant treatment or other treatment-enhancing interventions. When treatment interventions are delayed until needed, more cost-efficient strategies will result. Sequential multiple assignment randomized (SMAR) trials allow for unbiased estimation of the marginal effects of different sequences of history-dependent treatment decisions. Because a single SMAR trial enables evaluation of many different dynamic regimes at once, it is naturally thought to require larger sample sizes than the parallel randomized trial. In this paper, we compare power between SMAR trials studying a regime, where treatment boosting enters when triggered by an observed event, versus the parallel design, where a treatment boost is consistently prescribed over the entire study period. In some settings, we found that the dynamic design yields the more efficient trial for the detection of treatment activity. We develop one particular trial to compare a dynamic nursing intervention with telemonitoring for the enhancement of medication adherence in epilepsy patients. To this end, we derive from the SMAR trial data either an average of conditional treatment effects (‘conditional estimator’) or the population-averaged (‘marginal’) estimator of the dynamic regimes. Analytical sample size calculations for the parallel design and the conditional estimator are compared with simulated results for the population-averaged estimator. We conclude that in specific settings, well-chosen SMAR designs may require fewer data for the development of more cost-efficient treatment strategies than parallel designs. Copyright © 2012 John Wiley & Sons, Ltd.

Background The optimal strategy for abdominal wall closure has been an issue of ongoing debate. Available studies do not specifically enroll patients who undergo emergency laparotomy and thus do not consider the distinct biological characteristics of these patients. The present randomized controlled trial evaluates the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy. Methods/design The CONTINT trial is a multicenter, open label, randomized controlled trial with a two-group parallel design. Patients undergoing a primary emergency midline laparotomy are enrolled in the trial. The two most commonly applied strategies of abdominal wall closure after midline laparotomy are compared: the continuous, all-layer suture technique using slowly absorbable monofilament material (two Monoplus® loops) and the interrupted suture technique using rapidly absorbable braided material (Vicryl® sutures). The primary endpoint within the CONTINT trial is an incisional hernia within 12 months or a burst abdomen within 30 days after surgery. As reliable data on this primary endpoint is not available for patients undergoing emergency surgery, an adaptive interim analysis will be conducted after the inclusion of 80 patients, allowing early termination of the trial if necessary or modification of design characteristics such as recalculation of sample size. Discussion This is a randomized controlled multicenter trial with a two-group parallel design to assess the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy. Trial registration NCT00544583

Based on the arbiter template developed in [1], we presented an efficient, modular, and scalable decentralized parallel design of a new multi-facet arbiter. Moreover, with this modular and reusable hardware design, we have implemented a parametric arbiter generator that automatically generates various multi-facet arbiters. With the decentralized parallel design and the generator, not only a fastest and smallest round-robin arbiter but also other type arbiters were designed and generated on the fly. The experiment results were given to show the designs' excellent performances.

Background: Improving the mobility of hospitalized patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a priority of care. AECOPD-Mob is a clinical decision-making tool for physical therapists, especially those who are newly graduated or are new to caring for patients with AECOPDs in acute care settings. Although this tool has been available for several years, dissemination via publication is not sufficient to implement it in clinical practice. Objective: The primary objective of this study was to develop, implement, and evaluate different formats of AECOPD-Mob in an acute care setting. Methods: We used a mixed-methods, convergent parallel design. In addition to the paper format of AECOPD-Mob, we developed a smartphone app, a web-based learner module, and an in-service learning session. Newly graduated physical therapists (PTs) or PTs new to the practice area were recruited from urban acute care hospitals. Participants used the different formats for 3 weeks and then completed the Post-Study System Usability Questionnaire. User data were retrieved for the learning module. Participants participated in focus groups at 3 weeks and 3 months. Results: Eighteen (72% of eligible PTs, 100% female, 94% graduated within 3 yr) PTs participated. Post-Study System Usability Questionnaire scores for the learning module and smartphone indicated that participants were satisfied with these formats (median score 2.0 on 1–7 Likert Scale for both technology formats, lower scores indicating greater satisfaction). However, the participants reported in the focus group that the paper format was preferred over other formats. Concerns with the smartphone app included infection control and the perception of lack of professionalism when using a smartphone during clinical practice. The learning module and in-service were considered helpful as an introduction but not as an ongoing support. The paper format was seen as the most efficient way to access the necessary information and to facilitate communication between other members of the care team about the importance of mobility for hospitalized patients with AECOPDs. Conclusion: Newly graduated PTs strongly preferred the paper format of the AECOPD-Mob tool in the acute care setting. Future research will focus on knowledge translation strategies for other health disciplines.

International audience; Background Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. Objectives We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. Methods This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34 ± 8 years; weight, 74 ± 6 kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741 mg/d polyphenols, 2.1 g/d omega-3 fatty acids, 168 mg/d vitamin E, and 80 μg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. Results The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum β–C-telopeptide of type I collagen (β-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest–related changes were observed. Conclusions Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.

Summary Background At the clinical trial design stage, assumptions regarding the treatment effects to be detected should be appropriate so that the required sample size can be calculated. There is evidence in the medical literature that sample size assumption can be overoptimistic. The aim of this study was to compare the distribution of the assumed effects versus that of the observed effects as a proxy for overoptimistic treatment effect assumptions at the study design stage. Materials and method Systematic reviews (SRs) published between 1 January 2010 and 31 December 2019 containing at least one meta-analysis on continuous outcomes were identified electronically. SR and primary study level characteristics were extracted from the SRs and the individual trials. Details on the sample size calculation process and assumptions and the observed treatment effects were extracted. Results Eighty-five SRs with meta-analysis containing 347 primary trials were included. The median number of SR authors was 5 (interquartile range: 4–7). At the primary study level, the majority were single centre (78.1%), utilized a parallel design (52%), and rated as an unclear/moderate level of risk of bias (34.3%). A sample size was described in only 31.7% (110/347) of studies. From this cohort of 110 studies, in only 37 studies was the assumed clinical difference that the study was designed to detect reported (37/110). The assumed treatment effect was recalculated for the remaining 73 studies (73/110). The one-sided exact signed rank test showed a significant difference between the assumed and observed treatment effects (P < 0.001) suggesting greater values for the assumed effect sizes. Conclusions Careful consideration of the assumptions at the design stage of orthodontic studies are necessary in order to reduce the unreliability of clinical study results and research waste.

The aim of this study was to investigate the effects of an 8‑week powerlifting-type bench press (BP) resistance training (RT) program, either without (RAW) or with using a supportive elastic bench press device (EBD) on one-repetition maximum (1-RM), body weight (BW), mid-upper arm and chest circumference, as well as visual analogue pain scale (VAS) of the shoulder, elbow, and wrist. For this purpose, a matched pair parallel design based on initial 1‑RM was used (BPD n = 16, age 24.4 ± 4 years, RT experience 3.75 ± 1.83 years; RAW n = 16, age 25 ± 2 years, RT experience 5.66 ± 3.00 years). Following two weeks of familiarization with the protocol , BP RT was carried out twice weekly. The EBD group completed more than half of their BP sets with elastic assistance and 10% higher training intensity than the RAW group. There was a significant time × group interaction in BW (p = 0.008). Post hoc analysis showed a significant loss of 0.92 kg in the EBD group (p = 0.049; effect size [ES] = −0.08; 95%CI [−1.80, 0.04]). A significant time effect for 1‑RM was observed (p p

Context Consumption of lean fish and fish-derived proteins were effective for improving lipid profiles in published studies; however, evidence remains inconclusive. Objective To evaluate the effectiveness of lean fish or fish-derived protein on serum/plasma lipid and lipoprotein levels by conducting a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). Data sources Medline (Ovid), Scopus, CINAHL, and Food and Nutritional Sciences databases were searched from the start date of each database to September 2019 to identify RCTs determining the effect of lean fish on lipid profile. Study selection Included RCTs investigated lean fish and fish-derived proteins intake and determined at least 1 major lipid or lipoprotein measurement. Data extraction Two reviewers independently evaluated 1217 studies against the inclusion and exclusion criteria. Relevant studies were assessed for risks of bias, and random-effects meta-analysis was conducted to generate average estimates of effect. Results A total of 24 studies met the inclusion criteria. Meta-analysis of data from 18 to 21 eligible crossover and parallel-design RCTs with a total of 1392 to 1456 participants found triacylglycerol-lowering effects for lean fish compared with no fish consumption. Lean fish intake showed no significant differences related to total cholesterol or lipoprotein levels. Subanalysis showed that parallel-group RCTs tended to find greater reduction effects on circulating triacylglycerol than did crossover RCTs. Conclusion Additional better-designed, longer, and larger RCTs, particularly crossover RCTs, are needed to clarify the impact of lean fish and fish proteins on the serum/plasma lipid profile. Findings from such studies would enable practitioners to provide their patients evidence-based recommendations to meet the American Heart Association guidelines for fish consumption to reduce cardiovascular disease risk.

OBJECTIVE To determine whether the Dietary Approaches to Stop Hypertension (DASH) diet or an alternative, simplified diet, emphasizing high-fiber fruits and vegetables (the FV diet), lowers serum urate levels. METHODS We conducted a secondary study of the DASH feeding study, a 3-arm, parallel-design, randomized trial of 459 adults with systolic blood pressure (BP) of

Purpose Society has progressed in universal design guidelines and assistive devices for individuals with disabilities yet challenges due to affordability and attractiveness concerns remain to incorporate them into existing residences. Repurposing (i.e., replacing or adapting problematic fixtures or spaces, with others not originally intended for that purpose) may be the action to address the concerns of consumers. The purpose of this study was to elicit information on problems and solutions regarding home modifications and identify ways that consumers and professionals implement repurposing, that residents deemed accessible, affordable, and attractive. Methods This convergent parallel design study consisted of focus groups who rated images of repurposed spaces. The focus groups included consumers with functional mobility and visual limitations (n = 8); and professionals who devised or recommended home modifications (n = 8). Participants reviewed three images of home modification solutions and completed a Likert-scale rating based on accessibility and attractiveness. Results Focus group data indicated that high contrast, heights of fixtures, doors, and flooring - all pose threats to accessibility in the home. Consumers placed more value on attractiveness than professionals. Participants were aware and receptive to repurposing as a home modification technique but focused their discussion on adaptations. Conclusion Overall, adoption and implementation of home modifications promote accessibility, but professionals need to consider individualized needs and preferences, before suggesting modifications.IMPLICATIONS FOR REHABILITATIONRepurposing existing spaces, features, and fixtures can serve as a method of home modification.Consumer home modification recommendations are perceived to be more effective when collaboratively and individually developed with professionals.Data gathered through focus groups can be valuable for informing practice and research in home modifications.

International audience; Background: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects.Research question: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS?Study design and methods: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety.Results: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported.Interpretation: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity.

BACKGROUND: Composite end points are common in clinical trials. OBJECTIVE: To describe how composite outcomes are used, constructed, and reported in cardiovascular trials and to evaluate the contribution of individual end points to the composite estimate of effect in those trials. DESIGN: Review of 2-group, parallel-design, randomized cardiovascular trials that used composite end points and were published in 14 clinical journals from 1 January 2000 to 1 January 2007. SETTING: Published randomized trials in cardiovascular medicine and surgery. PARTICIPANTS: Two-group, parallel-design trials published in 14 leading general medical, cardiology, and cardiothoracic surgery journals from 1 January 2000 to 1 January 2007. MEASUREMENTS: The types and numbers of individual events included in the composite outcome and P values and risk estimates for the composite outcome. RESULTS: Of 304 trials published that used composite outcomes, 221 (73%) reported a composite primary outcome and 83 (27%) reported a composite secondary outcome. Composite outcomes comprised a median of 3 (interquartile range, 3 to 4) individual outcomes; death was the most common individual outcome. The total number of individual events and the total number of events represented by the composite outcome differed in 79% of trials. P values for composite outcomes were less than 0.050 more frequently than they were 0.050 or greater. Death as an individual end point made a relatively minimal contribution to estimates of effect summarized by the trials' composite end points, whereas revascularization made a greater contribution. LIMITATION: All-cause and cardiovascular mortality were not distinguished, and the findings might not apply to trials in other fields. CONCLUSION: Composite outcomes in cardiovascular trials are frequent and commonly comprise 3 to 4 individual end points that vary in clinical significance. Discrepancies between the total number of individual events in a trial and those reported for composite outcomes are common. Individual outcomes do not contribute equally to composite measures, so the overall estimate of effect for a composite measure cannot be assumed to apply equally to each of its individual outcomes.

Parallel firewalls offer a scalable low latency design for inspecting packets at high speeds. Typically consisting of an array of m firewalls, these systems filter arriving packets according to a security policy. Given the firewall array, the rules can be distributed in two fashions. Data parallel copies the entire policy to each firewall and distributes packets. In contrast, function parallel distributes the rules and duplicates packets. The function parallel design can provide significantly lower delays than an equivalent data parallel design, however performance is dependent on how the rules are distributed. Therefore, policy management is vital to the performance of the function parallel firewall system. This paper describes the guidelines necessary to maintain policy integrity, which guarantees that a function parallel and a traditional firewall provide the same action for a packet. Based on these requirements, a policy can be divided into autonomous chains (sub-policies) that can be distributed across the firewall array. Although determining the optimal distribution was shown to be NP-hard, an effective algorithm was described. Simulation results indicate the distribution algorithm can provide an 86% reduction in the average processing delay as compared to previous distribution methods.

Sleep disturbance is highly prevalent among shift-working nurses. We aimed to evaluate whether aerobic exercise (i.e., walking combined with jogging) improves objective sleep parameters among female nurses who met eligibility criterion as poor sleepers at the end of an 8-week exercise program and 4 weeks after study completion. This single-blinded, parallel-design, randomized controlled trial was conducted in a classroom of a hospital in northern Taiwan. Sixty eligible female nurses were randomly assigned to either the aerobic exercise (n = 30) or usual activity status (n = 30) group. A moderate-intensity aerobic exercise program was administered over 5 days (60 min per day) a week for 8 weeks after the nurses' day shifts. Objective sleep outcomes including total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), and sleep efficiency (SE) were retrieved using an actigraph device. A generalized estimating equation model was used for data analysis. The aerobic exercise group exhibited improvements in TST and SE at 4 and 8 weeks compared with the baseline evaluation (TST: B = 70.49 and 55.96; SE: B = 5.21 and 3.98). Between-group differences were observed in SOL and WASO at 4 weeks but not 8 weeks compared with the baseline evaluation (SOL: B = -7.18; WASO: B = -11.38). Positive lasting effects for TST were observed only until the 4-week follow-up. To improve sleep quality and quantity, we encourage female nurses who sleep poorly to regularly perform moderate-intensity aerobic exercise.

This study compared the effects of oral hygiene with a toothpaste formulated with zinc (test) to a fluoride dentifrice (control) for effects on oral polymorphonuclear leukocyte (PMN) as a measure of whole mouth inflammation along with effects on clinical parameters of dental plaque and gingivitis. Adults (age range 18–60 years, n = 212) completed this double-blind, parallel design study. After washout, a baseline oral rinse sample was evaluated for PMN prior to clinical assessments for gingivitis and dental plaque. Subjects were randomly assigned to brush twice daily with either the test or the control toothpaste. Post-treatment evaluations repeated all baseline assessments after 4-week, 6-week and 12-week use of dentifrice with all assessments conducted 12 hours after brushing. PMN reductions in the test were 16.8%, 18.7% and 42.5% at the 4-week, 6-week and 12-week evaluations respectively and significantly different from the control (p < 0.05). The test toothpaste also demonstrated progressively increasing reductions in gingivitis and dental plaque that ranged from 7.6 to 33.3% and 2.3 to 9.1% respectively versus the control (p < 0.05). The test dentifrice demonstrated progressive reductions in oral PMN representing whole mouth inflammation in conjunction with improvements in oral hygiene as compared to the control toothpaste. A hallmark of oral inflammation includes the accumulations of PMN in the afflicted gingival regions to reduce the influences of proliferating microorganisms. Brushing with a zinc dentifrice demonstrated progressive reductions in oral PMN and improvements in oral hygiene as evidenced by progressively lower dental plaque and gingival indices.

Objectives: The effects of anesthesia techniques and anesthetics on different systems and organs of the body, especially the immune system, in older patients undergoing surgery, have always been of interest to researchers. This study aims to compare the effects of general anesthesia with isoflurane and spinal anesthesia with lidocaine on oxidative and antioxidant parameters in older patients with inguinal hernia surgery. Methods & Materials: This is a double-blinded randomized clinical trial with parallel design conducted on 70 older patients referred to the surgery department of hospitals in Tehran, Iran during 2018-2019. They were randomly divided into two groups of 35; the first group received general anesthesia with isoflurane and the second group received spinal anesthesia with lidocaine. Blood sampling was performed in two stages; one day before and one day after surgery. Advanced Glycation End Products (AGEs), Advanced Oxidation Protein Products (AOPP), Malondialdehyde (MDA), oxidized Low-Density Lipoprotein (LDL), Ferric-Reducing Ability of Plasma (FRAP), glutathione peroxidase, superoxide dismutase and catalase levels were measured before and after anesthesia using standard methods. Collected data were analyzed in SPSS v.22 software. Results: The Mean±SD age of patients in the lidocaine group was 69.94±8.31 years and in the isoflurane as 70.23±4.98 (P>0.81). In the isoflurane group, there was a significant difference between pre- and postoperative levels of AOPP, MDA, oxidized LDL, FRAP, catalase, glutathione peroxidase and superoxide dismutase. In the lidocaine group, this difference was significant in MDA, oxidized LDL, catalase and superoxide dismutase. Conclusion: Given the positive effects of isoflurane on oxidative and antioxidant parameters in older patients with inguinal hernia surgery, it is recommended that this anesthetic be considered in the selection of anesthesia methods and drugs for this group of older patients.

Objectives Carbamazepine (CBZ) is a well-known drug prescribed to treat epilepsy and the preferred drug for trigeminal neuralgia. This study was conducted to investigate the effect of Panax ginseng extract (PGE) on the disposition of CBZ, a CYP3A4 substrate, in rabbits. Materials and methods An in vivo randomized parallel design was used to examine herb-drug interactions in 12 male rabbits distributed into 2 groups. In the 1st group (control group), 6 rabbits (control group) were administered orally with CBZ suspension (30 mg/kg/day) as a single daily dose for 10 days. In the 2nd group (test group), 6 rabbits was treated concomitantly with CBZ and a dose of PGE (2.5 mg/kg/day) at the same time as in the 1st group. Blood samples were withdrawn from the marginal ear vein of the rabbits at intervals of 0.0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 12.0, and 24.0 h. Results CBZ had no significantly different pharmacokinetic (PK) parameters, namely, Cmax, tmax, AUC0-24, AUC0-∞, t½, and Ke, when it was given alone or concurrently with PGE (p≥0.05). Conclusion PGE may unlikely interfere with the PK of CBZ when it is co-administered with CBZ. Therefore, PGE can be used safely without precautions or dose monitoring.

Objective We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). Methods Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. Results Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. Conclusions This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).

Cranberry (Vaccinium macrocarpon) extracts have been found to be rich in polyphenols specifically, including flavonoids, that have been found to exhibit beneficial properties to human health. Considering the recent inclination in the preference of people towards herbal based products and remedies, and taking into account the possible side-effects of chlorhexidine, the current study was undertaken to comparatively evaluate the antimicrobial efficacy of Vaccinium macrocarpon and chlorhexidine mouthwash on the Streptococcus mutans count in the dental plaque of caries, active children. The study follows a parallel design involving 50 children divided into two groups of 25 each - Group 1: chlorhexidine mouthwash; Group 2: cranberry mouthwash. The initial plaque samples and the samples were taken after 14 days were evaluated using a digital colony counter for determining the streptococcal colony count/ml. A statistically significant difference was found in both the groups with respect to the Streptococcal colony count when the intra-group comparison was made comparing the baseline values to the values after 14 days. However, no significant difference was seen in the percentage of reduction in the microbial CFU/ml between the two groups. Cranberry mouthwash can be considered to be an effective alternative to Chlorhexidine mouthwash, given its additional systemic effects apart from local beneficial effects in the oral region. Future scope in research should be aimed at evaluating its long term health benefits and any possible adverse effects.

Objectives: The objectives of the study were to estimate the relative impact of triple therapy on lung function, health status, and mortality risk compared with combination inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) therapy in symptomatic chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations in an Indian clinical population. Methodology: The GLIMPSE (Lung Function, Health Status, and Mortality Risk Assessment in COPD using Triple Therapy) was as a prospective, parallel design, single-center observational study comparing 24 weeks of triple therapy (twice-daily combination of budesonide [BUD]-formoterol [FOR] [100/6 μg] and once-daily tiotropium [TIO] [9 μg]) with ICS/LABA (twice daily BUD-FOR [100/6 μg]). The primary outcome was the mean change in forced expiratory volume in the 1st s (FEV1%) predicted and COPD assessment test total score from baseline at week 24. Secondary outcomes were variation in dyspnea grade and BODE total score from baseline. Results: At week 24 in triple therapy (n=70) and ICS/LABA therapy (n=70), mean difference from baseline in FEV1% predicted were 5.40 (95% confidence interval [CI]: 1.29–9.50) and 1.90 (95% CI: –1.87–5.68) respectively, and mean difference in CAT total score from baseline was –5.10 units (95% CI: –3.49–−6.71) and –1.80 units (95% CI: –0.052–−3.548), respectively. In addition, there was a statistically significant reduction in dyspnea grading and BODE score with comparable adverse events in both groups. Conclusion: Overall, the results favored triple therapy over dual therapy in advanced symptomatic COPD patients.

Background Antivirals for the treatment of hepatitis C virus (HCV) infection are effective, but many patients remain untreated and treatment is not yet routine in primary care. We evaluated the characteristics of patients who engaged in HCV treatment, and clinician perspectives on the barriers and facilitators to treatment. Methods Our mixed-method, parallel-design study was conducted at a multisite primary care centre in downtown Toronto. In a retrospective chart review, we searched records from 2011 to 2017 to collect quantitative data, including HCV infection status and HCV treatment status. To contextualize the data, we conducted in-depth interviews with select physicians between Aug. 1 and Nov. 1, 2017, and analyzed the transcripts using content analysis. Results Of the 40 381 charts reviewed, 727 patients (1.8%, 95% confidence interval [CI] 1.7%-1.9%) were infected with HCV, and 542 (74.6%) had HCV infection requiring treatment. Of those, 255 patients (47.0%) had engaged in treatment. Patients who had engaged in treatment were more likely to be male (odds ratio [OR] 1.63, 95% CI 1.10-2.42), older (OR 1.04 per year increase in age, 95% CI 1.02-1.05) and housed (OR 2.2, 95% CI 1.36-3.75), and they were more likely not to have engaged in injection drug use (OR 1.87, 95% CI 1.33-2.63). Based on interviews with 8 physicians, treatment barriers included a lack of knowledge about HCV treatment, concerns that patients would not adhere to medications and challenges related to medication access. Facilitators of treatment included access to specialist consultation, pharmacist support and primary care treatment guidelines. Common themes that emerged in both quantitative and qualitative components were the roles of unstable housing and intravenous drug use as barriers to engaging in and completing treatment. Interpretation Our study captured provider-identified barriers to HCV care and the key factors related to retention in HCV care, including gender, age, housing status and experience with drug use. Successful primary-care-led HCV treatment programs may incorporate specialist and pharmacy support and focus on younger, female, underhoused populations and people who use drugs.

Oxidative and immune dysfunctions during physical exertion can be associated with a violation of enzyme systems and antioxidant protection, the state of innate and adaptive immunity. This creates the preconditions for their pharmacological correction. The aim of this review is to summarize and analyze modern data on the role of curcumin, one of the components of the extract of turmeric rhizomes (Curcuma longa), in the correction of oxidative stress and immune disorders during physical exertion. Material and methods. When writing the review, a search has been carried out for the original articles presented in PubMed, Web of Science, Google Scholar databases, eLIBRARY.RU and CyberLeninka platforms, with a randomized controlled crossover or parallel design, in which the use of curcumin administered before and / or after exercise was compared with placebo. No filters were applied by type of exercise performed, gender or age of participants. Results. In randomized controlled trials conducted for 2008-2020, evidences were obtained that the use of complexes containing curcumin normalizes the general antioxidant status, restores quality, quantity and functional-metabolic status of immunocytes. Data from prospective epidemiological studies show that turmeric extract exhibits partial anti-inflammatory, immunotropic and antioxidant activity in vitro and in vivo, which provides a basis for further studies on the effectiveness and systemic use of turmeric long. Conclusion. The inclusion of turmeric extract in complex dietary regimens, including during physical activity, helps to prevent immune and oxidative disorders, and exert some anti-inflammatory effect.

IMPORTANCE: Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that "withdrawal" from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD). OBJECTIVE: To examine the role of estradiol withdrawal in PMD. DESIGN, SETTING, AND PARTICIPANTS: Initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance. INTERVENTIONS: After 3 weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions. MAIN OUTCOMES AND MEASURES: Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits. RESULTS: None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo. CONCLUSIONS AND RELEVANCE: In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00060736.

IntroductionHeart failure is a major contributor to morbidity and mortality in the geriatric population, with no promising therapy currently available with considerable benefit. Testosterone therapy is an emerging viable treatment option given its beneficial effects, including improving cardiac functional capacity, alleviating symptoms and low cost, among others.MethodsWe have planned an open-label, parallel design, 1:1 randomised controlled trial, which aims to recruit 986 adult males above the age of 60 diagnosed with chronic stable heart failure fulfilling the eligibility criteria. The participants will be randomised into 2 groups of 493 each. Both groups will receive standard recommended treatment regimen of chronic stable heart failure and intervention arm participants will receive additional testosterone gel. All participants will be assessed at baseline, 4 weeks, 6 weeks and 12 weeks. The primary endpoints will assess the differences in functional capacity, frailty and quality of life at 3 months compared with baseline. The secondary endpoints will include the mean change from baseline at 3 months in cardiac remodelling using echocardiography, serum brain natriuretic peptide levels, the incidence of adverse drug reaction.Statistical analysisThe data will be analysed with the help of SPSS 23 software. Primary objectives of change in 6-minute walk test, frailty index and quality of life will be analysed using the student’s t-test. The statistical significance will be defined as p valueEthical clearanceInstitutional Ethics Committee clearance taken via letter no AIIMS/IEC/20/847, dated 21 November 2020. This study involves human participants and was approved by institutional ethical committee, DHR Reg: EC/NEW/Inst/2020/1046CDSCO, Reg No: ECR/736/Inst/UK/2015/RR-18. Participants gave informed consent to participate in the study before taking part.Trial registration number(CTRI)—REF/2020/12/030292.

Several studies have tested non-pharmacological therapies for atrial tachyarrhythmias (ATs) by measuring the cumulative time (burden) the patient spends in arrhythmia. Contradictory results questioned either therapy efficacy or statistical power of the trials. We studied AT burden variability in patients paced for sinus node disease (SND) in order to interpret currently published data appropriately and to evaluate reliable sample sizes. METHODS AND RESULTS: One hundred and five patients with AT and SND received a dual chamber pacemaker with antitachyarrhythmia-pacing capability, and were followed for 13 months. Seventy-eight patients (74%) suffered AT recurrences. Device-gathered diagnostic measures were used to simulate results of randomized studies both with crossover and parallel design. The sample size required for statistically significant results was calculated as a function of the expected therapy-induced burden reduction. AT burden intra-patient variability was high: 43% of patients showed intrinsic fluctuations hiding any therapy-induced burden reduction lower than 30%. Demonstrating therapeutic breakthrough through a 6 month study would require 290 patients with crossover design and 5800 patients with parallel design. Doubling the study period requires 400 and 3000 patients, respectively. CONCLUSION: Patients with AT and paced for SND showed high intra-patient burden variability, which could possibly hide an AT burden reduction induced by a therapy. Previous studies involving non-pharmacological therapies utilizing AT burden endpoints could lack the power to reach statistical significance.